Pub Date : 2026-02-01DOI: 10.1016/j.intimp.2026.116305
Menghao Zeng, Wei Xing, Guibin Liang, Fangfang Yuan, Wenhua Wang, Jie Liu, Zhihui He
Excessive NLRP3 inflammasome activation is implicated in pathologies like sepsis. While the histone acetyltransferase inhibitor α-methylene-γ-butyrolactone 3 (MB-3) is typically studied in cancer and epigenetic research, its anti-inflammatory potential remains largely unexplored. This study investigated the effect of MB-3 on NLRP3 inflammasome activation in both cellular and animal models. Results demonstrated that MB-3 treatment significantly downregulated NLRP3-associated inflammatory cytokines and proteins in vitro and in vivo. Mechanistic studies revealed that MB-3 acts by dual inhibition of the NLRP3 inflammasome. It disrupted the critical protein interactions between NLRP3-ASC and NLRP3-NEK7 and reduced ASC and NLRP3 oligomerization, thereby blocking the inflammasome assembly. Furthermore, MB-3 exhibited a protective effect on mitochondrial integrity by rescuing the loss of mitochondrial membrane potential and reducing the production of reactive oxygen species (ROS). In conclusion, these findings identify MB-3 as an effective inhibitor of the NLRP3 inflammasome, operating by blocking both the priming and assembly stages of activation. The results suggests that MB-3 is a promising potential therapeutic candidate for the treatment of NLRP3-driven inflammatory diseases.
{"title":"α-Methylene-γ-butyrolactone 3 inhibits the activation of NLRP3 inflammasome in sepsis by blocking both the priming and inflammasome assembly.","authors":"Menghao Zeng, Wei Xing, Guibin Liang, Fangfang Yuan, Wenhua Wang, Jie Liu, Zhihui He","doi":"10.1016/j.intimp.2026.116305","DOIUrl":"https://doi.org/10.1016/j.intimp.2026.116305","url":null,"abstract":"<p><p>Excessive NLRP3 inflammasome activation is implicated in pathologies like sepsis. While the histone acetyltransferase inhibitor α-methylene-γ-butyrolactone 3 (MB-3) is typically studied in cancer and epigenetic research, its anti-inflammatory potential remains largely unexplored. This study investigated the effect of MB-3 on NLRP3 inflammasome activation in both cellular and animal models. Results demonstrated that MB-3 treatment significantly downregulated NLRP3-associated inflammatory cytokines and proteins in vitro and in vivo. Mechanistic studies revealed that MB-3 acts by dual inhibition of the NLRP3 inflammasome. It disrupted the critical protein interactions between NLRP3-ASC and NLRP3-NEK7 and reduced ASC and NLRP3 oligomerization, thereby blocking the inflammasome assembly. Furthermore, MB-3 exhibited a protective effect on mitochondrial integrity by rescuing the loss of mitochondrial membrane potential and reducing the production of reactive oxygen species (ROS). In conclusion, these findings identify MB-3 as an effective inhibitor of the NLRP3 inflammasome, operating by blocking both the priming and assembly stages of activation. The results suggests that MB-3 is a promising potential therapeutic candidate for the treatment of NLRP3-driven inflammatory diseases.</p>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"116305"},"PeriodicalIF":4.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146105330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-31DOI: 10.1016/j.intimp.2026.116303
Muhammed Ali Kizmaz, Abdurrahman Simsek, Tugce Bozkurt, Ali Eren Iskin, Ferah Budak
Adenosine triphosphate (ATP), a principal component of cellular energy metabolism, also functions as a significant extracellular signaling molecule under pathological conditions, including tissue damage and inflammation. The hydrolysis of extracellular ATP (eATP) to adenosine, catalyzed by ectonucleotidases including CD39 and CD73, is a key pathway involved in the control of immune responses. The objective of this study was to systematically examine the capacity of interleukin-9 (IL-9) to regulate ATP–adenosine metabolism and to assess the resultant impact of this regulation on T-cell responses.
Peripheral blood mononuclear cells (PBMCs) isolated from healthy donors were analyzed by flow cytometry (FC) and ELISA to characterize the phenotypic, functional, and metabolic changes induced by IL-9 and to investigate the underlying molecular mechanisms.
Our findings revealed that while IL-9 did not significantly change the frequency of major T-cell populations, it potentiated the conversion of ATP to adenosine by upregulating the expression of CD39 and CD73. This activity fostered an immunosuppressive microenvironment, especially within regulatory T (Treg) cells. Furthermore, IL-9 treatment suppressed the production of pro-inflammatory cytokines, increased anti-inflammatory cytokine levels, and inhibited T-cell proliferation. The pharmacological inhibition of CD39 and CD73 largely abrogated these IL-9-mediated effects.
Together, these findings suggest that IL-9 may act as a regulator of the CD39/CD73 axis and that its influence on ATP-adenosine metabolism may have relevance in inflammatory and immune-mediated conditions characterized by dysregulated purinergic signaling.
{"title":"IL-9 orchestrates immune regulation through CD39/CD73 dependent metabolic reprogramming","authors":"Muhammed Ali Kizmaz, Abdurrahman Simsek, Tugce Bozkurt, Ali Eren Iskin, Ferah Budak","doi":"10.1016/j.intimp.2026.116303","DOIUrl":"10.1016/j.intimp.2026.116303","url":null,"abstract":"<div><div>Adenosine triphosphate (ATP), a principal component of cellular energy metabolism, also functions as a significant extracellular signaling molecule under pathological conditions, including tissue damage and inflammation. The hydrolysis of extracellular ATP (eATP) to adenosine, catalyzed by ectonucleotidases including CD39 and CD73, is a key pathway involved in the control of immune responses. The objective of this study was to systematically examine the capacity of interleukin-9 (IL-9) to regulate ATP–adenosine metabolism and to assess the resultant impact of this regulation on T-cell responses.</div><div>Peripheral blood mononuclear cells (PBMCs) isolated from healthy donors were analyzed by flow cytometry (FC) and ELISA to characterize the phenotypic, functional, and metabolic changes induced by IL-9 and to investigate the underlying molecular mechanisms.</div><div>Our findings revealed that while IL-9 did not significantly change the frequency of major T-cell populations, it potentiated the conversion of ATP to adenosine by upregulating the expression of CD39 and CD73. This activity fostered an immunosuppressive microenvironment, especially within regulatory T (Treg) cells. Furthermore, IL-9 treatment suppressed the production of pro-inflammatory cytokines, increased anti-inflammatory cytokine levels, and inhibited T-cell proliferation. The pharmacological inhibition of CD39 and CD73 largely abrogated these IL-9-mediated effects.</div><div>Together, these findings suggest that IL-9 may act as a regulator of the CD39/CD73 axis and that its influence on ATP-adenosine metabolism may have relevance in inflammatory and immune-mediated conditions characterized by dysregulated purinergic signaling.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116303"},"PeriodicalIF":4.7,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-31DOI: 10.1016/j.intimp.2026.116294
Shilei Cheng , Lanyun Xie , Jianbo Wu , Fan Yang
Lipid metabolism is essential for cellular energy homeostasis, structural integrity, and signal transduction, and exerts a dual role in inflammation by acting as both an initiator and a regulator. This review comprehensively explores the molecular basis underlying the interactions among lipid metabolic pathways, lipid-derived mediators, and immune-inflammatory processes, while highlighting their profound significance in metabolic and chronic diseases. The core processes of lipid metabolism profoundly influence the initiation and resolution of inflammation through the regulation of oxidative stress, lipid mediators, and key signaling pathways. Furthermore, dysregulated lipid metabolism drives the formation of a chronic inflammatory microenvironment via inducing macrophage polarization, altering lipid droplet dynamics in immune cells, and disrupting adipokine secretion, thereby promoting the progression of metabolic diseases. In addition, this review summarizes intervention strategies targeting key lipid metabolic enzymes, signaling pathways, and epigenetic modifications, demonstrating their remarkable potential in anti-inflammatory and metabolic regulatory applications. As a molecular switch governing inflammation, lipid metabolism establishes a bidirectional regulatory network with inflammation through five core processes, namely lipid uptake and transport, lipogenesis, cholesterol metabolism, fatty acid β-oxidation, and lipolysis. Finally, this review emphasizes the pivotal role of technologies such as lipidomics and systems biology in deciphering the lipid-inflammation interplay, providing detailed insights for targeted anti-inflammatory interventions. Future research should prioritize multidisciplinary collaborations, focus on organ-specific regulatory targets, develop precision therapies, and advance dual-target combination therapies for metabolism and immunity. Moreover, multi-omics technologies should be leveraged to construct disease prediction models for individualized interventions, ultimately driving innovations in therapeutic strategies for chronic inflammation-driven diseases (see Fig. 1).
{"title":"Lipid metabolism: a molecular switch to control inflammation","authors":"Shilei Cheng , Lanyun Xie , Jianbo Wu , Fan Yang","doi":"10.1016/j.intimp.2026.116294","DOIUrl":"10.1016/j.intimp.2026.116294","url":null,"abstract":"<div><div>Lipid metabolism is essential for cellular energy homeostasis, structural integrity, and signal transduction, and exerts a dual role in inflammation by acting as both an initiator and a regulator. This review comprehensively explores the molecular basis underlying the interactions among lipid metabolic pathways, lipid-derived mediators, and immune-inflammatory processes, while highlighting their profound significance in metabolic and chronic diseases. The core processes of lipid metabolism profoundly influence the initiation and resolution of inflammation through the regulation of oxidative stress, lipid mediators, and key signaling pathways. Furthermore, dysregulated lipid metabolism drives the formation of a chronic inflammatory microenvironment via inducing macrophage polarization, altering lipid droplet dynamics in immune cells, and disrupting adipokine secretion, thereby promoting the progression of metabolic diseases. In addition, this review summarizes intervention strategies targeting key lipid metabolic enzymes, signaling pathways, and epigenetic modifications, demonstrating their remarkable potential in anti-inflammatory and metabolic regulatory applications. As a molecular switch governing inflammation, lipid metabolism establishes a bidirectional regulatory network with inflammation through five core processes, namely lipid uptake and transport, lipogenesis, cholesterol metabolism, fatty acid β-oxidation, and lipolysis. Finally, this review emphasizes the pivotal role of technologies such as lipidomics and systems biology in deciphering the lipid-inflammation interplay, providing detailed insights for targeted anti-inflammatory interventions. Future research should prioritize multidisciplinary collaborations, focus on organ-specific regulatory targets, develop precision therapies, and advance dual-target combination therapies for metabolism and immunity. Moreover, multi-omics technologies should be leveraged to construct disease prediction models for individualized interventions, ultimately driving innovations in therapeutic strategies for chronic inflammation-driven diseases (see <span><span>Fig. 1</span></span>).</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116294"},"PeriodicalIF":4.7,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-31DOI: 10.1016/j.intimp.2026.116292
Fan Xu , Yifan Chen , Yao Sun , Huiying Zhao , Lei Zhu
Acute Respiratory Distress Syndrome (ARDS) is a condition involving severe lung injury and respiratory failure that results in high rates of mortality. Although uncontrolled inflammation and alveolar barrier disruption have been reported, the core molecular mechanisms involved in ARDS pathogenesis require clarification. Here, we recruited 35 ARDS patients and investigated the clinical significance of circUBXN7 in ARDS and its molecular mechanism in lipopolysaccharide (LPS)-stimulated acute lung injury. The results revealed that circUBXN7 and IL6ST expression levels were significantly elevated in the plasma of ARDS patients, while miR-622 was downregulated. Plasma circUBXN7 levels were higher and plasma miR-622 levels were lower in patients with severe ARDS, when compared with those with mild and moderate ARDS, whereas IL6ST levels did not significantly differ with disease severity. Furthermore, the non-survivor group exhibited significantly elevated levels of circUBXN7 and IL-1β, when compared with the survivor group. Receiver operating characteristic curve analysis indicated that circUBXN7 and IL-1β may serve as biomarkers for ARDS prognosis. Cellular experiments indicated a significant increase in circUBXN7 levels after LPS treatment. Inhibition of circUBXN7 mitigated the inflammation and cellular barrier damage induced by LPS, whereas its overexpression exacerbated these effects. Additionally, an miR-622 inhibitor or miR-622 mimics significantly reversed the effects of circUBXN7 siRNA or overexpression on cells. These findings demonstrated that circUBXN7 induced an inflammatory response and disrupted barrier integrity by competitively binding to miR-622, thereby impairing its regulatory function on target genes, which provided a novel approach for molecular typing and targeted therapy of ARDS.
{"title":"CircUBXN7 as a prognostic risk biomarker for ARDS modulates LPS-stimulated lung epithelial cell injury and the inflammatory response by competitively binding miR-622","authors":"Fan Xu , Yifan Chen , Yao Sun , Huiying Zhao , Lei Zhu","doi":"10.1016/j.intimp.2026.116292","DOIUrl":"10.1016/j.intimp.2026.116292","url":null,"abstract":"<div><div>Acute Respiratory Distress Syndrome (ARDS) is a condition involving severe lung injury and respiratory failure that results in high rates of mortality. Although uncontrolled inflammation and alveolar barrier disruption have been reported, the core molecular mechanisms involved in ARDS pathogenesis require clarification. Here, we recruited 35 ARDS patients and investigated the clinical significance of circUBXN7 in ARDS and its molecular mechanism in lipopolysaccharide (LPS)-stimulated acute lung injury. The results revealed that circUBXN7 and IL6ST expression levels were significantly elevated in the plasma of ARDS patients, while miR-622 was downregulated. Plasma circUBXN7 levels were higher and plasma miR-622 levels were lower in patients with severe ARDS, when compared with those with mild and moderate ARDS, whereas IL6ST levels did not significantly differ with disease severity. Furthermore, the non-survivor group exhibited significantly elevated levels of circUBXN7 and IL-1β, when compared with the survivor group. Receiver operating characteristic curve analysis indicated that circUBXN7 and IL-1β may serve as biomarkers for ARDS prognosis. Cellular experiments indicated a significant increase in circUBXN7 levels after LPS treatment. Inhibition of circUBXN7 mitigated the inflammation and cellular barrier damage induced by LPS, whereas its overexpression exacerbated these effects. Additionally, an miR-622 inhibitor or miR-622 mimics significantly reversed the effects of circUBXN7 siRNA or overexpression on cells. These findings demonstrated that circUBXN7 induced an inflammatory response and disrupted barrier integrity by competitively binding to miR-622, thereby impairing its regulatory function on target genes, which provided a novel approach for molecular typing and targeted therapy of ARDS.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116292"},"PeriodicalIF":4.7,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-31DOI: 10.1016/j.intimp.2026.116264
Qi Chen, Na Huang, Mingfeng Liao, Xiqian Zhang, Sara Aiman, Sihui Li, Mei Chen, Junhuan Wang, Ping Ouyang, Ying Zhang, Jialou Zhu, Kaisong Huang, Guangxian Xu
Tuberculosis (TB) is an ancient disease caused by Mycobacterium tuberculosis (Mtb), and vaccination represents the most effective strategy for preventing and controlling TB infection. In this study, we screened 200 antigens distributed across different infection stages/types in the Mtb genome. Using IEDB and VaxiJen v2.0 algorithm, we identified 10 Mtb-specific T cell target antigens. Further selection based on IFN-γ expression levels in PBMC from QFT+ and QFT- individuals after stimulation with the 10 antigens, led to the identification of ESAT-6, PPE57, PPE68, and EsxV as four candidate antigens. These antigens were displayed on the surface of mi3 virus-like particles (VLP) via the Spycatcher/SpyTag system and formulated with adjuvant AS01E to construct a multivalent VLP nanoparticle vaccine (EPPE+mi3/AS01E). The immunogenicity of this vaccine was evaluated in C57BL/6 mice following a three-dose immunization schedule, and its protective efficacy was assessed using the mycobacterial growth inhibition assay (MGIA). Our results demonstrated that EPPE+mi3/AS01E elicited robust Th1, Th2, and Th17 cellular immune responses, as well as potent antigen-specific humoral immune responses. It significantly enhanced the capacity of splenic lymphocytes to inhibit the in vitro growth of Mtb H37Rv, outperforming both the subunit vaccine (EPPE/AS01E) and BCG alone. When administered as a BCG booster, EPPE+mi3/AS01E synergistically enhanced the immunological response and protective efficacy conferred by BCG. Collectively, the mi3 VLP multi-antigen nanovaccine developed in this study demonstrated strong immunogenicity and significant inhibition of Mtb growth, highlighting it as a promising vaccine candidate for further development.
{"title":"A novel mi3 VLP nanoparticle vaccine displaying ESAT-6 -PPE57 -PPE68 -EsxV antigens exhibits superior immunogenicity and Mycobacterium tuberculosis growth inhibition.","authors":"Qi Chen, Na Huang, Mingfeng Liao, Xiqian Zhang, Sara Aiman, Sihui Li, Mei Chen, Junhuan Wang, Ping Ouyang, Ying Zhang, Jialou Zhu, Kaisong Huang, Guangxian Xu","doi":"10.1016/j.intimp.2026.116264","DOIUrl":"https://doi.org/10.1016/j.intimp.2026.116264","url":null,"abstract":"<p><p>Tuberculosis (TB) is an ancient disease caused by Mycobacterium tuberculosis (Mtb), and vaccination represents the most effective strategy for preventing and controlling TB infection. In this study, we screened 200 antigens distributed across different infection stages/types in the Mtb genome. Using IEDB and VaxiJen v2.0 algorithm, we identified 10 Mtb-specific T cell target antigens. Further selection based on IFN-γ expression levels in PBMC from QFT<sup>+</sup> and QFT<sup>-</sup> individuals after stimulation with the 10 antigens, led to the identification of ESAT-6, PPE57, PPE68, and EsxV as four candidate antigens. These antigens were displayed on the surface of mi3 virus-like particles (VLP) via the Spycatcher/SpyTag system and formulated with adjuvant AS01E to construct a multivalent VLP nanoparticle vaccine (EPPE+mi3/AS01E). The immunogenicity of this vaccine was evaluated in C57BL/6 mice following a three-dose immunization schedule, and its protective efficacy was assessed using the mycobacterial growth inhibition assay (MGIA). Our results demonstrated that EPPE+mi3/AS01E elicited robust Th1, Th2, and Th17 cellular immune responses, as well as potent antigen-specific humoral immune responses. It significantly enhanced the capacity of splenic lymphocytes to inhibit the in vitro growth of Mtb H37Rv, outperforming both the subunit vaccine (EPPE/AS01E) and BCG alone. When administered as a BCG booster, EPPE+mi3/AS01E synergistically enhanced the immunological response and protective efficacy conferred by BCG. Collectively, the mi3 VLP multi-antigen nanovaccine developed in this study demonstrated strong immunogenicity and significant inhibition of Mtb growth, highlighting it as a promising vaccine candidate for further development.</p>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"116264"},"PeriodicalIF":4.7,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146099613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-31DOI: 10.1016/j.intimp.2026.116304
Gang Wang , Zhuang Tao , Jianhong Gao , Zhenzhen Jiang , Fei Wang , Jiafeng Zhou , Rui Wang , Shuai Kang , Meixia Wang
Background
Paeonia lactiflora Pall., a medicinal herb with a documented history of over one millennium in traditional Chinese medicine, has been widely employed for its hepatoprotective and antidepressant effects. Total glucosides of paeony (TGP) is a class of bioactive compounds derived from the roots of Paeonia lactiflora Pall., have attracted considerable scientific interest in recent years owing to their demonstrated anti-inflammatory, antidepressant, and neuroprotective properties. However, the exact molecular mechanisms by which TGP regulates inflammatory pathways and its therapeutic benefits on post-stroke depression (PSD)-like behaviors remain incompletely elucidated.
Methods
This study employed a combination of ultra-high-performance liquid chromatography coupled with quadrupole-Orbitrap mass spectrometry (UHPLC-Q-Orbitrap-MS) and network pharmacology to identify the key active components of TGP and their essential targets. A rat model of PSD was created using middle cerebral artery occlusion (MCAO) in conjunction with social isolation. Subsequent animal experiments were then conducted using this model to investigate the mechanisms underlying the therapeutic effects of TGP on PSD.
Results
UHPLC-Q-Orbitrap-MS and network pharmacology analysis results identified paeoniflorin, albiflorin, galloylpaeoniflorin, and benzoylpaeoniflorin were as the principal bioactive components targeting PSD. These active compounds demonstrated strong affinity for core targets, such as glucose-regulated protein 78 (GRP78), caspase-3, and IL-1β. Animal studies indicated that MCAO coupled with social isolation effectively elicited depressive-like behaviors in the rats. The TGP intervention markedly mitigated the inflammatory response in the ischemic penumbra, diminished neuronal apoptosis, facilitated synaptic remodeling, and effectively suppressed the overactivation of the GRP78/inositol-requiring enzyme 1 α/tumor necrosis factor receptor-associated factor 2/phosphorylated c-Jun N-terminal kinase signaling pathway, alleviating depressive symptoms in the PSD rat model.
Conclusions
Our findings highlight the beneficial role of TGP in preserving synaptic structural integrity and functionality and suggest a novel mechanism of synaptic dysfunction implicated in the pathophysiology of PSD. The results indicate that the regulation of the ERS signaling pathway by TGP presents therapeutic promise for the treatment of PSD.
{"title":"Total glucosides of paeony ameliorate post-stroke depression-like behaviors by modulating inflammasome activation via inhibition of endoplasmic reticulum stress","authors":"Gang Wang , Zhuang Tao , Jianhong Gao , Zhenzhen Jiang , Fei Wang , Jiafeng Zhou , Rui Wang , Shuai Kang , Meixia Wang","doi":"10.1016/j.intimp.2026.116304","DOIUrl":"10.1016/j.intimp.2026.116304","url":null,"abstract":"<div><h3>Background</h3><div><em>Paeonia lactiflora</em> Pall., a medicinal herb with a documented history of over one millennium in traditional Chinese medicine, has been widely employed for its hepatoprotective and antidepressant effects. Total glucosides of paeony (TGP) is a class of bioactive compounds derived from the roots of <em>Paeonia lactiflora</em> Pall., have attracted considerable scientific interest in recent years owing to their demonstrated anti-inflammatory, antidepressant, and neuroprotective properties. However, the exact molecular mechanisms by which TGP regulates inflammatory pathways and its therapeutic benefits on post-stroke depression (PSD)-like behaviors remain incompletely elucidated.</div></div><div><h3>Methods</h3><div>This study employed a combination of ultra-high-performance liquid chromatography coupled with quadrupole-Orbitrap mass spectrometry (UHPLC-Q-Orbitrap-MS) and network pharmacology to identify the key active components of TGP and their essential targets. A rat model of PSD was created using middle cerebral artery occlusion (MCAO) in conjunction with social isolation. Subsequent animal experiments were then conducted using this model to investigate the mechanisms underlying the therapeutic effects of TGP on PSD.</div></div><div><h3>Results</h3><div>UHPLC-Q-Orbitrap-MS and network pharmacology analysis results identified paeoniflorin, albiflorin, galloylpaeoniflorin, and benzoylpaeoniflorin were as the principal bioactive components targeting PSD. These active compounds demonstrated strong affinity for core targets, such as glucose-regulated protein 78 (GRP78), caspase-3, and IL-1β. Animal studies indicated that MCAO coupled with social isolation effectively elicited depressive-like behaviors in the rats. The TGP intervention markedly mitigated the inflammatory response in the ischemic penumbra, diminished neuronal apoptosis, facilitated synaptic remodeling, and effectively suppressed the overactivation of the GRP78/inositol-requiring enzyme 1 α/tumor necrosis factor receptor-associated factor 2/phosphorylated c-Jun N-terminal kinase signaling pathway, alleviating depressive symptoms in the PSD rat model.</div></div><div><h3>Conclusions</h3><div>Our findings highlight the beneficial role of TGP in preserving synaptic structural integrity and functionality and suggest a novel mechanism of synaptic dysfunction implicated in the pathophysiology of PSD. The results indicate that the regulation of the ERS signaling pathway by TGP presents therapeutic promise for the treatment of PSD.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116304"},"PeriodicalIF":4.7,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Blomia tropicalis is a clinically significant source of mite allergens, with Blo t 5 identified as a major component. This study aimed to produce recombinant Blo t 5 (rBlo t 5) and investigate its role in allergic immune responses. The rBlo t 5 protein (∼14 kDa) was successfully expressed in E. coli and purified with high purity. IgE-ELISA demonstrated specific IgE binding in 69% of serum samples from asthmatic children sensitized to B. tropicalis. Transcriptomic analysis of rBlo t 5-stimulated BEAS-2B bronchial epithelial cells revealed significant enrichment of genes associated with the interleukin-10 signaling and DDX58/IFIH1-mediated interferon-alpha/beta pathways. qPCR validation confirmed upregulation of key genes, including of CXCL1, CXCL2, CCL2, CCL5, IL1B, ICAM-1, RIG-I, IFIH1, IRF7, and ISG15. In a murine model of allergic airway inflammation, rBlo t 5 sensitization induced pronounced inflammatory cell infiltration, goblet cell hyperplasia, collagen deposition, and increased neutrophils in bronchoalveolar lavage fluid. Serum levels of allergen-specific IgE and IgG1 were elevated, accompanied by a Th2-skewed cytokine profile (increased IL-4 and IL-13, decreased IFN-γ and TGF-β). qPCR of lung tissues further confirmed upregulation of the same pathway-related genes.These findings indicate that rBlo t 5 elicits a type 2-polarized immune response initiated, in part, through the concurrent activation of the IL-10 and DDX58/IFIH1-interferon signaling axes in airway epithelium, providing new mechanistic insights into B. tropicalis-induced allergic inflammation.
{"title":"Recombinant allergen rBlo t 5 induces type 2 immune inflammation via Interleukin-10 and DDX58/IFIH1 Signaling pathways","authors":"Jinni Chen , Lingxiao Zhong , Kangdong Wang , Yaning Ren , Dongmei Zhou , Ying Zhou , Liuying Chen , Yuanfen Liao , Chuangli Hao , Yubao Cui","doi":"10.1016/j.intimp.2026.116282","DOIUrl":"10.1016/j.intimp.2026.116282","url":null,"abstract":"<div><div><em>Blomia tropicalis</em> is a clinically significant source of mite allergens, with Blo t 5 identified as a major component. This study aimed to produce recombinant Blo t 5 (rBlo t 5) and investigate its role in allergic immune responses. The rBlo t 5 protein (∼14 kDa) was successfully expressed in <em>E. coli</em> and purified with high purity. IgE-ELISA demonstrated specific IgE binding in 69% of serum samples from asthmatic children sensitized to <em>B. tropicalis</em>. Transcriptomic analysis of rBlo t 5-stimulated BEAS-2B bronchial epithelial cells revealed significant enrichment of genes associated with the interleukin-10 signaling and DDX58/IFIH1-mediated interferon-alpha/beta pathways. qPCR validation confirmed upregulation of key genes, including of CXCL1, CXCL2, CCL2, CCL5, IL1B, ICAM-1, RIG-I, IFIH1, IRF7, and ISG15. In a murine model of allergic airway inflammation, rBlo t 5 sensitization induced pronounced inflammatory cell infiltration, goblet cell hyperplasia, collagen deposition, and increased neutrophils in bronchoalveolar lavage fluid. Serum levels of allergen-specific IgE and IgG1 were elevated, accompanied by a Th2-skewed cytokine profile (increased IL-4 and IL-13, decreased IFN-γ and TGF-β). qPCR of lung tissues further confirmed upregulation of the same pathway-related genes.These findings indicate that rBlo t 5 elicits a type 2-polarized immune response initiated, in part, through the concurrent activation of the IL-10 and DDX58/IFIH1-interferon signaling axes in airway epithelium, providing new mechanistic insights into <em>B. tropicalis</em>-induced allergic inflammation.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116282"},"PeriodicalIF":4.7,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The constitutively active mutant of the tyrosine kinase Janus kinase 2 (JAK2V617F) is a major driver of myeloproliferative neoplasms (MPNs). We previously demonstrated that JAK2V617F activates the transcription factor signal transducer and activator of transcription 5 (STAT5), which upregulates the expression of the RNA helicase DDX5. DDX5 promotes activation of the mTOR pathway and is essential for the proliferation and tumorigenicity of JAK2V617F-positive hematopoietic cell models, even though its RNA helicase activity is dispensable for JAK2V617F-induced transformation. In the present study, we investigated the therapeutic potential of targeting DDX5 using FL118, a camptothecin (CPT) derivative known to induce the proteasomal degradation of DDX5. In Ba/F3 cells expressing JAK2V617F and the erythropoietin receptor (EpoR), as well as in human erythroleukemia (HEL) cells harboring JAK2V617F, FL118, but not CPT, successfully induced DDX5 degradation. Consist with this, FL118, but not CPT, suppressed mTOR pathway activation and triggered apoptosis in both Ba/F3 cells expressing JAK2V617F and EpoR and HEL cells. In a subcutaneous tumor model, in which Ba/F3 cells expressing JAK2V617F and EpoR were transplanted into nude mice, oral administration of FL118 significantly reduced tumor growth and hepatosplenomegaly. Collectively, these findings establish DDX5 as a promising therapeutic target in MPNs and underscore the potential of FL118 as a treatment strategy for JAK2V617F-driven disease.
{"title":"Targeting DDX5 using FL118 suppresses mTOR signaling and tumorigenicity in JAK2V617F-driven myeloproliferative neoplasms.","authors":"Kengo Takeda, Kenji Tago, Satoshi Ohta, Yosuke Nakazawa, Megumi Funakoshi-Tago","doi":"10.1016/j.intimp.2026.116284","DOIUrl":"https://doi.org/10.1016/j.intimp.2026.116284","url":null,"abstract":"<p><p>The constitutively active mutant of the tyrosine kinase Janus kinase 2 (JAK2V617F) is a major driver of myeloproliferative neoplasms (MPNs). We previously demonstrated that JAK2V617F activates the transcription factor signal transducer and activator of transcription 5 (STAT5), which upregulates the expression of the RNA helicase DDX5. DDX5 promotes activation of the mTOR pathway and is essential for the proliferation and tumorigenicity of JAK2V617F-positive hematopoietic cell models, even though its RNA helicase activity is dispensable for JAK2V617F-induced transformation. In the present study, we investigated the therapeutic potential of targeting DDX5 using FL118, a camptothecin (CPT) derivative known to induce the proteasomal degradation of DDX5. In Ba/F3 cells expressing JAK2V617F and the erythropoietin receptor (EpoR), as well as in human erythroleukemia (HEL) cells harboring JAK2V617F, FL118, but not CPT, successfully induced DDX5 degradation. Consist with this, FL118, but not CPT, suppressed mTOR pathway activation and triggered apoptosis in both Ba/F3 cells expressing JAK2V617F and EpoR and HEL cells. In a subcutaneous tumor model, in which Ba/F3 cells expressing JAK2V617F and EpoR were transplanted into nude mice, oral administration of FL118 significantly reduced tumor growth and hepatosplenomegaly. Collectively, these findings establish DDX5 as a promising therapeutic target in MPNs and underscore the potential of FL118 as a treatment strategy for JAK2V617F-driven disease.</p>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"116284"},"PeriodicalIF":4.7,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146099718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-30DOI: 10.1016/j.intimp.2026.116266
Li Jiamei , Li Keda
This letter to the editor comments on the study by Jiang et al. investigating the role of Asprosin in diabetes-associated depression. We acknowledge the novel finding that Asprosin mediates hippocampal dysfunction by triggering a cascade of “pyroptosis–neuroinflammation–kynurenine pathway” disruption. We further highlight several avenues for deeper exploration, including the brain-region specificity of Asprosin action, the specific cell types undergoing pyroptosis, and the direct mechanistic links within this pathway. Further investigation into these aspects may help translate this discovery into targeted therapeutic strategies.
{"title":"Comment on: Asprosin mediates diabetes-associated depression via provoking the cascade of pyroptosis-neuroinflammation-kynurenine pathway disorder in the hippocampus","authors":"Li Jiamei , Li Keda","doi":"10.1016/j.intimp.2026.116266","DOIUrl":"10.1016/j.intimp.2026.116266","url":null,"abstract":"<div><div>This letter to the editor comments on the study by Jiang et al. investigating the role of Asprosin in diabetes-associated depression. We acknowledge the novel finding that Asprosin mediates hippocampal dysfunction by triggering a cascade of “pyroptosis–neuroinflammation–kynurenine pathway” disruption. We further highlight several avenues for deeper exploration, including the brain-region specificity of Asprosin action, the specific cell types undergoing pyroptosis, and the direct mechanistic links within this pathway. Further investigation into these aspects may help translate this discovery into targeted therapeutic strategies.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116266"},"PeriodicalIF":4.7,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The immune environment at the maternal-fetal interface is reliant on the precise regulation of various immune cells and their secreted cytokines, resulting in a coordinated balance of immune nutrition, immune defense, and immune tolerance to meet the needs of different stages of pregnancy. Disruption in the immunological microenvironment can lead to several pregnancy problems. In recent years, immunotherapy medications have made substantial advances in the treatment of maternal-fetal interface diseases during pregnancy. This paper provides a cellular and molecular review of the immunological mechanisms behind various common maternal-fetal interface diseases (preterm birth, recurring spontaneous abortion, preeclampsia, and fetal growth restriction). It offers a novel analysis of the mechanisms of action, application strategies, current research status, and future challenges for distinct immunotherapeutic agents from three separate perspectives: targeting different phases of inflammatory pathways, targeting particular immune cells at the maternal-fetal interface, and targeting specific autoantibodies associated with autoimmunity. The aim is to provide new insights for medication discovery, as well as precision diagnosis and treatment of pregnancy-related illnesses. These advancements will provide vital evidence for precision treatment of maternal-fetal interface diseases throughout pregnancy.
{"title":"Immunological mechanisms and immunotherapeutic strategies for the maternal-fetal interface diseases during pregnancy","authors":"Shuo Zheng , Yulin Zhang , Yi Xing , Zhen Zhang , Yaqing Zhang , Liang Peng , Suya Chen , Yanli Zhang , Longquan Shao","doi":"10.1016/j.intimp.2026.116260","DOIUrl":"10.1016/j.intimp.2026.116260","url":null,"abstract":"<div><div>The immune environment at the maternal-fetal interface is reliant on the precise regulation of various immune cells and their secreted cytokines, resulting in a coordinated balance of immune nutrition, immune defense, and immune tolerance to meet the needs of different stages of pregnancy. Disruption in the immunological microenvironment can lead to several pregnancy problems. In recent years, immunotherapy medications have made substantial advances in the treatment of maternal-fetal interface diseases during pregnancy. This paper provides a cellular and molecular review of the immunological mechanisms behind various common maternal-fetal interface diseases (preterm birth, recurring spontaneous abortion, preeclampsia, and fetal growth restriction). It offers a novel analysis of the mechanisms of action, application strategies, current research status, and future challenges for distinct immunotherapeutic agents from three separate perspectives: targeting different phases of inflammatory pathways, targeting particular immune cells at the maternal-fetal interface, and targeting specific autoantibodies associated with autoimmunity. The aim is to provide new insights for medication discovery, as well as precision diagnosis and treatment of pregnancy-related illnesses. These advancements will provide vital evidence for precision treatment of maternal-fetal interface diseases throughout pregnancy.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116260"},"PeriodicalIF":4.7,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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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