Toxicology and applied pharmacology最新文献

{"title":"Isolicoflavonol alleviates UVB-induced photodamage via protecting mitochondria and blocking the activation of NLRP3 inflammasome","authors":"Xing-Jie Zhang ,&nbsp;Peng-Yun Yang ,&nbsp;Ling Ding ,&nbsp;Jun Wang ,&nbsp;Xiao-Li Li ,&nbsp;Wei-Lie Xiao","doi":"10.1016/j.taap.2025.117262","DOIUrl":"10.1016/j.taap.2025.117262","url":null,"abstract":"<div><div>Photodamage, a type of skin inflammation caused by excessive exposure to solar radiation, leads to skin redness, inflammation, and even the development of skin cancer, posing a severe threat to individuals living at high altitudes. UVB radiation is considered the primary factor contributing to photodamage. It stimulates macrophages within the epidermis, triggers inflammasome activation, and increases the inflammatory cytokine interleukin-1β (IL-1β) production. This study examined the protective effects of the compound isolicoflavonol (ILF) and its mechanism against UVB-induced photodamage. We irradiated UVB to create a photodamage model in mice and macrophages. Next, we assessed ILF's ability to protect the skin and cells from UVB photodamage and its inhibitory effects on UVB-mediated NLRP3 inflammasome. Our findings indicated that ILF reduced UVB-induced skin injury and inflammation in mouse skin, decreased cell death, NLRP3 inflammasome activation, ROS production, and mitochondrial dysfunction. These results suggest that ILF may be a potent agent for protecting the skin against UVB-induced photodamage.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"497 ","pages":"Article 117262"},"PeriodicalIF":3.3,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391977","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":"Inhibition of GRK2 reduced doxorubicin-induced oxidative stress and apoptosis through upregulating ADH1","authors":"Zihao Jiang ,&nbsp;Junyan Kan ,&nbsp;Dongchen Wang ,&nbsp;Yifei Lv,&nbsp;Chaohua Kong,&nbsp;Lida Wu,&nbsp;Yunwei Chen,&nbsp;Meng Yang,&nbsp;Yue Gu,&nbsp;ShaoLiang Chen","doi":"10.1016/j.taap.2025.117261","DOIUrl":"10.1016/j.taap.2025.117261","url":null,"abstract":"<div><h3>Objective</h3><div>Patients undergoing anti-cancer therapy with doxorubicin (DOX) face the risk of cumulative, irreversible cardiotoxicity. In failing hearts, the overexpressed and activated G protein-coupled receptor kinase 2 (GRK2) initiates pathological signaling, leading to cardiomyocyte death. This study aimed to investigate the potential role of GRK2 in DOX-induced cardiotoxicity (DIC).</div></div><div><h3>Methods</h3><div>Mice were administered intraperitoneal injections of DOX (5 mg/kg) weekly for four weeks to induce DIC. Small interfering RNAs (siRNAs) targeting GRK2, ADH1, and PABPC1 were employed in H9c2 cells. Oxidative stress and cell apoptosis were assessed using Reactive Oxygen Species (ROS) staining and TUNEL staining, respectively. Co-immunoprecipitation (Co-IP) was utilized to detect the interaction between GRK2 and PABPC1. RNA immunoprecipitation (RIP) assay was employed to evaluate the binding between PABPC1 and ADH1 mRNA.</div></div><div><h3>Results</h3><div>GRK2 was found to be upregulated in DOX-treated mouse hearts and H9c2 cells. Cardiomyocyte-specific <em>GRK2</em> knockout partially mitigated oxidative stress, apoptosis, and cardiac dysfunction. Additionally, GRK2 knockdown attenuated DOX-induced oxidative damage and apoptosis both <em>in vivo</em> and in H9c2 cells. Furthermore, a reduction in ADH1 expression was observed in DOX-treated hearts and cardiomyocytes, with a pronounced increase following GRK2 knockdown. Notably, the beneficial effects of GRK2 knockdown in H9c2 cells were abolished after ADH1 knockdown. Mechanistically, GRK2 knockdown promoted the binding of PABPC1 to ADH1 mRNA, thereby inhibiting the degradation of ADH1 mRNA. Increased ADH1 expression alleviated DOX-induced oxidative stress and apoptosis in cardiomyocytes.</div></div><div><h3>Conclusion</h3><div>In conclusion, our study demonstrates that targeting GRK2 may represent a promising therapeutic strategy for mitigating DOX-associated cardiotoxicity.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"497 ","pages":"Article 117261"},"PeriodicalIF":3.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143365995","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":"Nilotinib impairs relaxation and temporal electro-mechanical integrity in human iPS-derived cardiomyocyte sheets","authors":"Hiroko Izumi-Nakaseko ,&nbsp;Yuko Sekino ,&nbsp;Ryuichi Kambayashi ,&nbsp;Ai Goto ,&nbsp;Yoshinori Takei ,&nbsp;Yukiko Himeno ,&nbsp;Ayako Okado-Matsumoto ,&nbsp;Yoshinobu Nagasawa ,&nbsp;Atsuhiko T. Naito ,&nbsp;Yasunari Kanda ,&nbsp;Atsushi Sugiyama","doi":"10.1016/j.taap.2025.117258","DOIUrl":"10.1016/j.taap.2025.117258","url":null,"abstract":"<div><h3>Introduction</h3><div>Nilotinib, an anti-tumor tyrosine kinase inhibitor against BCR-ABL1, has been clinically reported to cause QT prolongation, but currently lacks evidence for a risk of torsade de pointes. Indeed, it is poorly understood why nilotinib rarely induces torsade de pointes.</div></div><div><h3>Methods and results</h3><div>We adopted two-dimensional human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) sheets to examine effects of nilotinib on their electrophysiological and mechanical properties besides intracellular calcium (Ca²⁺) dynamics. Nilotinib prolonged repolarization in concentration- and reverse-frequency-dependent manners but shortened the contraction-relaxation duration (CRD), which made the electro-mechanical window negative in hiPSC-CM sheets. These effects would correspond to “trigger” of drug-induced torsade de pointes. The drug also suppressed mitochondrial maximum respiration and decreased the peak amplitude and the decay rate of Ca²⁺ transients, which shortened the CRD and impaired relaxation function of the cell sheets, partly explaining the onset mechanism of nilotinib-induced heart failure in patients. Additionally, nilotinib-induced early afterdepolarization (EAD) fluctuated the conduction speed and repolarization, and shifted the electro-mechanical window in a negative direction. These phenomena increased beat-to-beat variability of repolarization and electrical vulnerability of the heart. Meanwhile, nilotinib caused the conduction delay by Na channel blockade, thereby blocking “substrate” formation for the arrhythmia persistence.</div></div><div><h3>Conclusion</h3><div>Nilotinib could deteriorate relaxation ability and temporal electrical integrity of the heart through impairing Ca²⁺ dynamics as well as repolarization phase, which were exacerbated by nilotinib-induced EAD. However, the drug only formed “trigger”, which would explain the lower occurrence of nilotinib-induced torsade de pointes.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"496 ","pages":"Article 117258"},"PeriodicalIF":3.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143351022","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":"Effects of hypoxia and iron on ascorbic acid-mediated cytotoxicity in prostate cancer cell lines","authors":"Samiksha Deme ,&nbsp;Ida Ramezani ,&nbsp;Jonathan Coulter ,&nbsp;Channing Paller ,&nbsp;Joseph Bressler","doi":"10.1016/j.taap.2025.117259","DOIUrl":"10.1016/j.taap.2025.117259","url":null,"abstract":"<div><div>Ascorbic acid (ASC) has long been proposed as a potential cancer co-treatment due to its specific toxicity towards cancer cells, but discrepancies between in vitro and in vivo studies suggest that external factors may modulate its cytotoxicity. Here, we investigate the impact of hypoxia and iron on the therapeutic effectiveness of ASC on prostate cancer cell lines. Hypoxia-induced increases in the EC₅₀ of ASC in the prostate cancer cell lines PC-3, DU 145, LNCaP, and CWR22Rv1 but not in the prostate non-cancer cell lines RWPE-1 and TERT-PrECs. The synthetic androgen dihydrotestosterone did not modify ASC's effectiveness in either normoxia or hypoxia, which was tested because both early and advanced prostate cancer maintain the androgen receptor pathway. The effects of hypoxia on cytotoxicity depend on the drug. Hypoxia did not affect the EC₅₀ for the DNA-damaging agent etoposide but decreased the sensitivity for the anti-microtubule agent paclitaxel in PC-3 and DU 145 cells. Although hypoxic cells were iron deficient, adding iron back to cells did not reverse the effects of the hypoxic atmosphere. Interestingly, the EC₅₀ for ASC was approximately two-fold higher in iron-treated cells than non‑iron-treated cells for the PC-3 line. The higher EC50 was not observed by knocking down ferritin heavy chain mRNA. In summary, both hypoxia and iron attenuate the effectiveness of high concentrations of ASC in prostate cancer cell lines, which may affect the therapeutic benefit of ASC for prostate cancer patients.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"497 ","pages":"Article 117259"},"PeriodicalIF":3.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143365991","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":"Complanatoside A disrupts copper homeostasis and induces cuproptosis via directly targeting ATOX1 in prostate cancer","authors":"Yi Zhao ,&nbsp;Ruonan Wang ,&nbsp;Chaoyu Hu ,&nbsp;Yan Wang ,&nbsp;Zengrui Li ,&nbsp;Dengke Yin ,&nbsp;Song Tan","doi":"10.1016/j.taap.2025.117257","DOIUrl":"10.1016/j.taap.2025.117257","url":null,"abstract":"<div><div>Complanatoside A (CA), a flavonoid derived from the Chinese medicinal herb <em>Semen Astragali Complanati</em>, exhibits anticancer activity. However, its effects on prostate cancer (PCa) remain unclear. We aimed to elucidate the anti-PCa effects and underlying mechanisms of action of CA, both <em>in vitro</em> and <em>in vivo</em>. MTT, transwell, wound-healing, and flow cytometry assays were used to detect PCa cell growth, invasion, migration, and apoptosis and cell cycle progression after CA treatment, respectively. The target of CA was predicted to be antioxidant 1 copper chaperone (ATOX1), and its expression levels were determined using immunoblotting analysis. As ATOX1 acts as copper carrier to maintain copper homeostasis and disrupted copper homeostasis leads to oxidative stress in mitochondria and cuproptosis, the concentration of copper, ATP，pyruvate, α-ketoglutamic acid, malondialdehyde, and glutathione were determined and markers of cuproptosis were analyzed by immunoblotting analysis. The copper chelator tetrathiomolybdate was used to identify CA-induced cuproptosis of PCa cells. Finally, a subcutaneous mouse model was constructed, and tumor growth, oxidative stress, and carcinogenesis were analyzed <em>in vivo</em>. Our investigation revealed that CA inhibited PCa cell growth, invasion, migration, and cell cycle progression and induced apoptosis. ATOX1 was downregulated by CA and promoted Cu ion accumulation, which inhibited mitochondrial activity and induced cuproptosis in PCa cells. In addition, CA markedly suppressed tumor growth <em>in vivo</em> and induced cuproptosis in tumor tissues. In conclusion, CA exerts its anti-PCa effects by reducing ATOX1 protein levels and promoting Cu ion accumulation, which in turn, inhibits mitochondrial activity and induces cuproptosis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"496 ","pages":"Article 117257"},"PeriodicalIF":3.3,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143193050","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":"Network pharmacological mechanism and molecular experimental validation of artemisinin in the treatment of lung adenocarcinoma","authors":"Zhimin Lu ,&nbsp;Jialu Jiang ,&nbsp;Xuming Yao ,&nbsp;Guoxin Hou","doi":"10.1016/j.taap.2025.117226","DOIUrl":"10.1016/j.taap.2025.117226","url":null,"abstract":"<div><h3>Background</h3><div>Lung cancer is a medical ailment with high mortality and prevalence rates. Artemisinin (ART) and its derivatives exhibit anti-cancer properties against various malignancies, including lung cancer. However, further research is required to determine the precise anti-cancer mechanisms of ART. Hence, this study aimed to utilize network pharmacology to preliminarily investigate the therapeutic effectiveness and mode of action of this medication.</div></div><div><h3>Methods</h3><div>Using a bioinformatics approach, five target proteins with the strongest connections were selected for docking. Gene enrichment analysis was performed, and the ART target proteins were predicted. Various methods, including methyl thiazolyl tetrazolium (MTT) assays, colony formation assays, microsphere formation assays, flow cytometry, and western blotting analysis, were employed to assess the impact of ART on the malignant characteristics of lung cancer cells.</div></div><div><h3>Results</h3><div>Bioinformatic analysis identified 51 ART target genes in lung adenocarcinoma for further analysis. Pathway enrichment analysis of target genes revealed 639 enriched Gene Ontology-Biological Process (GO BP) and 17 enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. These findings imply that ART may control the IL-6 signaling pathway by focusing on important molecules such as CDK4 and IL-6. The ART-treated group experienced apoptosis induction, cell cycle arrest, and inhibition of cell proliferation and microsphere formation compared with the control group (<em>p</em> &lt; 0.05, <em>p</em> &lt; 0.01). Additionally, ART reduced the protein expression of CDK4, COX2, ERBB2, CD44, and EpCAM while increasing that of caspase 3, IL-6, p53, and SRC (<em>p</em> &lt; 0.01).</div></div><div><h3>Conclusion</h3><div>ART inhibited the growth and stemness of HCC827 cells.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117226"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142955675","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":"Thymidine phosphorylase participates in platelet activation and promotes inflammation in rheumatoid arthritis","authors":"Bo Cai ,&nbsp;Zelin He ,&nbsp;Dandan Liu ,&nbsp;Yuping Zhang ,&nbsp;Zikang Yin ,&nbsp;Weijia Bao ,&nbsp;Qiaoyi Le ,&nbsp;Ju Shao ,&nbsp;Hongyan Du ,&nbsp;Ligang Jie","doi":"10.1016/j.taap.2024.117217","DOIUrl":"10.1016/j.taap.2024.117217","url":null,"abstract":"<div><div>The elevated risk of cardiovascular disease (CVD) associated with inflammatory rheumatic diseases has long been recognized. Patients with established rheumatoid arthritis (RA) have a higher mortality rate compared to the general population due to abnormal platelet activation. Thymidine phosphorylase (TYMP) plays a crucial role in platelet activation and thrombosis, following bridging the link between RA and CVD. Data from Gene Expression Omnibus (GEO) database exhibited that TYMP levels were highly expressed in synovial tissues, immune cells, and whole blood of RA patients especially those with high levels of inflammation. Platelet count (PLT) and plateletcrit (PCT) were positively correlated with the severity of inflammation in rheumatoid arthritis while platelet distribution width (PDW) and mean platelet volume (MPV) were adverse. Levels of CD62P and TYMP in platelets of patients with active RA were significantly elevated compared to patients in the inactive phase. In vivo experiments showed that reducing TYMP expression levels of platelets could relieve inflammation in Adjuvant-Induced Arthritis (AIA) mice. Platelet activation was significantly elevated in AIA model mice, along with increased levels of intracellular calcium (Ca²⁺), reactive oxygen species (ROS), and decreased Mitochondrial Membrane Potential (ΔΨm). However, treatment with Tipiracil hydrochloride (TPI) or the utilization of <em>Tymp</em>^{<em>−/−</em>} mice reversed these effects. In vitro stimulation of wild type (WT) mouse platelets with tumor necrosis factor-alpha (TNF-α) promoted platelet activation, elevated levels of intracellular Ca²⁺as well as ROS while decreased ΔΨm. Platelets of WT mice treated with TPI or platelets of <em>Tymp</em>^{<em>−/−</em>} mice exhibited the adverse results. Our study illustrates the vital role of TYMP in promoting RA inflammation and platelet activation, suggesting that TYMP may be a potential therapeutic target for RA.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117217"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142898147","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":"Hesperidin enhanced anti-breast cancer effect and alleviated cisplatin induced nephrotoxicity through silk fibroin delivery system","authors":"Yonglong Jin ,&nbsp;Nina Dong ,&nbsp;Shosei Shimizu ,&nbsp;Yinuo Li ,&nbsp;Yuan Yao ,&nbsp;Hong Qiao ,&nbsp;Xiguang Liu ,&nbsp;Shuai Liu ,&nbsp;Chuanlong Guo ,&nbsp;Lijie Wang","doi":"10.1016/j.taap.2025.117234","DOIUrl":"10.1016/j.taap.2025.117234","url":null,"abstract":"<div><div>The incidence rate and mortality rate of breast cancer remain high, and there is an urgent need for safe and effective drugs. The excellent biological activity of hesperidin (HE) is a potential drug for the treatment of breast cancer. In this study, silk fibroin peptides (SFP) were used as delivery carriers and HE loaded SFP nanofibers (SFP/HE NFs) was prepared. The <em>in vitro</em> results showed that SFP/HE NFs significantly inhibited the proliferation and migration of breast cancer cell MDA-MB-231 compared with free HE. The mechanism results demonstrated that SFP/HE NFs induced apoptosis and DNA double stranded damage (DSBs) and further activated the cyclic monophosphate guanosine adenosine monophosphate synthase- stimulator of interferon gene (cGAS-STING) pathway. The <em>in vivo</em> studies showed that SFP/HE NFs treatment significantly inhibited the growth of breast cancer, with an inhibition rate of 65.9 % (100 mg/kg). <em>In vivo</em> mechanism studies also demonstrated that the anti-tumor activity of SFP/HE NFs was related to the activation of the cGAS-STING pathway. Interestingly, we found that the combination of SFP/HE NFs and cisplatin not only enhanced the anti-tumor activity of cisplatin, but also alleviated cisplatin induced nephrotoxicity. In conclusion, our results demonstrate the benefits of activating the cGAS-STING pathway in the treatment of breast cancer, which is expected to provide potential candidates for combined treatment of breast cancer.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117234"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012084","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":"Baicalin nanoemulsion mitigates cisplatin-induced hepatotoxicity by alleviating oxidative stress, inflammation, and restoring cellular integrity","authors":"Hadir Farouk ,&nbsp;Maha Nasr ,&nbsp;Marawan Abd Elbaset ,&nbsp;Marwa E. Shabana ,&nbsp;Omar A.H. Ahmed-Farid ,&nbsp;Rania F. Ahmed","doi":"10.1016/j.taap.2025.117231","DOIUrl":"10.1016/j.taap.2025.117231","url":null,"abstract":"<div><div>Cisplatin is a widely used chemotherapeutic agent, but its clinical utility is limited by side effects affecting different systems and organs, including hepatotoxicity in some cases. Baicalin, a flavonoid isolated from Scutellaria baicalensis, possesses antioxidant, anti-inflammatory and hepatoprotective properties, but its low bioavailability limits its therapeutic use. This study aimed to investigate whether a nanoemulsion formulation of baicalin could enhance its efficacy against cisplatin-induced hepatic injury in rats. Rats were orally treated daily with baicalin either in nanoformulation (10 or 20 mg/kg body weight per day) or conventional form (100 mg/kg body weight per day) for 12 days. Cisplatin (10 mg/kg body weight) was injected intraperitoneally on day six and day twelve to induce hepatic injury. Samples were collected on day thirteen. Serum markers, oxidative stress parameters, inflammatory markers, cellular energy status, histopathology, and other endpoints were evaluated. Results revealed that cisplatin caused elevated serum enzymes, oxidative stress, inflammation, DNA damage, depleted cellular energy levels, and induced severe hepatic histological changes. The baicalin nanoemulsion especially the higher 20 mg/kg dose, significantly ameliorated cisplatin-induced abnormalities across the various parameters. The conventional baicalin suspension also provided protection, albeit to a lesser degree than the nanoemulsion. In conclusion, administering baicalin as a nanoemulsion potentiated its hepatoprotective effects against cisplatin toxicity. The nanoemulsion formulation strategy was proven promising for enhancing baicalin's therapeutic utility.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117231"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012079","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":"Cadmium-induced iron dysregulation contributes to functional impairment in brain endothelial cells via the ferroptosis pathway","authors":"Junkyung Gil,&nbsp;Donghyun Kim,&nbsp;Sungbin Choi,&nbsp;Ok-Nam Bae","doi":"10.1016/j.taap.2025.117233","DOIUrl":"10.1016/j.taap.2025.117233","url":null,"abstract":"<div><div>Cadmium (Cd²⁺) is a heavy metal that is a major hazardous environmental contaminant, ubiquitously present in the environment. Cd²⁺ exposure has been closely associated with an increased prevalence and severity of neurological and cardiovascular diseases (CVD). The blood-brain barrier (BBB) plays a crucial role in protecting the brain from external environmental factors. Mitochondria play an important role in maintaining the barrier function of brain endothelial cells by regulating energy metabolism and redox homeostasis. In this study, we aimed to assess the cytotoxic effects of Cd²⁺ on the integrity and function of brain endothelial cells. After 24 h of exposure, Cd²⁺ reduced cell survival, tight junction protein expression, and trans-endothelial electrical resistance (TEER) in bEnd.3 cells suggest a potential BBB integrity disruption by Cd²⁺ exposure. To clarify the underlying mechanism, we further investigated the role of mitochondria in iron overload-mediated cell death following Cd²⁺ exposure. Cd²⁺ induced a substantial reduction in mitochondrial basal respiration and ATP production in brain endothelial cells, suggesting mitochondrial dysfunction. In addition, Cd²⁺ exposure led to impaired autophagy, elevated iron levels, and increased lipid peroxidation, indicating the initiation of ferroptosis, a form of cell death triggered by iron. In summary, our research suggests that Cd²⁺ exposure can disrupt BBB function by causing mitochondrial dysfunction and disrupting iron homeostasis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117233"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143024792","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}