Pub Date : 2025-10-14DOI: 10.1016/j.molimm.2025.10.004
Jiao-jiao Li , Jia-he Chen , Yue Yuan , Ling Li , Chen Zhou , Hu Chen , Jia Geng , Qian Cao , Rui Jin
Asthma is a common inflammatory airway disorder characterized by recurrent cough, chest tightness, and dyspnea. The repeated inflammation of bronchial epithelial cells leading to epithelial-mesenchymal transition is believed to play a pivotal role in airway remodeling associated with asthma. Gasdermin B (GSDMB), a member of the gasdermin family of structurally related proteins, has been identified as having a strong association with asthma. However, the precise role of GSDMB in asthma pathophysiology remains ambiguous. This study aimed to elucidate the biological function of GSDMB in asthma and its upstream regulatory mechanisms. Our findings demonstrated that GSDMB expression was also increased in human bronchial epithelial cells stimulated with transforming growth factor-β1 (TGF-β1). Overexpression of GSDMB resulted in an upregulation of intermediate mesenchymal markers following TGF-β1 treatment, thereby facilitating epithelial-mesenchymal transition (EMT) processes. Furthermore, GSDMB enhanced both proliferation and migration capacity in TGF-β1-treated Beas-2B cells. Notably, the transcription factor GATA1 was found to bind to the promoter region of GSDMB and facilitate its expression levels. These results indicate that the transcriptional axis involving GATA1/GSDMB exerts functions promoting EMT along with enhancing cellular proliferation and migration within TGF-β1-stimulated bronchial epithelial cells; suggesting that targeting GSDMB may represent a viable therapeutic strategy for managing asthma.
哮喘是一种常见的炎症性气道疾病，其特征是反复咳嗽、胸闷和呼吸困难。支气管上皮细胞的反复炎症导致上皮-间质转化被认为在哮喘相关气道重塑中起关键作用。Gasdermin B （GSDMB）是Gasdermin结构相关蛋白家族的一员，已被确定与哮喘有很强的相关性。然而，GSDMB在哮喘病理生理中的确切作用仍不清楚。本研究旨在阐明GSDMB在哮喘中的生物学功能及其上游调控机制。我们的研究结果表明，在转化生长因子-β1 （TGF-β1）刺激的人支气管上皮细胞中，GSDMB的表达也增加。GSDMB过表达导致TGF-β1处理后中间间质标志物上调，从而促进上皮-间质转化（EMT）过程。此外，GSDMB还能增强TGF-β1处理的Beas-2B细胞的增殖和迁移能力。值得注意的是，转录因子GATA1被发现与GSDMB的启动子区域结合并促进其表达水平。这些结果表明，涉及GATA1/GSDMB的转录轴在TGF-β1刺激的支气管上皮细胞中发挥促进EMT的功能，同时增强细胞增殖和迁移；这表明靶向GSDMB可能是一种可行的治疗哮喘的策略。
{"title":"GATA1 promotes TGF-β1-induced epithelial-mesenchymal transition by regulating GSDMB in human bronchial epithelial cells","authors":"Jiao-jiao Li , Jia-he Chen , Yue Yuan , Ling Li , Chen Zhou , Hu Chen , Jia Geng , Qian Cao , Rui Jin","doi":"10.1016/j.molimm.2025.10.004","DOIUrl":"10.1016/j.molimm.2025.10.004","url":null,"abstract":"<div><div>Asthma is a common inflammatory airway disorder characterized by recurrent cough, chest tightness, and dyspnea. The repeated inflammation of bronchial epithelial cells leading to epithelial-mesenchymal transition is believed to play a pivotal role in airway remodeling associated with asthma. Gasdermin B (GSDMB), a member of the gasdermin family of structurally related proteins, has been identified as having a strong association with asthma. However, the precise role of GSDMB in asthma pathophysiology remains ambiguous. This study aimed to elucidate the biological function of GSDMB in asthma and its upstream regulatory mechanisms. Our findings demonstrated that GSDMB expression was also increased in human bronchial epithelial cells stimulated with transforming growth factor-β1 (TGF-β1). Overexpression of GSDMB resulted in an upregulation of intermediate mesenchymal markers following TGF-β1 treatment, thereby facilitating epithelial-mesenchymal transition (EMT) processes. Furthermore, GSDMB enhanced both proliferation and migration capacity in TGF-β1-treated Beas-2B cells. Notably, the transcription factor GATA1 was found to bind to the promoter region of GSDMB and facilitate its expression levels. These results indicate that the transcriptional axis involving GATA1/GSDMB exerts functions promoting EMT along with enhancing cellular proliferation and migration within TGF-β1-stimulated bronchial epithelial cells; suggesting that targeting GSDMB may represent a viable therapeutic strategy for managing asthma.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"187 ","pages":"Pages 229-239"},"PeriodicalIF":3.0,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145302134","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}
Pub Date : 2025-10-14DOI: 10.1016/j.molimm.2025.10.005
Yuanyuan Li , Jiajia Zeng , Xuan Zhong , Qiting Huang , Xianfei Wang , Shuya Sun , Huamin Wang , Xiaoqi Huang , Jiajun Ling , Rongfeng Lin
Background
Diosgenin, a well-known steroid sapogenin, has demonstrated anti-inflammatory effects; however, its therapeutic potential for sepsis remains unclear. Intestinal barrier dysfunction is a critical contributor to lethal sepsis, a systemic inflammatory response syndrome. This study investigated the protective effects of diosgenin on cecal ligation and puncture (CLP)-induced sepsis in mice, focusing on its impact on intestinal mucosal dysfunction and inflammation. Additionally, the effects of diosgenin on the expression of the endogenous antimicrobial peptide mCRAMP and the TLR4/MyD88 signaling pathway were investigated.
Methods
Sepsis was induced in male C57BL/6 mice via CLP. Survival rates were recorded, and serum and ileum tissue levels of TNF-α and IL-6 were quantified to assess the protective efficacy of diosgenin treatment. Intestinal barrier integrity was evaluated by hematoxylin and eosin (H&E) staining, while mucosal permeability was determined using serum D-lactic acid. Tight junction (TJ) proteins were detected via Western blotting. Immunohistochemistry was used to measure mCRAMP protein expression in the ileum, and quantitative real-time PCR (qRT-PCR) was employed to analyze the gene expression of mCRAMP, TLR4, and MyD88. Molecular docking was performed with Autodock4 software to predict the binding capacity between diosgenin and LL-37, TLR4 and MyD88.
Results
Diosgenin treatment significantly improve the survival of mice, decreased TNF-α and IL-6 production, and attenuated intestinal histopathological damage. Additionally, diosgenin decreased serum D-lactic acid levels, upregulated Claudin-1 and Occludin expression, and increased both mRNA and protein levels of mCRAMP while downregulating the gene expression of TLR4 and MyD88. Molecular docking analysis demonstrated favorable binding affinities of diosgenin to LL-37 (−6.3 kcal/mol), TLR4 (−8.3 kcal/mol), and MyD88 (−10.5 kcal/mol). All calculated binding energies were < −5.0 kcal/mol, suggesting potential effective binding of diosgenin to these targets.
Conclusion
Diosgenin improved survival, suppressed inflammatory responses, and preserving intestinal mucosal barrier integrity in CLP-induced septic mice. These protective effects might involve alterations in mCRAMP expression and TLR4/MyD88 signaling.
{"title":"Diosgenin ameliorates CLP-induced sepsis in mice via suppressing inflammatory responses and preserving intestinal mucosal barrier integrity","authors":"Yuanyuan Li , Jiajia Zeng , Xuan Zhong , Qiting Huang , Xianfei Wang , Shuya Sun , Huamin Wang , Xiaoqi Huang , Jiajun Ling , Rongfeng Lin","doi":"10.1016/j.molimm.2025.10.005","DOIUrl":"10.1016/j.molimm.2025.10.005","url":null,"abstract":"<div><h3>Background</h3><div>Diosgenin, a well-known steroid sapogenin, has demonstrated anti-inflammatory effects; however, its therapeutic potential for sepsis remains unclear. Intestinal barrier dysfunction is a critical contributor to lethal sepsis, a systemic inflammatory response syndrome. This study investigated the protective effects of diosgenin on cecal ligation and puncture (CLP)-induced sepsis in mice, focusing on its impact on intestinal mucosal dysfunction and inflammation. Additionally, the effects of diosgenin on the expression of the endogenous antimicrobial peptide mCRAMP and the TLR4/MyD88 signaling pathway were investigated.</div></div><div><h3>Methods</h3><div>Sepsis was induced in male C57BL/6 mice via CLP. Survival rates were recorded, and serum and ileum tissue levels of TNF-α and IL-6 were quantified to assess the protective efficacy of diosgenin treatment. Intestinal barrier integrity was evaluated by hematoxylin and eosin (H&E) staining, while mucosal permeability was determined using serum D-lactic acid. Tight junction (TJ) proteins were detected via Western blotting. Immunohistochemistry was used to measure mCRAMP protein expression in the ileum, and quantitative real-time PCR (qRT-PCR) was employed to analyze the gene expression of mCRAMP, TLR4, and MyD88. Molecular docking was performed with Autodock4 software to predict the binding capacity between diosgenin and LL-37, TLR4 and MyD88.</div></div><div><h3>Results</h3><div>Diosgenin treatment significantly improve the survival of mice, decreased TNF-α and IL-6 production, and attenuated intestinal histopathological damage. Additionally, diosgenin decreased serum D-lactic acid levels, upregulated Claudin-1 and Occludin expression, and increased both mRNA and protein levels of mCRAMP while downregulating the gene expression of TLR4 and MyD88. Molecular docking analysis demonstrated favorable binding affinities of diosgenin to LL-37 (−6.3 kcal/mol), TLR4 (−8.3 kcal/mol), and MyD88 (−10.5 kcal/mol). All calculated binding energies were < −5.0 kcal/mol, suggesting potential effective binding of diosgenin to these targets.</div></div><div><h3>Conclusion</h3><div>Diosgenin improved survival, suppressed inflammatory responses, and preserving intestinal mucosal barrier integrity in CLP-induced septic mice. These protective effects might involve alterations in mCRAMP expression and TLR4/MyD88 signaling.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"187 ","pages":"Pages 210-220"},"PeriodicalIF":3.0,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145302166","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}
Pub Date : 2025-10-07DOI: 10.1016/j.molimm.2025.09.008
Quansheng Wang , Chenyi Wang , Zhicheng Zhang , Siyu Fan , Ping Lei , Shiguo Liu , Mingzhi Li , Keyi Wang , Yanni Zhang , Lumei Kang , Shiqi Weng , Lingbao Kong , Ting Wang
The SARS-CoV-2 spike protein facilitates target recognition, cellular entry, and viral infection, leading to varying degrees of COVID-19 severity. Amino acid site mutations in the S protein RBD region can enhance the spread and immune evasion of the SARS-CoV-2 Omicron variant. The study aimed to construct a prokaryotic expression vector for the S protein RBD of the SARS-CoV-2 Omicron BF.7 variant strain. Escherichia coli was used to express the RBD protein, and a polyclonal antibody was generated to investigate the immunological functions of the Omicron (BF.7) RBD. Optimization of expression conditions in Escherichia coli was conducted to achieve stable expression of pET-28a-BF.7-RBD, including induced temperature, induced time, and IPTG concentration. Serum antibody titers in RBD-immunized mice reached up to 1: 204800 as determined by indirect enzyme-linked immunosorbent assay. The polyclonal antibody could detect prokaryotic and eukaryotic RBD proteins, as well as commercial RBD proteins, and splenocytes were found to produce high levels of IFN-γ. This study successfully demonstrated the production of a large quantity of RBD protein with strong immunogenicity in E. coli, eliciting robust humoral and cellular immune responses in mice. The generation of high-potency polyclonal antibodies provides valuable insights for further research on the biological functions of the RBD protein, detection of Omicron variants, and vaccine development.
{"title":"Antibody preparation and immunological analysis of RBD from the SARS-CoV-2 Omicron BF.7 variant","authors":"Quansheng Wang , Chenyi Wang , Zhicheng Zhang , Siyu Fan , Ping Lei , Shiguo Liu , Mingzhi Li , Keyi Wang , Yanni Zhang , Lumei Kang , Shiqi Weng , Lingbao Kong , Ting Wang","doi":"10.1016/j.molimm.2025.09.008","DOIUrl":"10.1016/j.molimm.2025.09.008","url":null,"abstract":"<div><div>The SARS-CoV-2 spike protein facilitates target recognition, cellular entry, and viral infection, leading to varying degrees of COVID-19 severity. Amino acid site mutations in the S protein RBD region can enhance the spread and immune evasion of the SARS-CoV-2 Omicron variant. The study aimed to construct a prokaryotic expression vector for the S protein RBD of the SARS-CoV-2 Omicron BF.7 variant strain. <em>Escherichia coli</em> was used to express the RBD protein, and a polyclonal antibody was generated to investigate the immunological functions of the Omicron (BF.7) RBD. Optimization of expression conditions in <em>Escherichia coli</em> was conducted to achieve stable expression of pET-28a-BF.7-RBD, including induced temperature, induced time, and IPTG concentration. Serum antibody titers in RBD-immunized mice reached up to 1: 204800 as determined by indirect enzyme-linked immunosorbent assay. The polyclonal antibody could detect prokaryotic and eukaryotic RBD proteins, as well as commercial RBD proteins, and splenocytes were found to produce high levels of IFN-γ. This study successfully demonstrated the production of a large quantity of RBD protein with strong immunogenicity in <em>E. coli</em>, eliciting robust humoral and cellular immune responses in mice. The generation of high-potency polyclonal antibodies provides valuable insights for further research on the biological functions of the RBD protein, detection of Omicron variants, and vaccine development.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"187 ","pages":"Pages 188-197"},"PeriodicalIF":3.0,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145251967","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}
Pub Date : 2025-10-06DOI: 10.1016/j.molimm.2025.09.009
Paula Gršković , Valentino Mihalić , Anja Krstulović , Peter Möller , Suzana Hančić , Slavko Gašparov , Petra Korać
Objectives
Primary mediastinal B-cell lymphoma (PMBCL) is an aggressive type of non-Hodgkin lymphoma (NHL) that shares features with diffuse large B-cell lymphoma (DLBCL), but also with classical Hodgkin lymphoma (cHL). PMBCL often contains aberrations of genes involved in the immune response such as cREL and PD-L1, whose expression is also influenced by cytokines TNF-α and IFN-γ.
Methods
In this study, cell lines Farage, U2940, MedB-1 and Karpas1106p were used as PMBCL models and treated with different concentrations of TNF-α and IFN-γ over 24 and 48 h, followed by the quantification of cREL, CXCL10 and PD-L1 expression. Additionally, the expression of TNF-α, IFN-γ, cREL, CXCL10, CXCR3, PD-L1 and PD-1 genes was compared between PMBCL tissue samples and B-cell and T-cell rich zones of non-tumour tonsils.
Results
Prolonged exposure to TNF-α increased cREL expression, while IFN-γ strongly induced CXCL10 expression. The change in the expression of PD-L1 in response to the treatments differed across various cell lines. There was no statistically significant difference in the expression of the target genes between tumour and non-tumour patient tissue samples.
Conclusions
the obtained results suggest that the immune checkpoints in PMBCL cells are affected by both their genetic profile and tumour microenvironment.
{"title":"TNF-α and IFN-γ modulate the evasion of the immune response in primary mediastinal B-cell lymphoma","authors":"Paula Gršković , Valentino Mihalić , Anja Krstulović , Peter Möller , Suzana Hančić , Slavko Gašparov , Petra Korać","doi":"10.1016/j.molimm.2025.09.009","DOIUrl":"10.1016/j.molimm.2025.09.009","url":null,"abstract":"<div><h3>Objectives</h3><div>Primary mediastinal B-cell lymphoma (PMBCL) is an aggressive type of non-Hodgkin lymphoma (NHL) that shares features with diffuse large B-cell lymphoma (DLBCL), but also with classical Hodgkin lymphoma (cHL). PMBCL often contains aberrations of genes involved in the immune response such as <em>cREL</em> and <em>PD-L1</em>, whose expression is also influenced by cytokines TNF-α and IFN-γ.</div></div><div><h3>Methods</h3><div>In this study, cell lines Farage, U2940, MedB-1 and Karpas1106p were used as PMBCL models and treated with different concentrations of TNF-α and IFN-γ over 24 and 48 h, followed by the quantification of <em>cREL</em>, <em>CXCL10</em> and <em>PD-L1</em> expression. Additionally, the expression of <em>TNF-α</em>, <em>IFN-γ</em>, <em>cREL</em>, <em>CXCL10</em>, <em>CXCR3</em>, <em>PD-L1</em> and <em>PD-1</em> genes was compared between PMBCL tissue samples and B-cell and T-cell rich zones of non-tumour tonsils.</div></div><div><h3>Results</h3><div>Prolonged exposure to TNF-α increased <em>cREL</em> expression, while IFN-γ strongly induced <em>CXCL10</em> expression. The change in the expression of <em>PD-L1</em> in response to the treatments differed across various cell lines. There was no statistically significant difference in the expression of the target genes between tumour and non-tumour patient tissue samples.</div></div><div><h3>Conclusions</h3><div>the obtained results suggest that the immune checkpoints in PMBCL cells are affected by both their genetic profile and tumour microenvironment.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"187 ","pages":"Pages 178-187"},"PeriodicalIF":3.0,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244784","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}
Pub Date : 2025-10-06DOI: 10.1016/j.molimm.2025.10.001
Jaewhoon Jeoung, Hyein Jo, Wonho Kim, Dooil Jeoung
We previously reported the anti-allergic effect of rocaglamide-A (roc-A). Molecular docking analysis showed the binding of roc-A to sphingosine-1-phospahe receptor 2 (S1PR2). This led us to hypothesize that S1PR2 might play a role in allergic reactions. Antigen stimulation increased the expression of S1PR2 in rat basophilic leukemia (RBL2H3 cells). Sphingosine-1-phosphate (S1P) increased the expression of S1PR2 in an antigen-independent manner. S1PR2 was necessary for both allergic reactions in vitro and anaphylaxis. Sphingosine prevented the antigen (DNP-HSA) from increasing the expression of S1PR2 and hallmarks of allergic reactions in RBL2H3 cells. Sphingosine also prevented antigen from increasing the level of reactive oxygen species (ROS). Animal model of passive systemic anaphylaxis (PSA) showed the increased expression of CXCL1. CXCL1 was shown to mediate allergic reactions in vitro. TargetScan predicted the binding of miR-212 to the 3 ´ UTR of S1PR2. The downregulation of S1PR2 prevented antigen from increasing the expression of CXCL1 at the transcriptional level. cmiR-212 was found to decrease the expression of S1PR2 in antigen stimulated RBL2H3 cells. miR-212 mimic decreased the luciferase activity associated with 3 ´ UTR of S1PR2. The miR-212 mimic exerted a negative effect on the passive cutaneous anaphylaxis (PCA). The downregulation of S1PR2 increased the expression of miR-212 in antigen stimulated RBL2H3 cells. This suggests that miR-212 and S1PR2 form negative feedback loops to regulate allergic reactions. Our results show that S1PR2-miR-212 negative feedback loop regulates allergic reactions in vitro and in vivo.
{"title":"S1PR2-miR-212 feedback loop regulates allergic reactions","authors":"Jaewhoon Jeoung, Hyein Jo, Wonho Kim, Dooil Jeoung","doi":"10.1016/j.molimm.2025.10.001","DOIUrl":"10.1016/j.molimm.2025.10.001","url":null,"abstract":"<div><div>We previously reported the anti-allergic effect of rocaglamide-A (roc-A). Molecular docking analysis showed the binding of roc-A to sphingosine-1-phospahe receptor 2 (S1PR2). This led us to hypothesize that S1PR2 might play a role in allergic reactions. Antigen stimulation increased the expression of S1PR2 in rat basophilic leukemia (RBL2H3 cells). Sphingosine-1-phosphate (S1P) increased the expression of S1PR2 in an antigen-independent manner. S1PR2 was necessary for both allergic reactions <em>in vitro</em> and anaphylaxis. Sphingosine prevented the antigen (DNP-HSA) from increasing the expression of S1PR2 and hallmarks of allergic reactions in RBL2H3 cells. Sphingosine also prevented antigen from increasing the level of reactive oxygen species (ROS). Animal model of passive systemic anaphylaxis (PSA) showed the increased expression of CXCL1. CXCL1 was shown to mediate allergic reactions <em>in vitro</em>. TargetScan predicted the binding of miR-212 to the 3 ´ UTR of S1PR2. The downregulation of S1PR2 prevented antigen from increasing the expression of CXCL1 at the transcriptional level. cmiR-212 was found to decrease the expression of S1PR2 in antigen stimulated RBL2H3 cells. miR-212 mimic decreased the luciferase activity associated with 3 ´ UTR of S1PR2. The miR-212 mimic exerted a negative effect on the passive cutaneous anaphylaxis (PCA). The downregulation of S1PR2 increased the expression of miR-212 in antigen stimulated RBL2H3 cells. This suggests that miR-212 and S1PR2 form negative feedback loops to regulate allergic reactions. Our results show that S1PR2-miR-212 negative feedback loop regulates allergic reactions in vitro and in vivo.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"187 ","pages":"Pages 166-177"},"PeriodicalIF":3.0,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244814","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}
Pub Date : 2025-10-01Epub Date: 2025-08-09DOI: 10.1016/j.molimm.2025.08.002
Qianrong Zhang, Aiping Jin, Haijuan Cheng, Yuanyuan Zheng, Bing Li
Background: Poly(C) binding protein 2 (PCBP2) was reported to alleviate cardiomyocyte damage, but its molecular mechanism remains unclear. The current study aimed to investigate the role and potential mechanism of PCBP2 in progression of MI.
Methods: An in vivo MI model was established by ligation of the left anterior descending (LAD) branch in mice. PCBP2 expression was detected in Normal and MI groups. H9C2 cells were treated with OGD for 0, 2, 4, and 6 h to screen for optimal time to establish MI model in vitro. H9C2 cells were transfected with pcDNA-PCBP2, and the effect of PCBP2 overexpression on OGD-induced oxidative stress, inflammation and ferroptosis was evaluated. Subsequently, the interaction of PCBP2 with NDUFS1 mRNA was predicted by the Starbase database and verified by RNA-immunoprecipitation (RIP) and RNA-protein pull-down assay. Next, a series of reversal experiments were performed to verify the regulation of PCBP2 on NDUFS1 expression. Then, pcDNA-NDUFS1 was transfected into H9C2 and MIND4-17 (NRF2 protein activator) treated for reversal experiments to assess the effect of NDUFS1 on NRF2-mediated ferroptosis. Finally, LV-PCBP2 and LV-NDUFS1 lentiviral vectors were intrapericardially injected into MI mice, and the role of PCBP2 and NDUFS1 in the progression of MI was verified in vivo.
Results: PCBP2 was downregulated in MI model and OGD-induced H9C2 cells. PCBP2 improved cell proliferation and inhibited oxidative stress, inflammation and ferroptosis in OGD-incubated H9C2 cells. PCBP2 bound with NDUFS1 mRNA and promoted NDUFS1 expression in H9C2 cells, which promoted NRF2 activation by enhancing NRF2 nuclear translocation and inhibited NRF2-mediated ferroptosis. Finally, administration of LV-PCBP2 and LV-NDUFS1 alleviated myocardial tissue injury and MI infarct in mice through suppressing cardiomyocyte ferroptosis and inflammation.
Conclusion: Our results suggested that PCBP2 alleviated MI by inhibiting cardiomyocyte ferroptosis through interacting with NDUFS1 mRNA and activating NRF2-Keap1 pathway.
{"title":"PCBP2 alleviates myocardial infarction by inhibiting cardiomyocyte ferroptosis via the NDUFS1/NRF2 pathway.","authors":"Qianrong Zhang, Aiping Jin, Haijuan Cheng, Yuanyuan Zheng, Bing Li","doi":"10.1016/j.molimm.2025.08.002","DOIUrl":"10.1016/j.molimm.2025.08.002","url":null,"abstract":"<p><strong>Background: </strong>Poly(C) binding protein 2 (PCBP2) was reported to alleviate cardiomyocyte damage, but its molecular mechanism remains unclear. The current study aimed to investigate the role and potential mechanism of PCBP2 in progression of MI.</p><p><strong>Methods: </strong>An in vivo MI model was established by ligation of the left anterior descending (LAD) branch in mice. PCBP2 expression was detected in Normal and MI groups. H9C2 cells were treated with OGD for 0, 2, 4, and 6 h to screen for optimal time to establish MI model in vitro. H9C2 cells were transfected with pcDNA-PCBP2, and the effect of PCBP2 overexpression on OGD-induced oxidative stress, inflammation and ferroptosis was evaluated. Subsequently, the interaction of PCBP2 with NDUFS1 mRNA was predicted by the Starbase database and verified by RNA-immunoprecipitation (RIP) and RNA-protein pull-down assay. Next, a series of reversal experiments were performed to verify the regulation of PCBP2 on NDUFS1 expression. Then, pcDNA-NDUFS1 was transfected into H9C2 and MIND4-17 (NRF2 protein activator) treated for reversal experiments to assess the effect of NDUFS1 on NRF2-mediated ferroptosis. Finally, LV-PCBP2 and LV-NDUFS1 lentiviral vectors were intrapericardially injected into MI mice, and the role of PCBP2 and NDUFS1 in the progression of MI was verified in vivo.</p><p><strong>Results: </strong>PCBP2 was downregulated in MI model and OGD-induced H9C2 cells. PCBP2 improved cell proliferation and inhibited oxidative stress, inflammation and ferroptosis in OGD-incubated H9C2 cells. PCBP2 bound with NDUFS1 mRNA and promoted NDUFS1 expression in H9C2 cells, which promoted NRF2 activation by enhancing NRF2 nuclear translocation and inhibited NRF2-mediated ferroptosis. Finally, administration of LV-PCBP2 and LV-NDUFS1 alleviated myocardial tissue injury and MI infarct in mice through suppressing cardiomyocyte ferroptosis and inflammation.</p><p><strong>Conclusion: </strong>Our results suggested that PCBP2 alleviated MI by inhibiting cardiomyocyte ferroptosis through interacting with NDUFS1 mRNA and activating NRF2-Keap1 pathway.</p>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"186 ","pages":"13-25"},"PeriodicalIF":3.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144817181","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}
Pub Date : 2025-09-30DOI: 10.1016/j.molimm.2025.09.002
Weijing Fan , Yang You , Yin Qu, Guobin Liu
Delayed wound recovery is a major health issue affecting people with diabetes. Histone lactylation is involved in tissue repair. However, it is not clear whether protocatechuic aldehyde (PCA) promotes diabetic wound healing through histone lactylation. In this study, a diabetic wound mouse model was constructed to delve into the role of PCA in vivo. Chromatin immunoprecipitation sequencing (ChIP-seq) was used to determine genes affected by H3K18 lactylation (H3K18la) under PCA treatment. The effects and mechanisms of PCA on histone lactylation and angiogenesis were investigated through cellular experiments. We found that PCA accelerated wound healing and angiogenesis in diabetic mice, and significantly reduced the inflammatory response in wound tissues. Lactate and H3K18la levels were augmented in the model group in comparison with the control group, however, PCA treatment remarkably reversed their levels. ChIP-seq analysis revealed a significant enrichment of H3K18la at the Acvr1c locus, and this histone modification was downregulated by PCA treatment. PCA remarkably enhanced Acvr1c expression through H3K18la in HUVECs. Moreover, PCA treatment markedly elevated cell viability, migration and tube formation in comparison with the control group. However, this effect was counteracted by Acvr1c knockdown. In conclusion, PCA promoted HUVEC angiogenesis by increasing H3K18la-mediated Acvr1c expression, thereby promoting diabetic wound healing. This could offer a new treatment approach to enhance the effectiveness of healing diabetic wounds.
{"title":"Protocatechuic aldehyde promotes diabetic wound healing by enhancing angiogenesis via H3K18 lactylation-mediated Acvr1c expression","authors":"Weijing Fan , Yang You , Yin Qu, Guobin Liu","doi":"10.1016/j.molimm.2025.09.002","DOIUrl":"10.1016/j.molimm.2025.09.002","url":null,"abstract":"<div><div>Delayed wound recovery is a major health issue affecting people with diabetes. Histone lactylation is involved in tissue repair. However, it is not clear whether protocatechuic aldehyde (PCA) promotes diabetic wound healing through histone lactylation. In this study, a diabetic wound mouse model was constructed to delve into the role of PCA in vivo. Chromatin immunoprecipitation sequencing (ChIP-seq) was used to determine genes affected by H3K18 lactylation (H3K18la) under PCA treatment. The effects and mechanisms of PCA on histone lactylation and angiogenesis were investigated through cellular experiments. We found that PCA accelerated wound healing and angiogenesis in diabetic mice, and significantly reduced the inflammatory response in wound tissues. Lactate and H3K18la levels were augmented in the model group in comparison with the control group, however, PCA treatment remarkably reversed their levels. ChIP-seq analysis revealed a significant enrichment of H3K18la at the Acvr1c locus, and this histone modification was downregulated by PCA treatment. PCA remarkably enhanced Acvr1c expression through H3K18la in HUVECs. Moreover, PCA treatment markedly elevated cell viability, migration and tube formation in comparison with the control group. However, this effect was counteracted by Acvr1c knockdown. In conclusion, PCA promoted HUVEC angiogenesis by increasing H3K18la-mediated Acvr1c expression, thereby promoting diabetic wound healing. This could offer a new treatment approach to enhance the effectiveness of healing diabetic wounds.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"187 ","pages":"Pages 152-165"},"PeriodicalIF":3.0,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145207018","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}
Pub Date : 2025-09-25DOI: 10.1016/j.molimm.2025.09.006
Shouming Cao , Yan Niu , Jinmei Ning , Nannan Wen , Rui Chen , Haiying Wu
Background
Chronic rhinosinusitis (CRS) is characterized by a high recurrence rate within five years post-surgery, posing a persistent challenge for otolaryngologists globally. Recent research has underscored the pivotal role of the Th17/Treg cell balance in the pathogenesis of CRS. This study aims to investigate the alterations in the Th17/Treg cell balance in CRS and elucidate the underlying molecular mechanisms.
Methods
CRS model was established to assess the levels of inflammatory cytokines, olfactory marker protein expression, SMAD4 expression, and ERK1/2 phosphorylation. We then overexpressed SMAD4 or treated CRS mice with ERK1/2 inhibitors, measuring the impact on Th17/Treg marker expression. Moreover, the influence of the SMAD4/ERK signaling axis on the Th17/Treg balance within the CD4 + T cell population was investigated.
Results
CRS mice exhibited significantly reduced olfactory marker protein and SMAD4 expression, alongside increased ERK1/2 phosphorylation. Histological analysis revealed an increased infiltration of eosinophils. Of particular note, the expression of Treg markers was markedly decreased, while Th17 marker expression exhibited a corresponding increase, suggesting a potential shift in the Th17/Treg balance. Interventions involving SMAD4 overexpression or ERK1/2 inhibition led to a reduction in eosinophil infiltration and successfully reversed the aberrant expression patterns of the aforementioned markers. Furthermore, SMAD4 knockdown resulted in a decreased proportion of Treg cells and an increased proportion of Th17 cells. This alteration in the Th17/Treg balance was effectively counteracted by ERK inhibitor.
Conclusions
The deletion of SMAD4 regulates the differentiation of Th17/Treg cells via ERK1/2 phosphorylation, thereby exacerbating the olfactory dysfunction of CRS.
{"title":"The mechanism of SMAD4/ERK pathway in regulating Th17/Treg cell differentiation leading to olfactory dysfunction in chronic rhinosinusitis","authors":"Shouming Cao , Yan Niu , Jinmei Ning , Nannan Wen , Rui Chen , Haiying Wu","doi":"10.1016/j.molimm.2025.09.006","DOIUrl":"10.1016/j.molimm.2025.09.006","url":null,"abstract":"<div><h3>Background</h3><div>Chronic rhinosinusitis (CRS) is characterized by a high recurrence rate within five years post-surgery, posing a persistent challenge for otolaryngologists globally. Recent research has underscored the pivotal role of the Th17/Treg cell balance in the pathogenesis of CRS. This study aims to investigate the alterations in the Th17/Treg cell balance in CRS and elucidate the underlying molecular mechanisms.</div></div><div><h3>Methods</h3><div>CRS model was established to assess the levels of inflammatory cytokines, olfactory marker protein expression, SMAD4 expression, and ERK1/2 phosphorylation. We then overexpressed SMAD4 or treated CRS mice with ERK1/2 inhibitors, measuring the impact on Th17/Treg marker expression. Moreover, the influence of the SMAD4/ERK signaling axis on the Th17/Treg balance within the CD4 + T cell population was investigated.</div></div><div><h3>Results</h3><div>CRS mice exhibited significantly reduced olfactory marker protein and SMAD4 expression, alongside increased ERK1/2 phosphorylation. Histological analysis revealed an increased infiltration of eosinophils. Of particular note, the expression of Treg markers was markedly decreased, while Th17 marker expression exhibited a corresponding increase, suggesting a potential shift in the Th17/Treg balance. Interventions involving SMAD4 overexpression or ERK1/2 inhibition led to a reduction in eosinophil infiltration and successfully reversed the aberrant expression patterns of the aforementioned markers. Furthermore, SMAD4 knockdown resulted in a decreased proportion of Treg cells and an increased proportion of Th17 cells. This alteration in the Th17/Treg balance was effectively counteracted by ERK inhibitor.</div></div><div><h3>Conclusions</h3><div>The deletion of SMAD4 regulates the differentiation of Th17/Treg cells via ERK1/2 phosphorylation, thereby exacerbating the olfactory dysfunction of CRS.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"187 ","pages":"Pages 142-151"},"PeriodicalIF":3.0,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145154974","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}
Pub Date : 2025-09-23DOI: 10.1016/j.molimm.2025.09.005
Ebru Ada , Volkan Seyrantepe
Lysosomal storage diseases (LSDs) are a class of hereditary metabolic disorders primarily caused by lysosomal enzyme defects, leading to the accumulation of undegraded substrates. Sphingolipidoses, a subset of LSDs, are primarily associated with profound involvement of the central nervous system (CNS), characterized by progressive neurodegeneration due to massive sphingolipid accumulation. A common pathological feature among many CNS-involved LSDs is the early activation of microglia and astrocytes, which often precedes and predicts regions of subsequent neuronal loss. The extent to which neuroinflammation disrupts CNS homeostasis appears to be determined by its onset, magnitude, and duration. Although neuroinflammatory processes are increasingly recognized as critical contributors to disease progression in sphingolipidoses, the molecular mechanisms underlying glial activation and the initiation of inflammatory cascades remain incompletely understood. Therefore, mouse models of sphingolipidoses have been instrumental in elucidating these pathogenic processes and provide valuable platforms for evaluating therapeutic strategies. This review critically examines the role of neuroinflammation in sphingolipidoses, summarizes insights derived from pre-clinical models, and discusses the therapeutic potential of anti-inflammatory interventions to mitigate CNS pathology and improve clinical outcomes.
{"title":"Therapeutic targeting of neuroinflammation in sphingolipidosis","authors":"Ebru Ada , Volkan Seyrantepe","doi":"10.1016/j.molimm.2025.09.005","DOIUrl":"10.1016/j.molimm.2025.09.005","url":null,"abstract":"<div><div>Lysosomal storage diseases (LSDs) are a class of hereditary metabolic disorders primarily caused by lysosomal enzyme defects, leading to the accumulation of undegraded substrates. Sphingolipidoses, a subset of LSDs, are primarily associated with profound involvement of the central nervous system (CNS), characterized by progressive neurodegeneration due to massive sphingolipid accumulation. A common pathological feature among many CNS-involved LSDs is the early activation of microglia and astrocytes, which often precedes and predicts regions of subsequent neuronal loss. The extent to which neuroinflammation disrupts CNS homeostasis appears to be determined by its onset, magnitude, and duration. Although neuroinflammatory processes are increasingly recognized as critical contributors to disease progression in sphingolipidoses, the molecular mechanisms underlying glial activation and the initiation of inflammatory cascades remain incompletely understood. Therefore, mouse models of sphingolipidoses have been instrumental in elucidating these pathogenic processes and provide valuable platforms for evaluating therapeutic strategies. This review critically examines the role of neuroinflammation in sphingolipidoses, summarizes insights derived from pre-clinical models, and discusses the therapeutic potential of anti-inflammatory interventions to mitigate CNS pathology and improve clinical outcomes.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"187 ","pages":"Pages 121-133"},"PeriodicalIF":3.0,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145118646","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}
Pub Date : 2025-09-23DOI: 10.1016/j.molimm.2025.09.003
Ivonne Pacheco-Alba , Blanca Bazán-Perkins
Sensitization with ovalbumin (OVA) in guinea pigs to induce anti-OVA IgE generates various allergic response phenotypes. One phenotype, characterized by the absence of bronchial obstruction and airway hyperresponsiveness in response to chronic antigen challenge, is termed non-responding (NR) and exhibits high IFN-γ levels. The Th1 cytokine profile is linked with high laminin β2 expression. This study evaluated laminin β2 expression in the chronic NR phenotype. Guinea pigs were sensitized and challenged with OVA three times (acute) or twelve times (chronic). Guinea pigs that responded to all challenges formed the asthma model phenotype. Controls were sensitized and challenged with saline. Immunohistochemistry was used to observe laminin β2 and its receptor, the α6 integrin subunit, in bronchial and arterial intrapulmonary smooth muscles. Only chronic NR guinea pigs showed increased laminin β2 expression in these muscles, while it remained similar in other groups. The α6 integrin subunit significantly increased in the acute and chronic asthma models, chronic controls, and NR guinea pigs in bronchial smooth muscle. In arterial intrapulmonary smooth muscle, the α6 integrin subunit increased in acute NR and chronic asthma model guinea pigs. The expression of laminin β2 in bronchial and arterial intrapulmonary smooth muscles correlates with α6 integrin subunit levels, and higher levels of laminin β2 were significantly related to reduced antigen-induced bronchial obstruction and reactivity to histamine. The expression of these proteins does not affect the proliferation of pulmonary blood vessels. Laminin β2 chain overexpression is likely involved in the chronic containment of the obstructive allergic response.
{"title":"Hypocontractile airway smooth muscle phenotype exhibits enhanced β2 laminin chain expression in lung allergy model","authors":"Ivonne Pacheco-Alba , Blanca Bazán-Perkins","doi":"10.1016/j.molimm.2025.09.003","DOIUrl":"10.1016/j.molimm.2025.09.003","url":null,"abstract":"<div><div>Sensitization with ovalbumin (OVA) in guinea pigs to induce anti-OVA IgE generates various allergic response phenotypes. One phenotype, characterized by the absence of bronchial obstruction and airway hyperresponsiveness in response to chronic antigen challenge, is termed non-responding (NR) and exhibits high IFN-γ levels. The Th1 cytokine profile is linked with high laminin β2 expression. This study evaluated laminin β2 expression in the chronic NR phenotype. Guinea pigs were sensitized and challenged with OVA three times (acute) or twelve times (chronic). Guinea pigs that responded to all challenges formed the asthma model phenotype. Controls were sensitized and challenged with saline. Immunohistochemistry was used to observe laminin β2 and its receptor, the α6 integrin subunit, in bronchial and arterial intrapulmonary smooth muscles. Only chronic NR guinea pigs showed increased laminin β2 expression in these muscles, while it remained similar in other groups. The α6 integrin subunit significantly increased in the acute and chronic asthma models, chronic controls, and NR guinea pigs in bronchial smooth muscle. In arterial intrapulmonary smooth muscle, the α6 integrin subunit increased in acute NR and chronic asthma model guinea pigs. The expression of laminin β2 in bronchial and arterial intrapulmonary smooth muscles correlates with α6 integrin subunit levels, and higher levels of laminin β2 were significantly related to reduced antigen-induced bronchial obstruction and reactivity to histamine. The expression of these proteins does not affect the proliferation of pulmonary blood vessels. Laminin β2 chain overexpression is likely involved in the chronic containment of the obstructive allergic response.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"187 ","pages":"Pages 134-141"},"PeriodicalIF":3.0,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145118645","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}
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