Cell Communication and Signaling最新文献

{"title":"CD69⁺CD103⁺CD8⁺ tissue-resident memory T cells possess stronger anti-tumor activity and predict better prognosis in colorectal cancer.","authors":"Zi-Xin Wu, Tian-Tian Da, Chuan Huang, Xiao-Qing Wang, Liang Li, Zhi-Bin Zhao, Ting-Ting Yin, Hai-Qing Ma, Zhe-Xiong Lian, Jie Long, Fei Wang, Jie Cao","doi":"10.1186/s12964-024-01990-3","DOIUrl":"10.1186/s12964-024-01990-3","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) is one of the most prevalent cancers worldwide. Despite advancements in therapeutic methodologies, it still causes a high rate of patient mortality. CD8⁺ tissue-resident memory T (TRM) cells are strategically positioned to mediate effective anti-tumor responses. However, the characteristic surface molecules and functions of CD8⁺ TRM cells exhibit significant heterogeneity.</p><p><strong>Methods: </strong>The roles and anti-tumor biological functions of different CD8⁺ TRM subsets in CRC were determined by clinical CRC samples, bioinformatics analysis, and in vitro experiments including co-culture experiments and transwell migration assays. The signaling pathways that synergistically regulate the differentiation of CD8⁺ TRM cells were identified by in vitro CD8⁺ T cell activation and inhibition assays, and the functioning transcription factors were predicted using the UCSC and JASPAR databases.</p><p><strong>Results: </strong>We found that different CD8⁺ TRM subsets existed in CRC tumor tissues, which were identified as CD69^-CD103^-CD8⁺ TRM, CD69⁺CD103^-CD8⁺ TRM (SP CD8⁺ TRM), and CD69⁺CD103⁺CD8⁺ TRM (DP CD8⁺ TRM) subsets. Compared with SP CD8⁺ TRM cells, increased infiltration of DP CD8⁺ TRM cells predicted better prognosis and played a protective role mainly in tumor invasion and lymph node metastasis of CRC. DP CD8⁺ TRM cells expressed higher levels of effector molecules and exerted stronger anti-tumor effects in a FAS/FASL pathway-dependent manner. Additionally, DP CD8⁺ TRM cells secreted higher levels of CXCL13 and recruited B cells into tumor tissues through the CXCL13/CXCR5 signaling axis to form tertiary lymphoid structures, participating in anti-tumor immune responses. Notch and TGF-β signaling pathways synergistically regulate the differentiation of DP CD8⁺ TRM cells.</p><p><strong>Conclusions: </strong>We clarified the roles and mechanisms of different CD8⁺ TRM subsets in CRC and identified that DP CD8⁺ TRM cells exert stronger anti-tumor effects and predict better prognosis, which provides ideas for developing new clinically available therapeutic targets.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"608"},"PeriodicalIF":8.2,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11657194/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142856850","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}

{"title":"Dust mite antigens endow dendritic cells with the capacity to induce a Th2 response by regulating their methylation profiles.","authors":"Xiwen Zhang, Haoyue Zheng, Yixuan Dong, Hanqing Zhang, Le Liu, Yuanyi Zhang, Lingzhi Xu, Bailing Xie, Lihua Mo, Yu Liu, Gui Yang, Pingchang Yang, Xiaoyu Liu","doi":"10.1186/s12964-024-01986-z","DOIUrl":"10.1186/s12964-024-01986-z","url":null,"abstract":"<p><strong>Background: </strong>It is well-known that Dendritic cells (DCs) are essential in the development of airway Th2 polarization and airway allergy (AA). The underlying mechanism is still not fully understood. The objective of this study is to examine the role of methyltransferase-like protein-5 (Mettl5), a methyltransferase involved in N6-methyladenosine (m6A) methylation, in altering DC's properties to facilitate the development of Th2 polarization and AA.</p><p><strong>Methods: </strong>Dust mite extracts (DME) were used as a specific antigen to establish an AA mouse model. The epigenetic status of DCs was examined using a Chromatin immunoprecipitation (ChIP) assay. A mouse strain carrying the Mettl5-deficient DCs was used to observe the role of Mettl5 in determining the phenotypes of DCs.</p><p><strong>Results: </strong>The results showed that the expression of Mettl5 was elevated in DCs, which was positively correlated with the AA response. The development of airway Th2 polarization was hindered by Mettl5 depletion in DCs. Mettl5 is involved in the transcription of the Timd4 gene in DCs caused by DME. The degradation of IRF5 by Mettl5 led to an increase in T cell immunoglobulin domain molecule-4 (TIM4) expression in DCs associated with DME. Inhibition of Mettl5 in DCs reconciled the DME-induced airway Th2 polarization and experimental AA.</p><p><strong>Conclusions: </strong>Airway DCs from AA mice showed elevated amounts of Mettl5, which led to the expression of TIM4. The experimental AA was mitigated by Mettl5 inhibition.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"606"},"PeriodicalIF":8.2,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11656822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142856941","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}

{"title":"Correction: A fully human IgG1 antibody targeting connexin 32 extracellular domain blocks CMTX1 hemichannel dysfunction in an in vitro model.","authors":"Abraham Tettey-Matey, Viola Donati, Chiara Cimmino, Chiara Di Pietro, Damiano Buratto, Mariateresa Panarelli, Alberto Reale, Arianna Calistri, Maria Vittoria Fornaini, Ruhong Zhou, Guang Yang, Francesco Zonta, Daniela Marazziti, Fabio Mammano","doi":"10.1186/s12964-024-01988-x","DOIUrl":"10.1186/s12964-024-01988-x","url":null,"abstract":"","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"591"},"PeriodicalIF":8.2,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11639108/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819901","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}

{"title":"Functional circuits of LYL1 controlled by supraphysiological androgen in prostate cancer cells to regulate cell senescence.","authors":"Mehdi Heidari Horestani, Katrin Schindler, Aria Baniahmad","doi":"10.1186/s12964-024-01970-7","DOIUrl":"10.1186/s12964-024-01970-7","url":null,"abstract":"<p><strong>Background: </strong>Prostate cancer (PCa) is a public health problem mostly reported in developed countries. The androgen receptor (AR) regulates the development and physiological function of normal prostate as well as the proliferation of cancerous prostate tissue. Treatment with supraphysiological androgen levels (SAL) is used in bipolar androgen therapy and inhibits PCa growth, suggesting SAL induces a tumor suppressive program. It was shown that SAL induces cellular senescence, in PCa cell lines, human tumor samples and in xenografted mouse tumor model.</p><p><strong>Methods: </strong>Transcriptome and ChIP-seq analysis, PCa spheroids, knockdown (KD), co-immunoprecipitation, qRT-PCR, immune detection, in situ histochemistry.</p><p><strong>Results: </strong>Here we show that LYL1 is upregulated by the clock gene BHLHE40 in both C4-2 and LNCaP cells and mediates SAL-induced cellular senescence. LYL1 is a transcriptional co-factor with oncogenic activity in leukemia. However, analysis of a large cohort of PCa patients shows that LYL1 expression is reduced during PCa development and reduced expression is significantly associated with reduced overall survival. SAL induces the expression of LYL1 through upregulation of BHLHE40. On the other hand, the KD of LYL1 enhances BHLHE40 expression via a negative feedback loop including p27kip1. Regulatory feedback loops were identified by rescue experiments. Functional analysis revealed that KD of BHLHE40 reduces whereas LYL1 KD enhances p27kip1 levels. The KD of p27kip1 suggests that this cell cycle inhibitor is a mediator of cellular senescence by the BHLHE40 - LYL1 regulatory loop. Interestingly, ChIP-seq data revealed recruitment of both AR and BHLHE40 to the LYL1 gene indicating that LYL1 is a novel direct target of both factors. Furthermore, RNA-seq data from C4-2 cells suggests that LYL1 and BHLHE40 encompass a large overlap of genes by SAL suggesting a co-regulatory activity controlled by androgens. In line with this, co-immunoprecipitation suggests LYL1 is in a complex with BHLHE40 and the AR.</p><p><strong>Conclusions: </strong>Three novel feed-back loops and a novel AR- BHLHE40 / LYL1 -p27kip1 axis has been identified mediating cellular senescence in PCa cells.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"590"},"PeriodicalIF":8.2,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11636232/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819955","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}

{"title":"Biological and pharmacological roles of pyroptosis in pulmonary inflammation and fibrosis: recent advances and future directions.","authors":"Ya Liu, Danxia Wang, Xiang Liu, Haibin Yuan, Dan Liu, Yixiang Hu, Shipeng Ning","doi":"10.1186/s12964-024-01966-3","DOIUrl":"10.1186/s12964-024-01966-3","url":null,"abstract":"<p><p>Pyroptosis, an inflammatory regulated cell death (RCD) mechanism, is characterized by cellular swelling, membrane rupture, and subsequent discharge of cellular contents, exerting robust proinflammatory effects. Recent studies have significantly advanced our understanding of pyroptosis, revealing that it can be triggered through inflammasome- and caspase-independent pathways, and interacts intricately with other RCD pathways (e.g., pyroptosis, necroptosis, ferroptosis, and cuproptosis). The pathogenesis of pulmonary fibrosis (PF), including idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases, involves a multifaceted interplay of factors such as pathogen infections, environmental pollutants, genetic variations, and immune dysfunction. This chronic and progressive interstitial lung disease is characterized by persistent inflammation, extracellular matrix (ECM) accumulation, and fibrotic alveolar wall thickening, which potentially contribute to deteriorated lung function. Despite recent advances in understanding pyroptosis, the mechanisms by which it regulates PF are not entirely elucidated, and effective strategies to improve clinical outcomes remain unclear. This review strives to deliver a comprehensive overview of the biological functions and molecular mechanisms of pyroptosis, exploring its roles in the pathogenesis of PF. Furthermore, it examines potential biomarkers and therapeutic agents for anti-fibrotic treatments.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"586"},"PeriodicalIF":8.2,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619304/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142787251","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}

{"title":"Extrajunctional CLDN10 cooperates with LAT1 and accelerates clear cell renal cell carcinoma progression.","authors":"Akifumi Onagi, Kotaro Sugimoto, Makoto Kobayashi, Yumi Sato, Yasuyuki Kobayashi, Kei Yaginuma, Satoru Meguro, Seiji Hoshi, Jyunya Hata, Yuko Hashimoto, Yoshiyuki Kojima, Hideki Chiba","doi":"10.1186/s12964-024-01964-5","DOIUrl":"10.1186/s12964-024-01964-5","url":null,"abstract":"<p><strong>Background & aims: </strong>In addition to their adhesive properties, cell adhesion molecules such as claudins (CLDNs) exhibit signaling ability to organize diverse cellular events. Although the CLDN-adhesion signaling stimulates or inhibits cancer progression, the underlying mechanism remains poorly established. Here, we verified whether and how CLDN10 promotes intracellular signals and malignant phenotypes in clear cell renal cell carcinoma (ccRCC).</p><p><strong>Methods: </strong>We developed a novel monoclonal antibody that specifically recognizes CLDN10. By immunohistochemistry using this antibody, the clinicopathological significance of aberrant CLDN10 expression in 165 ccRCC patients was determined. We next generated the ccRCC cells (786-O, ACHN, and OS-RC-2) expressing CLDN10, and compared their phenotypes with those of control cells. Immunoprecipitation-mass spectrometry was used to identify a CLDN10-interacting protein, followed by evaluation of its association with CLDN10 and loss-of-functions in ccRCC cells.</p><p><strong>Results: </strong>High CLDN10 expression predicted poor outcome in ccRCC patients and represented an independent prognostic marker for cancer-specific survival. Cell surface CLDN10 promoted cell viability, proliferation, and migration of ccRCC cells, as well as their tumor growth. CLDN10 also activated mTOR signaling and expression of downstream targets, including MYC target genes. Notably, we found that CLDN10 forms a complex with an amino acid transporter, LAT1, and that CLDN10-LAT1 signaling facilitates malignant phenotypes in ccRCC cells. Structural prediction and immunoprecipitation analysis results strongly suggest an interaction between CLDN10-TM1 (transmembrane domain 1) and LAT1-TM4.</p><p><strong>Conclusions: </strong>We conclude that CLDN10-LAT1 signaling drives ccRCC progression. Taken together with our previous findings on CLDN-Src-family kinases signaling, CLDNs propagate distinct intracellular signals depending on their association with different binding partners.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"588"},"PeriodicalIF":8.2,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619122/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142787267","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}

{"title":"Intrauterine administration of peripheral blood mononuclear cells helps manage recurrent implantation failure by normalizing dysregulated gene expression including estrogen-responsive genes in mice.","authors":"Yoshimi Kitawaki, Akihito Horie, Asami Ikeda, Shimpei Shitanaka, Akihiro Yanai, Tsutomu Ohara, Baku Nakakita, Yusuke Sagae, Asuka Okunomiya, Hirohiko Tani, Masaki Mandai","doi":"10.1186/s12964-024-01904-3","DOIUrl":"10.1186/s12964-024-01904-3","url":null,"abstract":"<p><strong>Background: </strong>Intrauterine peripheral blood mononuclear cell (PBMC) therapy for recurrent implantation failure (RIF) has been reported to improve embryo implantation by acting on the endometrium. However, the exact mode of action of PBMC on the endometrium of patients with RIF remains unclear. In addition, the differences in the therapeutic effects of PBMC therapy with and without human chorionic gonadotropin (hCG) are unknown. Therefore, in this study, we investigated the changes in the endometrium during the implantation phase induced by PBMC administration and the differences in the efficacy of this therapy with and without hCG using a mouse model of implantation failure (IF).</p><p><strong>Methods: </strong>IF model was established by the subcutaneous administration of low-dose RU486. Pregnant mice were randomly divided into five groups: control, IF, culture medium, PBMC, and PBMC-hCG (the latter three groups were IF model mice with intrauterine administration). The pregnancy rate and the number and size of implantation sites were recorded during early pregnancy (day 7.5). Uteri from the preimplantation phase (evening of day 3.5) were collected and analyzed using RNA-sequencing (RNA-seq).</p><p><strong>Results: </strong>The pregnancy rate, the number of implantation sites, and the number of normal-sized implantation sites were significantly decreased in the IF model and were improved in the medium, PBMC, and PBMC-hCG groups. RNA-seq data showed that PBMC treatment normalized the expression of the majority of dysregulated genes in the endometrium during the preimplantation phase in the IF model, especially the overexpression of estrogen-activated genes. In addition, PBMC treatment increased the expression of local glucocorticoid receptors and suppressed the expression of inflammation-related genes, whereas no significant changes in blood estradiol and glucocorticoid levels were observed. These changes were more pronounced in the PBMC-hCG group and were consistent with the pregnancy outcomes.</p><p><strong>Conclusions: </strong>Intrauterine administration of PBMC before embryo implantation promoted embryo implantation in the IF mouse model, and hCG enhanced pregnancy outcomes. PBMC modulated steroid receptor expression and suppressed inflammation and excessive estrogen action.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"587"},"PeriodicalIF":8.2,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619271/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142787506","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}

{"title":"A fully human IgG1 antibody targeting connexin 32 extracellular domain blocks CMTX1 hemichannel dysfunction in an in vitro model.","authors":"Abraham Tettey-Matey, Viola Donati, Chiara Cimmino, Chiara Di Pietro, Damiano Buratto, Mariateresa Panarelli, Alberto Reale, Arianna Calistri, Maria Vittoria Fornaini, Ruhong Zhou, Guang Yang, Francesco Zonta, Daniela Marazziti, Fabio Mammano","doi":"10.1186/s12964-024-01969-0","DOIUrl":"10.1186/s12964-024-01969-0","url":null,"abstract":"<p><p>Connexins (Cxs) are fundamental in cell-cell communication, functioning as gap junction channels (GJCs) that facilitate solute exchange between adjacent cells and as hemichannels (HCs) that mediate solute exchange between the cytoplasm and the extracellular environment. Mutations in the GJB1 gene, which encodes Cx32, lead to X-linked Charcot-Marie-Tooth type 1 (CMTX1), a rare hereditary demyelinating disorder of the peripheral nervous system (PNS) without an effective cure or treatment. In Schwann cells, Cx32 HCs are thought to play a role in myelination by enhancing intracellular and intercellular Ca²⁺ signaling, which is crucial for proper PNS myelination. Single-point mutations (p.S85C, p.D178Y, p.F235C) generate pathological Cx32 HCs characterized by increased permeability (\"leaky\") or excessive activity (\"hyperactive\").We investigated the effects of abEC1.1-hIgG1, a fully human immunoglobulin G1 (hIgG1) monoclonal antibody, on wild-type (WT) and mutant Cx32D178Y HCs. Using HeLa DH cells conditionally co-expressing Cx and a genetically encoded Ca²⁺ biosensor (GCaMP6s), we demonstrated that mutant HCs facilitated 58% greater Ca²⁺ uptake in response to elevated extracellular Ca²⁺ concentrations ([Ca²⁺]_ex) compared to WT HCs. abEC1.1-hIgG1 dose-dependently inhibited Ca²⁺ uptake, achieving a 50% inhibitory concentration (EC₅₀) of ~ 10 nM for WT HCs and ~ 80 nM for mutant HCs. Additionally, the antibody suppressed DAPI uptake and ATP release. An atomistic computational model revealed that serine 56 (S56) of the antibody interacts with aspartate 178 (D178) of WT Cx32 HCs, contributing to binding affinity. Despite the p.D178Y mutation weakening this interaction, the antibody maintained binding to the mutant HC epitope at sub-micromolar concentrations.In conclusion, our study shows that abEC1.1-hIgG1 effectively inhibits both WT and mutant Cx32 HCs, highlighting its potential as a therapeutic approach for CMTX1. These findings expand the antibody's applicability for treating diseases associated with Cx HCs and inform the rational design of next-generation antibodies with enhanced affinity and efficacy against mutant HCs.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"589"},"PeriodicalIF":8.2,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142787241","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}

{"title":"Machine learning-aided discovery of T790M-mutant EGFR inhibitor CDDO-Me effectively suppresses non-small cell lung cancer growth.","authors":"Rui Zhou, Ziqian Liu, Tongtong Wu, Xianwei Pan, Tongtong Li, Kaiting Miao, Yuru Li, Xiaohui Hu, Haigang Wu, Andrew M Hemmings, Beier Jiang, Zhenzhen Zhang, Ning Liu","doi":"10.1186/s12964-024-01954-7","DOIUrl":"10.1186/s12964-024-01954-7","url":null,"abstract":"<p><strong>Background: </strong>Epidermal growth factor receptor (EGFR) T790M mutation often occurs during long durational erlotinib treatment of non-small cell lung cancer (NSCLC) patients, leading to drug resistance and disease progression. Identification of new selective EGFR-T790M inhibitors has proven challenging through traditional screening platforms. With great advances in computer algorithms, machine learning improved the screening rates of molecules at full chemical spaces, and these molecules will present higher biological activity and targeting efficiency.</p><p><strong>Methods: </strong>An integrated machine learning approach, integrated by Bayesian inference, was employed to screen a commercial dataset of 70,413 molecules, identifying candidates that selectively and efficiently bind with EGFR harboring T790M mutation. In vitro cellular assays and molecular dynamic simulations was used for validation. EGFR knockout cell line was generated for cross-validation. In vivo xenograft moues model was constructed to investigate the antitumor efficacy of CDDO-Me.</p><p><strong>Results: </strong>Our virtual screening and subsequent in vitro testing successfully identified CDDO-Me, an oleanolic acid derivative with anti-inflammatory activity, as a potent inhibitor of NSCLC cancer cells harboring the EGFR-T790M mutation. Cellular thermal shift assay and molecular dynamic simulation validated the selective binding of CDDO-Me to T790M-mutant EGFR. Further experimental results revealed that CDDO-Me induced cellular apoptosis and caused cell cycle arrest through inhibiting the PI3K-Akt-mTOR axis by directly targeting EGFR protein, cross-validated by sgEGFR silencing in H1975 cells. Additionally, CDDO-Me could dose-depended suppress the tumor growth in a H1975 xenograft mouse model.</p><p><strong>Conclusion: </strong>CDDO-Me induced apoptosis and caused cell cycle arrest by inhibiting the PI3K-Akt-mTOR pathway, directly targeting the EGFR protein. In vivo studies in a H1975 xenograft mouse model demonstrated dose-dependent suppression of tumor growth. Our work highlights the application of machine learning-aided drug screening and provides a promising lead compound to conquer the drug resistance of NSCLC.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"585"},"PeriodicalIF":8.2,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619116/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142787704","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}

{"title":"The CCL5/CCR5/SHP2 axis sustains Stat1 phosphorylation and activates NF-κB signaling promoting M1 macrophage polarization and exacerbating chronic prostatic inflammation.","authors":"Chen Jin, Fei Zhang, Hailang Luo, Boyang Li, Xue Jiang, Christopher J Pirozzi, Chaozhao Liang, Meng Zhang","doi":"10.1186/s12964-024-01943-w","DOIUrl":"10.1186/s12964-024-01943-w","url":null,"abstract":"<p><strong>Background and objective: </strong>Chronic prostatitis (CP) is a condition markered by persistent prostate inflammation, yet the specific cytokines driving its progression remain largely undefined. This study aims to identify key cytokines involved in CP and investigate their role in driving inflammatory responses through mechanistic and therapeutic exploration.</p><p><strong>Methods: </strong>A 48-cytokine panel test was conducted to compare the plasma cytokine profiles between participants with CP-like symptoms (CP-LS) and healthy controls. Experimental autoimmune prostatitis (EAP) models were used for functional validation, with further mechanistic studies performed through in vivo and in vitro assays. Pharmacological inhibition was applied using maraviroc, and pathway inhibitors to assess therapeutic potential.</p><p><strong>Results: </strong>Our analysis identified CCL5 as one of the most prominently elevated cytokines in CP-LS patients. Further validation in the EAP model mice confirmed elevated CCL5 levels, highlighting its role in driving prostatic inflammation. Mechanistic studies revealed that CCL5 interacts with the CCR5 receptor, promoting M1 macrophage polarization and activating key inflammatory signaling pathways, including Stat1 and NF-κB, as indicated by increased phosphorylation of Stat1 and p65. In vitro, CCL5 combined with LPS stimulation amplified these effects, further promoting M1 polarization. CCL5 also sustained Stat1 activation by inhibiting its dephosphorylation through reduced interaction with SHP2, leading to prolonged inflammatory signaling. Single-cell transcriptomics confirmed high CCR5 expression in macrophages, correlating with inflammatory pathways. Pharmacological inhibition of CCR5, or its downstream signaling, significantly reduced macrophage-driven inflammation both in vivo and in vitro.</p><p><strong>Conclusion: </strong>These findings establish the CCL5/CCR5 axis as a critical driver of persistant prostatic inflammation and present it as a potential therapeutic target for CP.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":"22 1","pages":"584"},"PeriodicalIF":8.2,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619290/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142781893","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}