Pub Date : 2026-01-24DOI: 10.1016/j.intimp.2026.116258
Lipeng Sun , Shouxiang Kuang , Chang Wang , Yang Li , Guodong Wang , Jianmin Sun , Fengge Zhou , Chenggui Zhang
<div><h3>Background</h3><div>Delayed fracture healing and nonunion are commonly associated with impaired callus remodeling and dysregulated interleukin-6 (IL-6) signaling; however, the precise role of IL-6 in fracture repair remains controversial. Calcitonin gene-related peptide (CGRP), a sensory neuropeptide expressed at fracture sites, has been shown to suppress IL-6 expression and promote bone regeneration. Nevertheless, whether IL-6 reciprocally regulates CGRP expression or function, thereby influencing fracture healing, remains unclear. This study aimed to determine whether local inhibition of IL-6 enhances CGRP expression and subsequently promotes femoral fracture healing.</div></div><div><h3>Methods</h3><div>Adult male C57BL/6 J mice were randomly assigned to four groups to receive different post-fracture treatments. On day 7 after femoral fracture, MR16–1 (a monoclonal anti–mouse IL-6 receptor antibody) was locally administered using a poloxamer 407 hydrogel delivery system, with or without the CGRP receptor antagonist BIBN4096. The poloxamer 407 hydrogel was characterized <em>In vitro</em> for encapsulation efficiency, drug-loading capacity, gelation time, swelling behavior, degradation at 37 °C, and drug-release profile.</div><div>Fracture healing was assessed at 4 weeks post-fracture by X-ray imaging, micro-computed tomography, and histological analysis. Immunofluorescence staining was performed to examine the expression of bone-related proteins, CGRP, and IL-6. Protein expression levels of IL-6, CGRP, Alkaline Phosphatase (ALP), Runt-related transcription factor 2 (Runx2), Osteocalcin (OCN), Nuclear Factor of Activated T cells Cytoplasmic 1 (NFATC1), Cathepsin K (CTSK), Sclerostin, Cluster of Differentiation 68 (CD68), Cluster of Differentiation 86 (CD86), Cluster of Differentiation 206 (CD206), Tumor Necrosis Factor-alpha (TNF-α), Interleukin-1 beta (IL-1β), Inducible Nitric Oxide Synthase (iNOS), Interleukin-10 (IL-10), Transforming Growth Factor-beta (TGF-β), and Arginase-1 (Arg1) were analyzed by Western blotting.</div><div>Quantitative real-time PCR (qRT-PCR) was used to quantify mRNA expression of inflammatory cytokines, including the pro-inflammatory markers TNF-α, IL-1β, and iNOS, as well as the anti-inflammatory markers IL-10, TGF-β, and Arg1.</div></div><div><h3>Results</h3><div>X-ray assessment and healing scores showed that MR16–1 markedly accelerated fracture repair and the effects were largely reversed when combined with BIBN4096. μCT analysis further revealed that MR16–1 significantly increased callus volume and mineralization, while bone mass at distant sites, including the L5 vertebra and contralateral femur, remained unchanged. In contrast, its combination with BIBN4096 resulted in a reduction of callus volume and mineralization. Histological analysis showed that MR16–1 promoted collagen deposition, reduced cartilage content, and enhanced new bone formation, whereas combined treatment delayed bone maturation. At the
{"title":"IL-6 blockade at the fracture site accelerates bone healing via inflammatory modulation of sensory nerve CGRP signaling","authors":"Lipeng Sun , Shouxiang Kuang , Chang Wang , Yang Li , Guodong Wang , Jianmin Sun , Fengge Zhou , Chenggui Zhang","doi":"10.1016/j.intimp.2026.116258","DOIUrl":"10.1016/j.intimp.2026.116258","url":null,"abstract":"<div><h3>Background</h3><div>Delayed fracture healing and nonunion are commonly associated with impaired callus remodeling and dysregulated interleukin-6 (IL-6) signaling; however, the precise role of IL-6 in fracture repair remains controversial. Calcitonin gene-related peptide (CGRP), a sensory neuropeptide expressed at fracture sites, has been shown to suppress IL-6 expression and promote bone regeneration. Nevertheless, whether IL-6 reciprocally regulates CGRP expression or function, thereby influencing fracture healing, remains unclear. This study aimed to determine whether local inhibition of IL-6 enhances CGRP expression and subsequently promotes femoral fracture healing.</div></div><div><h3>Methods</h3><div>Adult male C57BL/6 J mice were randomly assigned to four groups to receive different post-fracture treatments. On day 7 after femoral fracture, MR16–1 (a monoclonal anti–mouse IL-6 receptor antibody) was locally administered using a poloxamer 407 hydrogel delivery system, with or without the CGRP receptor antagonist BIBN4096. The poloxamer 407 hydrogel was characterized <em>In vitro</em> for encapsulation efficiency, drug-loading capacity, gelation time, swelling behavior, degradation at 37 °C, and drug-release profile.</div><div>Fracture healing was assessed at 4 weeks post-fracture by X-ray imaging, micro-computed tomography, and histological analysis. Immunofluorescence staining was performed to examine the expression of bone-related proteins, CGRP, and IL-6. Protein expression levels of IL-6, CGRP, Alkaline Phosphatase (ALP), Runt-related transcription factor 2 (Runx2), Osteocalcin (OCN), Nuclear Factor of Activated T cells Cytoplasmic 1 (NFATC1), Cathepsin K (CTSK), Sclerostin, Cluster of Differentiation 68 (CD68), Cluster of Differentiation 86 (CD86), Cluster of Differentiation 206 (CD206), Tumor Necrosis Factor-alpha (TNF-α), Interleukin-1 beta (IL-1β), Inducible Nitric Oxide Synthase (iNOS), Interleukin-10 (IL-10), Transforming Growth Factor-beta (TGF-β), and Arginase-1 (Arg1) were analyzed by Western blotting.</div><div>Quantitative real-time PCR (qRT-PCR) was used to quantify mRNA expression of inflammatory cytokines, including the pro-inflammatory markers TNF-α, IL-1β, and iNOS, as well as the anti-inflammatory markers IL-10, TGF-β, and Arg1.</div></div><div><h3>Results</h3><div>X-ray assessment and healing scores showed that MR16–1 markedly accelerated fracture repair and the effects were largely reversed when combined with BIBN4096. μCT analysis further revealed that MR16–1 significantly increased callus volume and mineralization, while bone mass at distant sites, including the L5 vertebra and contralateral femur, remained unchanged. In contrast, its combination with BIBN4096 resulted in a reduction of callus volume and mineralization. Histological analysis showed that MR16–1 promoted collagen deposition, reduced cartilage content, and enhanced new bone formation, whereas combined treatment delayed bone maturation. At the ","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116258"},"PeriodicalIF":4.7,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146037436","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 : 2026-01-24DOI: 10.1016/j.intimp.2026.116267
Mohamed Gamal El-Din Ewees , Lobna A. Abdelzaher , Ehab A.M. El-Shoura , Fatema El-Zahraa S. Abdel Rahman , Amany M. Shabaan , Marwa Ahmed Embaby , Alshaymaa M.Abdelmenem , Yasmin Moustafa Ahmed
Background
Gentamicin (Genta) is a widely used aminoglycoside antibiotic, but its clinical value is limited by nephrotoxicity involving oxidative stress, inflammation, apoptosis, and dysregulation of the ADAM-17/ACE2/Ang (1–7)/MasR axis. β-Sitosterol (BSST) is a phytosterol with reported antioxidant and anti-inflammatory properties, yet its nephroprotective activity and mechanistic link to this signaling pathway have not been explored. This study investigated whether BSST mitigates Genta-induced renal injury in association with modulation of this axis together with autophagy and apoptotic pathways.
Methods
Male Wistar rats were assigned to five groups: control, BSST (40 mg/kg), Genta (100 mg/kg), and Genta combined with BSST (20 or 40 mg/kg). Renal function markers, oxidative stress indices, ELISA-based quantification of ADAM-17, ACE2, Ang (1–7), Ang II, and Cystatin-C, Western blot analyses of FOXO-1, LC3-II, P62, p38, and NF-κB, qRT-PCR for MasR, ATG5, TNF-α, and IL-6, histopathology, and caspase-3 immunostaining were performed.
Results
Genta significantly increased serum creatinine, BUN, uric acid, Cystatin-C, renal MDA, ADAM-17, Ang II, NF-κB, and p38, while decreasing GSH, ACE2, Ang (1–7), LC3-II, ATG5, and MasR (P < 0.05). BSST co-treatment attenuated these alterations in a dose-dependent manner and markedly reduced renal apoptosis and tissue damage. The 40 mg/kg BSST dose produced the most pronounced effects.
Conclusion
This study provides novel evidence that BSST protects against Genta-induced nephrotoxicity with findings consistent with restoring the ADAM-17/ACE2/Ang (1–7)/MasR balance, suppressing oxidative and inflammatory responses, re-establishing autophagy, and reducing apoptosis. BSST may represent a promising nephroprotective adjunct during aminoglycoside therapy.
{"title":"β-Sitosterol attenuates gentamicin-induced nephrotoxicity via ADAM-17/ACE2/Ang 1–7/MasR Axis modulation in rats","authors":"Mohamed Gamal El-Din Ewees , Lobna A. Abdelzaher , Ehab A.M. El-Shoura , Fatema El-Zahraa S. Abdel Rahman , Amany M. Shabaan , Marwa Ahmed Embaby , Alshaymaa M.Abdelmenem , Yasmin Moustafa Ahmed","doi":"10.1016/j.intimp.2026.116267","DOIUrl":"10.1016/j.intimp.2026.116267","url":null,"abstract":"<div><h3>Background</h3><div>Gentamicin (Genta) is a widely used aminoglycoside antibiotic, but its clinical value is limited by nephrotoxicity involving oxidative stress, inflammation, apoptosis, and dysregulation of the ADAM-17/ACE2/Ang (1–7)/MasR axis. β-Sitosterol (BSST) is a phytosterol with reported antioxidant and anti-inflammatory properties, yet its nephroprotective activity and mechanistic link to this signaling pathway have not been explored. This study investigated whether BSST mitigates Genta-induced renal injury in association with modulation of this axis together with autophagy and apoptotic pathways.</div></div><div><h3>Methods</h3><div>Male Wistar rats were assigned to five groups: control, BSST (40 mg/kg), Genta (100 mg/kg), and Genta combined with BSST (20 or 40 mg/kg). Renal function markers, oxidative stress indices, ELISA-based quantification of ADAM-17, ACE2, Ang (1–7), Ang II, and Cystatin-C, Western blot analyses of FOXO-1, LC3-II, P62, p38, and NF-κB, qRT-PCR for MasR, ATG5, TNF-α, and IL-6, histopathology, and caspase-3 immunostaining were performed.</div></div><div><h3>Results</h3><div>Genta significantly increased serum creatinine, BUN, uric acid, Cystatin-C, renal MDA, ADAM-17, Ang II, NF-κB, and p38, while decreasing GSH, ACE2, Ang (1–7), LC3-II, ATG5, and MasR (<em>P</em> < 0.05). BSST co-treatment attenuated these alterations in a dose-dependent manner and markedly reduced renal apoptosis and tissue damage. The 40 mg/kg BSST dose produced the most pronounced effects.</div></div><div><h3>Conclusion</h3><div>This study provides novel evidence that BSST protects against Genta-induced nephrotoxicity with findings consistent with restoring the ADAM-17/ACE2/Ang (1–7)/MasR balance, suppressing oxidative and inflammatory responses, re-establishing autophagy, and reducing apoptosis. BSST may represent a promising nephroprotective adjunct during aminoglycoside therapy.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116267"},"PeriodicalIF":4.7,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046558","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 : 2026-01-23DOI: 10.1016/j.intimp.2026.116255
Jinjin Liu , Zhao Wu , Jing Xun , Xiaolin Jiang , Bin Liu , Huichao Yang , Yingdi Han , Zhibo Hu , Qi Gao , Ai’min Zhang , Shimin Yang , Xiangyang Yu , Qi Zhang
Background
The immunosuppressive microenvironment severely constrains the efficacy of immunotherapy for colorectal cancer with peritoneal metastasis (CPM), urgently demanding strategies to reprogram it. Here, we aim to evaluate natural compound neogambogic acid (NGA) for its potential to modulate CPM progression and reshape the tumor immune microenvironment.
Methods
CPM mouse models were established via intraperitoneal injection of murine colorectal cancer cells, and then treated with NGA. Tumor burden and ascites, and immune microenvironment were assessed. Flow cytometry and RT-qPCR were performed to determine the impact of NGA on the differentiation of monocytic myeloid-derived suppressor cells (M-MDSCs) into M1 macrophages. Network pharmacology was used to screen the potential targets of NGA, and molecular docking, cellular thermal shift assay (CTESA) and drug affinity responsive target stability (DARTS) assays were employed to validate the interaction between NGA and STAT3. Finally, the synergistic effect of NGA combined with anti-PD-1/anti-CD47 blockade on inhibiting CPM progression was evaluated.
Results
NGA significantly reduced tumor burden, suppressed ascites formation, and reshaped immunosuppressive microenvironment by decreasing M-MDSCs, increasing tumor-infiltrating CD4+/CD8+T cells and M1 macrophage frequency. Notably, NGA promoted the differentiation of M-MDSCs toward M1 macrophages. Mechanically, NGA directly bound to STAT3 and inhibited its phosphorylation (pSTAT3). Therapeutically, NGA synergized with anti-PD-1/anti-CD47 combination therapy, leading to a marked reduction in tumor burden in CPM models.
Conclusion
NGA, a multi-targeted agent that prominently targets STAT3, enhances the immunotherapy efficacy in CPM by reshaping the immunosuppressive microenvironment through M-MDSC-to-M1 macrophage conversion. These findings provide a promising preclinical basis for NGA-based combinatorial strategies in advanced colorectal cancer.
{"title":"Neogambogic acid promotes M-MDSC differentiation into M1 macrophages to inhibit peritoneal metastasis of colorectal cancer","authors":"Jinjin Liu , Zhao Wu , Jing Xun , Xiaolin Jiang , Bin Liu , Huichao Yang , Yingdi Han , Zhibo Hu , Qi Gao , Ai’min Zhang , Shimin Yang , Xiangyang Yu , Qi Zhang","doi":"10.1016/j.intimp.2026.116255","DOIUrl":"10.1016/j.intimp.2026.116255","url":null,"abstract":"<div><h3>Background</h3><div>The immunosuppressive microenvironment severely constrains the efficacy of immunotherapy for colorectal cancer with peritoneal metastasis (CPM), urgently demanding strategies to reprogram it. Here, we aim to evaluate natural compound neogambogic acid (NGA) for its potential to modulate CPM progression and reshape the tumor immune microenvironment.</div></div><div><h3>Methods</h3><div>CPM mouse models were established via intraperitoneal injection of murine colorectal cancer cells, and then treated with NGA. Tumor burden and ascites, and immune microenvironment were assessed. Flow cytometry and RT-qPCR were performed to determine the impact of NGA on the differentiation of monocytic myeloid-derived suppressor cells (M-MDSCs) into M1 macrophages. Network pharmacology was used to screen the potential targets of NGA, and molecular docking, cellular thermal shift assay (CTESA) and drug affinity responsive target stability (DARTS) assays were employed to validate the interaction between NGA and STAT3. Finally, the synergistic effect of NGA combined with anti-PD-1/anti-CD47 blockade on inhibiting CPM progression was evaluated.</div></div><div><h3>Results</h3><div>NGA significantly reduced tumor burden, suppressed ascites formation, and reshaped immunosuppressive microenvironment by decreasing M-MDSCs, increasing tumor-infiltrating CD4<sup>+</sup>/CD8<sup>+</sup>T cells and M1 macrophage frequency. Notably, NGA promoted the differentiation of M-MDSCs toward M1 macrophages. Mechanically, NGA directly bound to STAT3 and inhibited its phosphorylation (pSTAT3). Therapeutically, NGA synergized with anti-PD-1/anti-CD47 combination therapy, leading to a marked reduction in tumor burden in CPM models.</div></div><div><h3>Conclusion</h3><div>NGA, a multi-targeted agent that prominently targets STAT3, enhances the immunotherapy efficacy in CPM by reshaping the immunosuppressive microenvironment through M-MDSC-to-M1 macrophage conversion. These findings provide a promising preclinical basis for NGA-based combinatorial strategies in advanced colorectal cancer.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116255"},"PeriodicalIF":4.7,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146037434","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 : 2026-01-23DOI: 10.1016/j.intimp.2026.116237
Guyi Cong , Di Ao , Xuelian Mei , Rui Zhao , Rui Guo , Xiquan Ke , Zhenzeng Ma , Lin Gu , Hailun Zheng
Patients with inflammatory bowel disease (IBD) commonly exhibit psychiatric symptoms, such as anxiety and depression. However, studies on drugs addressing the concurrent amelioration of these symptoms in this patient population are rare. Previous studies have suggested that dihydromyricetin (DHM) may show therapeutic potential for IBD. This study investigated the therapeutic effects of DHM on dextran sulfate sodium (DSS)-induced colitis and associated behavioral disorders in mice. The findings of the experiments indicated that DHM could ameliorate colitis symptoms, including changes in body weight, colon length, disease activity index (DAI) scores, and histopathological damage. Furthermore, DHM improved the behavioral impairments observed in colitis mouse model, as evidenced by results from the open field test, elevated plus maze test, and tail suspension test, along with hippocampal histopathological assessments. Molecular analysis revealed that DHM notably suppressed the activation of NLRP3 inflammasome and IL-1β in both the colon and the hippocampus. DHM enhanced the intestinal barrier, elevated brain-derived neurotrophic factor (BDNF) levels in the hippocampus and serum, and concurrently reduced microglia activation. DHM lowered the levels of IL-1β, tumor necrosis factor-α (TNF-α), and lipopolysaccharide (LPS) in the serum. 16S rDNA sequencing results indicated that DHM could modulate DSS-induced gut microbiota dysbiosis, enriching various beneficial metabolic and neuromodulatory pathways. Metabolomic analysis demonstrated that DHM notably elevated acetic acid, propionic acid, and butyric acid levels in intestinal feces. Network pharmacology analysis identified the central intersecting genes of DHM, ulcerative colitis (UC), and neuroinflammation. Differential gene expression analysis underscored IL-1 β as a pivotal target for the co-occurrence of UC and psychiatric conditions. These findings imply that DHM may ameliorate DSS-induced colitis and concomitant behavioral disturbances in mice, underscoring its potential as a natural therapeutic agent for IBD accompanied by psychiatric comorbidities.
{"title":"Dihydromyricetin improves DSS-induced colitis and behavioral disorders by regulating the microbiota-gut-brain axis balance and inhibiting the activation of NLRP3 inflammasome","authors":"Guyi Cong , Di Ao , Xuelian Mei , Rui Zhao , Rui Guo , Xiquan Ke , Zhenzeng Ma , Lin Gu , Hailun Zheng","doi":"10.1016/j.intimp.2026.116237","DOIUrl":"10.1016/j.intimp.2026.116237","url":null,"abstract":"<div><div>Patients with inflammatory bowel disease (IBD) commonly exhibit psychiatric symptoms, such as anxiety and depression. However, studies on drugs addressing the concurrent amelioration of these symptoms in this patient population are rare. Previous studies have suggested that dihydromyricetin (DHM) may show therapeutic potential for IBD. This study investigated the therapeutic effects of DHM on dextran sulfate sodium (DSS)-induced colitis and associated behavioral disorders in mice. The findings of the experiments indicated that DHM could ameliorate colitis symptoms, including changes in body weight, colon length, disease activity index (DAI) scores, and histopathological damage. Furthermore, DHM improved the behavioral impairments observed in colitis mouse model, as evidenced by results from the open field test, elevated plus maze test, and tail suspension test, along with hippocampal histopathological assessments. Molecular analysis revealed that DHM notably suppressed the activation of NLRP3 inflammasome and IL-1β in both the colon and the hippocampus. DHM enhanced the intestinal barrier, elevated brain-derived neurotrophic factor (BDNF) levels in the hippocampus and serum, and concurrently reduced microglia activation. DHM lowered the levels of IL-1β, tumor necrosis factor-α (TNF-α), and lipopolysaccharide (LPS) in the serum. 16S rDNA sequencing results indicated that DHM could modulate DSS-induced gut microbiota dysbiosis, enriching various beneficial metabolic and neuromodulatory pathways. Metabolomic analysis demonstrated that DHM notably elevated acetic acid, propionic acid, and butyric acid levels in intestinal feces. Network pharmacology analysis identified the central intersecting genes of DHM, ulcerative colitis (UC), and neuroinflammation. Differential gene expression analysis underscored IL-1 β as a pivotal target for the co-occurrence of UC and psychiatric conditions. These findings imply that DHM may ameliorate DSS-induced colitis and concomitant behavioral disturbances in mice, underscoring its potential as a natural therapeutic agent for IBD accompanied by psychiatric comorbidities.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116237"},"PeriodicalIF":4.7,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015884","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 : 2026-01-23DOI: 10.1016/j.intimp.2026.116247
Zhen Sun , Xiaochang Zhang , Sha Liao , Zhe Zhou
The emerging field of immunometabolism posits that endogenous metabolites are pivotal regulators of immune responses, yet their therapeutic exploitation remains nascent. Investigating this paradigm in lung injury, we observed that agmatine, a decarboxylation product of L-arginine, was significantly depleted in poly(I:C)-induced murine lung injury and in a clinical cohort characterized by virus-associated pulmonary involvement, suggesting a potential association with lung pathology. In mice, exogenous agmatine supplementation ameliorated lung pathology and weight loss, effects that were contingent upon reprogramming of macrophage inflammatory responses. Mechanistically, agmatine exerts its anti-inflammatory effects through macrophage-specific mechanisms: it selectively inhibits macrophage-derived TNF-α and CXCL10 without affecting the NF-κB signaling pathway. Transcriptomic analysis of murine macrophages revealed that agmatine significantly upregulates IL-10 expression, and its protective effects were reversed using either IL-10R neutralizing antibody or macrophages from IL-10-deficient mice. In murine macrophages, further investigation confirmed that agmatine promotes STAT3 phosphorylation and nuclear translocation, while STAT3 knockdown partially abrogated its anti-inflammatory efficacy. Our findings position agmatine within the expanding realm of immunometabolic therapy, highlighting its potential as a therapeutic strategy for lung injury by harnessing an endogenous anti-inflammatory circuit.
{"title":"Agmatine ameliorates poly(I:C)-induced lung injury through IL-10/STAT3-dependent reprogramming of macrophage inflammatory responses","authors":"Zhen Sun , Xiaochang Zhang , Sha Liao , Zhe Zhou","doi":"10.1016/j.intimp.2026.116247","DOIUrl":"10.1016/j.intimp.2026.116247","url":null,"abstract":"<div><div>The emerging field of immunometabolism posits that endogenous metabolites are pivotal regulators of immune responses, yet their therapeutic exploitation remains nascent. Investigating this paradigm in lung injury, we observed that agmatine, a decarboxylation product of L-arginine, was significantly depleted in poly(I:C)-induced murine lung injury and in a clinical cohort characterized by virus-associated pulmonary involvement, suggesting a potential association with lung pathology. In mice, exogenous agmatine supplementation ameliorated lung pathology and weight loss, effects that were contingent upon reprogramming of macrophage inflammatory responses. Mechanistically, agmatine exerts its anti-inflammatory effects through macrophage-specific mechanisms: it selectively inhibits macrophage-derived TNF-α and CXCL10 without affecting the NF-κB signaling pathway. Transcriptomic analysis of murine macrophages revealed that agmatine significantly upregulates IL-10 expression, and its protective effects were reversed using either IL-10R neutralizing antibody or macrophages from IL-10-deficient mice. In murine macrophages, further investigation confirmed that agmatine promotes STAT3 phosphorylation and nuclear translocation, while STAT3 knockdown partially abrogated its anti-inflammatory efficacy. Our findings position agmatine within the expanding realm of immunometabolic therapy, highlighting its potential as a therapeutic strategy for lung injury by harnessing an endogenous anti-inflammatory circuit.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116247"},"PeriodicalIF":4.7,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146037431","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 : 2026-01-23DOI: 10.1016/j.intimp.2026.116251
Ziyi Wang , Shuyuan Liu , Mengyao Gao , Ying Shen , Miao Sun , Songli Hao
The biological role reactive oxygen species (ROS), both as byproduct of cellular respiration and as crucial secondary messengers, has been extensively acknowledged in scientific literature. Key ROS-generating enzymes and organelles, including mitochondria, NADPH oxidase, and the endoplasmic reticulum, have been found closely linked to the regulation of metabolic processes. An imbalance between oxidative and antioxidant systems, resulting from abnormal ROS production and leading to oxidative stress (OS), has been implicated as a significant pathogenic in a variety of diseases, such as polycystic ovary syndrome (PCOS). PCOS is a prevalent endocrine disorder that adversely affects reproductive health and metabolic homeostasis in women of reproductive age. This review provides a systematic examination of the three primary sources of ROS production, and explores the mechanisms through which excessive ROS production triggers the dysregulation of key signalling pathways. These pathways are central to the fundamental pathological features of PCOS, such as ovulatory dysfunction, obesity phenotype, insulin resistance, and hyperandrogenism, with a specific emphasis on the interactions within ROS signalling pathways. Grounded in the holistic regulation principles of Chinese medicine and targeting the core signalling pathway as the intervention focal point, we propose a comprehensive intervention strategy. This strategy incorporates natural compounds, herbal compounds, acupuncture, dietary supplements, and other therapeutic approaches, which will provide a new theoretical framework and research direction for enhancing the clinical management of PCOS.
{"title":"Role of reactive oxygen species in polycystic ovary syndrome: signalling pathways, mechanisms, and traditional Chinese medicine treatment strategies","authors":"Ziyi Wang , Shuyuan Liu , Mengyao Gao , Ying Shen , Miao Sun , Songli Hao","doi":"10.1016/j.intimp.2026.116251","DOIUrl":"10.1016/j.intimp.2026.116251","url":null,"abstract":"<div><div>The biological role reactive oxygen species (ROS), both as byproduct of cellular respiration and as crucial secondary messengers, has been extensively acknowledged in scientific literature. Key ROS-generating enzymes and organelles, including mitochondria, NADPH oxidase, and the endoplasmic reticulum, have been found closely linked to the regulation of metabolic processes. An imbalance between oxidative and antioxidant systems, resulting from abnormal ROS production and leading to oxidative stress (OS), has been implicated as a significant pathogenic in a variety of diseases, such as polycystic ovary syndrome (PCOS). PCOS is a prevalent endocrine disorder that adversely affects reproductive health and metabolic homeostasis in women of reproductive age. This review provides a systematic examination of the three primary sources of ROS production, and explores the mechanisms through which excessive ROS production triggers the dysregulation of key signalling pathways. These pathways are central to the fundamental pathological features of PCOS, such as ovulatory dysfunction, obesity phenotype, insulin resistance, and hyperandrogenism, with a specific emphasis on the interactions within ROS signalling pathways. Grounded in the holistic regulation principles of Chinese medicine and targeting the core signalling pathway as the intervention focal point, we propose a comprehensive intervention strategy. This strategy incorporates natural compounds, herbal compounds, acupuncture, dietary supplements, and other therapeutic approaches, which will provide a new theoretical framework and research direction for enhancing the clinical management of PCOS.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116251"},"PeriodicalIF":4.7,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146037432","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 : 2026-01-22DOI: 10.1016/j.intimp.2026.116240
Cong Xie , Jiahui Yue , Wenying He , Changbin Yu
Ethanol-induced gastric ulcer, driven by intricate inflammatory and oxidative stress pathways, lacks optimally effective treatments. Utilizing an integrated approach combining network pharmacology and experimental validation in vivo using a mouse model and in vitro with gastric epithelial cells, this study elucidates the gastroprotective mechanism of the compound MPTA. Network pharmacology identified NOS2 as a central hub gene, guiding subsequent experimental investigation. In an ethanol-induced ulcer mouse model, MPTA administration dose-dependently ameliorated gastric mucosal damage, suppressed pro-inflammatory cytokines including TNF-α, IL-6, IL-1β and IL-8, elevated TGF-β and NO levels, and reduced oxidative stress; these protective effects were attenuated by a NOS2 inhibitor. Proteomic and molecular analyses demonstrated that MPTA downregulated the AGE-RAGE/NF-κB/p38 MAPK inflammatory pathway and activated the NRF2/HO-1/SOD2 antioxidant axis. In vitro, MPTA enhanced cell viability and migration while diminishing apoptosis and ROS accumulation in gastric epithelial cells, primarily through NOS2-centered regulation of the AGE-RAGE signaling pathway. We conclude that MPTA protects against ethanol-induced gastric injury by inhibiting NOS2 to mitigate inflammatory and oxidative stress via the AGE-RAGE pathway. This study unveils a novel gastroprotective mechanism centered on the downregulation of NOS2, underscoring its potential as a protective candidate for ethanol-induced gastric ulcer.
{"title":"A novel triazole derivative ameliorates ethanol-induced gastric ulcer via a NOS2-centered inhibition of the AGE-RAGE pathway","authors":"Cong Xie , Jiahui Yue , Wenying He , Changbin Yu","doi":"10.1016/j.intimp.2026.116240","DOIUrl":"10.1016/j.intimp.2026.116240","url":null,"abstract":"<div><div>Ethanol-induced gastric ulcer, driven by intricate inflammatory and oxidative stress pathways, lacks optimally effective treatments. Utilizing an integrated approach combining network pharmacology and experimental validation in vivo using a mouse model and in vitro with gastric epithelial cells, this study elucidates the gastroprotective mechanism of the compound MPTA. Network pharmacology identified NOS2 as a central hub gene, guiding subsequent experimental investigation. In an ethanol-induced ulcer mouse model, MPTA administration dose-dependently ameliorated gastric mucosal damage, suppressed pro-inflammatory cytokines including TNF-α, IL-6, IL-1β and IL-8, elevated TGF-β and NO levels, and reduced oxidative stress; these protective effects were attenuated by a NOS2 inhibitor. Proteomic and molecular analyses demonstrated that MPTA downregulated the AGE-RAGE/NF-κB/p38 MAPK inflammatory pathway and activated the NRF2/HO-1/SOD2 antioxidant axis. In vitro, MPTA enhanced cell viability and migration while diminishing apoptosis and ROS accumulation in gastric epithelial cells, primarily through NOS2-centered regulation of the AGE-RAGE signaling pathway. We conclude that MPTA protects against ethanol-induced gastric injury by inhibiting NOS2 to mitigate inflammatory and oxidative stress via the AGE-RAGE pathway. This study unveils a novel gastroprotective mechanism centered on the downregulation of NOS2, underscoring its potential as a protective candidate for ethanol-induced gastric ulcer.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"172 ","pages":"Article 116240"},"PeriodicalIF":4.7,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035389","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 : 2026-01-22DOI: 10.1016/j.intimp.2026.116183
Muhammad Alaa Eldeen , Dalal Sulaiman Alshaya , Waleed K. Abdulsahib , Nuha Almulla , Mohamed A. Ali , Maha A. Aljumaa , Eman Fayad , Jawaher Alharthi , Hassan M. Otifi , Mohamed Alshehri , Reem S. Alazragi , Hesham M. Hassan
Background
CD8+ T cell exhaustion in the tumor microenvironment acts as a barrier to tumor immunotherapy development. Therefore, studying that cell in vitro and in vivo is essential for developing a successful cancer immunotherapeutic drug.
Methods
While repeated stimulation of CD8+ T cells in vitro is a must to acquire their exhaustion state, it is important to keep that to a limit that allows for exhaustion of the CD8+ T cells without accelerated cell death, so we can obtain enough exhausted CD8+ T cells to be studied. In the current study, we demonstrated the role of 2-mercaptoethanol (2-ME) as an essential media component by performing repeated CD8+ T cell stimulation with or without 2-ME.
Results
In the absence of 2-ME, CD8+ T cell suffers from overstimulation that allows for their accelerated death. Mechanistically, the absence of 2-ME elevates the oxidative stress on the CD8+ T cells, leading to a shift in their metabolic pathways by adopting lipid peroxidation, which hastens CD8+ T cells' terminal differentiation and over-activates the AKT-mTOR signaling pathway, and finally, cell death. These findings were reflected in our in vivo experiment, where adoptive transfer of antigen-specific CD8+ T cells that have been in vitro activated without 2-ME experienced a lower tumor infiltration frequency and diminished stemness characteristics and effector functions.
Conclusion
Our study confirms the importance of 2-ME as a media component for CD8+ T cells stimulation and supports the potential of antioxidant agents to be used with immunotherapeutic agents to generate enhanced effects.
{"title":"Antioxidant activity of 2-mercaptoethanol protects against CD8+ T cell overstimulation or accelerated exhaustion: evidence from an in vitro exhausted CD8+ T model and in vivo adoptive cell transfer","authors":"Muhammad Alaa Eldeen , Dalal Sulaiman Alshaya , Waleed K. Abdulsahib , Nuha Almulla , Mohamed A. Ali , Maha A. Aljumaa , Eman Fayad , Jawaher Alharthi , Hassan M. Otifi , Mohamed Alshehri , Reem S. Alazragi , Hesham M. Hassan","doi":"10.1016/j.intimp.2026.116183","DOIUrl":"10.1016/j.intimp.2026.116183","url":null,"abstract":"<div><h3>Background</h3><div>CD8+ T cell exhaustion in the tumor microenvironment acts as a barrier to tumor immunotherapy development. Therefore, studying that cell in vitro and in vivo is essential for developing a successful cancer immunotherapeutic drug.</div></div><div><h3>Methods</h3><div>While repeated stimulation of CD8+ T cells in vitro is a must to acquire their exhaustion state, it is important to keep that to a limit that allows for exhaustion of the CD8+ T cells without accelerated cell death, so we can obtain enough exhausted CD8+ T cells to be studied. In the current study, we demonstrated the role of 2-mercaptoethanol (2-ME) as an essential media component by performing repeated CD8+ T cell stimulation with or without 2-ME.</div></div><div><h3>Results</h3><div>In the absence of 2-ME, CD8+ T cell suffers from overstimulation that allows for their accelerated death. Mechanistically, the absence of 2-ME elevates the oxidative stress on the CD8+ T cells, leading to a shift in their metabolic pathways by adopting lipid peroxidation, which hastens CD8+ T cells' terminal differentiation and over-activates the AKT-mTOR signaling pathway, and finally, cell death. These findings were reflected in our in vivo experiment, where adoptive transfer of antigen-specific CD8+ T cells that have been in vitro activated without 2-ME experienced a lower tumor infiltration frequency and diminished stemness characteristics and effector functions.</div></div><div><h3>Conclusion</h3><div>Our study confirms the importance of 2-ME as a media component for CD8+ T cells stimulation and supports the potential of antioxidant agents to be used with immunotherapeutic agents to generate enhanced effects.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"172 ","pages":"Article 116183"},"PeriodicalIF":4.7,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035622","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 : 2026-01-22DOI: 10.1016/j.intimp.2026.116243
Zan Xing , Xin-Mu Li , Yuan-Chun Wang , Peng-Yu Chen , Xue-Ying Yang , Hui-Qin Wang , Meng Zhang , Ai-Ping Chen , Shi-Feng Chu , Zhen-Zhen Wang , Nai-Hong Chen
Background
Ginsenoside Rg1 (GRg1), a principal neuroactive constituent of ginseng, has demonstrated promising antidepressant potential. Beyond its well-documented roles in mitigating oxidative stress, suppressing neuroinflammation, and protecting mitochondrial function, our study further demonstrates that GRg1 exerts its protective effects on the organism by upregulating the expression of connexin 43 (Cx43) in astrocytes. However, it remains unknown whether Cx43 mediates the antidepressant effects of GRg1 by regulating astrocyte pyroptosis.
Objective
This study aimed to elucidate the role of the Cx43-mitophagy-pyroptosis axis in the antidepressant mechanism of GRg1.
Methods
The model of depression was established using an 8-week chronic unpredictable stress (CUS). The optimal therapeutic dose of GRg1 was determined in vivo. Subsequently, we employed Western blotting, immunofluorescence, and fMRI to assess the effects of GRg1 on Cx43 expression and its protective effects on astrocytes. The causal role of Cx43 was verified using Cx43flox/flox mice. Furthermore, we used corticosterone (CORT) to stimulate primary mouse astrocytes and conducted in vitro studies on the relationship between the “Cx43-mitophagy-pyroptosis” pathway and depression.
Conclusion
GRg1 exerts its antidepressant effects by upregulating Cx43 expression, which restores mitophagy flux and facilitates the clearance of damaged mitochondria. This process, in turn, suppresses NLRP3 inflammasome activation and subsequent GSDMD-N-mediated astrocyte pyroptosis.
{"title":"Ginsenoside Rg1 ameliorates depression-like behaviors in mice by inhibiting astrocyte pyroptosis via Cx43-dependent restoration of mitophagy flux","authors":"Zan Xing , Xin-Mu Li , Yuan-Chun Wang , Peng-Yu Chen , Xue-Ying Yang , Hui-Qin Wang , Meng Zhang , Ai-Ping Chen , Shi-Feng Chu , Zhen-Zhen Wang , Nai-Hong Chen","doi":"10.1016/j.intimp.2026.116243","DOIUrl":"10.1016/j.intimp.2026.116243","url":null,"abstract":"<div><h3>Background</h3><div>Ginsenoside Rg1 (GRg1), a principal neuroactive constituent of ginseng, has demonstrated promising antidepressant potential. Beyond its well-documented roles in mitigating oxidative stress, suppressing neuroinflammation, and protecting mitochondrial function, our study further demonstrates that GRg1 exerts its protective effects on the organism by upregulating the expression of connexin 43 (Cx43) in astrocytes. However, it remains unknown whether Cx43 mediates the antidepressant effects of GRg1 by regulating astrocyte pyroptosis.</div></div><div><h3>Objective</h3><div>This study aimed to elucidate the role of the Cx43-mitophagy-pyroptosis axis in the antidepressant mechanism of GRg1.</div></div><div><h3>Methods</h3><div>The model of depression was established using an 8-week chronic unpredictable stress (CUS). The optimal therapeutic dose of GRg1 was determined in vivo. Subsequently, we employed Western blotting, immunofluorescence, and fMRI to assess the effects of GRg1 on Cx43 expression and its protective effects on astrocytes. The causal role of Cx43 was verified using Cx43<sup>flox/flox</sup> mice. Furthermore, we used corticosterone (CORT) to stimulate primary mouse astrocytes and conducted in vitro studies on the relationship between the “Cx43-mitophagy-pyroptosis” pathway and depression.</div></div><div><h3>Conclusion</h3><div>GRg1 exerts its antidepressant effects by upregulating Cx43 expression, which restores mitophagy flux and facilitates the clearance of damaged mitochondria. This process, in turn, suppresses NLRP3 inflammasome activation and subsequent GSDMD-N-mediated astrocyte pyroptosis.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"172 ","pages":"Article 116243"},"PeriodicalIF":4.7,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146029522","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：