Toxicology and applied pharmacology最新文献

{"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}

{"title":"Fucoxanthin ameliorates ulcerative colitis by maintaining the epithelial barrier via blocking JAK2/STAT3 signaling pathway","authors":"Jingjing Ma ,&nbsp;Simei Yue ,&nbsp;Yinghui Liu ,&nbsp;Lingjiao Gong ,&nbsp;Pengzhan He ,&nbsp;Yingjie Yang ,&nbsp;Zhengxin Fu ,&nbsp;Danxiang Han ,&nbsp;Qiang Hu ,&nbsp;Fei Liao ,&nbsp;Lin Xu","doi":"10.1016/j.taap.2024.117213","DOIUrl":"10.1016/j.taap.2024.117213","url":null,"abstract":"<div><h3>Background</h3><div>The clinical efficacies of Ulcerative colitis (UC) are far from satisfactory. Fucoxanthin (FUC) is a marine carotenoid that is abundant in seaweed and microalgae. It has been reported that FUC can possess anti-inflammatory and antioxidant. However, its mechanism and role in UC is yet to be clarified. This study aimed to investigate the protective effect and potential mechanism of FUC extracted from the diatom <em>Phaeodactylum tricornutm</em> on dextran sodium sulfate (DSS) -induced colitis.</div></div><div><h3>Methods</h3><div>Animal UC model was induced by DSS and cellular model was established by TNF-α. Immunohistochemical staining, Western blot, RT-qPCR, and immunofluorescence were used to assess the inflammatory responses and epithelial barrier <em>in vivo</em> and <em>in vitro</em> models.</div></div><div><h3>Results</h3><div>The results showed that FUC attenuates DSS-induced colitis by ameliorating the epithelial mucosal barrier. Moreover, FUC possessed antioxidant and anti-inflammatory effects on NCM460 cells. JAK/STAT activator RO8191 could reverse these changes.</div></div><div><h3>Conclusion</h3><div>FUC exerted anti-inflammatory and antioxidant effects via the JAK2/STAT3 signaling pathway, and served as a potential therapeutic agent for the treatment of UC.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117213"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885468","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 ,&nbsp;Jixian Liu","doi":"10.1016/j.taap.2024.117177","DOIUrl":"10.1016/j.taap.2024.117177","url":null,"abstract":"<div><div>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-<span>d</span>-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 <em>in vivo</em>. 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.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117177"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","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":"Exposure to environmentally relevant concentrations of di-(2-ethylhexyl) phthalate (DEHP) induced reproductive toxicity in female koi carp (Cyprinus carpio)","authors":"Kampan Bisai ,&nbsp;Vikash Kumar ,&nbsp;Basanta Kumar Das ,&nbsp;Bijay Kumar Behera ,&nbsp;Manoj Kumar Pati","doi":"10.1016/j.taap.2024.117200","DOIUrl":"10.1016/j.taap.2024.117200","url":null,"abstract":"<div><div>A frequently utilized plasticizer is di-(2-ethylhexyl) phthalate (DEHP), considered a ubiquitous contaminant in the environment and reported to have severe impacts on animals. Although it disrupts the female reproductive system in mammals, little is known about how it effects on fish reproduction. The reproductive parameters of female adult koi carp (<em>Cyprinus carpio</em>) were investigated in this study subjected to environmentally relevant exposure of DEHP (1, 10 and 100 μg/L). After 60 days experiment, significantly lower GSI was recorded in females of 10 and 100 μg/L DEHP-exposed groups. The examination of ovarian histology showed defective histoarchitecture, which included the existence of atretic oocytes, the emergence of intra-oocyte vacuoles as well as necrosis. The groups exposed to DEHP (10 and 100 μg/L) showed significant decreases in fecundity and ova-diameter values. Significant changes in the biochemical (total protein, glucose and cholesterol) and ionic (sodium, potassium, calcium and magnesium) composition were noticed in the ovarian fluid of exposed groups. The groups treated with DEHP showed higher levels of 11-ketotestosterone along with reduced levels of 17β-estradiol. Using real-time PCR, the mRNA expression of several genes linked to reproduction, such as <em>Fshr</em>, <em>Lhr</em>, <em>Ar</em>, <em>Erα</em> and <em>Erβ</em> were assessed and observed that there was a concentration-dependent alternation. The pairing of exposed females with untreated males significantly lowered the rates of fertilization, hatching and larval survival. In summary, the results of this investigation validated that exposure to DEHP in a nominal concentration could potentially reduce the reproductive health of female fish.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117200"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814236","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":"Investigating the anticancer properties of urolithin B in triple negative breast cancer: In vivo and in vitro insights","authors":"Saeide Mansoori ,&nbsp;Seyed Isaac Hashemy ,&nbsp;Moein Eskandari ,&nbsp;Azar Khorrami ,&nbsp;Masoud Homayouni ,&nbsp;Atefeh Ghahremanloo","doi":"10.1016/j.taap.2024.117224","DOIUrl":"10.1016/j.taap.2024.117224","url":null,"abstract":"<div><div>Breast cancer (BC) is a leading cause of cancer-related mortality among women worldwide, with incidence rates rising globally. Urolithin B (UB), a bioactive metabolite of ellagic acid, has demonstrated promising anticancer effects in various cancer models. This study aimed to evaluate the effects of UB on the growth, angiogenesis, and metastasis of BC cells using both in vivo and in vitro approaches. Cytotoxic effects of UB were assessed on MDA-MB-231 cells and normal HFF cells using the MTT assay. Scratch assays and gelatin zymography demonstrated UB's suppression of cell migration and reduced enzymatic activities of MMP-2 and MMP-9. In a xenograft mouse model, UB significantly reduced tumor growth, enhanced necrosis, and decreased vascularity in tumor tissues. It downregulated mRNA expression levels of VEGF, VEGFR, MMP-2, and MMP-9, indicating potent anti-angiogenic and anti-metastatic properties. Additionally, UB exhibited antioxidant effects by increasing total thiol content and the activities of superoxide dismutase (SOD) and catalase (CAT) while reducing malondialdehyde (MDA) levels in tumor tissues. In conclusion, our results highlight the anticancer potential of UB, through its ability to suppress the proliferation, angiogenesis, and metastatic properties of BC both in vitro and in vivo. Coupled with its antioxidant properties, UB emerges as a promising and safe candidate for further pre-clinical and clinical research and therapeutic applications in BC management.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117224"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928291","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":"Exploring the role of Bisphenol A in obesity-driven colorectal cancer progression: network toxicology and multi-organ pathology in animal models","authors":"Muhamad Fikri Shazlan Saad ,&nbsp;Muhammad Nazrul Hakim Abdullah ,&nbsp;Vuanghao Lim ,&nbsp;Hasnah Bahari ,&nbsp;Boon Yin Khoo ,&nbsp;Jun Jie Tan ,&nbsp;Yoke Keong Yong","doi":"10.1016/j.taap.2025.117227","DOIUrl":"10.1016/j.taap.2025.117227","url":null,"abstract":"<div><div>Bisphenol A (BPA), an endocrine disruptor, is linked to cancer progression in estrogen-responsive tissues, but its role in promoting colorectal cancer (CRC) progression in the context of obesity remains underexplored. This study examines BPA's influence on CRC in obese Sprague-Dawley rats using network toxicology and experimental models. Computational analysis using the Database for Annotation, Visualization, and Integrated Discovery identified pathways such as “CRC” and “chemical carcinogenesis-receptor activation”, implicating the PI3K-AKT pathway in IL-1 beta upregulation and BPA's role in CRC during obesity. Thirty male rats were grouped (<em>n</em> = 6) as follows: N (normal diet), NC (normal diet + CRC), HC (high-fat diet + CRC), NCB (normal diet + CRC + BPA), and HCB (high-fat diet + CRC + BPA). CRC was induced with 1,2-dimethylhydrazine (40 mg/kg), and BPA (25 mg/kg) was administered for 19 weeks. Although BPA exposure did not affect body weight or biochemical parameters, the HCB group exhibited significant histopathological changes in the colon, including lymphoid hyperplasia, liver damage, and increased IL-1β levels. Furthermore, diet influenced adipocyte size, exacerbating BPA's effects on CRC progression. Findings suggest BPA may worsen CRC progression in obese rats through identified pathways, promoting multi-organ pathology and underscoring the need for stricter regulations, especially for vulnerable populations.</div></div><div><h3>Environmental implication</h3><div>Bisphenol A (BPA), a widespread environmental contaminant, is increasingly linked to serious health issues, including cancer, in susceptible populations. Our study highlights BPA's role in promoting obesity-driven colorectal cancer (CRC) progression, demonstrating its carcinogenic potential in high-risk contexts. These findings emphasize the urgent need for regulatory scrutiny of BPA exposure, particularly in obese individuals, and support the development of safer alternatives. Addressing BPA's impact can contribute to preventive health strategies and inform policies aimed at reducing environmental and public health risks associated with endocrine-disrupting chemicals.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117227"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142955579","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":"Fangchinoline alleviates the progression of osteoarthritis through the nuclear factor kappa B signaling pathway","authors":"Wei He ,&nbsp;Xinhuo Li ,&nbsp;Qiannan Ding ,&nbsp;Tan Zhang ,&nbsp;Jiewen Zheng ,&nbsp;Xuanyuan Lu ,&nbsp;Jianlei Li ,&nbsp;Cong Jin ,&nbsp;Yangjun Xu","doi":"10.1016/j.taap.2025.117241","DOIUrl":"10.1016/j.taap.2025.117241","url":null,"abstract":"<div><div>Osteoarthritis is a progressive, chronic joint disease characterized by pain, stiffness, and limited mobility, which can lead to physical disability in severe cases. Owing to its complex pathological features, effective treatments for osteoarthritis are lacking. Fangchinoline is a natural alkaloid found in the tuberous roots of plants belonging to the Menispermaceae family. Fangchinoline reportedly possesses anti-inflammatory, antioxidant, and anticancer properties; however, its role in osteoarthritis progression remains unclear. In this study, we investigated the protective effects and potential mechanisms of fangchinoline against osteoarthritis. In vitro, we confirmed that fangchinoline alleviates interleukin-1β-induced cartilage inflammation, reduces the levels of metabolic factors, such as inducible nitric oxide synthase and matrix metalloproteinase-3, and modulates the expression of aggrecan, which enhances extracellular matrix synthesis. In vivo, we demonstrated that fangchinoline can ameliorate articular cartilage degeneration and reduce inflammatory destruction in a destabilization of the medial meniscus mouse model. The nuclear factor kappa B (NF-κB) signaling pathway in osteoarthritis has been a primary target for drug development, and our results suggest that fangchinoline exerts anti-inflammatory effects by inhibiting the activity of IKKα/β. Using an in vitro human cartilage culture model, we further validated that fangchinoline significantly mitigates cartilage degeneration and inflammation by modulating the NF-κB signaling pathway. This evidence highlights its dual action in preserving cartilage integrity and suppressing inflammatory responses. These findings collectively underscore fangchinoline as a potent inhibitor of NF-κB, capable of attenuating key pathological processes associated with osteoarthritis. Therefore, fangchinoline emerges as a promising therapeutic candidate for slowing the progression of osteoarthritis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"496 ","pages":"Article 117241"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143081140","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":"Dehydrodiisoeugenol inhibits PDGF-BB-induced proliferation and migration of human pulmonary artery smooth muscle cells via the mTOR/HIF1-α/HK2 signaling pathway","authors":"Shishun Xie ,&nbsp;Jianjun Zhao ,&nbsp;Fan Zhang ,&nbsp;Xiangjun Li ,&nbsp;Xiaoyan Yu ,&nbsp;Zhiyun Shu ,&nbsp;Hongyuan Cheng ,&nbsp;Siyao Liu ,&nbsp;Shaomin Shi","doi":"10.1016/j.taap.2024.117212","DOIUrl":"10.1016/j.taap.2024.117212","url":null,"abstract":"<div><div>Abnormal proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) leading to pulmonary vascular remodeling are critical factors in the development of pulmonary hypertension (pH). Dehydrodiisoeugenol (DEH), a natural phenolic compound, is renowned for its antioxidant and anti-inflammatory properties. However, the precise role and mechanisms of DEH in PH remain unclear. In this study, human PASMCs were exposed to PDGF-BB for 48 h to establish an in vitro model. Subsequently, cells were treated with DEH, and assessments of cell proliferation, migration, and apoptosis were performed using CCK-8/EdU assays, scratch/transwell assays, and flow cytometry. The results showed that PDGF-BB induced phenotypic modulation, proliferation, and migration of PASMCs while reducing apoptosis. Treatment with DEH effectively reversed these effects. Bioinformatics analysis identified mTOR as a target of DEH action. Western blot experiments were conducted to evaluate the expression of proteins involved in the mTOR/HIF1-α/HK2 signaling pathway, suggesting that DEH modulates this pathway by targeting and inhibiting mTOR. After treating cells with mTOR inhibitors, cellular glycolysis was assessed using the extracellular acidification rate (ECAR) assay. The results indicated that inhibition of mTOR phosphorylation decreased aerobic glycolysis in PASMCs and suppressed cell proliferation, migration, and apoptosis resistance, regardless of PDGF-BB treatment. Activation of mTOR reversed the inhibition of PDGF-BB-induced PASMC-related protein expression by DEH. These findings suggest that DEH inhibits aerobic glycolysis in PDGF-BB-induced PASMCs through the mTOR/HIF1-α/HK2 signaling pathway, thereby suppressing cell proliferation, migration, and resistance to apoptosis. Consequently, DEH holds promise as a novel therapeutic agent for treating pulmonary arterial hypertension.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117212"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884846","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":"Chronic cadmium exposure to minimal-risk doses causes dysfunction of epididymal adipose tissue and metabolic disorders","authors":"Victor Enrique Sarmiento-Ortega ,&nbsp;Daniel Issac Alcántara-Jara ,&nbsp;Diana Moroni-González ,&nbsp;Alfonso Diaz ,&nbsp;Rubén Antonio Vázquez-Roque ,&nbsp;Eduardo Brambila ,&nbsp;Samuel Treviño","doi":"10.1016/j.taap.2024.117203","DOIUrl":"10.1016/j.taap.2024.117203","url":null,"abstract":"<div><div>Cadmium (Cd) is among the top seven most hazardous environmental contaminants. Minimal risk levels for daily exposure have been established, such as no observable adverse effect level (NOAEL) and lowest observable adverse effect level (LOAEL). Chronic exposure to Cd, at both NOAEL and LOAEL doses, causes toxicity in diverse tissues. However, Cd toxicity in adipose tissue, an endocrine and metabolic organ, remains relatively understudied. We aimed to investigate the potentially toxic effects of chronic Cd exposure (at NOAEL and LOAEL doses) on epidydimal adipose tissue of adult male Wistar rats. Ninety male Wistar rats were divided into three groups (<em>n</em> = 30): Control Cd-free, NOAEL, and LOAEL that received CdCl₂ in drinking water for 15 days to 5 months. We evaluated over time zoometry, serum and adipose Cd concentration, redox balance, GLUT4 and Nrf2 expression, histology, leptin, adiponectin, adipose insulin resistance index, free fatty acids, and glucose tolerance. The higher dose group showed a more pronounced and sustained increase in serum and adipose tissue of Cd concentration. Zoometry was similarly affected in both Cd-exposed groups with adipocyte hypertrophy. The redox balance was maintained due to the augmenting of Nrf2 expression. Leptin concentration augmented, while adiponectin diminished. Adipose insulin resistance increased simultaneously to lipolysis and glucose intolerance despite high GLUT4 expression. In conclusion, this study provides strong evidence that chronic Cd exposure, even at minimal risk levels (LOAEL and NOAEL doses), has toxic effects, disrupting the function of epididymal adipose tissue and contributing to metabolic disorders.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117203"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865549","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}

{"title":"Shikonin modulates activated fibroblast apoptosis in silicosis fibrosis via the PI3K/Akt signaling pathway: A network pharmacology approach","authors":"Shengpeng Wen ,&nbsp;Sirong Chang ,&nbsp;Huning Zhang ,&nbsp;Wenyue Zhang ,&nbsp;Yi Guo ,&nbsp;Na Zhang ,&nbsp;Anning Yang ,&nbsp;Yue Sun ,&nbsp;Zhihong Liu","doi":"10.1016/j.taap.2025.117236","DOIUrl":"10.1016/j.taap.2025.117236","url":null,"abstract":"<div><h3>Background</h3><div>Silicosis is a lung disease caused by the inhalation of free crystalline silica and is characterized mainly by lung inflammation and progressive pulmonary fibrosis. Shikonin, a biologically active compound isolated from the traditional Chinese medicine Comfrey, has been shown to have significant antifibrotic effects. However, the molecular mechanisms underlying the antifibrotic effects of SHK in silicosis remain unclear.</div></div><div><h3>Methods</h3><div>This study used a combination of network pharmacology, molecular docking, molecular dynamics simulation, and in vitro experimental validation to investigate the potential targets of SHK in silicosis.</div></div><div><h3>Results</h3><div>Network pharmacology analysis identified 208 cross genes associated with disease drugs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis show that these intersecting genes are significantly associated with the PI3K/Akt signaling pathway. Protein protein interaction (PPI) network analysis further revealed 10 core crossover genes, namely ALB, Akt1, STAT3, CASP3, EGFR, MMP9, Bcl-2, ESR1, HSP90AA1, and NF-κB1. Among them, Akt1 and Bcl-2 have the strongest binding ability to SHK. The in vitro experimental results showed that SHK can significantly inhibit the activation of fibroblasts and promote apoptosis of activated fibroblasts through the PI3K/Akt signaling pathway.</div></div><div><h3>Conclusion</h3><div>SHK alleviates silica induced silicosis fibrosis by inhibiting the transformation of fibroblasts into myofibroblasts through the PI3K/Akt signaling pathway.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117236"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143041987","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}