{"title":"Network pharmacological mechanism and molecular experimental validation of artemisinin in the treatment of lung adenocarcinoma","authors":"Zhimin Lu , Jialu Jiang , Xuming Yao , 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> < 0.05, <em>p</em> < 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> < 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}
Bo Cai , Zelin He , Dandan Liu , Yuping Zhang , Zikang Yin , Weijia Bao , Qiaoyi Le , Ju Shao , Hongyan Du , Ligang Jie
{"title":"Thymidine phosphorylase participates in platelet activation and promotes inflammation in rheumatoid arthritis","authors":"Bo Cai , Zelin He , Dandan Liu , Yuping Zhang , Zikang Yin , Weijia Bao , Qiaoyi Le , Ju Shao , Hongyan Du , 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 (Ca<sup>2+</sup>), reactive oxygen species (ROS), and decreased Mitochondrial Membrane Potential (ΔΨm). However, treatment with Tipiracil hydrochloride (TPI) or the utilization of <em>Tymp</em><sup><em>−/−</em></sup> 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 Ca<sup>2+</sup>as well as ROS while decreased ΔΨm. Platelets of WT mice treated with TPI or platelets of <em>Tymp</em><sup><em>−/−</em></sup> 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}
Yonglong Jin , Nina Dong , Shosei Shimizu , Yinuo Li , Yuan Yao , Hong Qiao , Xiguang Liu , Shuai Liu , Chuanlong Guo , Lijie Wang
{"title":"Hesperidin enhanced anti-breast cancer effect and alleviated cisplatin induced nephrotoxicity through silk fibroin delivery system","authors":"Yonglong Jin , Nina Dong , Shosei Shimizu , Yinuo Li , Yuan Yao , Hong Qiao , Xiguang Liu , Shuai Liu , Chuanlong Guo , 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}
Hadir Farouk , Maha Nasr , Marawan Abd Elbaset , Marwa E. Shabana , Omar A.H. Ahmed-Farid , Rania F. Ahmed
{"title":"Baicalin nanoemulsion mitigates cisplatin-induced hepatotoxicity by alleviating oxidative stress, inflammation, and restoring cellular integrity","authors":"Hadir Farouk , Maha Nasr , Marawan Abd Elbaset , Marwa E. Shabana , Omar A.H. Ahmed-Farid , 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}
Junkyung Gil, Donghyun Kim, Sungbin Choi, Ok-Nam Bae
{"title":"Cadmium-induced iron dysregulation contributes to functional impairment in brain endothelial cells via the ferroptosis pathway","authors":"Junkyung Gil, Donghyun Kim, Sungbin Choi, Ok-Nam Bae","doi":"10.1016/j.taap.2025.117233","DOIUrl":"10.1016/j.taap.2025.117233","url":null,"abstract":"<div><div>Cadmium (Cd<sup>2+</sup>) is a heavy metal that is a major hazardous environmental contaminant, ubiquitously present in the environment. Cd<sup>2+</sup> 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 Cd<sup>2+</sup> on the integrity and function of brain endothelial cells. After 24 h of exposure, Cd<sup>2+</sup> reduced cell survival, tight junction protein expression, and trans-endothelial electrical resistance (TEER) in bEnd.3 cells suggest a potential BBB integrity disruption by Cd<sup>2+</sup> exposure. To clarify the underlying mechanism, we further investigated the role of mitochondria in iron overload-mediated cell death following Cd<sup>2+</sup> exposure. Cd<sup>2+</sup> induced a substantial reduction in mitochondrial basal respiration and ATP production in brain endothelial cells, suggesting mitochondrial dysfunction. In addition, Cd<sup>2+</sup> 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 Cd<sup>2+</sup> 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}
Jingjing Ma , Simei Yue , Yinghui Liu , Lingjiao Gong , Pengzhan He , Yingjie Yang , Zhengxin Fu , Danxiang Han , Qiang Hu , Fei Liao , Lin Xu
{"title":"Fucoxanthin ameliorates ulcerative colitis by maintaining the epithelial barrier via blocking JAK2/STAT3 signaling pathway","authors":"Jingjing Ma , Simei Yue , Yinghui Liu , Lingjiao Gong , Pengzhan He , Yingjie Yang , Zhengxin Fu , Danxiang Han , Qiang Hu , Fei Liao , 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 , 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":"Investigating the anticancer properties of urolithin B in triple negative breast cancer: In vivo and in vitro insights","authors":"Saeide Mansoori , Seyed Isaac Hashemy , Moein Eskandari , Azar Khorrami , Masoud Homayouni , 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}
Muhamad Fikri Shazlan Saad , Muhammad Nazrul Hakim Abdullah , Vuanghao Lim , Hasnah Bahari , Boon Yin Khoo , Jun Jie Tan , Yoke Keong Yong
{"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 , Muhammad Nazrul Hakim Abdullah , Vuanghao Lim , Hasnah Bahari , Boon Yin Khoo , Jun Jie Tan , 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}
Wei He , Xinhuo Li , Qiannan Ding , Tan Zhang , Jiewen Zheng , Xuanyuan Lu , Jianlei Li , Cong Jin , Yangjun Xu
{"title":"Fangchinoline alleviates the progression of osteoarthritis through the nuclear factor kappa B signaling pathway","authors":"Wei He , Xinhuo Li , Qiannan Ding , Tan Zhang , Jiewen Zheng , Xuanyuan Lu , Jianlei Li , Cong Jin , 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}