International immunopharmacology最新文献

{"title":"The protective effects of water-soluble non-starch polysaccharides from Arctium lappa on LPS-induced acute lung injury in vitro and in vivo","authors":"Dan Wang ,&nbsp;Haibo Yin ,&nbsp;Liang Xu ,&nbsp;Tingguo Kang ,&nbsp;Qian Cai ,&nbsp;Xianqun Meng","doi":"10.1016/j.intimp.2025.115196","DOIUrl":"10.1016/j.intimp.2025.115196","url":null,"abstract":"<div><div>The lung, a fragile yet crucial organ for breathing in humans, is susceptible to harm from harmful external elements. This study advances the extraction of <em>Arctium lappa</em> polysaccharide (ALP) by our team, aiming to broaden the possibilities for novel medications targeting lung conditions. The structure of ALP was further analyzed by congo red analysis. Effect of ALP pre-treatment was checked by assessing antioxidant markers, inflammatory cytokines and antiapoptosis <em>in vitro</em> and <em>in vivo</em>. Congo red analysis showed that ALP had a stable three-helical conformation. ALP conferred protection against acute lung injury (ALI) induced by lipopolysaccharide (LPS) through the attenuation of lung tissue injury and inhibition of cell apoptosis. The apoptosis rate in lung tissues was markedly reduced in ALP-treated groups compared to the LPS group (<em>P</em> &lt; 0.01). This protective effect is primarily attributed to dual mechanisms: the suppression of inflammatory cytokine synthesis and the enhancement of antioxidant responses. ALP significantly reduced the levels of LPS-induced inflammatory cytokines (<em>P</em> &lt; 0.05) including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) <em>in vitro</em> and <em>in vivo</em> experiments. In addition, ALP alleviated LPS-induced lung injury by reducing malondialdehyde (MDA) and upregulating superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and the overall antioxidant capacity (T-AOC) contents. The western blot analysis of mice lung tissues revealed that ALP pretreatment significantly attenuated the LPS-induced upregulation of key inflammatory signaling proteins (<em>P</em> &lt; 0.05), including TLR4, MyD88, p65, P-p65, i-κB, p-i-κB, JNK, and p38 protein levels. The results of RAW264.7 cell experiments further veriffed that ALP inhibited TLR4/NF-κB/MAPK pathway. In conclusion, ALP can reduce LPS-induced ALI by inhibiting inflammation and oxidative stress.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"162 ","pages":"Article 115196"},"PeriodicalIF":4.8,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144587412","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}

{"title":"Targeting Nav1.5 with DKK678 attenuates NF-κB–driven inflammatory injury in skeletal muscle","authors":"Wenyao Yang ,&nbsp;Juanzhu Han ,&nbsp;Liping Zhang ,&nbsp;Yunsong Sun ,&nbsp;Yuchen Zhu ,&nbsp;Yiyu Liu ,&nbsp;Jingyu Chen ,&nbsp;Xiaoyao Liao ,&nbsp;Hui Liao ,&nbsp;Weizhuo Xu ,&nbsp;Yongbo Song","doi":"10.1016/j.intimp.2025.115173","DOIUrl":"10.1016/j.intimp.2025.115173","url":null,"abstract":"&lt;div&gt;&lt;div&gt;Skeletal muscle inflammation associated with sepsis has been identified as a critical pathological process contributing to metabolic dysfunction and poor clinical outcomes. Voltage-gated sodium channels (VGSCs) have been implicated in immune modulation; however, their specific roles in skeletal muscle inflammation remain poorly understood. In this study, the VGSC subtype Nav1.5 was investigated as a potential regulator of inflammation, and the therapeutic efficacy of a novel recombinant scorpion peptide, DKK678, was evaluated.&lt;/div&gt;&lt;div&gt;An in vitro model using lipopolysaccharide (LPS)-stimulated C2C12 cells and an in vivo cecal ligation and puncture (CLP) model in septic mice were established. In both models, Nav1.5 expression was significantly upregulated in response to inflammatory stimuli, while Nav1.4 expression remained unchanged. The nuclear factor kappa B (NF-κB) signaling pathway was found to be activated, contributing to increased expression of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), adhesion molecules (VCAM-1), and gap junction proteins (Cx43). Suppression of VGSC activity using lidocaine resulted in the inhibition of NF-κB phosphorylation and downregulation of inflammatory markers, while the expression of interleukin-10 (IL-10) and interleukin-4 (IL-4) were restored. Tetrodotoxin (TTX) treatment did not replicate these effects, suggesting Nav1.5-specific involvement.&lt;/div&gt;&lt;div&gt;DKK678 was developed through bioinformatic design and molecular docking simulations, which predicted a stronger binding affinity and structural stability with Nav1.5 compared to Nav1.4. These predictions were validated through functional experiments. In vitro, DKK678 treatment dose-dependently inhibited LPS-induced NF-κB pathway activation and reversed abnormal expression of VCAM-1 and Cx43. In vivo, DKK678 significantly ameliorated CLP-induced skeletal muscle damage, suppressed inflammatory cytokine production, and improved tissue histopathology. Furthermore, the structural integrity of immune organs such as the thymus and spleen was preserved in DKK678-treated septic mice, with partial restoration of lymphocyte populations and organ indices. Notably, Nav1.5 expression was downregulated by DKK678, while Nav1.4 expression remained unaffected.&lt;/div&gt;&lt;div&gt;These results demonstrate that Nav1.5 serves as a critical inflammatory modulator in skeletal muscle and immune tissues. Its upregulation was shown to drive NF-κB pathway activation and inflammatory cytokine production. By targeting Nav1.5, DKK678 was able to exert dual protective effects on both skeletal muscle and immune organs under septic conditions. The therapeutic potential of DKK678 was found to be comparable to that of dexamethasone (DEX) at high doses, without altering Nav1.4 expression.&lt;/div&gt;&lt;div&gt;In conclusion, the present study provides new mechanistic insight into the role of Nav1.5 in skeletal muscle inflammation and identifies DKK678 as a promising peptide therapeutic that","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"162 ","pages":"Article 115173"},"PeriodicalIF":4.8,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144587424","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}

{"title":"Role of the renin-angiotensin-aldosterone system in sepsis and its therapeutic targets","authors":"Xinsen Chen ,&nbsp;Meng Shao ,&nbsp;Yancun Liu ,&nbsp;Juan Zhou ,&nbsp;Fengsheng Cao ,&nbsp;Yang Liu ,&nbsp;Guangyu Qiu ,&nbsp;Ting Jiang ,&nbsp;Min Huang ,&nbsp;Lu Zhang","doi":"10.1016/j.intimp.2025.115192","DOIUrl":"10.1016/j.intimp.2025.115192","url":null,"abstract":"<div><div>An imbalance in the host's response to infection causes sepsis, a potentially fatal condition. Sepsis may advance to septic shock, organ dysfunction (including the brain, liver, lung, kidney, and heart), skeletal muscle atrophy, and an array of severe complications. The renin-angiotensin-aldosterone system (RAAS) undergoes significant alterations during sepsis, and the expression of its principal bioactive components is closely associated with the prognosis of patients with sepsis. Targeting RAAS may offer an effective approach to managing sepsis and its complications. Consequently, this review primarily summarizes the impact of sepsis on the activity and expression of key RAAS components in the circulation and tissues. We also discuss the effects and mechanisms of selectively modulating the RAAS in the context of sepsis and its associated complications. Furthermore, we introduce innovative perspectives on the precise regulation of the RAAS with the aim of optimizing treatment strategies tailored to different stages of sepsis and diverse complications.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"162 ","pages":"Article 115192"},"PeriodicalIF":4.8,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144597534","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}

{"title":"Naltrexone reduces bleomycin-induced lung fibrosis in rats by attenuating fibrosis, inflammation, oxidative stress, and extracellular matrix remodeling","authors":"Amirabbas Mohammadi Hamaneh ,&nbsp;Fatemeh Nejati ,&nbsp;Mohammad Teymoori Masuleh ,&nbsp;Mohammad Amin Manavi ,&nbsp;Houman Kazemzadeh ,&nbsp;Hamed Shafaroodi ,&nbsp;Seyed Mohammad Tavangar ,&nbsp;Ahmad Reza Dehpour","doi":"10.1016/j.intimp.2025.115182","DOIUrl":"10.1016/j.intimp.2025.115182","url":null,"abstract":"<div><div>Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease characterized by excessive extracellular matrix (ECM) accumulation, fibroblast activation, and chronic inflammation. This study examined the antifibrotic effects of naltrexone (NTX), an opioid receptor antagonist, in a bleomycin (BLM)-induced pulmonary fibrosis model in Wistar rats. Daily administration of NTX significantly reduced alveolar wall thickening, collagen deposition, and histopathological injury scores. At higher doses, NTX markedly decreased levels of pro-inflammatory cytokines (TNF-α, IL-6, TGF-β), oxidative stress markers (MPO, NO), and key fibrotic markers including α-SMA and delta opioid receptor (DOR). Additionally, NTX restored antioxidant defenses (GSH, TAC) and enhanced GSK-3β phosphorylation, thereby modulating the Wnt/β-catenin and NF-κB signaling pathways. To further investigate the cellular mechanisms underlying NTX's antifibrotic activity, in vitro experiments were conducted using BLM-stimulated NIH-3 T3 fibroblasts. NTX inhibited the production of collagen type I and III, tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2), and matrix metalloproteinases (MMP-2 and MMP-9) in a dose- and time-dependent manner. This dual regulation of ECM synthesis and degradation suggests a more balanced therapeutic strategy compared to merely inhibiting collagen accumulation. Molecular docking analyses revealed strong interactions between NTX and key proteins involved in inflammatory and fibrotic signaling cascades. Notably, NTX at a dose of 20 mg/kg demonstrated antifibrotic efficacy comparable to that of pirfenidone. Collectively, these findings suggest that NTX exerts protective effects in pulmonary fibrosis by simultaneously targeting inflammation, oxidative stress, and ECM remodeling. Given its favorable tolerability and potential cost-effectiveness, NTX emerges as a promising candidate for IPF therapy. Further clinical investigations are warranted to evaluate its translational potential.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"162 ","pages":"Article 115182"},"PeriodicalIF":4.8,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144596978","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}

{"title":"Decoding inflammatory mediators in the Correa's cascade: From chronic gastritis to carcinogenesis and targeted therapies","authors":"Jun Zhou ,&nbsp;Jiqiang Li ,&nbsp;Jie Chen ,&nbsp;Xi Lan ,&nbsp;Yanling Ai ,&nbsp;Peiyao Liu ,&nbsp;Jing Peng ,&nbsp;Xinyu Pan ,&nbsp;Yuanhao Zhang ,&nbsp;Hebin Zhang ,&nbsp;Xueyi Li ,&nbsp;Yueqiang Wen ,&nbsp;Wei Jiang ,&nbsp;Jinhao Zeng","doi":"10.1016/j.intimp.2025.115191","DOIUrl":"10.1016/j.intimp.2025.115191","url":null,"abstract":"<div><div>Gastric cancer (GC) stands as one of the most prevalent malignant tumors worldwide, with its pathogenesis remaining incompletely elucidated. Correa's cascade delineates a sequential progression from normal gastric mucosa through chronic gastritis, atrophic gastritis (AG), intestinal metaplasia (IM), and dysplasia, ultimately culminating in adenocarcinoma. Inflammation serves as the initiating phase of this cascade, predominantly triggered by <em>Helicobacter pylori</em> (<em>H. pylori</em>) infection. <em>H. pylori</em> induces substantial production of inflammatory mediators, including cytokines, chemokines, growth factors, and others. These mediators orchestrate multi-step regulation of Correa's cascade through mechanisms encompassing recruitment and infiltration of inflammatory cells, oxidative stress, dysregulation of cell proliferation and apoptosis, immunosuppression/immune evasion, angiogenesis, epithelial-mesenchymal transition (EMT), and tumor invasion and metastasis. This study represents the first systematic investigation comprehensively elucidating the specific mechanisms through which inflammatory mediators promote Correa's cascade progression. Furthermore, we explore the therapeutic potential of novel intervention strategies targeting inflammatory mediators across multiple stages, including natural products, cytokine antagonists, and emerging nanotechnology-based approaches, which may enable reversal of Correa's cascade. These findings provide new insights for developing preventive and therapeutic regimens against gastric carcinogenesis.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"162 ","pages":"Article 115191"},"PeriodicalIF":4.8,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144580051","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}

{"title":"Fibrotic extracellular matrix microenvironment induces alveolar type II epithelial cell senescence via integrin-β1/FAK/YAP signaling pathway","authors":"Jingwen Yang ,&nbsp;Yuan Ma ,&nbsp;Ran Zhang ,&nbsp;Xiangyi Liu ,&nbsp;Wenjing Liu ,&nbsp;Chen Liu ,&nbsp;Jiangan Guan ,&nbsp;Wenwen Chen ,&nbsp;Jie Weng ,&nbsp;Mengying Xie ,&nbsp;Zhibin Wang ,&nbsp;Xinlong Wan ,&nbsp;Zhiyi Wang ,&nbsp;Chan Chen","doi":"10.1016/j.intimp.2025.115169","DOIUrl":"10.1016/j.intimp.2025.115169","url":null,"abstract":"<div><div>Senescent alveolar epithelial cells (AEC) play a pivotal role in the progression of idiopathic pulmonary fibrosis (IPF), attracting increasing attention from researchers. Central to the pathogenesis of pulmonary fibrosis (PF) is the excessive deposition of extracellular matrix (ECM). However, there remains a significant gap in understanding how the ECM microenvironment influences senescence in type II alveolar epithelial cells (AEC II). This study investigates the activation of the integrin-β₁/FAK/YAP signaling pathway and its role in inducing cellular senescence in both in vivo and in vitro models of bleomycin (BLM)-induced PF. We employed decellularized lung scaffolds (DLS) to replicate the natural ECM microenvironment, aiming to elucidate whether the fibrotic ECM promotes AEC II senescence through the integrin-β₁/FAK/YAP pathway. Notably, our findings indicate that exogenous integrin-β₁ does not induce AEC II senescence. This suggests that the fibrotic ECM microenvironment regulates AEC II senescence via the integrin-β₁/FAK/YAP pathway independently of exogenous integrin-β₁. Therefore, targeting alterations in the fibrotic ECM microenvironment may represent a promising therapeutic strategy for IPF by modulating AEC II senescence.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"162 ","pages":"Article 115169"},"PeriodicalIF":4.8,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144587554","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}

{"title":"Hypoxia-induced tumor cell-intrinsic PLAU activation drives immunotherapy resistance in collagenic lung adenocarcinoma","authors":"Li Wan ,&nbsp;Tianyun Ma ,&nbsp;Boye Li ,&nbsp;Xiaoming Shi ,&nbsp;Shuwen Chen ,&nbsp;Xiaoli Sun ,&nbsp;Haotian Ge ,&nbsp;Chuqiao Lu ,&nbsp;Weiyong Yu ,&nbsp;Ning Zhou ,&nbsp;Yue Xu ,&nbsp;Li Ma ,&nbsp;Zhaoxia Wang","doi":"10.1016/j.intimp.2025.115161","DOIUrl":"10.1016/j.intimp.2025.115161","url":null,"abstract":"<div><h3>Background</h3><div>Hypoxia, as one of the hallmarks in the progression of solid tumors, has been established as critically important for tumor adaptive survival; however, its role in mediating tumor microenvironment remodeling in advanced lung adenocarcinoma (LUAD) remains incompletely defined.</div></div><div><h3>Methods</h3><div>Bioinformatics methods were conducted to establish a “hypoxia gene module” and perform molecular subtyping of advanced LUAD patients.Western blotting and immunohistochemistry analyses were performed to elucidate the role of PLAU-PLAUR (also known as uPA-uPAR) signaling activation in hypoxia-associated “Collagenic” LUAD development. Primary pulmonary fibroblasts were isolated, and a co-culture system was established for further investigation. QRT-PCR, Western blotting, and ELISA assays were employed to assess PLAU-PLAUR pathway involvement in CAFs activation. Additionally, CUT&amp;RUN, mass spectrometry, immunofluorescence, and co-immunoprecipitation experiments were conducted to explore the molecular mechanisms of HIF1A-induced PLAU upregulation. In vivo studies were undertaken to examine PLAU-PLAUR activation's impact on the formation of a collagen-rich tumor microenvironment.</div></div><div><h3>Results</h3><div>We observed that advanced LUAD patients with high hypoxia exhibited higher fibrosis and increased infiltration of immunosuppressive cells in their microenvironment. Screening intercellular communication signals revealed abnormal activation of the PLAU-PLAUR pathway between tumor cells and fibroblasts in hypoxia-induced “Collagenic” LUAD. In vitro experiments confirmed that hypoxia upregulates PLAU in tumor cells, promoting CAFs activation. Furthermore, hypoxia-inducible factor 1α(HIF1A) recruits the mitophagy protein NIX for a non-canonical role: under hypoxia, NIX translocates to the nucleus, interacts with the PLAU transcription factor YY1, and enhances its binding to the PLAU promoter. We also identified that PLAU activates Hippo-YAP signaling upon binding to PLAUR on lung fibroblasts. In vitro studies demonstrated that Upamostat significantly attenuated fibroblast activation at tumor borders, enhanced CD8⁺T cell infiltration, and shifted macrophages from immunosuppressive to immunogenic states.</div></div><div><h3>Conclusions</h3><div>Activation of the PLAU-PLAUR pathway is essential for the progression of hypoxia-associated LUAD exhibiting a collagenous phenotype. Blocking the pathway provides a new research perspective for the development of immunotherapy for LUAD.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"162 ","pages":"Article 115161"},"PeriodicalIF":4.8,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144580054","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}

{"title":"Engineered IFNγ-loaded exosomes reprogram macrophage polarization and suppress tumor cell proliferation in vitro","authors":"Yun Chen ,&nbsp;Zhuoling Du ,&nbsp;Weiwei Jiang ,&nbsp;Linghong Kong ,&nbsp;Dan Huang ,&nbsp;Changchun Zeng ,&nbsp;Hanping Liu","doi":"10.1016/j.intimp.2025.115170","DOIUrl":"10.1016/j.intimp.2025.115170","url":null,"abstract":"<div><div>Macrophages are part of the immune system and play a complex role in the development of cancer. Tumor-associated macrophages (TAMs) exhibit dynamic plasticity between pro-tumorigenic (M2) and anti-tumorigenic (M1) phenotypes, presenting a promising therapeutic target for cancer immunotherapy. While pharmacological modulation of M2 to M1 repolarization shows therapeutic potential, current cytokine delivery strategies face critical challenges including non-specific macrophage clearance. To address these limitations, we developed an engineered exosome system (EXO-IFNγ) through efficient loading of interferon-γ (IFNγ) into THP-1 macrophage-derived exosomes. Functional investigations demonstrated that EXO-IFNγ effectively reprogrammed human peripheral blood mononuclear cells (PBMCs) derived M2 macrophages toward the M1 phenotype, exhibiting significantly superior polarization-modulating capacity compared to free IFNγ. To elucidate the therapeutic implications of phenotypic conversion, the bioactivity of conditioned medium (CM) derived from repolarized M1 macrophages was evaluated. The conditioned medium from repolarized M1 macrophages demonstrated potent tumor-suppressive activity, effectively inhibiting tumor cell growth and migration. Notably, the engineered exosomal delivery system demonstrated unique sustained payload release properties, endowing EXO-IFNγ generated CM with prolonged bioactivity compared to the CM produced by using IFNγ alone. Thus, EXO-IFNγ is a new macrophage polarization strategy to achieve good tumor cell killing effect by combining chemotherapy and immunotherapy.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"162 ","pages":"Article 115170"},"PeriodicalIF":4.8,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144580052","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}

{"title":"YTHDF1-mediated mitochondrial dysfunction and allergic airway inflammation by interaction with β-catenin/TCF4 signaling","authors":"Cancan Xie ,&nbsp;Junwen Huang ,&nbsp;Ying Chen ,&nbsp;Bing Huang ,&nbsp;Yaoxin Chen ,&nbsp;Yuemao Li ,&nbsp;Zhaoqian Gong ,&nbsp;Yanyan Ma ,&nbsp;Maosheng Xu ,&nbsp;Keke Fan ,&nbsp;Dapeng Hu ,&nbsp;Xueying Zhao ,&nbsp;Peng Huang ,&nbsp;Xianru Peng ,&nbsp;Shaoxi Cai ,&nbsp;Wenqu Zhao ,&nbsp;Haijin Zhao","doi":"10.1016/j.intimp.2025.115181","DOIUrl":"10.1016/j.intimp.2025.115181","url":null,"abstract":"<div><h3>Background</h3><div>Although N6-methyladenosine (m6A) modification and its reader protein YTHDF1 have been implicated in allergic airway inflammation, their roles in TDI-induced steroid-insensitive asthma remains unclear. β-catenin signaling is vital for airway inflammation and mitochondrial function in asthma. In this study, we investigated the interplay between β-catenin/TCF4 signaling and m6A-dependent regulation in a TDI-induced asthma model (TDI-AM).</div></div><div><h3>Method</h3><div>Mice were sensitized and challenged with TDI or house dust mite (HDM) to establish asthma models. Mice were administered the YHTDF1 m6A modification inhibitor (Tegaserod), the β-catenin/TCF4 signaling inhibitor (LF3), and the mitochondrial stabilizing drug SS-31 triacetate. Human serum albumin-containing TDI was introduced to human bronchial epithelial cells and macrophages to mimic the asthma model.</div></div><div><h3>Result</h3><div>YTHDF1 was upregulated in the TDI-AM. Pretreatment with a 1 mg/kg concentration of Tegaserod in TDI-AM revealed significant alleviation of TDI-induced airway hyperresponsiveness, airway inflammation, airway remodeling, and mitochondrial dysfunction, but pretreatment with 5 mg/kg concentration of Tegaserod showed the opposite effect. The changes above corroborated in HDM-induced asthmatic mice. JASPAR software predicted the β-catenin signaling downstream transcription factor TCF4 combined with YTHDF1 promoter region, suggesting a possible interaction between TCF4 and YTHDF1. Blockade of β-catenin/TCF4 signaling with LF3 largely inhibited airway inflammation, mitochondrial dysfunction, and the expression of YTHDF1 in the TDI-AM. Treatment with LF3 can significantly inhibit the expression of YTHDF1 protein. The TDI-induced airway inflammation, as well as mitochondrial dysfunction, were both significantly decreased after treatment with SS-31 triacetate.</div></div><div><h3>Conclusion</h3><div>YTHDF1-mediated mitochondrial dysfunction and allergic airway inflammation by interaction with β-catenin/TCF4 signaling.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"162 ","pages":"Article 115181"},"PeriodicalIF":4.8,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144580049","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}

{"title":"Machine learning-driven programmed cell death signature for prognosis and drug candidate discovery in diffuse large B-cell lymphoma: Multi-cohort study and experimental validation","authors":"Bin Luo ,&nbsp;Le Yu ,&nbsp;Wei Zhang ,&nbsp;Jiawei Fan ,&nbsp;Mengdi Wan ,&nbsp;Huangming Hong ,&nbsp;Yizhun Zhu ,&nbsp;Tongyu Lin","doi":"10.1016/j.intimp.2025.115157","DOIUrl":"10.1016/j.intimp.2025.115157","url":null,"abstract":"<div><h3>Background</h3><div>Relapse and drug resistance are major contributor to chemotherapy failure in diffuse large B-cell lymphoma (DLBCL). Programmed cell death (PCD), a key mechanism in tumor progression and resistance, has emerged as a promising biomarker for predicting prognosis and chemotherapy sensitivity in DLBCL.</div></div><div><h3>Materials and methods</h3><div>This study integrated 15 PCD patterns and RNA-seq data from 3428 DLBCL patients (eight cohorts). PCD Score (PCDS) was developed using 101 machine learning algorithm combinations. Using PCDS, patients were stratified into high/low-risk groups through integrated bioinformatics analyses. The antitumor activity of candidate agents was validated through CCK-8, dual Hoechst 33342/Annexin V-PI apoptosis assays, and xenograft models, demonstrating tumor-suppressive efficacy.</div></div><div><h3>Results</h3><div>A 17-gene PCDS developed by machine learning demonstrated high prognostic accuracy across cohorts, with high-risk patients showing significantly worse survival (<em>P</em> &lt; 0.001). PCDS was integrated with clinical features to construct a nomogram with high predictive performance. Enrichment analysis showed upregulated proliferation pathways and suppressed immune/cell adhesion pathways in high-risk group, with increased Tregs and decreased cytotoxic CD8+ T cells (activated/effector memory subsets) and NK cells (<em>P</em> &lt; 0.05). High-risk patients showed reduced sensitivity to standard chemotherapy (cyclophosphamide/doxorubicin/vincristine). Network pharmacology predicted Phloretin and Parthenolide as high-risk-specific therapeutic agents, with in vitro validation confirming their antitumor activity (Phloretin: 80.77 μM; Parthenolide: 0.93 μM). Furthermore, Parthenolide exhibited high sensitivity against DLBCL cells. Subsequent in vitro and in vivo experiments demonstrated its efficacy in inducing apoptosis and suppressing tumor growth in xenograft models. Enrichment analysis showed downregulation of the Phagosome, Lysosome, and Antigen processing and presentation pathways in the high-risk group, which were upregulated following treatment with Phloretin and Parthenolide. These findings that they may inhibit tumor progression by regulating these pathways.</div></div><div><h3>Conclusion</h3><div>The PCDS effectively predicts the post-chemotherapy prognosis of DLBCL patients. Moreover, Phloretin and Parthenolide exhibit promising potential as therapeutic agents for high-risk DLBCL patients with poor prognosis.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"162 ","pages":"Article 115157"},"PeriodicalIF":4.8,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144571634","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}