Pub Date : 2025-12-02DOI: 10.1016/j.molimm.2025.11.012
Meijuan Han , Xuetao Dong , Ruxin Zhao , Xiao Hu , Dan Li , Xinchen Yan , Yandi Liu , Qiupeng Du , Muran Li
The gut microbiota is widely recognized as a key component in the pathogenesis of inflammatory bowel disease (IBD), and one of its primary modes of interaction with the host occurs via metabolites. Studies have confirmed that gut microbiota dysbiosis affects immune maturation, immune homeostasis, host energy metabolism, and the maintenance of mucosal integrity. However, the specific metabolites that influence the differentiation of mucosal CD4+ T cells remain insufficiently elucidated. This study aimed to identify and validate unknown metabolites capable of affecting the differentiation of CD4+ T cell subsets by characterizing changes in fecal metabolites between IBD patients and non-IBD controls. Using untargeted metabolomics, we quantitatively detected a total of 1480 metabolites in positive ion mode and 1178 metabolites in negative ion mode. Regression analysis results showed that N-Acetylglutamine was significantly downregulated in IBD patients and was identified as a key differential metabolite. Further in vitro functional experiments confirmed that this metabolite could directly regulate the differentiation balance of CD4+ T cells, specifically inhibiting the differentiation of pathogenic Th17 (pTh17) cells while promoting the generation of Treg. This study verifies the critical role of the metabolite N-Acetylglutamine in regulating the Treg/pTh17 cell balance, providing a theoretical basis for its potential as a therapeutic target for IBD.
{"title":"Fecal metabolomics in Crohn’s disease reveal N-Acetylglutamine as a Th17/Treg modulator","authors":"Meijuan Han , Xuetao Dong , Ruxin Zhao , Xiao Hu , Dan Li , Xinchen Yan , Yandi Liu , Qiupeng Du , Muran Li","doi":"10.1016/j.molimm.2025.11.012","DOIUrl":"10.1016/j.molimm.2025.11.012","url":null,"abstract":"<div><div>The gut microbiota is widely recognized as a key component in the pathogenesis of inflammatory bowel disease (IBD), and one of its primary modes of interaction with the host occurs via metabolites. Studies have confirmed that gut microbiota dysbiosis affects immune maturation, immune homeostasis, host energy metabolism, and the maintenance of mucosal integrity. However, the specific metabolites that influence the differentiation of mucosal CD4<sup>+</sup> T cells remain insufficiently elucidated. This study aimed to identify and validate unknown metabolites capable of affecting the differentiation of CD4<sup>+</sup> T cell subsets by characterizing changes in fecal metabolites between IBD patients and non-IBD controls. Using untargeted metabolomics, we quantitatively detected a total of 1480 metabolites in positive ion mode and 1178 metabolites in negative ion mode. Regression analysis results showed that N-Acetylglutamine was significantly downregulated in IBD patients and was identified as a key differential metabolite. Further in vitro functional experiments confirmed that this metabolite could directly regulate the differentiation balance of CD4<sup>+</sup> T cells, specifically inhibiting the differentiation of pathogenic Th17 (pTh17) cells while promoting the generation of Treg. This study verifies the critical role of the metabolite N-Acetylglutamine in regulating the Treg/pTh17 cell balance, providing a theoretical basis for its potential as a therapeutic target for IBD.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"189 ","pages":"Pages 82-97"},"PeriodicalIF":3.0,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145668457","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 : 2025-12-01DOI: 10.1016/j.molimm.2025.11.019
Narjes Noori Goodarzi , Mohammad Reza Pourmand
Neisseria gonorrhoeae, the causative agent of gonorrhea, accounts for over 87 million new cases annually. It poses a serious threat to global health due to its high antimicrobial resistance. The development of an effective gonorrhea vaccine has been severely hampered by unique characteristics of this pathogen, particularly antigenic and phase variation of surface antigens. Additionally, the difficulty of eliciting effective mucosal immune responses and the inability of natural infection to produce long-lasting immunity further complicate vaccine development. In this review, the main obstacles to gonococcal vaccine development are discussed. Clinical trials evaluating the cross-protective effects (approximately 31–46 %) of 4CMenB vaccine against N. gonorrhoeae have been explored, along with recent advances such as recombinant proteins, multivalent and epitope-based approaches, and emerging mRNA platforms. Promising findings from preclinical studies are highlighted, together with growing role of artificial intelligence and machine learning in antigen discovery and vaccine optimization. Despite these innovations, translating theoretical approaches into safe, immunogenic, and broadly protective vaccines remains a major challenge. This review underscores the urgent need for continued interdisciplinary research to close existing gaps and develop a feasible efficient vaccine to combat drug-resistant gonorrhea.
{"title":"Innovations, challenges, and gaps in the development of an effective vaccine against Neisseria gonorrhoeae, a narrative review","authors":"Narjes Noori Goodarzi , Mohammad Reza Pourmand","doi":"10.1016/j.molimm.2025.11.019","DOIUrl":"10.1016/j.molimm.2025.11.019","url":null,"abstract":"<div><div><em>Neisseria gonorrhoeae</em>, the causative agent of gonorrhea, accounts for over 87 million new cases annually. It poses a serious threat to global health due to its high antimicrobial resistance. The development of an effective gonorrhea vaccine has been severely hampered by unique characteristics of this pathogen, particularly antigenic and phase variation of surface antigens. Additionally, the difficulty of eliciting effective mucosal immune responses and the inability of natural infection to produce long-lasting immunity further complicate vaccine development. In this review, the main obstacles to gonococcal vaccine development are discussed. Clinical trials evaluating the cross-protective effects (approximately 31–46 %) of 4CMenB vaccine against <em>N. gonorrhoeae</em> have been explored, along with recent advances such as recombinant proteins, multivalent and epitope-based approaches, and emerging mRNA platforms. Promising findings from preclinical studies are highlighted, together with growing role of artificial intelligence and machine learning in antigen discovery and vaccine optimization. Despite these innovations, translating theoretical approaches into safe, immunogenic, and broadly protective vaccines remains a major challenge. This review underscores the urgent need for continued interdisciplinary research to close existing gaps and develop a feasible efficient vaccine to combat drug-resistant gonorrhea.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"189 ","pages":"Pages 13-30"},"PeriodicalIF":3.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145661432","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 : 2025-12-01DOI: 10.1016/j.molimm.2025.11.006
Rong Guo , Ziyun Li , Jie Wu , Zilin Zhang , Junxiang Shu , Xiaoxi Zhou , Wenfang Zhou , Yiming Chen , Dongxia Guan , Qian Wang , Qiping Shi , Hengwen Yang , Guangqiang Li
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a globally prevalent disorder linked to metabolic syndrome, currently lacking approved therapies, and existing treatments offer only limited benefits. Complement factor D (CFD), a rate-limiting serine protease in the alternative complement pathway, has been suggested to be associated with metabolic diseases in previous studies. Its inhibitor, danicopan, is primarily used for paroxysmal nocturnal hemoglobinuria (PNH), but its role in metabolic liver diseases remains underexplored. Here, we assessed the role of CFD in MAFLD and danicopan therapy using HFD mice, patient sera, and hepatocytes via CRISPR knockout and pharmacological interventions. Key findings demonstrated significant upregulation of CFD in MAFLD mice livers and patient sera. Genetic CFD ablation attenuated hepatocyte lipid deposition. Danicopan reduced intracellular triglycerides/cholesterol, improved glucose tolerance, lowered ALT, and alleviated hepatic steatosis in obese mice without weight change. Mechanistically, danicopan suppressed NF-κB signaling, inhibiting lipid-related genes (CD36/FASN/ FATP2) and inflammatory mediators (MMP12/IL-6/TNF-α). These results establish CFD as a novel MAFLD mediator, validating FDA-approved danicopan's therapeutic efficacy and translational potential. This work provides critical evidence for targeting the CFD pathway in MAFLD management.
{"title":"Complement factor D is a drug target for metabolic-associated fatty liver disease","authors":"Rong Guo , Ziyun Li , Jie Wu , Zilin Zhang , Junxiang Shu , Xiaoxi Zhou , Wenfang Zhou , Yiming Chen , Dongxia Guan , Qian Wang , Qiping Shi , Hengwen Yang , Guangqiang Li","doi":"10.1016/j.molimm.2025.11.006","DOIUrl":"10.1016/j.molimm.2025.11.006","url":null,"abstract":"<div><div>Metabolic dysfunction-associated fatty liver disease (MAFLD) is a globally prevalent disorder linked to metabolic syndrome, currently lacking approved therapies, and existing treatments offer only limited benefits. Complement factor D (CFD), a rate-limiting serine protease in the alternative complement pathway, has been suggested to be associated with metabolic diseases in previous studies. Its inhibitor, danicopan, is primarily used for paroxysmal nocturnal hemoglobinuria (PNH), but its role in metabolic liver diseases remains underexplored. Here, we assessed the role of CFD in MAFLD and danicopan therapy using HFD mice, patient sera, and hepatocytes via CRISPR knockout and pharmacological interventions. Key findings demonstrated significant upregulation of CFD in MAFLD mice livers and patient sera. Genetic CFD ablation attenuated hepatocyte lipid deposition. Danicopan reduced intracellular triglycerides/cholesterol, improved glucose tolerance, lowered ALT, and alleviated hepatic steatosis in obese mice without weight change. Mechanistically, danicopan suppressed NF-κB signaling, inhibiting lipid-related genes (CD36/FASN/ FATP2) and inflammatory mediators (MMP12/IL-6/TNF-α). These results establish CFD as a novel MAFLD mediator, validating FDA-approved danicopan's therapeutic efficacy and translational potential. This work provides critical evidence for targeting the CFD pathway in MAFLD management.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"188 ","pages":"Pages 192-200"},"PeriodicalIF":3.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145614932","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 : 2025-12-01DOI: 10.1016/j.molimm.2025.11.009
Lucia Gaetani , Matthew Jenner , James A. Schouten , Paul Davis , Richard Napier , Ann M. Dixon
Understanding the molecular interactions that govern antibody recognition of glycated epitopes is crucial for developing advanced diagnostics and therapeutics. This requires identification of the region of the antigen that is recognized (the epitope) and the regions of the antibody that bind the antigen (the paratope). Recently, we developed a single-chain variable fragment antibody (scFv) with high affinity and specificity for a complex, non-A1c epitope of haemoglobin that is both glycated and conformational. Here, we have used immunochemical and biophysical methods, including carbene footprinting mass spectrometry, to map the scFv’s epitope in human glycated haemoglobin. The epitope is composed of a glycation site at Lys-66 on the β globin chain and two α-helical regions spanning residues 9–17 and 67–72 that form a contiguous binding site on the protein’s surface. The identity of the paratope within the scFv was also determined, and we found that only a subset of the predicted complementarity determining regions (CDRs) participate in interactions with the antigen. A computational model of the scFv-HbA1c complex was created and used to indicate key residues in the CDRs and framework regions that mediate paratope-epitope interaction. This work advances our understanding of the molecular basis for high-affinity binding antibodies to complex glycated epitopes and provides a foundation upon which to develop innovative diagnostics that can detect multiple glycated species in parallel.
{"title":"Novel single-chain antibody recognises complex glycan/alpha helix epitope in glycated haemoglobin using a subset of its complementarity determining regions","authors":"Lucia Gaetani , Matthew Jenner , James A. Schouten , Paul Davis , Richard Napier , Ann M. Dixon","doi":"10.1016/j.molimm.2025.11.009","DOIUrl":"10.1016/j.molimm.2025.11.009","url":null,"abstract":"<div><div>Understanding the molecular interactions that govern antibody recognition of glycated epitopes is crucial for developing advanced diagnostics and therapeutics. This requires identification of the region of the antigen that is recognized (the epitope) and the regions of the antibody that bind the antigen (the paratope). Recently, we developed a single-chain variable fragment antibody (scFv) with high affinity and specificity for a complex, non-A1c epitope of haemoglobin that is both glycated and conformational. Here, we have used immunochemical and biophysical methods, including carbene footprinting mass spectrometry, to map the scFv’s epitope in human glycated haemoglobin. The epitope is composed of a glycation site at Lys-66 on the β globin chain and two α-helical regions spanning residues 9–17 and 67–72 that form a contiguous binding site on the protein’s surface. The identity of the paratope within the scFv was also determined, and we found that only a subset of the predicted complementarity determining regions (CDRs) participate in interactions with the antigen. A computational model of the scFv-HbA1c complex was created and used to indicate key residues in the CDRs and framework regions that mediate paratope-epitope interaction. This work advances our understanding of the molecular basis for high-affinity binding antibodies to complex glycated epitopes and provides a foundation upon which to develop innovative diagnostics that can detect multiple glycated species in parallel.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"188 ","pages":"Pages 168-178"},"PeriodicalIF":3.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145588271","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 : 2025-12-01DOI: 10.1016/j.molimm.2025.11.017
Dan Li , Yuna Du , Huiqing Zhang, Hui Fang, Jing You, Qicheng Fan, Yiguo Chen, Zhe Fang, Rong Li
Background
Diabetic nephropathy (DN), the leading cause of end-stage renal disease (ESRD), imposes substantial burdens on patients' health and socioeconomic status. Although current therapies targeting blood pressure, glycemic control, and the renin-angiotensin system provide partial relief for DN, their efficacy remains limited. CD38, a 46-kilodalton type II transmembrane glycoprotein, is reported involved in the development of diabetes mellitus. However, the specific role and molecular mechanisms of CD38 in DN pathogenesis require further elucidation. This study aims to investigate these mechanisms.
Methods
Analyze the expression of CD38 in DN through the GEO database.Type 2 diabetic mouse models were established by using high-fat diet and streptozocin (STZ) injection. Four groups of mice were used in this experiment: WT group, DM group, CD38-/- group and CD38-/-+DM group. Body weight and fasting blood glucose were monitored longitudinally. After Post-euthanasia, kidney weight and body weight were weighed, then calculated kidney weight/body weight ratio. Renal tissues underwent histopathological evaluation (H&E, PAS, PAM staining) and molecular analyses (immunohistochemistry, RT-qPCR, Western blot).
Results
CD38 expression was significantly higher (P < 0.05) in DN than in normal humans. And CD38 deletion ameliorated renal histopathological injury in type 2 diabetic mice in H&E staining, glycogen staining, PAM staining. RT-qPCR and Western blot results showed expressions of p53 and Bax in kidney tissues of CD38-/-+DM group mice was significantly decreased (P < 0.05) and Bcl-2 was significantly increased (P < 0.01) compared with that of the DM group mice. Bax expression was decreased and Bcl-2 expression was increased in the renal tissues of mice of CD38-/-+DM group when compared with mice in the DM group in immunohistochemical staining. CD38 deletion could alleviate ERK, JNK and p38 of MAPK signaling pathway(P < 0.05). Inhibition of ERK and JNK in high glucose condition ameliorated apoptosis by down-regulating p53 and Bax (P < 0.05).
Conclusion
CD38 deletion regulated body weight and fasting blood glucose, improved renal histopathological injury and apoptosis by inhibiting MAPK signaling pathway; CD38 deficiency alleviates diabetic nephropathy by inhibiting MAPK/p53-mediated apoptosis, highlighting its role as a potential therapeutic target.
Clinical trial number
Not applicable, and this study does not yet involve clinical data.
{"title":"CD38 knockout attenuates type 2 diabetic renal injury by downregulating p53 and Bax via the ERK/JNK signaling pathway","authors":"Dan Li , Yuna Du , Huiqing Zhang, Hui Fang, Jing You, Qicheng Fan, Yiguo Chen, Zhe Fang, Rong Li","doi":"10.1016/j.molimm.2025.11.017","DOIUrl":"10.1016/j.molimm.2025.11.017","url":null,"abstract":"<div><h3>Background</h3><div>Diabetic nephropathy (DN), the leading cause of end-stage renal disease (ESRD), imposes substantial burdens on patients' health and socioeconomic status. Although current therapies targeting blood pressure, glycemic control, and the renin-angiotensin system provide partial relief for DN, their efficacy remains limited. CD38, a 46-kilodalton type II transmembrane glycoprotein, is reported involved in the development of diabetes mellitus. However, the specific role and molecular mechanisms of CD38 in DN pathogenesis require further elucidation. This study aims to investigate these mechanisms.</div></div><div><h3>Methods</h3><div>Analyze the expression of CD38 in DN through the GEO database.Type 2 diabetic mouse models were established by using high-fat diet and streptozocin (STZ) injection. Four groups of mice were used in this experiment: WT group, DM group, CD38<sup>-/-</sup> group and CD38<sup>-/-</sup>+DM group. Body weight and fasting blood glucose were monitored longitudinally. After Post-euthanasia, kidney weight and body weight were weighed, then calculated kidney weight/body weight ratio. Renal tissues underwent histopathological evaluation (H&E, PAS, PAM staining) and molecular analyses (immunohistochemistry, RT-qPCR, Western blot).</div></div><div><h3>Results</h3><div>CD38 expression was significantly higher (<em>P</em> < 0.05) in DN than in normal humans. And CD38 deletion ameliorated renal histopathological injury in type 2 diabetic mice in H&E staining, glycogen staining, PAM staining. RT-qPCR and Western blot results showed expressions of p53 and Bax in kidney tissues of CD38<sup>-/-</sup>+DM group mice was significantly decreased (<em>P</em> < 0.05) and Bcl-2 was significantly increased (<em>P</em> < 0.01) compared with that of the DM group mice. Bax expression was decreased and Bcl-2 expression was increased in the renal tissues of mice of CD38<sup>-/-</sup>+DM group when compared with mice in the DM group in immunohistochemical staining. CD38 deletion could alleviate ERK, JNK and p38 of MAPK signaling pathway(<em>P < 0.05</em>). Inhibition of ERK and JNK in high glucose condition ameliorated apoptosis by down-regulating p53 and Bax (<em>P < 0.05</em>).</div></div><div><h3>Conclusion</h3><div>CD38 deletion regulated body weight and fasting blood glucose, improved renal histopathological injury and apoptosis by inhibiting MAPK signaling pathway; CD38 deficiency alleviates diabetic nephropathy by inhibiting MAPK/p53-mediated apoptosis, highlighting its role as a potential therapeutic target.</div></div><div><h3>Clinical trial number</h3><div>Not applicable, and this study does not yet involve clinical data.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"189 ","pages":"Pages 31-40"},"PeriodicalIF":3.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145661478","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 : 2025-12-01DOI: 10.1016/j.molimm.2025.11.004
Linmao Lyu , Yanfei Ma , Xuyan Sun , Meng Luo , Zhong Wang , Lijun Fang , Wenqiang Li , Yuguo Chen , Shize Liu , Xiaopeng Jia
Background
Cord blood mononuclear cells (CB–MNCs) are a potential alternative therapy for inflammatory bowel disease (IBD). Gut metabolites, T helper 17 (Th17) and regulatory T (Treg) cells are crucial for intestinal hemeostasis and recovery. However, the role of CB–MNCs in modulating IBD, gut metabolites and the Th17/Treg balance remains unclear.
Methods
In this study, dextran sodium sulfate (DSS) was used to induce acute colitis in male C57BL/6 J mice, followed by treatment with CB–MNCs, umbilical cord-derived mesenchymal stem cells (UC–MSCs), or mesalazine. The severity of colitis was assessed daily using the disease activity index (DAI), and feces were collected for metabolomic analysis. Upon sacrifice, the colons, mesenteric lymph nodes (MLNs) and spleens of the mice were preserved for further study.
Results
Our findings demonstrated that compared with UC–MSCs and mesalazine, CB–MNCs treatment had superior efficacy in improving clinical symptoms, tissue repair, promoting intestinal regeneration and integrity. While CB-MNCs were equivalent to UC–MSCs and mesalazine in terms of preserving colon length and anti-inflammatory activity. At the molecular level, CB-MNCs exhibited unique and powerful effects. CB-MNCs were found to significantly increase the abundance of cortisol, corticosterone, and several metabolites with anti-inflammatory and antioxidant activities in the feces of colitis mice. CB–MNCs were also more effective than UC–MSCs and mesalazine at maintaining Th17/Treg balance than UC–MSC and mesalazine in colitis mice.
Conclusions
The intravenous injection of CB-MNCs can alleviate intestinal inflammation and barrier dysfunction by modulating gut metabolites and the Th17/Treg balance. Therefore, CB-MNCs be a promising treatment for IBD.
{"title":"Human cord blood mononuclear cells alleviate intestinal inflammation and barrier dysfunction by regulating gut metabolites and Th17/Treg balance","authors":"Linmao Lyu , Yanfei Ma , Xuyan Sun , Meng Luo , Zhong Wang , Lijun Fang , Wenqiang Li , Yuguo Chen , Shize Liu , Xiaopeng Jia","doi":"10.1016/j.molimm.2025.11.004","DOIUrl":"10.1016/j.molimm.2025.11.004","url":null,"abstract":"<div><h3>Background</h3><div>Cord blood mononuclear cells (CB–MNCs) are a potential alternative therapy for inflammatory bowel disease (IBD). Gut metabolites, T helper 17 (Th17) and regulatory T (Treg) cells are crucial for intestinal hemeostasis and recovery. However, the role of CB–MNCs in modulating IBD, gut metabolites and the Th17/Treg balance remains unclear.</div></div><div><h3>Methods</h3><div>In this study, dextran sodium sulfate (DSS) was used to induce acute colitis in male C57BL/6 J mice, followed by treatment with CB–MNCs, umbilical cord-derived mesenchymal stem cells (UC–MSCs), or mesalazine. The severity of colitis was assessed daily using the disease activity index (DAI), and feces were collected for metabolomic analysis. Upon sacrifice, the colons, mesenteric lymph nodes (MLNs) and spleens of the mice were preserved for further study.</div></div><div><h3>Results</h3><div>Our findings demonstrated that compared with UC–MSCs and mesalazine, CB–MNCs treatment had superior efficacy in improving clinical symptoms, tissue repair, promoting intestinal regeneration and integrity. While CB-MNCs were equivalent to UC–MSCs and mesalazine in terms of preserving colon length and anti-inflammatory activity. At the molecular level, CB-MNCs exhibited unique and powerful effects. CB-MNCs were found to significantly increase the abundance of cortisol, corticosterone, and several metabolites with anti-inflammatory and antioxidant activities in the feces of colitis mice. CB–MNCs were also more effective than UC–MSCs and mesalazine at maintaining Th17/Treg balance than UC–MSC and mesalazine in colitis mice.</div></div><div><h3>Conclusions</h3><div>The intravenous injection of CB-MNCs can alleviate intestinal inflammation and barrier dysfunction by modulating gut metabolites and the Th17/Treg balance. Therefore, CB-MNCs be a promising treatment for IBD.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"188 ","pages":"Pages 179-191"},"PeriodicalIF":3.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145614933","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}
Rheumatoid arthritis (RA) is a chronic autoimmune disease in which regulatory T (Treg) cell dysfunction contributes to its pathogenesis, although the mechanisms regulating Treg differentiation remain unclear. In this study, the effects of Catalpol (CAT) on Treg differentiation and its underlying mechanisms were investigated using a CIA mouse model, with animals randomly allocated to CIA, CIA+CAT, and No CIA groups. Synovial pathology was assessed by HE staining, while naive CD4+ T cells were differentiated into Tregs in vitro, and treated with CAT. Molecular docking predicted CAT-target interactions, and the mTORC1 activator NV5138 was used alongside CAT for intervention. Treg proportions and mitochondrial membrane potential were analyzed by flow cytometry, IL-10 levels were measured by ELISA, NAD+/NADH was detected by assay kit, and mRNA expression of FOXP3, mTOR, Raptor, HIF-1α, and PDHK1 were determined by RT-qPCR, while protein expression was assessed by Western blotting. The results demonstrated that CAT alleviated joint symptoms in CIA mice, promoted Treg differentiation both in vivo and in vitro, and increased mitochondrial membrane potential, NAD+/NADH and acetyl-CoA levels in Tregs. CAT also downregulated HIF-1α and PDHK1 mRNA and inhibited p-P70S6K/P70S6K, p-4EBP1/4EBP1, HIF-1α, and PDHK1 protein expression. Treatment with NV5138 was observed to reduce Treg differentiation and oxidative metabolism, effects which were reversed by CAT. These findings demonstrate that CAT promotes Treg differentiation and exerts anti-RA effects through inhibition of the mTORC1/HIF-1α/PDHK1 signaling pathway and enhancement of pyruvate aerobic oxidation.
{"title":"Catalpol enhances mTORC1/HIF-1α/PDHK1-mediated oxidative metabolism that leads to promote the differentiation of Treg cells in RA","authors":"Qiaoyu Zhang , Furong Wang , Peng Ding , Yu Ge, Yujie Bao, Baoping Jiang, Lingling Zhou","doi":"10.1016/j.molimm.2025.11.016","DOIUrl":"10.1016/j.molimm.2025.11.016","url":null,"abstract":"<div><div>Rheumatoid arthritis (RA) is a chronic autoimmune disease in which regulatory T (Treg) cell dysfunction contributes to its pathogenesis, although the mechanisms regulating Treg differentiation remain unclear. In this study, the effects of Catalpol (CAT) on Treg differentiation and its underlying mechanisms were investigated using a CIA mouse model, with animals randomly allocated to CIA, CIA+CAT, and No CIA groups. Synovial pathology was assessed by HE staining, while naive CD4<sup>+</sup> T cells were differentiated into Tregs in vitro, and treated with CAT. Molecular docking predicted CAT-target interactions, and the mTORC1 activator NV5138 was used alongside CAT for intervention. Treg proportions and mitochondrial membrane potential were analyzed by flow cytometry, IL-10 levels were measured by ELISA, NAD<sup>+</sup>/NADH was detected by assay kit, and mRNA expression of FOXP3, mTOR, Raptor, HIF-1α, and PDHK1 were determined by RT-qPCR, while protein expression was assessed by Western blotting. The results demonstrated that CAT alleviated joint symptoms in CIA mice, promoted Treg differentiation both in vivo and in vitro, and increased mitochondrial membrane potential, NAD<sup>+</sup>/NADH and acetyl-CoA levels in Tregs. CAT also downregulated HIF-1α and PDHK1 mRNA and inhibited p-P70S6K/P70S6K, p-4EBP1/4EBP1, HIF-1α, and PDHK1 protein expression. Treatment with NV5138 was observed to reduce Treg differentiation and oxidative metabolism, effects which were reversed by CAT. These findings demonstrate that CAT promotes Treg differentiation and exerts anti-RA effects through inhibition of the mTORC1/HIF-1α/PDHK1 signaling pathway and enhancement of pyruvate aerobic oxidation.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"189 ","pages":"Pages 1-12"},"PeriodicalIF":3.0,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145622911","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 : 2025-11-22DOI: 10.1016/j.molimm.2025.11.003
Md Abu Hanif , Doo Hyun Cho , Soo Cheol Kim , Ji Do Han , Won Kyo Lee , Kang Hee Kho
Glycogen synthase kinases (GSKs) regulate key physiological processes in eukaryotes, but their role in Pacific abalone remains unexplored. In this study, the GSK gene was identified and characterized from Pacific abalone (Haliotis discus hannai), and the expression was analyzed to investigate the role of GSK in early development, stress response, and innate immunity. The Hdh-GSK cDNA sequence comprised 1436 bp, with a 456 bp open reading frame (ORF) that encodes 151 deduced amino acid residues. Structurally, the Hdh-GSK protein contains a binding site for the Batabulin ligand (an anti-tumor agent). Hdh-GSK was significantly expressed in the digestive gland, a prime immune organ in aquatic organisms. Notably, higher expression during embryonic and larval development suggests the Hdh-GSK performs a dynamic role in the early development of Pacific abalone. Furthermore, Hdh-GSK expression was significantly higher in individuals exhibiting average and rapid growth than those with stunted or minimal growth. Further, Hdh-GSK expression was upregulated during starvation. Short-term heat stress (6–12 h) upregulated its expression, while prolonged stress led to downregulation, likely linked to ROS production. Cd-toxicity downregulated Hdh-GSK expression in a dose- and time-dependent manner. Immune challenges with Vibrio parahaemolyticus, LPS and poly(I:C) significantly downregulated Hdh-GSK expression (aside from an initial slight increase with bacteria and LPS), suggesting its role in anti-inflammatory responses. Overall, this study’s findings suggest that Hdh-GSK may be a key candidate gene for elucidating molecular processes during early development, growth, and innate immunity in Pacific abalone.
{"title":"Hdh-GSK in Pacific abalone: Insights into its roles in metamorphosis, stress response, and innate immunity","authors":"Md Abu Hanif , Doo Hyun Cho , Soo Cheol Kim , Ji Do Han , Won Kyo Lee , Kang Hee Kho","doi":"10.1016/j.molimm.2025.11.003","DOIUrl":"10.1016/j.molimm.2025.11.003","url":null,"abstract":"<div><div>Glycogen synthase kinases (GSKs) regulate key physiological processes in eukaryotes, but their role in Pacific abalone remains unexplored. In this study, the GSK gene was identified and characterized from Pacific abalone (<em>Haliotis discus hannai</em>), and the expression was analyzed to investigate the role of GSK in early development, stress response, and innate immunity. The <em>Hdh-</em>GSK cDNA sequence comprised 1436 bp, with a 456 bp open reading frame (ORF) that encodes 151 deduced amino acid residues. Structurally, the <em>Hdh</em>-GSK protein contains a binding site for the Batabulin ligand (an anti-tumor agent). <em>Hdh-</em>GSK was significantly expressed in the digestive gland, a prime immune organ in aquatic organisms. Notably, higher expression during embryonic and larval development suggests the <em>Hdh-</em>GSK performs a dynamic role in the early development of Pacific abalone. Furthermore, <em>Hdh-</em>GSK expression was significantly higher in individuals exhibiting average and rapid growth than those with stunted or minimal growth. Further, <em>Hdh-</em>GSK expression was upregulated during starvation. Short-term heat stress (6–12 h) upregulated its expression, while prolonged stress led to downregulation, likely linked to ROS production. Cd-toxicity downregulated <em>Hdh-</em>GSK expression in a dose- and time-dependent manner. Immune challenges with <em>Vibrio parahaemolyticus</em>, LPS and poly(I:C) significantly downregulated <em>Hdh</em>-GSK expression (aside from an initial slight increase with bacteria and LPS), suggesting its role in anti-inflammatory responses. Overall, this study’s findings suggest that <em>Hdh-</em>GSK may be a key candidate gene for elucidating molecular processes during early development, growth, and innate immunity in Pacific abalone.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"188 ","pages":"Pages 154-167"},"PeriodicalIF":3.0,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145569738","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 : 2025-11-21DOI: 10.1016/j.molimm.2025.11.011
Xili Yan , Zhongxing Hou , Wenxin Li , Shuang Miao , Zejia Zhang , Jie Luo , Yinan Tao , Qiang Li , Jian Zhao , Zhiliang Xu
Background
Skeletal muscle injury is a common sports injury. Although the cGAS-STING signaling pathway is implicated in myoblast differentiation and muscle regeneration, its precise mechanisms remain unclear. Yin Yang 1 (YY1), a multifunctional transcriptional and chromatin regulator involved in various pathologies, also requires investigation for its specific role in regeneration.
Objectives
This study aimed to investigate the association between YY1 and cGAS-STING pathway activation during early muscle regeneration, and explore its potential role in the inflammatory phase of myoblast differentiation.
Methods
A skeletal muscle injury model was established in C57BL/6 mice using 1.2 % barium chloride. H&E staining evaluated muscle regeneration. Immunohistochemistry (IHC) quantified MyoG, YY1, H2Bub, and RNF20 expression. Immunofluorescence (IF) determined STING and YY1 expression. Western blotting measured cGAS, STING, YY1, caspase-3, IRF3, P-IRF3,P-TBK1, H2Bub and RNF20 protein levels. qPCR analyzed mRNA of inflammatory factors (IL-6, IL-17, IL-1β, TNF-α), myogenic regulators (MyoD, MyoG, Myf5), and signaling molecules (cGAS, STING, YY1, IRF3, caspase-3). Co-immunoprecipitation (Co-IP) assessed STING-YY1 interaction.
Results
Post-injury histology revealed significant pathology and inflammation. qPCR indicated upregulated mRNA levels of inflammatory factors and myogenic/signaling molecules at day 3, with partial recovery by day 7. Consistently, IHC (YY1, H2Bub, RNF20), IF (STING, YY1), and WB (cGAS, STING, YY1, caspase-3, IRF3, P-IRF3,P-TBK1, H2Bub and RNF20) all demonstrated elevated expression at day 3, declining by day 7. Co-IP confirmed a direct STING-YY1 interaction.
Conclusion
Our findings reveal a significant association between YY1 and cGAS-STING signaling activation, suggesting that this interplay contributes to the modulation of the inflammatory response during the early phase of skeletal muscle repair.
{"title":"Association of YY1 with STING activation and the inflammatory response during early muscle injury repair","authors":"Xili Yan , Zhongxing Hou , Wenxin Li , Shuang Miao , Zejia Zhang , Jie Luo , Yinan Tao , Qiang Li , Jian Zhao , Zhiliang Xu","doi":"10.1016/j.molimm.2025.11.011","DOIUrl":"10.1016/j.molimm.2025.11.011","url":null,"abstract":"<div><h3>Background</h3><div>Skeletal muscle injury is a common sports injury. Although the cGAS-STING signaling pathway is implicated in myoblast differentiation and muscle regeneration, its precise mechanisms remain unclear. Yin Yang 1 (YY1), a multifunctional transcriptional and chromatin regulator involved in various pathologies, also requires investigation for its specific role in regeneration.</div></div><div><h3>Objectives</h3><div>This study aimed to investigate the association between YY1 and cGAS-STING pathway activation during early muscle regeneration, and explore its potential role in the inflammatory phase of myoblast differentiation.</div></div><div><h3>Methods</h3><div>A skeletal muscle injury model was established in C57BL/6 mice using 1.2 % barium chloride. H&E staining evaluated muscle regeneration. Immunohistochemistry (IHC) quantified MyoG, YY1, H2Bub, and RNF20 expression. Immunofluorescence (IF) determined STING and YY1 expression. Western blotting measured cGAS, STING, YY1, caspase-3, IRF3, P-IRF3,P-TBK1, H2Bub and RNF20 protein levels. qPCR analyzed mRNA of inflammatory factors (IL-6, IL-17, IL-1β, TNF-α), myogenic regulators (MyoD, MyoG, Myf5), and signaling molecules (cGAS, STING, YY1, IRF3, caspase-3). Co-immunoprecipitation (Co-IP) assessed STING-YY1 interaction.</div></div><div><h3>Results</h3><div>Post-injury histology revealed significant pathology and inflammation. qPCR indicated upregulated mRNA levels of inflammatory factors and myogenic/signaling molecules at day 3, with partial recovery by day 7. Consistently, IHC (YY1, H2Bub, RNF20), IF (STING, YY1), and WB (cGAS, STING, YY1, caspase-3, IRF3, P-IRF3,P-TBK1, H2Bub and RNF20) all demonstrated elevated expression at day 3, declining by day 7. Co-IP confirmed a direct STING-YY1 interaction.</div></div><div><h3>Conclusion</h3><div>Our findings reveal a significant association between YY1 and cGAS-STING signaling activation, suggesting that this interplay contributes to the modulation of the inflammatory response during the early phase of skeletal muscle repair.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"188 ","pages":"Pages 142-153"},"PeriodicalIF":3.0,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145569737","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 : 2025-11-21DOI: 10.1016/j.molimm.2025.11.005
Genshan Gao , Baixiang Zhang , Nannuan Liu , Nan Liu , Yixian Zhang , Houwei Du
Ischemic stroke (IS), a leading cause of disability and mortality, is characterized by cerebral ischemia-reperfusion injury, inflammation, and ferroptosis. RNA 5-methylcytosine (m5C) modification is a dynamic epigenetic mark involved in various pathological processes, yet its role in IS remains unclear. This study aimed to investigate the role of m5C modification in IS and its underlying mechanisms. In vitro, human brain microvascular endothelial cells (HBMECs) were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R), while in vivo, a transient middle cerebral artery occlusion (tMCAO) mouse model was established. Reverse transcription-quantitative polymerase chain reaction was used to analyze the mRNA levels of NSUN2 and heat shock protein family B member 1 (HSPB1). The contents of pro-inflammatory cytokines and ferroptosis-related indicators were measured using enzyme-linked immunosorbent assay and commercial kits. The expression of nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1)/NAD(P)H quinone dehydrogenase 1 (NQO-1) pathway proteins was detected by Western blot. RNA immunoprecipitation and dual-luciferase reporter assays were performed to assess the interaction between NSUN2 and HSPB1. Results showed that NSUN2 was downregulated in OGD/R-treated HBMECs and tMCAO mice. Furthermore, NSUN2 overexpression mitigated OGD/R-induced inflammation and ferroptosis. Mechanistically, NSUN2 mediated m5C methylation at site 621 in HSPB1 mRNA, enhancing its stability. Knockdown of HSPB1 abolished the protective effects of NSUN2, exacerbating inflammation and ferroptosis in OGD/R-treated HBMECs. Further investigations revealed that the NSUN2/HSPB1 axis exerted its protective role by activating the NRF2/HO-1/NQO-1 pathway. Inhibition of this pathway reversed the beneficial effects of HSPB1 overexpression. In tMCAO mice, NSUN2 overexpression reduced cerebral infarct volume, improved antioxidant capacity, and activated the NRF2/HO-1/NQO-1 pathway. In conclusion, NSUN2-mediated m⁵C methylation stabilized HSPB1 and activated the NRF2/HO-1/NQO-1 pathway, thereby mitigating inflammation and ferroptosis in IS. Targeting the NSUN2/HSPB1 axis may represent a novel therapeutic strategy for IS.
{"title":"NSUN2-mediated m⁵C methylation of HSPB1 mRNA suppresses inflammation and ferroptosis in ischemic stroke via activating the NRF2/HO-1/NQO-1 pathway","authors":"Genshan Gao , Baixiang Zhang , Nannuan Liu , Nan Liu , Yixian Zhang , Houwei Du","doi":"10.1016/j.molimm.2025.11.005","DOIUrl":"10.1016/j.molimm.2025.11.005","url":null,"abstract":"<div><div>Ischemic stroke (IS), a leading cause of disability and mortality, is characterized by cerebral ischemia-reperfusion injury, inflammation, and ferroptosis. RNA 5-methylcytosine (m5C) modification is a dynamic epigenetic mark involved in various pathological processes, yet its role in IS remains unclear. This study aimed to investigate the role of m5C modification in IS and its underlying mechanisms. <em>In vitro</em>, human brain microvascular endothelial cells (HBMECs) were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R), while <em>in vivo</em>, a transient middle cerebral artery occlusion (tMCAO) mouse model was established. Reverse transcription-quantitative polymerase chain reaction was used to analyze the mRNA levels of NSUN2 and heat shock protein family B member 1 (HSPB1). The contents of pro-inflammatory cytokines and ferroptosis-related indicators were measured using enzyme-linked immunosorbent assay and commercial kits. The expression of nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1)/NAD(P)H quinone dehydrogenase 1 (NQO-1) pathway proteins was detected by Western blot. RNA immunoprecipitation and dual-luciferase reporter assays were performed to assess the interaction between NSUN2 and HSPB1. Results showed that NSUN2 was downregulated in OGD/R-treated HBMECs and tMCAO mice. Furthermore, NSUN2 overexpression mitigated OGD/R-induced inflammation and ferroptosis. Mechanistically, NSUN2 mediated m5C methylation at site 621 in HSPB1 mRNA, enhancing its stability. Knockdown of HSPB1 abolished the protective effects of NSUN2, exacerbating inflammation and ferroptosis in OGD/R-treated HBMECs. Further investigations revealed that the NSUN2/HSPB1 axis exerted its protective role by activating the NRF2/HO-1/NQO-1 pathway. Inhibition of this pathway reversed the beneficial effects of HSPB1 overexpression. In tMCAO mice, NSUN2 overexpression reduced cerebral infarct volume, improved antioxidant capacity, and activated the NRF2/HO-1/NQO-1 pathway. In conclusion, NSUN2-mediated m⁵C methylation stabilized HSPB1 and activated the NRF2/HO-1/NQO-1 pathway, thereby mitigating inflammation and ferroptosis in IS. Targeting the NSUN2/HSPB1 axis may represent a novel therapeutic strategy for IS.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"188 ","pages":"Pages 131-141"},"PeriodicalIF":3.0,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145569740","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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