Yuyao Zou , Jiancheng Zhang , Wenjing Qin, Ali Danish Alvi, Ye Zhao
{"title":"Integrative network toxicology and transcriptomic analysis reveals molecular mechanisms of zinc pyrithione induced sperm damage in zebrafish","authors":"Yuyao Zou , Jiancheng Zhang , Wenjing Qin, Ali Danish Alvi, Ye Zhao","doi":"10.1016/j.taap.2025.117547","DOIUrl":"10.1016/j.taap.2025.117547","url":null,"abstract":"<div><div>Zinc Pyrithione (ZPT), a broad-spectrum antimicrobial agent widely employed in marine antifouling coatings, industrial biocides, and consumer products, has raised growing concerns regarding its male reproductive toxicity. However, the exact mechanisms are still unclear. In this study, adult male zebrafish were kept for 14 days to adapt and subsequently exposed to 0.30 μM ZPT for 21 days. To elucidate the molecular basis of ZPT-induced sperm damage, network toxicology and transcriptomic profiling were integrated. Database mining (Gene Expression Omnibus, PubChem, PharmGKB) identified 483 overlapping targets linking ZPT exposure to sperm damage. Protein-protein interaction networks and functional enrichment analyses indicated critical involvement of apoptosis, oxidative stress response, TP53 signaling, and neuroactive ligand-receptor pathways. Transcriptomic validation in zebrafish further demonstrated dose-dependent dysregulation of key genes (<em>tdo2b, ctsba, gdf2, slc45a2, ungb</em>). Moreover, molecular docking revealed stable Z interactions between ZPT and proteins associated with these pathways. Collectively, these findings establish oxidative stress, apoptotic cascades, and endocrine disruption as central mechanisms underlying ZPT-induced sperm toxicity, thereby providing critical insights for environmental risk assessment and regulatory policy development.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"505 ","pages":"Article 117547"},"PeriodicalIF":3.4,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145041224","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}
Xue Li , Yimeng Liu , Guiying Xu , Sisi Wang , Zhili Hou , Hongxia Shao , Junping Wu , Wanjie Yang , Huaiyong Chen
{"title":"Effects of anti-tuberculosis drugs on the proliferation and differentiation of alveolar stem cells","authors":"Xue Li , Yimeng Liu , Guiying Xu , Sisi Wang , Zhili Hou , Hongxia Shao , Junping Wu , Wanjie Yang , Huaiyong Chen","doi":"10.1016/j.taap.2025.117546","DOIUrl":"10.1016/j.taap.2025.117546","url":null,"abstract":"<div><div>Tuberculosis (TB), a disease caused by <em>Mycobacterium tuberculosis</em> (<em>Mtb</em>), not only inflicts damage on lung epithelium but also poses a challenge to the regenerative capacity of the lung. Using lung organoid culture techniques, we assessed the effects of anti-<em>Mtb</em> drugs on the proliferation and differentiation of type II alveolar (AT2) cells. We found that rifampicin, pyrazinamide, ethambutol, and levofloxacin decreased the organoid-forming efficiency (OFE) of AT2 cells. Additionally, rifampicin and levofloxacin inhibited the size of organoids derived from AT2 cells. Isoniazid, ethambutol, and levofloxacin promoted type I alveolar (AT1) cell differentiation. Moxifloxacin considerably promoted the OFE and clone diameter while exerting minimal effects on AT1 cell differentiation. Furthermore, we performed metabolomics to elucidate the molecular mechanisms underlying lung epithelial stem cell regeneration. The differentially expressed metabolites were closely associated with energy metabolism, which is essential for cell proliferation and differentiation. Altogether, our data suggest that anti-<em>Mtb</em> drugs exhibit diverse and specific impacts on the growth and differentiation of AT2 cells. This may be directly related to the effect of drugs on the energy metabolism of alveolar stem cells, providing new insights and tools for the evaluation of anti-<em>Mtb</em> drugs.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"505 ","pages":"Article 117546"},"PeriodicalIF":3.4,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145041277","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}
Hongjin Chu , Chen Li , Ailu Wu , Honghong Gao , Jian Chen , Yipeng Song
{"title":"Cyclophilin J inhibited oxidative stress and apoptosis in triple-negative breast cancer cell through activating the PI3K/Akt signaling pathway","authors":"Hongjin Chu , Chen Li , Ailu Wu , Honghong Gao , Jian Chen , Yipeng Song","doi":"10.1016/j.taap.2025.117545","DOIUrl":"10.1016/j.taap.2025.117545","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) was a highly aggressive and metastatic subtype of breast cancer characterized by a poor prognosis and limited treatment options. Clarifying the underlying molecular mechanisms was of significant clinical importance. In this study, we plotted Kaplan-Meier survival curves based on data from the Human Cancer Database and found that elevated CYPJ expression increased patient mortality risk and decreased survival rates. CYPJ was expressed at low levels in normal breast epithelial cells but was highly expressed in various TNBC, particularly in MDA-MB-231 and BT-549 cell lines. Subsequently, we employed lentiviral transfection technology to induce overexpression or knockdown of CYPJ in these two cell lines and validated the transfection efficiency using RT-qPCR and Western blot. The results showed that CYPJ overexpression promoted TNBC cell proliferation, facilitated the transition of the cell cycle from the G0/G1 phase to the S phase, and increased the activity of superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GPX). Additionally, it inhibited apoptosis and reduced the production of reactive oxygen species (ROS) and malondialdehyde (MDA). To further investigate the mechanism of action, a BT-549 tumor-bearing mouse model was established, and the pathway inhibitor MK2206 was administered. The results showed that MK2206 could reverse the pro-proliferative and anti-apoptotic effects of CYPJ overexpression, while also diminishing its protective effect against oxidative stress-induced damage. In summary, this study concluded that CYPJ functioned as an oncogene in TNBC. CYPJ overexpression promoted TNBC progression by activating the PI3K/Akt signaling pathway, inhibiting cellular oxidative stress responses, and suppressing apoptosis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"505 ","pages":"Article 117545"},"PeriodicalIF":3.4,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145016183","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}
Cole S. Hudson , James E. Smith , Rongjin Sun , Linh T. Vuong , Luan D. Truong , David Sheikh-Hamad , Masayuki Nigo , Ming Hu , Vincent H. Tam
{"title":"Exploration of zileuton protective mechanisms against vancomycin-associated nephrotoxicity","authors":"Cole S. Hudson , James E. Smith , Rongjin Sun , Linh T. Vuong , Luan D. Truong , David Sheikh-Hamad , Masayuki Nigo , Ming Hu , Vincent H. Tam","doi":"10.1016/j.taap.2025.117543","DOIUrl":"10.1016/j.taap.2025.117543","url":null,"abstract":"<div><div>Vancomycin is one of the most commonly used parenteral antibiotics for treating drug-resistant bacterial infections, however, it is hindered by nephrotoxicity. We previously demonstrated that zileuton could delay the onset of vancomycin-associated nephrotoxicity in rats. Here, we sought to understand the mechanism(s) of zileuton renal protection. Sprague-Dawley rats were administered vancomycin (200 mg/kg) and zileuton (1 and 4 mg/kg) daily for 10 days. After 3 days, kidneys were collected from select animals for histopathological analysis of renal injury. Single-dose vancomycin serum pharmacokinetics and renal tissue spatial distribution with adjuvant zileuton were evaluated. <em>In vitro,</em> proximal tubular cells were exposed to vancomycin and zileuton; cell viability, vancomycin accumulation, ROS levels, and p62/KEAP1 and ferroptosis-related protein levels were measured. Vancomycin was associated with increased serum creatinine and proximal tubule injury in rats including tubular cell necrosis, cytoplasmic vacuolization, interstitial edema, and mononuclear inflammatory cell infiltration. Adjuvant zileuton reduced renal injury and serum creatinine elevation without altering vancomycin serum pharmacokinetics or renal tissue distribution. <em>In vitro</em>, vancomycin exposure resulted in cellular injury, increased ROS, and significantly decreased HO-1 levels. Concomitant zileuton reduced cellular injury, decreased ROS, and rescued HO-1 levels. These preliminary findings indicate that zileuton may be protective against vancomycin-associated renal injury potentially by rescuing HO-1 levels and reducing oxidative stress in proximal tubular cells. Attenuation of nephrotoxicity would allow the optimal clinical use of vancomycin to treat drug-resistant bacterial infections, which could reduce patient harm and hospitalization costs.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"505 ","pages":"Article 117543"},"PeriodicalIF":3.4,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008444","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}
{"title":"Transcriptomic analysis of the mechanism of male reproductive injuries caused by the mixture of three phthalates in rats","authors":"Ling-Zi Xia , Jun-Zhe Yue , Li-Jun Wu , Qian-Ying Jin , Yi-Pei Yang , Jing-Yang Yu , Rui-Zhe Pan , Xin Zhang , Xiao-Ying Wu , Jiayin Zhu , Hai-Tao Gao","doi":"10.1016/j.taap.2025.117544","DOIUrl":"10.1016/j.taap.2025.117544","url":null,"abstract":"<div><div>Phthalates (PEs) are widespread in environment, and human beings are unavoidably exposing to the mixture of PEs, which may induce male reproductive health risks. In order to investigate the mechanism of male reproductive injuries caused by the mixture of di-2-ethylhexyl phthalate, dibutyl phthalate and butyl benzyl phthalate (MPEs), male rats were orally exposed to 16 mg/kg/d MPEs (L-MPEs) and 450 mg/kg/d MPEs (H-MPEs) for 90 days, and the results showed that MPEs decreased the weights of testes, epididymis and periepididymis fat, decreased serum levels of male hormones, increased abnormal sperm rate, and caused testicular histopathological damages, such as atrophy and cavitation of seminiferous tubules, spermatids exfoliation, Leydig cells hyperplasia and accumulation of lipid droplets in the testicular interstitium. Testicular transcriptomic analysis identified 100 differently expressed genes (DEGs) in L-MPEs group and 10,880 DEGs in H-MPEs group, and these DEGs mainly involved in signaling pathways of focal adhesion, PI3K-Akt, AGE-RAGE, axon guidance, PPAR, MAPK and <em>etc.</em> Testicular Paxillin and vinculin were significantly upregulated in MPEs treated groups, initially verified that focal adhesion was a pathway of male reproductive injuries induced by MPEs. This study provides new ideas for the further researches on the mechanism of MPEs' male reproductive toxicity.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"504 ","pages":"Article 117544"},"PeriodicalIF":3.4,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008463","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}
Kinza Rafi , Shaheen Faizi , Syed Saad Hussain , Shumaila Shamshad , Muhammad Ali Versiani , Shabana U. Simjee
{"title":"Quinic acid and its derivatives protect against phytohaemagglutinin-induced Alzheimer's-like neurotoxicity in SH-SY5Y cells by down-regulating p38 MAPK signaling pathway","authors":"Kinza Rafi , Shaheen Faizi , Syed Saad Hussain , Shumaila Shamshad , Muhammad Ali Versiani , Shabana U. Simjee","doi":"10.1016/j.taap.2025.117539","DOIUrl":"10.1016/j.taap.2025.117539","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is the most common type of dementia with a complex pathobiology. The clinically approved treatments against AD attempt to provide only symptomatic relief. Therefore, the current findings highlighted the neuroprotective effect and the potential signaling mechanism of quinic acid (<strong>1</strong>) and its amide derivatives (<strong>2–4</strong>) against phytohaemagglutinin (PHA)-induced neurotoxicity. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was conducted to assess the proliferative potential of <strong>1</strong>–<strong>4</strong> which were observed to increase the viability of SH-SY5Y cells. Microscopic examination of the cells induced with PHA and post treated with the respective test compound showed that <strong>1</strong> as well as its derivatives (<strong>2</strong>–<strong>4</strong>) improved morphology of the cells and subside the toxic effects of PHA. Evaluation of reactive oxygen species (ROS) production demonstrated that the test compounds except <strong>4</strong> decreased PHA-induced ROS in SH-SY5Y cells. The mRNA expression analysis of IL-1β, TNF-α, p38-α, p38-β and the disease associated ADAM10 and BACE1 genes revealed that <strong>1</strong> and its derivatives (<strong>2</strong>–<strong>4</strong>) reduced the PHA-induced elevated levels of inflammatory molecules whereas the compounds did not positively modulate the expression of proteolytic secretases. Moreover, the compounds reduced the disease specific increased expression of amyloid beta (Aβ), phosphorylated tau and activated p38 MAPK observed through fluorescence microscopy.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"504 ","pages":"Article 117539"},"PeriodicalIF":3.4,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145004130","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}
Xiaoxiao Chen , Zhibin Zhang , Huizhong Hu , Yang Cai , Ting Yang , Ougen Liu
{"title":"All-trans retinoic acid exacerbates Stevens-Johnson syndrome and toxic epidermal necrolysis via TNF signaling pathways: A network toxicology, molecular docking, and experimental study","authors":"Xiaoxiao Chen , Zhibin Zhang , Huizhong Hu , Yang Cai , Ting Yang , Ougen Liu","doi":"10.1016/j.taap.2025.117542","DOIUrl":"10.1016/j.taap.2025.117542","url":null,"abstract":"<div><div>Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe hypersensitivity reactions characterized by extensive epidermal necrosis, often induced by medications. This research aims to investigate the involvement of all-trans retinoic acid (ATRA), a derivative of vitamin A known to induce dermatological toxicity resembling SJS/TEN, in the development of these conditions. Utilizing network toxicology methodologies, molecular docking technology, and experimental validation, we identified 159 common targets between ATRA and SJS, 38 with TEN, and 27 shared among all three conditions through databases such as SwissTargetPrediction and GeneCards. Protein-protein interaction (PPI) network analyses highlighted key targets like TNF, MAPK1, and IL6, associated with apoptosis, inflammation, and immune regulation. Enrichment analyses identified significant pathways, particularly TNF, MAPK, and JAK-STAT signaling pathways. Molecular docking studies confirmed strong binding interactions between ATRA and these central targets. Experimental results demonstrated that ATRA treatment reduced keratinocyte viability, increased apoptosis, raised lactate dehydrogenase (LDH) release, and upregulated pro-inflammatory cytokines such as TNF-α, IL1B, IL6, and PTGS2 in human keratinocyte cell lines (HaCaT) and primary keratinocytes (NHEK).Western blot analysis revealed ATRA-induced upregulation of cleaved caspase-3 and phosphorylated NF-κB p65, alongside increased COX-2 and TNF-α protein levels, confirming activation of apoptotic and inflammatory pathways downstream of TNF signaling. These findings suggest that ATRA may exacerbate SJS/TEN pathogenesis by influencing apoptotic pathways and inflammatory responses via TNF-related mechanisms, offering insights for exploring therapeutic targets and enhancing drug safety in clinical settings.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"504 ","pages":"Article 117542"},"PeriodicalIF":3.4,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144996930","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}
Guang Yang , Yan Mo , Honghong Rong , Bihui Guo , Qingbing Zha , Hanli Shuai , Minghua Wang , Ping Li
{"title":"Caulerpin suppresses tumor-associated angiogenesis and tumor growth via Hippo signaling in cervical cancer","authors":"Guang Yang , Yan Mo , Honghong Rong , Bihui Guo , Qingbing Zha , Hanli Shuai , Minghua Wang , Ping Li","doi":"10.1016/j.taap.2025.117541","DOIUrl":"10.1016/j.taap.2025.117541","url":null,"abstract":"<div><div>Caulerpin, a bisindole alkaloid derived from green algae of the genus <em>Caulerpa</em>, has exhibited a promising anti-proliferative effect on various tumor cells in vitro. However, its pharmacological potential has not been intensively explored in cervical cancer. In this study, the antitumor property of caulerpin was assessed in cervical cancer cells (HeLa and SiHa cells) and xenograft mouse models. It was found that caulerpin significantly inhibited cell growth, colony formation, migration, invasion and induced cell apoptosis in HeLa and SiHa cells, and inhibited the tumor growth of HeLa xenografts in vivo. In human umbilical vein endothelial cells (HUVECs), caulerpin significantly suppressed proliferation, migration, and tube formation with (indirect) or without (direct effects) tumor-conditioned medium stimulation. Mechanically, caulerpin treatment blocked angiogenesis in vitro and in vivo through suppressing YAP1 nuclear translocation and angiogenesis-related proteins expression, including HIF-1α and VEGFA expression in tumor cells, VEGFR2 and CD31 expression in HUVECs. TDI-011536 (a specific inhibitor of Hippo) effectively reversed the effect of caulerpin. These results demonstrate the anti-angiogenic effect of caulerpin in cervical cancer that Hippo/YAP1 mediates tumor-endothelial cell interaction via VEGF/VEGFR2 signaling, which supports it as a natural product for the management of cervical cancer.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"504 ","pages":"Article 117541"},"PeriodicalIF":3.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144988424","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}
Ningjie Chen , Doudou Chai , Liping Gao , Wei Zhang , Haitao Wang , Jincun Yang , Xiuxiang Yu , Shuang Yan , Qingpeng Xu , Siqing Wang
{"title":"The graphene oxide/alginate gel loaded with platelet-rich plasma-derived exosomes regulate notch 1 signaling pathway to promote diabetic foot wound healing","authors":"Ningjie Chen , Doudou Chai , Liping Gao , Wei Zhang , Haitao Wang , Jincun Yang , Xiuxiang Yu , Shuang Yan , Qingpeng Xu , Siqing Wang","doi":"10.1016/j.taap.2025.117536","DOIUrl":"10.1016/j.taap.2025.117536","url":null,"abstract":"<div><div>Exosomes have promising applications in accelerating wound healing; however, it remains a challenge for exosomes to effectively promote healing of damaged wounds such as diabetic foot ulcers. The aim of this study was to produce an exosome that promotes wound healing in diabetic foot ulcers and to investigate its potential mechanism. Firstly, graphene oxide/alginate gel loaded with platelet-rich plasma-derived exosomes (GO/Alg + Exo) was prepared and characterized, and then the cytotoxicity and function of the gel were detected in vitro by cell survival, immunofluorescence and scratch test. In vitro experiments were performed to investigate the molecular mechanism of GO/Alg + Exo in promoting diabetic wound healing. Finally, an animal model of diabetic foot ulcer was prepared to study the bioactivity of the gel and the molecular mechanism in vivo. GO/Alg + Exo can promote skin fibrosis, enhance cell proliferation, reduce apoptosis, and promote neoangiogenesis to promote the skin repair of diabetic chronic wounds. In addition, in vitro and in vivo experiments demonstrated that GO/Alg + Exo could promote cell proliferation and angiogenesis by regulating the Notch 1 signaling pathway. GO/Alg + Exo promotes the healing of diabetic foot ulcer wounds by inhibiting the Notch 1 signaling pathway.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"504 ","pages":"Article 117536"},"PeriodicalIF":3.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144993298","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}
Jingjing Chen , Lu Zhou , Mengxin Li , Jun Wang , Yaru Chen , Jing Xia , Yue Lin , Huizhen Chen , Zibo Dong
{"title":"Atraric acid attenuates chronic intermittent hypoxia-induced lung injury by inhibiting ferroptosis through activation of the NRF2 pathway","authors":"Jingjing Chen , Lu Zhou , Mengxin Li , Jun Wang , Yaru Chen , Jing Xia , Yue Lin , Huizhen Chen , Zibo Dong","doi":"10.1016/j.taap.2025.117540","DOIUrl":"10.1016/j.taap.2025.117540","url":null,"abstract":"<div><div>Chronic Intermittent Hypoxia (CIH) is a central pathological feature of diseases such as obstructive sleep apnea hypopnea syndrome (OSAHS), which induces oxidative stress in lung tissues and leads to lung injury. Atraric acid (AA), a lichen-derived compound, has been reported to possess anti-inflammatory and antioxidant activities. In this study, we investigated the functions and mechanisms of AA in CIH-induced lung injury by constructing a CIH mouse model and an in vitro hypoxia/reoxygenation model in MLE-12 cells. Various methods were employed, including hematoxylin and eosin (H&E) staining, biochemical assay kits, quantitative polymerase chain reaction (qPCR) analysis, protein blotting, immunofluorescence, and flow cytometry. The results showed that AA pretreatment significantly attenuated pathological injury of mouse lung tissue, reduced pulmonary edema, reactive oxygen species (ROS) and malondialdehyde production, as well as the depletion of total antioxidant capacity, catalase and glutathione, and lowered the expression levels of inflammatory factors. Mechanistic studies showed that AA up-regulated solute transport family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression and down-regulated prostaglandin-endoperoxide synthase 2 (PTGS2) through activation of the Nrf2 signaling pathway, whereas the Nrf2 inhibitor ML385 completely blocked this protective effect. In conclusion, the present study demonstrates that AA targets the Nrf2 axis, attenuated CIH-induced inflammation, alleviates ROS accumulation, and blocks the vicious cycle of oxidative stress, ferroptosis, and inflammation, making it a promising therapeutic strategy for the treatment of CIH-induced lung injury.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"504 ","pages":"Article 117540"},"PeriodicalIF":3.4,"publicationDate":"2025-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144922527","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}