Toxicology and applied pharmacology最新文献

{"title":"Induction of GPX4-regulated ferroptotic stress promotes epithelial-to-mesenchymal transition in renal tubule cells induced by PM2.5.","authors":"Chien-Hung Lin, Wen-Sheng Liu, Chuan Wan, Hsin-Hui Wang","doi":"10.1016/j.taap.2024.117184","DOIUrl":"10.1016/j.taap.2024.117184","url":null,"abstract":"<p><p>Increasing evidence links exposure to fine particulate matter (PM2.5) with an elevated risk of kidney disease. In this study, we investigated the effect of PM2.5 exposure on human proximal tubular epithelial (HK-2) cells and found that it elevated ferroptotic stress markers, including increased iron, reactive oxygen species (ROS), and malondialdehyde (MDA), along with reducing glutathione (GSH) levels. PM2.5 promotes the epithelial-to-mesenchymal transition (EMT) in these cells, which is associated with the loss of epithelial morphology, lowered expression of E-cadherin, and elevated expression of α-smooth muscle actin (α-SMA). Notably, a reduction in PM2.5-induced EMT characteristics was observed using either a ferroptosis-specific inhibitor (Fer-1) or a mitochondrial ROS scavenger (Mito-Tempo). Moreover, Fer-1 effectively counteracted ferroptotic stress and restored glutathione peroxidase 4 (GPX4) expression in PM2.5-exposed cells, which may explain its efficacy in inhibiting EMT induced by PM2.5. In contrast, GPX4 knockdown exacerbated EMT features in PM2.5-treated cells. Further studies showed that GPX4 overexpression alleviated EMT markers in mouse tubular cells following PM2.5 exposure, indicating the role of GPX4 in reducing ferroptotic stress and may prevent tubular injury caused by PM2.5 exposure. Our study highlights that PM2.5 may induce GPX4-regulated ferroptotic stress in tubular cells, potentially triggering the EMT process and contributing to kidney injury.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117184"},"PeriodicalIF":3.3,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780770","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":"Female rat liver after sub-acute dibutyl phthalate treatment: Histological, stereological, biochemical, and global gene expression study.","authors":"Ivana Ivelja, Jelena Vukcevic, Bojana Stanic, Danijela Kojic, Kristina Pogrmic-Majkic, Nebojsa Andric, Jelena Markovic Filipovic","doi":"10.1016/j.taap.2024.117182","DOIUrl":"10.1016/j.taap.2024.117182","url":null,"abstract":"<p><p>Although it has been recognized that females are more susceptible to chemical-induced liver injury, the effects of dibutyl phthalate (DBP), a widely used synthetic chemical, on female liver structure and function are under-researched. Here, we sought to investigate the effects of DBP on histological, stereological, and biochemical parameters, as well as global gene expression in female rat liver. Female Wistar rats were exposed to 100, 500, and 5000 mg DBP/kg diet for 28 days, corresponding to 8.6, 41.43, and 447.33 mg DBP/kg body weight (B.W.)/day, respectively. The highest dose (447.33 mg DBP/kg B.W./day) was between the no-observed-adverse-effect level (NOAEL) and the lowest-observed-adverse-effect level for liver toxicity, whereas two lower doses (8.6 and 41.43 mg DBP/kg B.W./day) were below the NOAEL. Analysis of hematoxylin and eosin-stained sections revealed an increased volume of hepatocytes, their nuclei and cytoplasm, while the volume of sinusoids decreased in DBP-exposed groups compared to the control. Examination of Periodic acid-Schiff-stained sections showed reduced glycogen content, which was the most prominent in the highest dose group. Increased glutathione S-transferase and catalase activities, and decreased GSH content and superoxide dismutase activity were observed in DBP-exposed groups. The mRNA sequencing revealed DBP-induced dose-specific changes in various genes and biological functions in female rat liver. The highest number of deregulated genes was observed in the 500 mg DBP/kg diet group. In summary, exposure to DBP caused significant liver microstructural changes, decreased glycogen content, disturbed the redox status, and affected global gene expression in female rat liver.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117182"},"PeriodicalIF":3.3,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780568","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":"CALML3-AS1 enhances malignancies and stemness of small cell lung cancer cells through interacting with DAXX protein and promoting GLUT4-mediated aerobic glycolysis.","authors":"Guangxian Mao, Jixian Liu","doi":"10.1016/j.taap.2024.117177","DOIUrl":"10.1016/j.taap.2024.117177","url":null,"abstract":"<p><p>The lncRNA CALML3 antisense RNA 1 (CALML3-AS1) is a biomarker for various cancers, including non-small cell lung cancer (NSCLC). However, the role of CALM3-AS1 in small cell lung cancer (SCLC) is still unclear. Here, we found that the CALML3-AS1 was upregulated in SCLC tissues and cells. SCLC cells (NCI-H69 and NCI-H466 cells) were transfected with small interfering RNA of CALML-AS1 (si-CALML3-AS1) and Death domain-associated protein (DAXX) (si-DAXX) or an overexpression vector of CALML-AS1 (dCas9-CALML3-AS1) and DAXX (dCas9-DAXX). The results showed that silencing CALML3-AS1 inhibited SCLC cell proliferation, colony formation, migration, invasion, and spheroid formation, and reduced the expression of stemness marker proteins (Nanog. Oct4, and Lin28). Moreover, silencing CALML3-AS1 reduced glycolysis rate, glucose utilization, and lactate production, and decreased the levels of key glycolytic regulatory proteins (GLUT1, GLUT4, HK2, and PKM2) in SCLC cells, while overexpression of CALML3-AS1 promoted malignant growth and stemness and enhanced glucose transporters type 4 (GLUT4)-mediated aerobic glycolysis by interacting with DAXX in NCI-H69 and NCI-H466 cells. Silencing DAXX or GLUT4, or treatment with 2-Deoxy-d-glucose (2-DG, a glycolysis inhibitor) reversed the effects of CALML3-AS1 overexpression on aerobic glycolysis, malignant growth, and stemness of SCLC cells. Finally, NCI-H69 cells transfected with CALML3-AS1, sh-CALML3-AS1, and sh-DAXX lentiviral vectors were subcutaneously injected into nude mice to construct xenograft models. Knockdown of CALML3-AS1 or DAXX inhibited tumor growth in SCLC in vivo. In conclusion, CALML3-AS1, an oncogene, promotes the malignancy and stemness of SCLC cells by interacting with DAXX to enhance GLUT4-mediated aerobic glycolysis, thereby promoting SCLC progression.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117177"},"PeriodicalIF":3.3,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142772636","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":"Model-based analysis for investigating the impact of tumor size, lymphocyte and neutrophil on the survival of breast cancer 4T1 tumor-bearing mice","authors":"Qing-yu Yao ,&nbsp;Xin-yu Hou ,&nbsp;Wei-zhe Jian ,&nbsp;Tian-yu Wang ,&nbsp;Ping-yao Luo ,&nbsp;Jun-sheng Xue ,&nbsp;Rong Chen ,&nbsp;Tian-yan Zhou","doi":"10.1016/j.taap.2024.117176","DOIUrl":"10.1016/j.taap.2024.117176","url":null,"abstract":"<div><div>Survival is one of the foremost endpoints in cancer therapy, and parametric survival analysis could comprehensively demonstrate the overall result of various different baseline and longitudinal factors. In this study, the survival of triple negative breast cancer 4T1 tumor-bearing mice treated by gemcitabine (GEM) and dexamethasone (DEX) was investigated with model-based analysis. The tumor size, lymphocyte (LY) and neutrophil (NE) of 4T1 tumor-bearing BALB/c mice were collected, and the PK/PD models of these longitudinal data were established in a sequential manner, respectively. The parametric time-to-event (TTE) model of survival was developed and the PK/PD models were tested and integrated as time-varying prognostic factors. The final model was evaluated and externally validated. LY and NE influence the survival directly, while tumor size showed its indirect impact on survival by affecting LY. The exposure of GEM significantly improved the survival results but DEX did not bring extra benefit. The models established in this study quantitatively characterized the abnormal increasing of LY and NE due to tumor progression in T1 tumor-bearing mice and also demonstrate their relationship with survival outcomes, and further provide a modeling framework to demonstrate potential prognostic factors of survival and evaluate the efficacy of different therapies.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"494 ","pages":"Article 117176"},"PeriodicalIF":3.3,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142756674","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":"Electronic cigarettes alter cardiac rhythm and heart rate variability hyperacutely in mice.","authors":"Jocelyn A Castellanos, Carson G Cornett, David H Gonzalez, Liqiao Li, Karla Luna, Holly R Middlekauff, Rajat Gupta, Maria C Jordan, Dennis Rünger, Yifang Zhu, Xuesi M Shao, Kenneth P Roos, Jesus A Araujo","doi":"10.1016/j.taap.2024.117174","DOIUrl":"10.1016/j.taap.2024.117174","url":null,"abstract":"<p><strong>Aims: </strong>There has been an unprecedented rise in electronic cigarette (EC) usage likely because of its perception of being safer than smoking. Recent studies show that EC exposures impact heart rate (HR) and heart rate variability (HRV), but how they are affected by the timing and frequency of exposures remain unclear. We examined the electrocardiographic (EKG) effects induced by brief EC exposures over time, their relation to EC aerosol particle and mass concentrations, and potential to promote prooxidative effects in the lungs.</p><p><strong>Methods & results: </strong>Six 10-week-old C57BL/6J mice, implanted with telemetry devices to monitor EKG activity continuously, were exposed once per week for three weeks to two EC exposures, each lasting 15-min followed by 45-min post-exposure periods. Filtered air (primary) and PBS aerosol (secondary) were used as controls. After combining weeks, EC aerosol induced bradycardia and increased time domain parameters during EC exposures with significant reductions in the post-exposure periods. Log-transformed frequency domain parameters were significantly elevated during and after exposures (p < 0.001). HRV changes occurred within minutes with similar trends observed in particle number and mass concentrations of EC aerosol. HR and HRV varied by week and parameter, with Week 2 and 3 effects overshadowing those in Week 1. ECs induced prooxidative effects in the lungs as evidenced by elevated potential for hydroxyl radical generation in bronchoalveolar lavage fluid of exposed mice (p = 0.003).</p><p><strong>Conclusion: </strong>Short-term EC exposures altered murine HR and HRV within minutes during and after exposures, effects that were modulated by the timing and frequency of EC exposures.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117174"},"PeriodicalIF":3.3,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142751682","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":"Curcumin alleviated dextran sulfate sodium-induced ulcerative colitis via inhibition of the Wnt/β-catenin signaling pathway and regulation of the differentiation of intestinal stem cells","authors":"Shaojie Liang ,&nbsp;Kun Wang ,&nbsp;Dabin Mao ,&nbsp;Qianqian Ouyang ,&nbsp;Xiaoping Lv ,&nbsp;Liwei Xie ,&nbsp;Dajian Zhu","doi":"10.1016/j.taap.2024.117175","DOIUrl":"10.1016/j.taap.2024.117175","url":null,"abstract":"<div><div>In this study, we investigated the regulatory role of curcumin in the differentiation of intestinal stem cells (ISCs) in dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) model mice and explored whether this effect was mediated by the Wnt/β-catenin signaling pathway. We conducted experiments in DSS-induced UC model mice to observe changes in intestinal morphology through HE staining and detect the expression of key proteins in the Wnt/β-catenin signaling pathway. According to these findings, curcumin was found to have a significant impact on the differentiation of ISCs. These results indicated that curcumin inhibited the Wnt/β-catenin signaling pathway and restored ISC differentiation. The effects of curcumin on the Wnt/β-catenin signaling pathway were further confirmed using Wnt/β-catenin agonists. These findings provide a new perspective for understanding the behavior of ISCs in the context of inflammation and offer new insights into the development of novel therapeutic strategies and drugs for UC.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"494 ","pages":"Article 117175"},"PeriodicalIF":3.3,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142747923","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":"Metabolism of inorganic arsenic in mice carrying the human AS3MT gene and fed folate deficient or folate supplemented diet.","authors":"Madison Miller, Christelle Douillet, Peter H Cable, Sergey A Krupenko, Bingzhen Shang, Hadley J Hartwell, Fei Zou, Beverly H Koller, Rebecca C Fry, Fernando Pardo-Manuel de Villena, Miroslav Stýblo","doi":"10.1016/j.taap.2024.117173","DOIUrl":"10.1016/j.taap.2024.117173","url":null,"abstract":"<p><p>Arsenic (+3 oxidation state) methyltransferase (AS3MT) catalyzes the S-adenosylmethionine (SAM)-dependent methylation of inorganic arsenic (iAs), yielding monomethyl‑arsenic (MAs) and dimethyl‑arsenic (DMAs) metabolites. The formation of DMAs in this pathway is considered a key mechanism for iAs detoxification. Availability of SAM for iAs methylation depends in part on dietary intake of folate. Results of population studies suggest that supplementation with folate stimulates iAs methylation, increasing DMAs and decreasing iAs and MAs proportions in urine and/or blood. The goal of the present study was to determine if folate intake affects methylation and clearance of iAs in a recently established mouse strain that expresses human AS3MT and exhibits a human-like pattern of iAs metabolism. The humanized male and female mice were fed folate-deficient (FD) or folate-supplemented (FS) diet for 6 weeks, followed by exposure to 0 ppb or 400 ppb iAs in drinking water for 5 weeks, while on the same types of diet. The concentrations and proportions of iAs, MAs and DMAs were determined in urine, liver, kidneys, and spleen. The diet-, sex- and dose-related differences were assessed by t-test or a non-parametric test; Bonferroni test was used to correct for multiple comparisons. In general, proportions of DMAs were greater and proportions of iAs were smaller in urine and tissues of FS mice as compared to FD mice. However, folate supplementation also increased MAs proportions. Notably, the folate intake had no effect on the concentrations of total arsenic either in the urine or the tissues. These results suggest that, similar to humans, folate supplementation stimulates iAs methylation in the humanized mice. However, the stimulation of iAs methylation is not associated with clearance of arsenic from tissues, possibly due to an inefficient conversion of MAs to DMAs.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117173"},"PeriodicalIF":3.3,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142740731","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":"Synthesis and evaluation of novel ethyl ferulate derivatives as potent Keap1 inhibitors to activate the Nrf2/ARE pathway in Parkinson's disease","authors":"Amritha Chakkittukandiyil ,&nbsp;Deepak Vasudevan Sajini ,&nbsp;Emdormi Rymbai ,&nbsp;Deepa Sugumar ,&nbsp;Jinu Mathew ,&nbsp;Suresh Arumugam ,&nbsp;Vadivelan Ramachandran ,&nbsp;Divakar Selvaraj","doi":"10.1016/j.taap.2024.117172","DOIUrl":"10.1016/j.taap.2024.117172","url":null,"abstract":"<div><div>The Kelch-like ECH-associated protein 1/Nuclear factor erythroid 2 related factor 2/Antioxidant Response Elements (Keap1/Nrf2/ARE) pathway is essential for neuronal resilience against the complex pathogenesis of Parkinson's disease (PD). Activating this pathway by covalently modifying Keap1 cysteine residues is a promising strategy for regulating neuroprotective gene expression. Our study aimed to identify phytochemicals that could irreversibly inhibit Keap1. A preliminary docking analysis revealed that ethyl ferulate could covalently bind with Cys151 of Keap1 by Michael's addition reaction. Further, we designed several ethyl ferulate derivatives with improved lipophilicity and assessed their binding affinity with Keap1. The molecules with good binding scores were synthesized and structures were confirmed through ¹H NMR, ¹³C NMR, FT-IR, and mass spectroscopy. Neuroprotection screening was conducted in all-trans retinoic acid differentiated SH-SY5Y cells using rotenone as a disease-inducing agent. Pre-treatment with compounds C2 and C4 significantly mitigated rotenone toxicity. Additionally, C2 and C4 decreased rotenone-induced ROS production and mitochondrial membrane potential loss. C2 and C4 also induced Nrf2 nuclear translocation in SH-SY5Y cells and increased mRNA expression of heme oxygenase-1, an Nrf2-regulated antioxidant response element. In vivo<em>,</em> pretreatment with C2 (50, 100 mg/kg, p.o.) and C4 (50, 100 mg/kg, p.o.) protected against neurodegenerative phenotypes associated with rotenone (1.5 mg/kg, s.c.) induction in Wistar rats. Results indicate, C2 and C4 dose-dependently improved muscle rigidity, catalepsy, and cognitive deficits in rotenone-induced Wistar rats, and mitigated dopaminergic neurodegeneration in the substantia nigra<em>.</em> These findings highlight the potential of ethyl ferulate derivatives in modulating oxidative stress and neurodegeneration in PD via activation of Nrf2.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"494 ","pages":"Article 117172"},"PeriodicalIF":3.3,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142740732","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":"Cisplatin caused highly delayed cytotoxicity in the immortalized cells derived from S3 segment of mouse kidney proximal tubules","authors":"Hiroki Taguchi,&nbsp;Daigo Sumi,&nbsp;Ayumi Uemura,&nbsp;Kanako Matsumoto,&nbsp;Hitomi Fujishiro","doi":"10.1016/j.taap.2024.117171","DOIUrl":"10.1016/j.taap.2024.117171","url":null,"abstract":"<div><div>Anti-cancer drug cisplatin (CDDP) causes severe acute kidney injury (AKI). CDDP-induced AKI does not occur immediately after administration, but rather 6 to 10 days after administration. However, the mechanism underling the delayed renal injury by CDDP is not well understood. In a previous investigation using immortalized cells derived from the S1, S2, and S3 segments of the proximal tubules, we found that S3 cells were more sensitive to CDDP than S1 and S2 cells. In this study, we examined whether S1, S2, and S3 cells would be useful in elucidating the mechanism of CDDP-induced delayed renal injury and whether the high sensitivity of S3 cells contributes to CDDP-induced delayed renal injury. Measurement of platinum (Pt) content by ICP-MS showed that Pt accumulation peaked at 15 min after CDDP exposure in each cell type. Even when the medium was replaced with CDDP-free medium after the 15-min CDDP exposure and the cells were further incubated, delayed cytotoxicity was still observed. The S3 cells exhibited greater sensitivity to CCDP than the S1 and S2 cells at all time points after the medium change. To investigate the mechanism of the CDDP-induced delayed cytotoxicity, we examined the cell cycle distribution of cells after CDDP exposure. The results showed that CDDP-induced perturbation of cell cycle was greater in S3 than in S1 and S2 cells. These results suggest that perturbation of the cell cycle in S3 cells due to enhanced CDDP–DNA adduct formation contributes to the high susceptibility of S3 cells to CDDP-induced delayed cytotoxicity.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"494 ","pages":"Article 117171"},"PeriodicalIF":3.3,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142719856","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":"Curcumin ameliorates astrocyte inflammation through AXL in cuprizone-induced mice","authors":"Wenjing Zhang,&nbsp;Mengjiao Sun,&nbsp;Ning Liu,&nbsp;Xiaoling Li,&nbsp;Jing Sun,&nbsp;Manxia Wang","doi":"10.1016/j.taap.2024.117170","DOIUrl":"10.1016/j.taap.2024.117170","url":null,"abstract":"<div><div>Curcumin has gained global attention owning to its anti-inflammatory, antioxidant, anticancer, and antimicrobial activities. Curcumin has recently been shown to have well-documented effects on neuroinflammation in multiple sclerosis (MS). Astrocytes, the most widely distributed glial cells in the brain, have a significant influence on the regulation of neuroinflammation in MS. However, it is unknown how curcumin exerts neuroprotective effects in astrocytes. To elucidate the mechanism underlying the effects of curcumin on astrocytes, we explored the effect of curcumin on cuprizone (CPZ)-induced mice <em>in vivo</em> and on primary astrocytes <em>in vitro</em>. In this study, we observed that curcumin significantly ameliorated myelin loss and reduced astrocyte activation in the corpus callosum (CC) region in mice induced with CPZ, and in primary astrocytes stimulated with lipopolysaccharide (LPS). Meanwhile, our research indicated that curcumin may exert neuroprotective effects in CPZ-induced mice by downregulating astrocyte-mediated inflammation by AXL. This study provides new insights into possible targeted therapies for MS.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"494 ","pages":"Article 117170"},"PeriodicalIF":3.3,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142717198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}