Cellular signalling最新文献

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The m6A RNA demethylase FTO promotes radioresistance and stemness maintenance of glioma stem cells
IF 4.4 2区 生物学
Cellular signalling Pub Date : 2025-04-02 DOI: 10.1016/j.cellsig.2025.111782
Junhao Zhang , Guoxi Li , Runqiu Wu , Lin Shi , Cong Tian , Hongyan Jiang , Hongyu Che , Yongang Jiang , Zhiyong Jin , Rutong Yu , Xuejiao Liu , Xu Zhang
{"title":"The m6A RNA demethylase FTO promotes radioresistance and stemness maintenance of glioma stem cells","authors":"Junhao Zhang ,&nbsp;Guoxi Li ,&nbsp;Runqiu Wu ,&nbsp;Lin Shi ,&nbsp;Cong Tian ,&nbsp;Hongyan Jiang ,&nbsp;Hongyu Che ,&nbsp;Yongang Jiang ,&nbsp;Zhiyong Jin ,&nbsp;Rutong Yu ,&nbsp;Xuejiao Liu ,&nbsp;Xu Zhang","doi":"10.1016/j.cellsig.2025.111782","DOIUrl":"10.1016/j.cellsig.2025.111782","url":null,"abstract":"<div><div>Glioblastoma (GBM) was the most common and deadliest malignant brain tumor in adults, with a poor prognosis. Effective targeted drugs are still lacking, and the presence of glioblastoma stem cells (GSC) is a major factor contributing to radiotherapy resistance. Screening for targeted drugs that can sensitize GBM to radiotherapy is crucial. FTO is considered an attractive potential target for tumor therapy, as it mediates m6A demethylation to regulate the stability of target genes. In this study, we evaluated the role of FTO inhibition in promoting the sensitivity of GSC cells to radiotherapy through tumor sphere formation assays, cell apoptosis assays, and in situ GSC tumor models. We preliminarily explored the molecular mechanisms by transcriptome sequencing and m6A methylation sequencing to investigate how inhibiting FTO increases radiotherapy sensitivity. The results showed that downregulation of FTO expression or FTO inhibitor FB23-2 combined with radiotherapy significantly inhibited GSC cell proliferation and self-renewal and increased apoptosis. FB23-2 combined with radiotherapy effectively inhibited intracranial tumor growth in mice and prolonged the survival of tumor-bearing mice. Furthermore, FTO inhibition sustained the increase of γH2AX expression induced by radiotherapy while decreasing Rad51 expression. Importantly, we found that inhibiting FTO could increase m6A methylation modification of VEGFA, thereby downregulating both mRNA and protein expression of VEGFA. Our findings provide a new therapeutic strategy for enhancing GBM radiotherapy sensitivity and lay the theoretical and experimental groundwork for clinical trials targeting FTO.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"132 ","pages":"Article 111782"},"PeriodicalIF":4.4,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143768635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Precision peptide disruptors: The next generation of targeted therapeutics in oncology
IF 4.4 2区 生物学
Cellular signalling Pub Date : 2025-04-01 DOI: 10.1016/j.cellsig.2025.111783
Bria O'Gorman , Sean F. Cooke , Connor M. Blair
{"title":"Precision peptide disruptors: The next generation of targeted therapeutics in oncology","authors":"Bria O'Gorman ,&nbsp;Sean F. Cooke ,&nbsp;Connor M. Blair","doi":"10.1016/j.cellsig.2025.111783","DOIUrl":"10.1016/j.cellsig.2025.111783","url":null,"abstract":"<div><div>Therapeutically targeting the pathologically remodelled protein-protein interaction network in cancer with peptide disruptors increasingly represents a clinically attractive approach to treating recalcitrant cancers. In this review, we map the pre-clinical and clinical-stage peptide disruptor landscape within an oncology-specific context and discuss key clinical examples that are making significant impact to patients; demonstrating a key role for peptide disruptors in precision medicine as a next-generation targeted therapeutic.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"132 ","pages":"Article 111783"},"PeriodicalIF":4.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143768258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Extracellular vesicles derived from EZH2-high ovarian cancer cells facilitate omental metastasis by inducing Periostin+ fibroblasts
IF 4.4 2区 生物学
Cellular signalling Pub Date : 2025-04-01 DOI: 10.1016/j.cellsig.2025.111773
Hongmei Liu , Jingni Zhang , Jing Cai , Qiulei Wu , Guoqing Li , Wenhan Li , Tong Liu , Ping Yang , Zehua Wang , Xiaoqing Yi
{"title":"Extracellular vesicles derived from EZH2-high ovarian cancer cells facilitate omental metastasis by inducing Periostin+ fibroblasts","authors":"Hongmei Liu ,&nbsp;Jingni Zhang ,&nbsp;Jing Cai ,&nbsp;Qiulei Wu ,&nbsp;Guoqing Li ,&nbsp;Wenhan Li ,&nbsp;Tong Liu ,&nbsp;Ping Yang ,&nbsp;Zehua Wang ,&nbsp;Xiaoqing Yi","doi":"10.1016/j.cellsig.2025.111773","DOIUrl":"10.1016/j.cellsig.2025.111773","url":null,"abstract":"<div><div>The frequent omental metastasis of ovarian cancer (OvCa) at initial diagnosis is due to the omental premetastatic microenvironment, which is rich in activated fibroblasts. However, the molecular events driving the phenotypic transformation of omental fibroblasts that favor metastasis remain largely unexplored. Previously, we found that tumoral enhancer of zest homolog 2 (EZH2), a key epigenetic regulator catalyzing trimethylation at H3K27, played a crucial role in OvCa metastasis. In this study, we revealed that extracellular vesicles (EVs) derived from EZH2-high OvCa cells induce the expression of Periostin (POSTN), but not α-SMA, in omental fibroblasts, facilitating tumor metastasis. Nude mice with intraperitoneal injection of EVs before tumor cell inoculation showed that EVs derived from EZH2-high ovarian cancer cells promote omental metastasis. Human primary omental fibroblasts cocultured with EVs, especially those derived from EZH2-high OvCa cells, exhibited boosted migration, invasion capacities and conditioned medium from EV-activated fibroblasts promotes cancer cell migration, invasion and proliferation. These results may provide novel insight into EZH2-targeted therapy for ovarian carcinoma with intraperitoneal dissemination.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"132 ","pages":"Article 111773"},"PeriodicalIF":4.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143768259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Mechanisms of constitutive and agonist-induced 5-HT2B internalization, persistent endosomal signaling and paradoxical regulation of agonist pharmacology
IF 4.4 2区 生物学
Cellular signalling Pub Date : 2025-03-30 DOI: 10.1016/j.cellsig.2025.111769
Ibragim Gaidarov, John Frazer, Xiaohua Chen, Huong Dang, Isabel Cordova, Chen Liaw, Carleton Sage, David J. Unett
{"title":"Mechanisms of constitutive and agonist-induced 5-HT2B internalization, persistent endosomal signaling and paradoxical regulation of agonist pharmacology","authors":"Ibragim Gaidarov,&nbsp;John Frazer,&nbsp;Xiaohua Chen,&nbsp;Huong Dang,&nbsp;Isabel Cordova,&nbsp;Chen Liaw,&nbsp;Carleton Sage,&nbsp;David J. Unett","doi":"10.1016/j.cellsig.2025.111769","DOIUrl":"10.1016/j.cellsig.2025.111769","url":null,"abstract":"<div><div>Certain ergot derivatives, particularly cabergoline, produce wash-resistant signaling through the 5-HT<sub>2B</sub> receptor persisting for many hours without loss of potency or efficacy. Previously, we reported that this signaling may be mediated by sequestered or internalized receptors. Here, we evaluated numerous mechanistic aspects of 5-HT<sub>2B</sub> internalization and wash-resistant signaling and directly addressed the role of internalization. In the absence of an agonist, 5-HT<sub>2B</sub> undergoes robust, constitutive internalization and recycling and is distributed at equilibrium between cell surface and intracellular compartments. Both constitutive and agonist-induced internalization are mediated through dynamin-dependent clathrin-mediated endocytosis. Constitutive internalization is unaffected by application of 5-HT<sub>2B</sub> inverse agonists. We identified two, adjacent di-leucine motifs followed by a di-acidic cluster in the C-terminal tail of 5-HT<sub>2B</sub> that are responsible for constitutive internalization of the receptor. Mutations in either of the leucine clusters or in the di-acidic motif partially inhibit constitutive 5-HT<sub>2B</sub> internalization. A 5-HT<sub>2B</sub> mutant in which both di-leucine clusters are disrupted, displays no constitutive internalization while undergoing robust agonist induced internalization. We demonstrate that wash-resistant signaling of ergots is mediated by persistently/irreversibly internalized signaling receptor complexes. Paradoxically, the potencies of ergot agonists are influenced by receptor internalization; measured potencies are reduced upon inhibition of receptor internalization, while potencies for 5-HT or other conventional agonists are unaffected. This phenomenon represents a novel mechanism by which agonist-dependent kinetics of receptor internalization and recycling affects not only the duration of receptor signaling, but also a basic pharmacological parameter such as agonist potency.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"131 ","pages":"Article 111769"},"PeriodicalIF":4.4,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143746494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Circadian clock regulation of myofibroblast fate
IF 4.4 2区 生物学
Cellular signalling Pub Date : 2025-03-30 DOI: 10.1016/j.cellsig.2025.111774
Yoanna Tsoneva , Tsvetelina Velikova , Georgi Nikolaev
{"title":"Circadian clock regulation of myofibroblast fate","authors":"Yoanna Tsoneva ,&nbsp;Tsvetelina Velikova ,&nbsp;Georgi Nikolaev","doi":"10.1016/j.cellsig.2025.111774","DOIUrl":"10.1016/j.cellsig.2025.111774","url":null,"abstract":"<div><div>Fibrosis-related disorders represent an increasing medical and economic burden on a worldwide scale, accounting for one-third of all disease-related deaths with limited therapeutic options. As central mediators in fibrosis development, myofibroblasts have been gaining increasing attention in the last 20 years as potential targets for fibrosis attenuation and reversal. While various aspects of myofibroblast physiology have been proposed as treatment targets, many of these approaches have shown limited long-term efficacy so far. However, ongoing research is uncovering new potential strategies for targeting myofibroblast activity, offering hope for more effective treatments in the future. The circadian molecular clock is a feature of almost every cell in the human body that dictates the rhythmic nature of various aspects of human physiology and behavior in response to changes in the surrounding environment. The dysregulation of these rhythms with aging is considered to be one of the underlying reasons behind the development of multiple aging-related chronic disorders, with fibrotic tissue scarring being a common pathological complication among the majority of them. Myofibroblast dysregulation due to skewed circadian clockwork might significantly contribute to fibrotic scar persistence. In the current review, we highlight the role of the circadian clock in the context of myofibroblast activation and deactivation and examine its dysregulation as a driver of fibrogenesis.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"131 ","pages":"Article 111774"},"PeriodicalIF":4.4,"publicationDate":"2025-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143746625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
An update on the role and mechanisms of periodontitis in cardiovascular diseases
IF 4.4 2区 生物学
Cellular signalling Pub Date : 2025-03-29 DOI: 10.1016/j.cellsig.2025.111770
Yuping Lai , Sibo Liu , Chenxin Song , Ting Long , Li Song , Meixiu Jiang
{"title":"An update on the role and mechanisms of periodontitis in cardiovascular diseases","authors":"Yuping Lai ,&nbsp;Sibo Liu ,&nbsp;Chenxin Song ,&nbsp;Ting Long ,&nbsp;Li Song ,&nbsp;Meixiu Jiang","doi":"10.1016/j.cellsig.2025.111770","DOIUrl":"10.1016/j.cellsig.2025.111770","url":null,"abstract":"<div><div>Cardiovascular diseases (CVDs) are the leading cause of death worldwide. Despite extensive studies into the causes and therapies for CVDs, their incidence and prevalence continue to increase. Periodontitis is a multifactorial, chronic inflammatory disease related to systemic health. Current research suggests that periodontitis may be an unconventional risk factor for CVDs and it may increase the risk of CVDs such as atherosclerosis, coronary heart disease, myocardial infarction, hypertension, heart failure as well as cardiomyopathy. For all these reasons, it is quite plausible that prevention of periodontitis has an impact on the onset or progression of CVDs. Therefore, in this review, we investigated the association between periodontitis caused by oral microorganisms and different CVDs. In addition, we discuss the various mechanisms by which periodontitis contributes to the onset and progression of CVDs. Our review aims to raise global awareness of periodontitis, particularly its role in CVDs, provide a basis for the prevention and treatment of CVDs and offer potential therapeutic targets</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"132 ","pages":"Article 111770"},"PeriodicalIF":4.4,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Annexin A2 binds the 3′-UTR of H2AX mRNA and regulates histone-H2AX-derived hypoxia-inducible factor 1-alpha activation
IF 4.4 2区 生物学
Cellular signalling Pub Date : 2025-03-29 DOI: 10.1016/j.cellsig.2025.111781
Shiyin Zhang , Yu-Shi Wang , Yang Li , Kwang-Il To , En-Ting Zhang , Ying-Hua Jin
{"title":"Annexin A2 binds the 3′-UTR of H2AX mRNA and regulates histone-H2AX-derived hypoxia-inducible factor 1-alpha activation","authors":"Shiyin Zhang ,&nbsp;Yu-Shi Wang ,&nbsp;Yang Li ,&nbsp;Kwang-Il To ,&nbsp;En-Ting Zhang ,&nbsp;Ying-Hua Jin","doi":"10.1016/j.cellsig.2025.111781","DOIUrl":"10.1016/j.cellsig.2025.111781","url":null,"abstract":"<div><div>Annexin A2 (Anxa2), a multifunctional protein with RNA-binding capabilities, is frequently overexpressed in various tumors, and its expression is highly correlated with malignant progression. In this study, we demonstrate for the first time that Anxa2 was co-expressed with glycolytic genes, suggesting its potential role as a regulator of glycolysis. RNA-protein interaction assay revealed that Anxa2 interacted with 3′-UTR of H2AX mRNA and protected it from miRNA-mediated degradation. Up-regulated Histone-H2AX enhances the expression of glycolytic genes including GLUT1, HK2, PGK1, ENO1, PKM2, GAPDH and LDHA via stabilizing hypoxia-inducible factor 1-alpha (HIF1α), thereby accelerating lactic acid production and secretion. (20S) G-Rh2, a natural compound targeting Anxa2, significantly interfered the Anxa2-H2AX mRNA interaction, and inhibited subsequent glycolysis progression. We propose that Anxa2 acts as a novel regulator in glycolysis via enhancing H2AX expression, and (20S) G-Rh2 may exert its anti-cancer activity by targeting Anxa2-H2AX-HIF1α-glycolysis axis in human hepatoma HepG2 cells.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"132 ","pages":"Article 111781"},"PeriodicalIF":4.4,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Catharanthine tartrate ameliorates osteoclastogenesis by destabilizing HIF-1α
IF 4.4 2区 生物学
Cellular signalling Pub Date : 2025-03-29 DOI: 10.1016/j.cellsig.2025.111779
Luqiong Cai , Chenxin Yu , Binli Zhao , Qihang Wu , Haibo Liang , Meng Zhou , Jiansen Miao , Jiangtao Luo , Jiake Xu , Haiming Jin , Youjin Pan
{"title":"Catharanthine tartrate ameliorates osteoclastogenesis by destabilizing HIF-1α","authors":"Luqiong Cai ,&nbsp;Chenxin Yu ,&nbsp;Binli Zhao ,&nbsp;Qihang Wu ,&nbsp;Haibo Liang ,&nbsp;Meng Zhou ,&nbsp;Jiansen Miao ,&nbsp;Jiangtao Luo ,&nbsp;Jiake Xu ,&nbsp;Haiming Jin ,&nbsp;Youjin Pan","doi":"10.1016/j.cellsig.2025.111779","DOIUrl":"10.1016/j.cellsig.2025.111779","url":null,"abstract":"<div><div>With the aging population, postmenopausal osteoporosis (PMOP), clinically manifested by reduced bone density, weakened skeletal strength, and compromised skeletal microstructure, has become the most prevalent type. The decline in estrogen levels fosters oxidative stress and osteoclastogenesis, which significantly enhance the activity of osteoclasts. Current treatments prefer to adopt relevant strategies to inactivate osteoclasts but come with unavoidable side effects. In our study, Catharanthine Tartrate (CAT), a derivative of the alkaloid catharanthine found in <em>Catharanthus roseus</em>, promised to be an effective therapy for PMOP. CAT inhibited RANKL-induced osteoclast differentiation and bone resorption in vitro. Moreover, CAT inhibited osteoclast activity by enhancing the ubiquitination-mediated proteasomal degradation of HIF-1α, which reduced oxidative stress and subsequently suppressed osteoclast activity. The inhibitory effects of CAT on osteoclast function and oxidative stress were reversed by DMOG, a known inhibitor of HIF-1α degradation. Next, an in vivo mouse experiment using the Ovariectomized (OVX) model to induce osteoporosis indicated that CAT enhanced bone mass density, bone structure, and bone remodeling. Our findings revealed that CAT inhibits PMOP through facilitating HIF-1α ubiquitination and degradation, suggesting a promising therapeutic approach for this disorder.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"131 ","pages":"Article 111779"},"PeriodicalIF":4.4,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143746499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Oncogenic small extracellular vesicles enriched in sphingosine-1-phosphate play a crucial role in pancreatic cancer progression.
IF 4.4 2区 生物学
Cellular signalling Pub Date : 2025-03-28 DOI: 10.1016/j.cellsig.2025.111775
Pratibha Malhotra, Jordan Fyfe, Aikaterini Emmanouilidi, Ilaria Casari, Natalie A Mellett, Kevin Huynh, Marina Pajic, David W Greening, Peter J Meikle, Marco Falasca
{"title":"Oncogenic small extracellular vesicles enriched in sphingosine-1-phosphate play a crucial role in pancreatic cancer progression.","authors":"Pratibha Malhotra, Jordan Fyfe, Aikaterini Emmanouilidi, Ilaria Casari, Natalie A Mellett, Kevin Huynh, Marina Pajic, David W Greening, Peter J Meikle, Marco Falasca","doi":"10.1016/j.cellsig.2025.111775","DOIUrl":"https://doi.org/10.1016/j.cellsig.2025.111775","url":null,"abstract":"<p><p>Small extracellular vesicles (sEVs) from tumour cells mediate intercellular communication and signalling to regulate the progression of pancreatic ductal adenocarcinoma (PDAC). While we and others have shown that PDAC-derived sEVs comprise oncogenic protein and nucleic acid cargo, understanding the lipid landscape of these sEVs remains unknown. Lipids influence both the composition of sEVs and their roles in lipid metabolism and signalling pathways within the tumour microenvironment and tumorigenesis. We hypothesised that specific lipids in oncogenic sEVs might provide insights into PDAC. Comprehensive mass spectrometry-based lipidomic analysis was performed using liquid chromatography-electrospray ionisation-tandem mass spectrometry on sEVs isolated from PDAC and non-malignant pancreatic cell lines, patient-derived xenograft cell lines and plasma from the PDAC transgenic mouse model KPC (KRASWT/G12D/ TP53WT/R172H/Pdx1-Cre+/+). The sEV lipidomic analyses identified over 700 lipid species from 25 lipid classes and subclasses. Our results showed that, compared to non-malignant cells, PDAC-derived sEVs were enriched in specific lysophospholipids, particularly sphingosine-1-phosphate (S1P), a lipid known for its pivotal role in cancer pathogenesis. S1P enrichment was validated in plasma-derived sEVs from KPC mice compared to WT. To explore the functional implications of S1P enrichment, we conducted assays demonstrating that S1P in sEVs facilitated tubule formation in human microvascular endothelial cells and promoted cancer-associated fibroblast cell migration. We show that PDAC-derived sEVs are differentially enriched in specific lipids associated with cancer phenotype. Our findings highlight that PDAC-derived sEVs are enriched in specific lipids, particularly S1P, which plays a crucial role in promoting cancer progression.</p>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":" ","pages":"111775"},"PeriodicalIF":4.4,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Ingenol ameliorates silicosis via targeting the PTGS2/PI3K/AKT signaling axis: Implications for therapeutic intervention
IF 4.4 2区 生物学
Cellular signalling Pub Date : 2025-03-28 DOI: 10.1016/j.cellsig.2025.111780
Yifan Jing , Ying Bai , Chao Liang , Yafeng Liu , Jiawei Zhou , Jianqiang Guo , Xiaolong Cai , Xiaofei Hu , Yujing Fang , Xuansheng Ding , Jing Wu , Dong Hu
{"title":"Ingenol ameliorates silicosis via targeting the PTGS2/PI3K/AKT signaling axis: Implications for therapeutic intervention","authors":"Yifan Jing ,&nbsp;Ying Bai ,&nbsp;Chao Liang ,&nbsp;Yafeng Liu ,&nbsp;Jiawei Zhou ,&nbsp;Jianqiang Guo ,&nbsp;Xiaolong Cai ,&nbsp;Xiaofei Hu ,&nbsp;Yujing Fang ,&nbsp;Xuansheng Ding ,&nbsp;Jing Wu ,&nbsp;Dong Hu","doi":"10.1016/j.cellsig.2025.111780","DOIUrl":"10.1016/j.cellsig.2025.111780","url":null,"abstract":"<div><div>Silicosis, formerly known as silico, is an irreversible disease caused by prolonged inhalation of substantial amounts of free crystalline silica dust, characterized by pulmonary inflammation and extensive nodular fibrosis. The etiology of the disease remains unclear, which currently hinders the development of effective therapeutic drugs and interventions. Ingenol (Ing), a terpenoid active ingredient found in plants of the Euphorbiaceae family, including the entire herb of <em>Euphorbia helioscopia</em>, <em>Euphorbia kansui</em>, or <em>Euphorbia lathyris</em>, demonstrates significant anti-inflammatory and antiviral activities. In this study, we identified and confirmed that Ingenol can significantly ameliorate silicosis induced by silica dioxide by inhibiting the PTGS2/PI3K/AKT signaling pathway. In vivo, Ingenol improves pulmonary respiratory function and reduces inflammation and fibrosis in a murine model of CS-induced silicosis. In vitro, Ingenol inhibits the expression of cellular factors associated with inflammation and fibrosis, as well as macrophage apoptosis and fibroblast migration. Furthermore, it can modulate the expression of fibrosis-related proteins, thereby inhibiting CS-induced fibrotic responses. Mechanistically, a combination of bioinformatics, network pharmacology, and experimental validation indicates that Ingenol mitigates the progression of silicosis by modulating the PTGS2/PI3K/AKT signaling pathway. In summary, these findings suggest that Ingenol is a potential candidate for the treatment of silicosis.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"131 ","pages":"Article 111780"},"PeriodicalIF":4.4,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143746624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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