Pub Date : 2026-04-01Epub Date: 2026-01-22DOI: 10.1016/j.taap.2026.117734
Yi Zhang , Jiajun Wang , Zhongjie Deng , Huoying Zhuang , Xianquan Chen , Xinwen Zhou , Weiwei Huang , Suhong Yu
Albumin-bound paclitaxel (Nab-PTX), a nanoparticle albumin-bound formulation in which paclitaxel is conjugated to human serum albumin, has emerged as a pivotal agent in cancer therapy. Its significance stems not only from direct cytotoxic effects on cancer cells but also from multifaceted interactions with angiogenesis, a critical driver of tumor progression and metastasis. Nevertheless, the underlying mechanism of its anti-angiogenesis in breast cancer remains elusive. In the present study, we employed the iTRAQ (isobaric tags for relative and absolute quantification) technique to assess the effect of Nab-PTX on Triple-negative breast cancer cells (MDA-MB-231). A total of 5145 exosomal proteins were identified, of which 941 exhibited significant differences between Nab-PTX-treated cells and the control group (P-value<0.05). Notably, we found that CYR61 (Cysteine-rich angiogenic inducer 61), a secreted matricellular protein belonging to the CCN family, was significantly inhibited by Nab-PTX. Furthermore, our study demonstrated for the first time that Nab-PTX inhibits angiogenesis via the CYR61/Integrin αvβ3 signaling pathway. These findings elucidate a potential anti-angiogenesis mechanism of Nab-PTX and highlight CYR61's promise as a therapeutic target in human breast cancer.
{"title":"Nab-paclitaxel inhibits angiogenesis via the CYR61/integrin αvβ3 Axis: Exosomal proteomics insights into breast cancer chemoprevention","authors":"Yi Zhang , Jiajun Wang , Zhongjie Deng , Huoying Zhuang , Xianquan Chen , Xinwen Zhou , Weiwei Huang , Suhong Yu","doi":"10.1016/j.taap.2026.117734","DOIUrl":"10.1016/j.taap.2026.117734","url":null,"abstract":"<div><div>Albumin-bound paclitaxel (Nab-PTX), a nanoparticle albumin-bound formulation in which paclitaxel is conjugated to human serum albumin, has emerged as a pivotal agent in cancer therapy. Its significance stems not only from direct cytotoxic effects on cancer cells but also from multifaceted interactions with angiogenesis, a critical driver of tumor progression and metastasis. Nevertheless, the underlying mechanism of its anti-angiogenesis in breast cancer remains elusive. In the present study, we employed the iTRAQ (isobaric tags for relative and absolute quantification) technique to assess the effect of Nab-PTX on Triple-negative breast cancer cells (MDA-MB-231). A total of 5145 exosomal proteins were identified, of which 941 exhibited significant differences between Nab-PTX-treated cells and the control group (<em>P</em>-value<0.05). Notably, we found that CYR61 (Cysteine-rich angiogenic inducer 61), a secreted matricellular protein belonging to the CCN family, was significantly inhibited by Nab-PTX. Furthermore, our study demonstrated for the first time that Nab-PTX inhibits angiogenesis via the CYR61/Integrin α<sub>v</sub>β<sub>3</sub> signaling pathway. These findings elucidate a potential anti-angiogenesis mechanism of Nab-PTX and highlight CYR61's promise as a therapeutic target in human breast cancer.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"509 ","pages":"Article 117734"},"PeriodicalIF":3.4,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044038","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 : 2026-04-01Epub Date: 2026-02-02DOI: 10.1016/j.taap.2026.117748
Ang-Kun Yang , Yong-Liang Li , Yan-Ying Chen , Yan Liu , Zhi-Yun Du , Chang-Zhi Dong , Bernard Meunier , Hui-Xiong Chen
Worldwide incidence and prevalence of ulcerative colitis (UC) has been rising in recent years, which can occur at any age, with a high frequency seen in young children and people aged 40 to 50. The aryl hydrocarbon receptor (AhR) activation axis is well known for its important role in the regulation of intestinal inflammation, intestinal homeostasis, intestinal immune system and improvement of colitis outcomes. This study investigated the therapeutic efficacy of the thiophene-based styrene derivative (TBSD), a novel AhR agonist against UC in vitro and in vivo. TBSD decreased FITC-dextran hyperpermeability, upregulated the tight junction (TJ)-related protein expression levels and regulated the inflammatory mediators including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-22 and cyclooxygenase 2 (COX-2) in the Caco-2/RAW264.7 co-culture system and in DSS-induced UC-like mice. Overall, TBSD may be considered as a promising therapeutic agent to improve UC severity through mitigating inflammation, maintaining intestinal mucosal homeostasis and enhancing the intestinal barrier integrity.
{"title":"Thiophene-based styrene derivative improves colitis symptoms in DSS-induced BALB/C mice through AhR-mediated gut barrier function and inflammatory responses","authors":"Ang-Kun Yang , Yong-Liang Li , Yan-Ying Chen , Yan Liu , Zhi-Yun Du , Chang-Zhi Dong , Bernard Meunier , Hui-Xiong Chen","doi":"10.1016/j.taap.2026.117748","DOIUrl":"10.1016/j.taap.2026.117748","url":null,"abstract":"<div><div>Worldwide incidence and prevalence of ulcerative colitis (UC) has been rising in recent years, which can occur at any age, with a high frequency seen in young children and people aged 40 to 50. The aryl hydrocarbon receptor (AhR) activation axis is well known for its important role in the regulation of intestinal inflammation, intestinal homeostasis, intestinal immune system and improvement of colitis outcomes. This study investigated the therapeutic efficacy of the thiophene-based styrene derivative (TBSD), a novel AhR agonist against UC in vitro and in vivo. TBSD decreased FITC-dextran hyperpermeability, upregulated the tight junction (TJ)-related protein expression levels and regulated the inflammatory mediators including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-22 and cyclooxygenase 2 (COX-2) in the Caco-2/RAW264.7 co-culture system and in DSS-induced UC-like mice. Overall, TBSD may be considered as a promising therapeutic agent to improve UC severity through mitigating inflammation, maintaining intestinal mucosal homeostasis and enhancing the intestinal barrier integrity.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"509 ","pages":"Article 117748"},"PeriodicalIF":3.4,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146119614","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 : 2026-04-01Epub Date: 2026-02-04DOI: 10.1016/j.taap.2026.117752
Jun-jie Gao , Li-zhu Huang , Tao Wang , Yun-long Zhang , Kai Ye , Wei-hua Lu , Pu-hong Zhang
Sepsis poses a significant global health burden, and ICU patients are disproportionately exposed to di(2-ethylhexyl) phthalate (DEHP), an immunotoxic plasticizer that leaches from PVC medical devices; however, whether this exposure causally influences sepsis outcomes remains unclear. To investigate this relationship, we conducted a prospective cohort study comparing 90 ICU sepsis patients with 50 controls, quantifying urinary DEHP metabolites using LC-MS/MS. Sepsis patients demonstrated significantly elevated DEHP metabolite levels (p < 0.001), and high exposure (≥341.58 μg/g creatinine) was independently associated with reduced 28-day survival (35% vs 55%, p = 0.04; HR = 1.92, 95%CI:1.01–3.65). To identify the molecular mechanisms underlying this association, we integrated seven sepsis transcriptomic datasets with predicted DEHP targets, revealing 46 overlapping genes. Subsequently, machine learning algorithms (LASSO, SVM-RFE, and Random Forest) prioritized seven core genes, with SHAP analysis identifying MAPK14 as the predominant contributor. Molecular docking further confirmed high-affinity binding between DEHP and these target proteins. To establish causality, Mendelian randomization analysis using cis-eQTLs and FinnGen GWAS data demonstrated that genetically predicted higher MAPK14 expression increases sepsis susceptibility (OR = 1.18, p = 0.045). In conclusion, these findings provide converging evidence that high iatrogenic DEHP exposure is associated with increased sepsis mortality, potentially through MAPK14-mediated pathways, suggesting that DEHP exposure represents a modifiable risk factor in critical care settings and supporting the evaluation of DEHP-free alternatives for high-leach medical devices.
{"title":"Iatrogenic plasticizer Di(2-ethylhexyl) phthalate (DEHP) exposure increases Sepsis mortality risk: Machine learning implicates monocyte-driven immune dysregulation","authors":"Jun-jie Gao , Li-zhu Huang , Tao Wang , Yun-long Zhang , Kai Ye , Wei-hua Lu , Pu-hong Zhang","doi":"10.1016/j.taap.2026.117752","DOIUrl":"10.1016/j.taap.2026.117752","url":null,"abstract":"<div><div>Sepsis poses a significant global health burden, and ICU patients are disproportionately exposed to di(2-ethylhexyl) phthalate (DEHP), an immunotoxic plasticizer that leaches from PVC medical devices; however, whether this exposure causally influences sepsis outcomes remains unclear. To investigate this relationship, we conducted a prospective cohort study comparing 90 ICU sepsis patients with 50 controls, quantifying urinary DEHP metabolites using LC-MS/MS. Sepsis patients demonstrated significantly elevated DEHP metabolite levels (<em>p</em> < 0.001), and high exposure (≥341.58 μg/g creatinine) was independently associated with reduced 28-day survival (35% vs 55%, <em>p</em> = 0.04; HR = 1.92, 95%CI:1.01–3.65). To identify the molecular mechanisms underlying this association, we integrated seven sepsis transcriptomic datasets with predicted DEHP targets, revealing 46 overlapping genes. Subsequently, machine learning algorithms (LASSO, SVM-RFE, and Random Forest) prioritized seven core genes, with SHAP analysis identifying MAPK14 as the predominant contributor. Molecular docking further confirmed high-affinity binding between DEHP and these target proteins. To establish causality, Mendelian randomization analysis using cis-eQTLs and FinnGen GWAS data demonstrated that genetically predicted higher MAPK14 expression increases sepsis susceptibility (OR = 1.18, <em>p</em> = 0.045). In conclusion, these findings provide converging evidence that high iatrogenic DEHP exposure is associated with increased sepsis mortality, potentially through MAPK14-mediated pathways, suggesting that DEHP exposure represents a modifiable risk factor in critical care settings and supporting the evaluation of DEHP-free alternatives for high-leach medical devices.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"509 ","pages":"Article 117752"},"PeriodicalIF":3.4,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146133062","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 : 2026-04-01Epub Date: 2026-02-06DOI: 10.1016/j.taap.2026.117753
Milad MazloumiBakhshayesh , Russell P. Hunter , Brenna Baird , Rui Liu , Anahi Gabriela Jimenez-Campos , Siem Goitom , Edward B. Barr , Guy W. Herbert , Selita N. Lucas , Charlotte M. McVeigh , Jorge Moreno , Yiliang Zhu , Barry E. Bleske , Matthew J. Campen , Alicia M. Bolt
Tungsten exposure is associated with multiple cardiovascular diseases, but limited information exists on the mechanistic underpinnings of these relationships. The current study investigated the individual and combined effects of angiotensin II (AT-II) treatment, as a model of accelerated cardiovascular disease risk, and tungsten (W) exposure on cardiac function, to provide insights into potential mechanisms involved in tungsten-mediated cardiac injury. Mice received AT-II (0.73 mg/kg/d) or saline (Veh) for 24 days through osmotic mini-pumps. The final 2-weeks of treatment, mice were exposed 4 times (4 h each) to filtered air (FA) or 1.50 ± 0.22 mg/m3 W particles by whole-body inhalation. Laser ablation and bulk inductively-coupled plasma mass spectrometry (ICP-MS) of lung samples indicated an accumulation of iron in AT-II treatment groups and confirmed the deposition of W and decreases in essential elements zinc, magnesium, and molybdenum in exposure groups. Echocardiographic data showed W exposure decreased cardiac output and stroke volume; however treatment with AT-II did not further exacerbate W's effects. The A'/E' ratio was significantly elevated in the AT-II + W group compared to the W + Veh group and trending significant compared to the FA + AT-II group. Blood cardiac troponin I was elevated in the W + AT-II group compared to either FA + Veh or W + Veh groups. Results suggest an interactive effect of both W and AT-II to drive cardiac injury following exposure. However, neither W exposure nor AT-II treatment resulted in pulmonary inflammation at the terminal endpoint of the study. Data illustrate pathophysiological effects of inhaled W and AT-II that contribute to cardiac injury.
{"title":"The effects of tungsten inhalation and continuous administration of angiotensin II on cardiac injury and pulmonary outcomes","authors":"Milad MazloumiBakhshayesh , Russell P. Hunter , Brenna Baird , Rui Liu , Anahi Gabriela Jimenez-Campos , Siem Goitom , Edward B. Barr , Guy W. Herbert , Selita N. Lucas , Charlotte M. McVeigh , Jorge Moreno , Yiliang Zhu , Barry E. Bleske , Matthew J. Campen , Alicia M. Bolt","doi":"10.1016/j.taap.2026.117753","DOIUrl":"10.1016/j.taap.2026.117753","url":null,"abstract":"<div><div>Tungsten exposure is associated with multiple cardiovascular diseases, but limited information exists on the mechanistic underpinnings of these relationships. The current study investigated the individual and combined effects of angiotensin II (AT-II) treatment, as a model of accelerated cardiovascular disease risk, and tungsten (W) exposure on cardiac function, to provide insights into potential mechanisms involved in tungsten-mediated cardiac injury. Mice received AT-II (0.73 mg/kg/d) or saline (Veh) for 24 days through osmotic mini-pumps. The final 2-weeks of treatment, mice were exposed 4 times (4 h each) to filtered air (FA) or 1.50 ± 0.22 mg/m<sup>3</sup> W particles by whole-body inhalation. Laser ablation and bulk inductively-coupled plasma mass spectrometry (ICP-MS) of lung samples indicated an accumulation of iron in AT-II treatment groups and confirmed the deposition of W and decreases in essential elements zinc, magnesium, and molybdenum in exposure groups. Echocardiographic data showed W exposure decreased cardiac output and stroke volume; however treatment with AT-II did not further exacerbate W's effects. The A'/E' ratio was significantly elevated in the AT-II + W group compared to the W + Veh group and trending significant compared to the FA + AT-II group. Blood cardiac troponin I was elevated in the W + AT-II group compared to either FA + Veh or W + Veh groups. Results suggest an interactive effect of both W and AT-II to drive cardiac injury following exposure. However, neither W exposure nor AT-II treatment resulted in pulmonary inflammation at the terminal endpoint of the study. Data illustrate pathophysiological effects of inhaled W and AT-II that contribute to cardiac injury.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"509 ","pages":"Article 117753"},"PeriodicalIF":3.4,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137295","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 : 2026-04-01Epub Date: 2026-02-06DOI: 10.1016/j.taap.2026.117747
Ayushi Sandhu, Amarjit S. Naura
Viral respiratory infections are the major cause of exacerbation of allergic asthma, often resulting in increased emergency visits and hospitalizations. However, the understanding of the immune pathways at the cellular/molecular level under the conditions is lacking. Therefore, the present work was designed to elucidate the complex interplay of immune response under the settings mimicking exacerbation of allergic asthma upon viral infection using mouse model of the condition. Mice were sensitized & challenged with Ovalbumin (OVA) to induce allergic asthma, and subsequently subjected to intranasal administration of poly(I:C), a viral mimetic. Poly(I:C) administration at a dose of 200 μg in OVA sensitized & challenged mice resulted in shift of airway inflammation from eosinophils to neutrophils and was accompanied by enhanced airway hyper-responsiveness. Interestingly, down-regulation of Th2 cytokines (IL-4/IL-5/IL-13), and steep production of pro-inflammatory cytokines (TNF-α/IL-6/KC/MCP-1) upon poly(I:C) exposure in allergic mice indicates a switch of immune response from adaptive to innate type. Further, poly(I:C) exposure exaggerated the OVA induced oxidative stress along with over-activation of MAPK/NF-κB in lung tissue. Such changes were accompanied with Th17/Treg imbalance. Despite the proven efficacy of corticosteroids in controlling eosinophilic inflammation in OVA-induced allergic asthma, failure of dexamethasone, a steroid class of drug to mitigate neutrophil-driven inflammation upon poly(I:C) exposure in allergic mice, suggests that innate immune mediators may contribute considerably during viral infection mediated exacerbation of allergic asthma. Overall, our study highlights the complexity of the immune response during viral induced exacerbation of allergic asthma and may provide new insights to tackle such steroid insensitive conditions.
{"title":"Intranasal exposure of poly (I:C) exacerbates OVA-induced allergic asthma by causing a major shift in the immune response","authors":"Ayushi Sandhu, Amarjit S. Naura","doi":"10.1016/j.taap.2026.117747","DOIUrl":"10.1016/j.taap.2026.117747","url":null,"abstract":"<div><div>Viral respiratory infections are the major cause of exacerbation of allergic asthma, often resulting in increased emergency visits and hospitalizations. However, the understanding of the immune pathways at the cellular/molecular level under the conditions is lacking. Therefore, the present work was designed to elucidate the complex interplay of immune response under the settings mimicking exacerbation of allergic asthma upon viral infection using mouse model of the condition. Mice were sensitized & challenged with Ovalbumin (OVA) to induce allergic asthma, and subsequently subjected to intranasal administration of poly(I:C), a viral mimetic. Poly(I:C) administration at a dose of 200 μg in OVA sensitized & challenged mice resulted in shift of airway inflammation from eosinophils to neutrophils and was accompanied by enhanced airway hyper-responsiveness. Interestingly, down-regulation of Th2 cytokines (IL-4/IL-5/IL-13), and steep production of pro-inflammatory cytokines (TNF-α/IL-6/KC/MCP-1) upon poly(I:C) exposure in allergic mice indicates a switch of immune response from adaptive to innate type. Further, poly(I:C) exposure exaggerated the OVA induced oxidative stress along with over-activation of MAPK/NF-κB in lung tissue. Such changes were accompanied with Th17/Treg imbalance. Despite the proven efficacy of corticosteroids in controlling eosinophilic inflammation in OVA-induced allergic asthma, failure of dexamethasone, a steroid class of drug to mitigate neutrophil-driven inflammation upon poly(I:C) exposure in allergic mice, suggests that innate immune mediators may contribute considerably during viral infection mediated exacerbation of allergic asthma. Overall, our study highlights the complexity of the immune response during viral induced exacerbation of allergic asthma and may provide new insights to tackle such steroid insensitive conditions.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"509 ","pages":"Article 117747"},"PeriodicalIF":3.4,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146143514","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 : 2026-04-01Epub Date: 2026-01-24DOI: 10.1016/j.taap.2026.117736
Jingwen Zhang , Xin Jin , Yajiao Sun , Rongyao Xia , Fuhui Chen
Epithelial-mesenchymal transition (EMT)-inducing signals trigger the accumulation of extracellular matrix, thereby contributing to organ pathology, including idiopathic pulmonary fibrosis (IPF). Transcription factor AP-2 alpha (TFAP2A) has been reported to facilitate the EMT process, but its function in IPF remain unknown. A mouse IPF model was established via single intratracheal instillation of bleomycin (BLM). Adenovirus carrying shRNA specifically targeting TFAP2A was administered 24 h prior to BLM challenge to achieve TFAP2A silencing. For in vitro studies, human bronchial epithelial cells (BEAS-2B) underwent lentivirus infection for 48 h to achieve TFAP2A silencing, followed by BLM treatment. We found that the expression of TFAP2A at both mRNA and protein levels was significantly upregulated in fibrotic lung tissue. TFAP2A knockdown alleviated BLM-induced lung injury and fibrosis, as evidenced by reduced collagen deposition and decreased expression of the fibrotic biomarkers α-SMA and Collagen I. Furthermore, TFAP2A silencing inhibited BLM-induced EMT in in the lungs of fibrotic mice, characterized by the upregulation of epithelial markers (Cytokeratin-8 and E-cadherin) and downregulation of mesenchymal markers (Fibronectin, Vimentin, and N-cadherin). In vitro assays demonstrated that BLM exposure increased α-SMA protein expression and promoted the EMT process in BEAS-2B cells, which were reversed by TFAP2A knockdown. Interestingly, TFAP2A significantly upregulated the RNA level of bradykinin receptor B1 (BDKRB1), a fibrosis-inducing factor. Mechanistically, TFAP2A activated BDKRB1 transcription by binding to the promoter of BDKRB1. Overexpression of BDKRB1 abrogated the protective effects of TFAP2A knockdown against lung fibrosis. Overall, our findings demonstrate that TFAP2A drives EMT progression and promotes IPF development by transcriptionally activating BDKRB1, identifying the TFAP2A/BDKRB1 axis as a potential therapeutic target in IPF.
{"title":"Transcription factor TFAP2A drives EMT progress by activating BDKRB1 transcription: The potential mechanism by which TFAP2A promotes idiopathic pulmonary fibrosis","authors":"Jingwen Zhang , Xin Jin , Yajiao Sun , Rongyao Xia , Fuhui Chen","doi":"10.1016/j.taap.2026.117736","DOIUrl":"10.1016/j.taap.2026.117736","url":null,"abstract":"<div><div>Epithelial-mesenchymal transition (EMT)-inducing signals trigger the accumulation of extracellular matrix, thereby contributing to organ pathology, including idiopathic pulmonary fibrosis (IPF). Transcription factor AP-2 alpha (TFAP2A) has been reported to facilitate the EMT process, but its function in IPF remain unknown. A mouse IPF model was established via single intratracheal instillation of bleomycin (BLM). Adenovirus carrying shRNA specifically targeting TFAP2A was administered 24 h prior to BLM challenge to achieve TFAP2A silencing. For in vitro studies, human bronchial epithelial cells (BEAS-2B) underwent lentivirus infection for 48 h to achieve TFAP2A silencing, followed by BLM treatment. We found that the expression of TFAP2A at both mRNA and protein levels was significantly upregulated in fibrotic lung tissue. TFAP2A knockdown alleviated BLM-induced lung injury and fibrosis, as evidenced by reduced collagen deposition and decreased expression of the fibrotic biomarkers α-SMA and Collagen I. Furthermore, TFAP2A silencing inhibited BLM-induced EMT in in the lungs of fibrotic mice, characterized by the upregulation of epithelial markers (Cytokeratin-8 and E-cadherin) and downregulation of mesenchymal markers (Fibronectin, Vimentin, and N-cadherin). In vitro assays demonstrated that BLM exposure increased α-SMA protein expression and promoted the EMT process in BEAS-2B cells, which were reversed by TFAP2A knockdown. Interestingly, TFAP2A significantly upregulated the RNA level of bradykinin receptor B1 (BDKRB1), a fibrosis-inducing factor. Mechanistically, TFAP2A activated BDKRB1 transcription by binding to the promoter of BDKRB1. Overexpression of BDKRB1 abrogated the protective effects of TFAP2A knockdown against lung fibrosis. Overall, our findings demonstrate that TFAP2A drives EMT progression and promotes IPF development by transcriptionally activating BDKRB1, identifying the TFAP2A/BDKRB1 axis as a potential therapeutic target in IPF.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"509 ","pages":"Article 117736"},"PeriodicalIF":3.4,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146053944","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 : 2026-04-01Epub Date: 2026-02-02DOI: 10.1016/j.taap.2026.117746
Xin Li , Yueting Wu , Min Mao , Hong Xu , Caijun Liu , Yang Liu , Haiyang Zhang , Hanmin Liu
Asthma is a heterogeneous disorder driven by inflammatory processes that promote pathogenic airway remodeling. Human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-Exos) emerge as a compelling therapeutic candidate to disrupt this disease cycle, with potential intergenerational benefits. In a chronic OVA-induced asthma model using C57BL/6 mice, hucMSC-Exos were delivered via serial injections during the sensitization phase. Airway structural changes were evaluated through histological analysis (H&E staining, Masson's trichrome) and immunofluorescence for key remodeling markers including α-SMA, CC-10, and the proliferation marker Ki67. Molecular pathway analyses specifically targeted the TGF-β/Smad and STAT6 signaling cascades. We found that hucMSC-Exos intervention effectively ameliorated the core pathological features of asthma-induced lung injury and significantly reduced the levels of IL-6 and TNF-α in bronchoalveolar lavage fluid (BALF) in a dose-dependent manner. Additionally, this treatment reduced asthma susceptibility in offspring of mothers with chronic asthma. Compared to the OVA group, the Exos group showed restored CC-10 expression and decreased pulmonary Ki67 levels. In offspring, Hopx (but not SPC) expression was significantly elevated at PN1 and PN4 relative to the OVA group, though these differences lost statistical significance at PN14, consistent with Western blotting (WB) validation. Notably, unlike maternal findings, both CC-10 and Ki67 expression in the lungs of treated offspring were lower than in controls. Furthermore, we observed that OVA-induced activation of PECAM-1, α-SMA, p-ROCK1, and Caspase-8 was attenuated by hucMSC-Exos treatment. RNA sequencing of hucMSC-Exos identified asthma-associated miRNAs, including let7a-5p and miR-125a-5p. The therapeutic efficacy of hucMSC-Exos against asthma was partially abolished when these miRNA inhibitors were applied, underscoring their critical regulatory role in exosome-based asthma therapy. In conclusion, hucMSC-Exos have demonstrated significant efficacy in the treatment of asthma, capable of alleviating airway remodeling and related symptoms. What is particularly important is that they have a cross-generational protective effect, which can reduce the asthma susceptibility of children born to asthmatic mothers. Mechanistically, this benefit may be achieved through the transfer of asthma-related miRNAs. These findings elucidate the key molecular pathways of the cross-generational therapeutic effect mediated by hucMSC-Exos, providing a scientific basis for their clinical application in the management of maternal and offspring asthma.
{"title":"Human umbilical cord mesenchymal stem cells-derived exosomes restore lung architecture and reduce the susceptibility to asthma of offspring in maternal asthma","authors":"Xin Li , Yueting Wu , Min Mao , Hong Xu , Caijun Liu , Yang Liu , Haiyang Zhang , Hanmin Liu","doi":"10.1016/j.taap.2026.117746","DOIUrl":"10.1016/j.taap.2026.117746","url":null,"abstract":"<div><div>Asthma is a heterogeneous disorder driven by inflammatory processes that promote pathogenic airway remodeling. Human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-Exos) emerge as a compelling therapeutic candidate to disrupt this disease cycle, with potential intergenerational benefits. In a chronic OVA-induced asthma model using C57BL/6 mice, hucMSC-Exos were delivered via serial injections during the sensitization phase. Airway structural changes were evaluated through histological analysis (H&E staining, Masson's trichrome) and immunofluorescence for key remodeling markers including α-SMA, CC-10, and the proliferation marker Ki67. Molecular pathway analyses specifically targeted the TGF-β/Smad and STAT6 signaling cascades. We found that hucMSC-Exos intervention effectively ameliorated the core pathological features of asthma-induced lung injury and significantly reduced the levels of IL-6 and TNF-α in bronchoalveolar lavage fluid (BALF) in a dose-dependent manner. Additionally, this treatment reduced asthma susceptibility in offspring of mothers with chronic asthma. Compared to the OVA group, the Exos group showed restored CC-10 expression and decreased pulmonary Ki67 levels. In offspring, Hopx (but not SPC) expression was significantly elevated at PN1 and PN4 relative to the OVA group, though these differences lost statistical significance at PN14, consistent with Western blotting (WB) validation. Notably, unlike maternal findings, both CC-10 and Ki67 expression in the lungs of treated offspring were lower than in controls. Furthermore, we observed that OVA-induced activation of PECAM-1, α-SMA, p-ROCK1, and Caspase-8 was attenuated by hucMSC-Exos treatment. RNA sequencing of hucMSC-Exos identified asthma-associated miRNAs, including let7a-5p and miR-125a-5p. The therapeutic efficacy of hucMSC-Exos against asthma was partially abolished when these miRNA inhibitors were applied, underscoring their critical regulatory role in exosome-based asthma therapy. In conclusion, hucMSC-Exos have demonstrated significant efficacy in the treatment of asthma, capable of alleviating airway remodeling and related symptoms. What is particularly important is that they have a cross-generational protective effect, which can reduce the asthma susceptibility of children born to asthmatic mothers. Mechanistically, this benefit may be achieved through the transfer of asthma-related miRNAs. These findings elucidate the key molecular pathways of the cross-generational therapeutic effect mediated by hucMSC-Exos, providing a scientific basis for their clinical application in the management of maternal and offspring asthma.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"509 ","pages":"Article 117746"},"PeriodicalIF":3.4,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146119521","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 : 2026-04-01Epub Date: 2026-01-22DOI: 10.1016/j.taap.2026.117733
Jinku Guo , Jun Xie , Ankai Xu , Wei Wang , Zhiqiang Fu , Kening Zhou , Shengkun Hong
Osteoporosis is a prevalent metabolic bone disorder characterized by diminished bone mineral density and elevated fracture susceptibility. Although isoorientin (ISO) has emerged as a promising candidate for osteoporosis treatment, its molecular mechanisms remain unclear. In this study, a comprehensive network pharmacology approach was employed to identify potential therapeutic targets by systematically mining the GeneCards and DisGeNET databases. ISO-target interactions were predicted through an integrated analysis of multiple chemoinformatic platforms, including Super-Pred, SwissTargetPrediction, PharmMapper, and ChemMapper. Hub targets were identified via protein-protein interaction (PPI) network analysis, complemented by functional enrichment assessments and molecular docking simulations. The computational findings were experimentally validated using an ovariectomy (OVX)-induced osteoporotic murine model. Network pharmacological analysis revealed 332 putative ISO targets, 45 of which significantly overlapped with 610 osteoporosis-associated targets. Functional enrichment analysis highlighted the critical involvement of these genes in hormone-mediated signaling pathways and cellular responses to nutrient levels. KEGG pathway analysis further implicated these targets in key regulatory cascades, including the MAPK, relaxin signaling, and lipid metabolism-associated atherosclerosis pathways. Molecular docking simulations demonstrated strong binding affinities between ISO and pivotal targets, including MAPK14, TLR4, and ESR1. In vivo validation using OVX mice confirmed ISO's capacity to attenuate bone loss by suppressing osteoclast activation, as evidenced by micro-CT analysis and histomorphometric quantification. Further in vitro studies demonstrated that ISO inhibits RANKL-induced osteoclastogenesis via suppression of the MAPK pathway. This study elucidates the key targets and pathways through which ISO exerts anti-osteoporotic effects, highlighting its therapeutic potential in osteoporosis management.
{"title":"Identification of key targets and mechanisms of isoorientin in osteoporosis treatment through integrated network pharmacology and experimental validation","authors":"Jinku Guo , Jun Xie , Ankai Xu , Wei Wang , Zhiqiang Fu , Kening Zhou , Shengkun Hong","doi":"10.1016/j.taap.2026.117733","DOIUrl":"10.1016/j.taap.2026.117733","url":null,"abstract":"<div><div>Osteoporosis is a prevalent metabolic bone disorder characterized by diminished bone mineral density and elevated fracture susceptibility. Although isoorientin (ISO) has emerged as a promising candidate for osteoporosis treatment, its molecular mechanisms remain unclear. In this study, a comprehensive network pharmacology approach was employed to identify potential therapeutic targets by systematically mining the GeneCards and DisGeNET databases. ISO-target interactions were predicted through an integrated analysis of multiple chemoinformatic platforms, including Super-Pred, SwissTargetPrediction, PharmMapper, and ChemMapper. Hub targets were identified via protein-protein interaction (PPI) network analysis, complemented by functional enrichment assessments and molecular docking simulations. The computational findings were experimentally validated using an ovariectomy (OVX)-induced osteoporotic murine model. Network pharmacological analysis revealed 332 putative ISO targets, 45 of which significantly overlapped with 610 osteoporosis-associated targets. Functional enrichment analysis highlighted the critical involvement of these genes in hormone-mediated signaling pathways and cellular responses to nutrient levels. KEGG pathway analysis further implicated these targets in key regulatory cascades, including the MAPK, relaxin signaling, and lipid metabolism-associated atherosclerosis pathways. Molecular docking simulations demonstrated strong binding affinities between ISO and pivotal targets, including MAPK14, TLR4, and ESR1. In vivo validation using OVX mice confirmed ISO's capacity to attenuate bone loss by suppressing osteoclast activation, as evidenced by micro-CT analysis and histomorphometric quantification. Further in vitro studies demonstrated that ISO inhibits RANKL-induced osteoclastogenesis via suppression of the MAPK pathway. This study elucidates the key targets and pathways through which ISO exerts anti-osteoporotic effects, highlighting its therapeutic potential in osteoporosis management.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"509 ","pages":"Article 117733"},"PeriodicalIF":3.4,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044082","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 : 2026-04-01Epub Date: 2026-02-04DOI: 10.1016/j.taap.2026.117754
Yijing Xin , Hui Ma , Xiang Li , Ruiyang Sun , Luo Fang , Libin Pan
The gut microbiota plays a crucial role in the progression of chronic kidney disease (CKD). The adenine-induced CKD mouse model is widely employed in preclinical research, yet the effects of adenine on the composition and metabolic function of the gut microbiota remain to be elucidated. This study aimed to test the hypothesis that adenine-induced alterations in the structure and function of the gut microbiota are significantly associated with the onset and progression of CKD. To this end, a mouse CKD model was established by alternating feeding with 0.15% and 0.20% adenine for 7 weeks. Multi-omics analysis (untargeted metabolomics, metagenomics, and spatial metabolomics) was performed to compare the adenine-induced CKD group with a standard diet-fed normal control group. Integrated analysis of plasma metabolomics and intestinal content metabolomics identified 94 differentially co-regulated metabolites: among these, indolelactic acid was significantly upregulated, while indole-3-propionic acid was significantly downregulated. The bile acid metabolic pathway also underwent marked perturbations: taurochenodeoxycholic acid and tauro-β-muricholic acid (two taurine-conjugated bile acids) were significantly elevated, whereas nordeoxycholic acid and norcholic acid were notably reduced. Integrated metabolomics-metagenomics analysis further demonstrated that Lactobacillus exhibited a significant positive correlation with a subset of upregulated metabolites (including indolelactic acid), while Taurinivorans muris showed a strong negative correlation with the taurine-conjugated bile acids. Additionally, renal spatial metabolomics revealed that phospholipid metabolic disorders in the adenine-induced CKD group directly contributed to the aggravation of renal inflammatory responses. Collectively, these findings reveal a gut microbiota-metabolite-kidney axis perturbed by adenine, providing novel insights into the pathogenesis of CKD and potential targets for metabolic intervention.
{"title":"Multi-omics reveal the key role of gut microbiota metabolism in adenine-induced chronic kidney disease","authors":"Yijing Xin , Hui Ma , Xiang Li , Ruiyang Sun , Luo Fang , Libin Pan","doi":"10.1016/j.taap.2026.117754","DOIUrl":"10.1016/j.taap.2026.117754","url":null,"abstract":"<div><div>The gut microbiota plays a crucial role in the progression of chronic kidney disease (CKD). The adenine-induced CKD mouse model is widely employed in preclinical research, yet the effects of adenine on the composition and metabolic function of the gut microbiota remain to be elucidated. This study aimed to test the hypothesis that adenine-induced alterations in the structure and function of the gut microbiota are significantly associated with the onset and progression of CKD. To this end, a mouse CKD model was established by alternating feeding with 0.15% and 0.20% adenine for 7 weeks. Multi-omics analysis (untargeted metabolomics, metagenomics, and spatial metabolomics) was performed to compare the adenine-induced CKD group with a standard diet-fed normal control group. Integrated analysis of plasma metabolomics and intestinal content metabolomics identified 94 differentially co-regulated metabolites: among these, indolelactic acid was significantly upregulated, while indole-3-propionic acid was significantly downregulated. The bile acid metabolic pathway also underwent marked perturbations: taurochenodeoxycholic acid and tauro-β-muricholic acid (two taurine-conjugated bile acids) were significantly elevated, whereas nordeoxycholic acid and norcholic acid were notably reduced. Integrated metabolomics-metagenomics analysis further demonstrated that <em>Lactobacillus</em> exhibited a significant positive correlation with a subset of upregulated metabolites (including indolelactic acid), while <em>Taurinivorans muris</em> showed a strong negative correlation with the taurine-conjugated bile acids. Additionally, renal spatial metabolomics revealed that phospholipid metabolic disorders in the adenine-induced CKD group directly contributed to the aggravation of renal inflammatory responses. Collectively, these findings reveal a gut microbiota-metabolite-kidney axis perturbed by adenine, providing novel insights into the pathogenesis of CKD and potential targets for metabolic intervention.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"509 ","pages":"Article 117754"},"PeriodicalIF":3.4,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146133052","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 : 2026-04-01Epub Date: 2026-01-29DOI: 10.1016/j.taap.2026.117738
Je Yeon Lee , Jin Su Kim , Javeria Zaheer , Sun Hee Chang , Kyungho Choi , Dong Won Hwang , Jisun Lee , Young Ah. Kim , Yoon Hee Cho
Objective
To investigate the effects of long-term Di(2-ethylhexyl) phthalate (DEHP) exposure on the female reproductive system, employing different dosages and durations of exposure.
Methods
Pregnant female CD-1 mice (F0) were orally exposed to DEHP at doses of 0, 100, and 500 mg/kg/day during gestation. Following birth, the female offspring (F1) were allocated into three groups as F0 mice. Both F0 and F1 mice were consequently subjected to ongoing DEHP exposure until they were sacrificed. Body weight, anogenital distance, anogenital index (AGI), and histopathologic outcomes of the uterus were examined at 21 and 35 weeks for F0 mice and at 10 and 24 weeks for F1 mice.
Results
Both low and high DEHP exposures significantly decreased body weight in F0 at 21 weeks and in F1 at 10 and 24 weeks, while AGI was not significantly changed in response to DEHP exposure in both F0 and F1 mice. DEHP exposure induced endometrial stromal fibrosis, endometrial hyperplasia, and myometrial atrophy in the uterus of F1mice, while cystic hyperplasia and endometrial stromal sarcoma (ESS) were seen in the F0 after DEHP exposure at 35 weeks.
Conclusions
Long-term Exposure to DEHP significantly reduced body weight and induced pathological alterations in the uterus of both F0 and F1 mice. Dams exposed to high doses of DEHP developed ESS, suggesting that DEHP may have carcinogenic potential in the uterus. However, further research is necessary to confirm this finding.
{"title":"Long-term exposure to Di(2-ethylhexyl) phthalate induced uterine histopathologic alterations in female mice","authors":"Je Yeon Lee , Jin Su Kim , Javeria Zaheer , Sun Hee Chang , Kyungho Choi , Dong Won Hwang , Jisun Lee , Young Ah. Kim , Yoon Hee Cho","doi":"10.1016/j.taap.2026.117738","DOIUrl":"10.1016/j.taap.2026.117738","url":null,"abstract":"<div><h3>Objective</h3><div>To investigate the effects of long-term Di(2-ethylhexyl) phthalate (DEHP) exposure on the female reproductive system, employing different dosages and durations of exposure.</div></div><div><h3>Methods</h3><div>Pregnant female CD-1 mice (F0) were orally exposed to DEHP at doses of 0, 100, and 500 mg/kg/day during gestation. Following birth, the female offspring (F1) were allocated into three groups as F0 mice. Both F0 and F1 mice were consequently subjected to ongoing DEHP exposure until they were sacrificed. Body weight, anogenital distance, anogenital index (AGI), and histopathologic outcomes of the uterus were examined at 21 and 35 weeks for F0 mice and at 10 and 24 weeks for F1 mice.</div></div><div><h3>Results</h3><div>Both low and high DEHP exposures significantly decreased body weight in F0 at 21 weeks and in F1 at 10 and 24 weeks, while AGI was not significantly changed in response to DEHP exposure in both F0 and F1 mice. DEHP exposure induced endometrial stromal fibrosis, endometrial hyperplasia, and myometrial atrophy in the uterus of F1mice, while cystic hyperplasia and endometrial stromal sarcoma (ESS) were seen in the F0 after DEHP exposure at 35 weeks.</div></div><div><h3>Conclusions</h3><div>Long-term Exposure to DEHP significantly reduced body weight and induced pathological alterations in the uterus of both F0 and F1 mice. Dams exposed to high doses of DEHP developed ESS, suggesting that DEHP may have carcinogenic potential in the uterus. However, further research is necessary to confirm this finding.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"509 ","pages":"Article 117738"},"PeriodicalIF":3.4,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146094287","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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