International immunopharmacology最新文献

{"title":"β-Sitosterol suppresses NLRP3 Inflammasome activation and Pyroptosis in myocardial ischemia/reperfusion injury via inhibition of PPARγ2","authors":"Zheyi Wu ,&nbsp;Niwen Huang ,&nbsp;Chao Li ,&nbsp;Muzhi Lin ,&nbsp;Zhangrong Chen ,&nbsp;Wei Li ,&nbsp;Haiyan Zhou","doi":"10.1016/j.intimp.2025.114543","DOIUrl":"10.1016/j.intimp.2025.114543","url":null,"abstract":"<div><h3>Background</h3><div>β-Sitosterol, a plant-derived sterol, has demonstrated potential therapeutic effects in cardiovascular diseases, particularly myocardial ischemia-reperfusion injury (MIRI). Our study investigates its underlying mechanism through regulation of pyroptosis.</div></div><div><h3>Methods</h3><div>To understand the role of β-sitosterol in protecting cardiomyocytes, MIRI rats were treated with β-sitosterol. Rats' cardiac functions were monitored, and hearts were harvested for histology and Western Blot analysis. Immunofluorescence, immunoblot, enzyme-linked immunosorbent assay, as well as overexpression and knockdown techniques were utilized in this study to investigate the molecular mechanisms underlying the cardioprotective effects of β-sitosterol.</div></div><div><h3>Results</h3><div>Our results showed that β-Sitosterol significantly reduced H/R-induced pyroptosis in cardiomyocytes by decreasing cleaved caspase-1, gasdermin D (GSDMD), interleukin-1β (IL-1β), and interleukin-18 (IL-18). Immunofluorescence staining confirmed suppression of NLRP3 inflammasome activation. Notably, β-Sitosterol inhibited pyroptosis induced by ATP and ATP/LPS through the regulation of PPARγ2. Moreover, PPARγ2 upregulation promoted ATP and ATP/LPS-induced pyroptosis through the NLRP3/caspase-1/GSDMD pathway. In vivo, β-sitosterol alleviates myocardial ischemia-reperfusion injury-induced cardiac dysfunction and myocardial fibrosis in rats.</div></div><div><h3>Conclusions</h3><div>These findings provide new evidence supporting β-sitosterol as a potential therapeutic agent for cardiovascular diseases involving ischemic injury. Its protective effects may be mediated through targeting PPARγ2 and modulating NLRP3-dependent pyroptosis.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"154 ","pages":"Article 114543"},"PeriodicalIF":4.8,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143714659","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":"Melatonin alleviates retinal injury induced by vigabatrin and partially enhances its antiepileptic effects","authors":"Mengdie Ma ,&nbsp;Min Fan ,&nbsp;Songlin Xu ,&nbsp;Qiang Zheng ,&nbsp;Chuanyu Wang ,&nbsp;Pengquan Chen ,&nbsp;Yadong Wei ,&nbsp;JinFang Ge","doi":"10.1016/j.intimp.2025.114516","DOIUrl":"10.1016/j.intimp.2025.114516","url":null,"abstract":"<div><div>Structural optimization and combinational use with additive agents might help expand the clinical use of vigabatrin (VGB). Aiming to investigate the combinational effect of melatonin (MLT) on the antiepileptic action and retinal damage of VGB, a rat epilepsy model was induced by intraperitoneal injection of kainic acid (KA) and evaluated via both Racine grading and electroencephalogram (EEG). MLT (5, 10, 20 mg/kg) and VGB (50, 150 mg/kg) were administered intragastrically for 4 weeks, alone or together. The behavioral performance was measured during the remission of seizures via a series of tasks including the open field test (OFT), beam walking test (BW), Y-maze, and novel object recognition test (NOR). The morphological changes of the hippocampus and retina were observed using HE, Nissl, or immunofluorescence staining. Furthermore, the expression of proteins associated with synaptic plasticity and the Wnt/β-catenin/GSK3β signaling pathway were assessed. The results showed that intraperitoneal injection of KA could induce not only seizure, but also long-term behavioral impairments of sense, motion, and learning and memory in rats. Moreover, VGB could alleviate the neuroinflammation and balance the expression of synaptic plasticity and Wnt/β-catenin/GSK3β pathway proteins of epileptic rats. A combination of MLT couldn't enhance the effect of VGB in prolonging the seizure latency but presented an additive effect in alleviating the seizures grading V and improving the behavioral performance in the BW. Crucially, the combination of MLT considerably reduced the retinal cell damage caused by VGB. These results suggested that MLT could be a beneficial combination for VGB in the treatment of epilepsy, which might provide fresh insight into the clinical application of VGB and MLT.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"153 ","pages":"Article 114516"},"PeriodicalIF":4.8,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143715233","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":"Corrigendum to “Brain-derived extracellular vesicles mediate systemic coagulopathy and inflammation after traumatic brain injury” [International Immunopharmacology 130 (2024) 111674]","authors":"Fanjian Li ,&nbsp;Lei Li ,&nbsp;Ruilong Peng ,&nbsp;Chuan Liu ,&nbsp;Xiao Liu ,&nbsp;Yafan Liu ,&nbsp;Cong Wang ,&nbsp;Jianye Xu ,&nbsp;Qiaoling Zhang ,&nbsp;Guili Yang ,&nbsp;Ying Li ,&nbsp;FangLian Chen ,&nbsp;Shenghui Li ,&nbsp;Weiyun Cui ,&nbsp;Li Liu ,&nbsp;Xin Xu ,&nbsp;Shu Zhang ,&nbsp;Zilong Zhao ,&nbsp;Jianning Zhang","doi":"10.1016/j.intimp.2025.114514","DOIUrl":"10.1016/j.intimp.2025.114514","url":null,"abstract":"","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"153 ","pages":"Article 114514"},"PeriodicalIF":4.8,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identifying cardiovascular toxicity associated with sphingosine 1-phosphate receptor modulators: A case-control study based on the FDA adverse event reporting system","authors":"Ying Li ,&nbsp;Jingmin Zhang ,&nbsp;Guangrui Yang ,&nbsp;Shujie Jiao ,&nbsp;Mingyuan Guan","doi":"10.1016/j.intimp.2025.114520","DOIUrl":"10.1016/j.intimp.2025.114520","url":null,"abstract":"<div><h3>Introduction</h3><div>Cardiovascular events represent a significant safety concern associated with sphingosine 1-phosphate receptor (S1PR) modulators. However, as S1PR modulators are primarily indicated for rare diseases characterized by multiple complex confounding factors, evidence regarding potential or long-term cardiovascular risks related to these drugs remains limited. This study aimed to comprehensively assess cardiovascular safety signals associated with S1PR modulators.</div></div><div><h3>Methods</h3><div>This case-control study was conducted based on the FDA adverse event reporting system (FAERS) database. The dataset included reports from September 10, 2010 to September 30, 2023. Reporting odds ratios (ROR) were calculated by logistic regression in four different models to examine the robustness of the results. Additionally, to assess adverse event profiles based on clinical trial data, a systematic literature review and subsequent data synthesis were conducted.</div></div><div><h3>Results</h3><div>We included 81,077 cases treated with S1PR modulators (median [IQR] age, 45 [36–54]; 60,245 [74.31 %] female), and 12,087,627 cases with no prior use of S1PR modulators as comparators. Besides signals of hypertension and bradyarrhythmias, QT interval prolongation in the fingolimod group (ROR = 1.92 [95 % CI, 1.73–2.12]; <em>P</em> &lt; 0.001), and central nervous system ischemia in the siponimod group (ROR = 1.26 [95 % CI, 1.04–1.52]; <em>P</em> = 0.02) were also detected in all models. Signals of tachyarrhythmias and ischaemic heart disease in the fingolimod group as well as QT interval prolongation in the siponimod group were consistent in all adjusted models.</div></div><div><h3>Conclusion</h3><div>In this study, signals of bradyarrhythmias, hypertension, QT interval prolongation, central nervous system ischemia, tachyarrhythmias, and ischaemic heart disease were significant with one or more S1PR modulators, which warrant clinical attention and ongoing monitoring.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"153 ","pages":"Article 114520"},"PeriodicalIF":4.8,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143706184","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":"Structural characterization of raw and wine-steamed Polygonatum cyrtonema Hua oligosaccharides and their bioactivity on immune regulation via modifying the gut microbiota","authors":"Shuanghui Shi ,&nbsp;Jingqiu Zhang ,&nbsp;Junli Zhang,&nbsp;Siyuan Ma,&nbsp;Yufeng Hu,&nbsp;Haiting Zhu,&nbsp;Huinan Wang,&nbsp;Mingrui Jiang,&nbsp;Yingzi Wang","doi":"10.1016/j.intimp.2025.114468","DOIUrl":"10.1016/j.intimp.2025.114468","url":null,"abstract":"<div><div><em>Polygonatum cyrtonema</em> Hua (PC) is a traditional Chinese medicine with a long history of use as pharmaceuticals or functional foods. Wine steaming is the main processing method of PC, which changes the structure of polysaccharides and oligosaccharides in PC and enhances biological activities. This study investigated the structural characterization of raw and wine-steamed PC oligosaccharides and the differences in the immunomodulatory effects using cyclophosphamide (CTX)-induced immunosuppression rat model. The oligosaccharides content and molecular weight of PC after wine steaming decreased, the proportion of oligosaccharides in total sugars and the reducing sugars content increased, and the monosaccharides composition of oligosaccharides changed. The raw <em>Polygonatum cyrtonema</em> Hua oligosaccharides (PCCO) and the wine-steamed <em>Polygonatum cyrtonema</em> Hua oligosaccharides (PCWO) exerted regulatory effects on organ index, immunoglobulin G (IgG), complement 3 (C3) spleen and colon tissue morphology, hematopoietic function of immunosuppressive rats treated by cyclophosphamide (CTX). Both PCCO and PCWO significantly regulated and improved the diversity and abundance of gut microbiota in immunosuppressed rats and increased the content of short-chain fatty acids (SCFAs) in the feces of rats, and the regulating effect of PCWO was better than PCCO. Differential microbiota analysis showed that PCWO could promote the proliferation of <em>Bifidobacterium</em>, <em>Bacteroides</em>, <em>Oscillibacter</em>, <em>Roseburia</em>, and <em>Alistipes</em>. In summary, the difference in the structural characteristics of PC oligosaccharides might be the reason for immune enhancement. This study could provide a theoretical basis for clarifying the scientific connotation of wine steaming to enhance the efficacy of PC, and promote the application of wine-steamed PC as an immunomodulator in pharmaceuticals or functional foods.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"153 ","pages":"Article 114468"},"PeriodicalIF":4.8,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143706186","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":"PM2.5 regulates TGF-β1/Smads-mediated pulmonary fibrosis via ROS/SnoN in vitro and in vivo","authors":"Xiaohong Li ,&nbsp;Xuan Ma ,&nbsp;Limin Zhang ,&nbsp;Wenbo Wu ,&nbsp;Ruixi Zhou ,&nbsp;Siqi Li ,&nbsp;Yumei Liu ,&nbsp;Fengjiao Tan ,&nbsp;Xiaolin Han ,&nbsp;Qin Wang ,&nbsp;Jinfeng Tan ,&nbsp;Li Yu ,&nbsp;Wanwei Li","doi":"10.1016/j.intimp.2025.114477","DOIUrl":"10.1016/j.intimp.2025.114477","url":null,"abstract":"<div><div>PM2.5 can result in a chronic lung disease, such as pulmonary fibrosis (PF), but the precise mechanism is unclear. In vivo, 40 male C57BL/6 mice were exposed to three concentrations of PM2.5 (0.5 mg/kg·Wt, 5 mg/kg·Wt and 8 mg/kg·Wt) and PM2.5 was administered by tracheal drip every three days for a total of 15 times. Then all mice were euthanized, blood and lung tissue were collected for testing of various indicators. In vitro, rat alveolar type II epithelial cells (RLE-6TN) were pretreated with different concentrations of PM2.5, ROS inhibitor (Vitamin C) and ubiquitin proteasome inhibitor (MG132) separately. Our results indicated that PM2.5 resulted in inflammation and oxidative stress, which in turn caused pathological damage and collagen deposition of lung tissue. In addition, exposure to PM2.5 increased TGF-β1 protein expression and Smad3 phosphorylation both in cells and in lung tissue, which involved collapse of antioxidant reduction system and degradation of SnoN. Additionally, in order to explored potential mechanisms, we used MG132 and VC pretreated cells and found that MG132 and VC pretreatment both inhibited ROS production, and increased SnoN protein expression levels. Further testing of EMT related indicators revealed that MG132 and VC pretreatment reversed the changes under PM2.5 exposure. Moreover, MG132 pretreatment reversed the increase of TGF-β1 protein expression and the Smad3 phosphorylation induced by PM2.5, but the effects were not as strong as those of VC pretreatment, which was related to the fact that VC inhibited both ROS production and SnoN degradation, which further clarifies the key role of ROS and SnoN in PM2.5-induced EMT. Therefore, this study conjectured that ROS/SnoN functioned as a key regulating factor in PM2.5-induced PF and EMT.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"153 ","pages":"Article 114477"},"PeriodicalIF":4.8,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143706185","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":"Prediction of a novel synthetic peptide vaccine against tuberculosis and validation of its immunogenicity","authors":"Dongdong Zhang ,&nbsp;Donghui Wang ,&nbsp;Shuo Jiang ,&nbsp;Yue Wan ,&nbsp;Yukun Zhao ,&nbsp;Weiqi Dong ,&nbsp;Xiaodi Li ,&nbsp;Lu Fu ,&nbsp;Wenhui Zhang","doi":"10.1016/j.intimp.2025.114531","DOIUrl":"10.1016/j.intimp.2025.114531","url":null,"abstract":"<div><h3>Background</h3><div>Tuberculosis (TB) is an infectious disease transmitted through the respiratory system that affects people worldwide. Bacillus Calmette-Guérin (BCG), the only approved TB vaccine, has been shown to have highly variable protective efficacy in different populations and is ineffective at protecting adults. Therefore, the development of more effective TB vaccines is vital.</div></div><div><h3>Methods</h3><div>Three dominant antigens (ESAT6, CFP10, and MPT64) from the region of difference were selected for this study. Their physicochemical properties, spatial structures, and immune responses were evaluated using bioinformatics screening of dominant T cell and B cell epitopes. Three vaccine constructs were developed. After selecting the appropriate linkers, their physicochemical properties, spatial structures, and immune responses of the vaccines were evaluated, and molecular dynamics simulations were performed to test their ability to bind to major histocompatibility complex (MHC) receptors within 100 ns.</div><div>This process aimed to create highly antigenic vaccine constructs capable of eliciting an immune response. The effects of the vaccine constructs on the host immune response were assessed using enzyme-linked immunosorbent assays, flow cytometry, and hematoxylin and eosin staining.</div></div><div><h3>Results</h3><div>A novel peptide vaccine, designated ECM-64, was developed by screening six immunodominant peptides from three antigens and constructing independent T-epitope and B-epitope vaccines. Compared weith BCG-immunized mice, ECM-64-immunized mice exhibited a substantial augmentation in Th1/Th2 cytokine secretion and CD3⁺CD4⁺T and CD3⁺CD8⁻T lymphocyte counts. ECM-64-specific IgG and IgG1 antibodies were produced after immunization. The immunoinformatics findings were largely consistent with those obtained from the analysis of immunized mice.</div></div><div><h3>Conclusion</h3><div>ECM-64 is a promising multipeptide TB vaccine with the advantage of inducing high levels of Th1/Th2 cytokines, antibodies, and CD3⁺CD4⁺T and CD3⁺CD8⁻T lymphocytes in mice. This study also provides preliminary evidence that bioinformatic methods can be used to screen for dominant epitopes.</div><div>These findings lay the groundwork for the development of peptide-based TB vaccines.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"153 ","pages":"Article 114531"},"PeriodicalIF":4.8,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143715140","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":"Screening and validation of active components in Rosa roxburghii Tratt for anti-pulmonary fibrosis based on a spectrum-effect relationship","authors":"Xiaomeng Wang ,&nbsp;Ting Zhou ,&nbsp;Shaolin Huang ,&nbsp;Heting Zhou ,&nbsp;Yihan Ling ,&nbsp;Tao Chen ,&nbsp;Shuwen Zhang ,&nbsp;Wenxi Wang ,&nbsp;Chuan Wu ,&nbsp;Wenya Yin","doi":"10.1016/j.intimp.2025.114536","DOIUrl":"10.1016/j.intimp.2025.114536","url":null,"abstract":"<div><div><em>Rosa roxburghii</em> Tratt (RRT), a fruit with dual medicinal and nutritional applications, exhibits therapeutic potential against pulmonary fibrosis, yet the specific bioactive constituents underlying this effect remain uncharacterized. This study employed an integrated spectrum-effect relationship to systematically identify RRT's principal anti-pulmonary fibrosis components. Our findings demonstrate that five different polar extracts of RRT (RRTEs) differentially attenuated bleomycin-induced pulmonary fibrosis in murine models, with the ethyl acetate fraction (EAE) showing superior therapeutic efficacy. HPLC-Q-Exactive Orbitrap MS identified 56 compounds, and screened out four active ingredients related to anti-pulmonary fibrosis by spectrum-effect relationship. In vitro experiments revealed that ellagic acid, gallic acid and syringic acid inhibited fibroblast migration, attenuated intracellular ROS overproduction, and downregulated the expression levels of α-SMA and collagen I. In summary, we established for the first time a spectrum-effect relationship between RRT and pulmonary fibrosis, elucidated the key components, and provided a foundation for future clinical applications.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"153 ","pages":"Article 114536"},"PeriodicalIF":4.8,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143715232","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":"A novel postoperative delayed neurocognitive recovery model established based on preoperative rapid eye movement sleep deprivation in adult mice","authors":"Kaixi Liu ,&nbsp;Jingshu Hong ,&nbsp;Yitong Li ,&nbsp;Qian Wang ,&nbsp;Rui Dong ,&nbsp;Taotao Liu ,&nbsp;Xiangyang Guo ,&nbsp;Lei Chen ,&nbsp;Zhengqian Li","doi":"10.1016/j.intimp.2025.114508","DOIUrl":"10.1016/j.intimp.2025.114508","url":null,"abstract":"<div><h3>Backgrounds</h3><div>Postoperative delayed neurocognitive recovery (dNCR) usually occurs in older patients, however, the extremely high cost of older animals has hindered postoperative dNCR research to some extent. Preoperative sleep disturbance increases the risk of postoperative dNCR in patients. Therefore, this study aimed to construct a dNCR model in adult mice based on preoperative sleep disturbance.</div></div><div><h3>Methods</h3><div>A modified multiple platform method was used to induce rapid eye movement sleep deprivation (REM-SD), and the surgical model was established by laparotomy in 3-month-old C57BL/6 J mice. The Morris water maze and fear conditioning test were used to assess the cognitive function of mice. Immunofluorescence was used to detect microglia and astrocyte activation, and quantitative real-time PCR was used to measure the mRNA levels of inflammatory cytokines.</div></div><div><h3>Results</h3><div>Neither laparotomy nor 12 h of REM-SD caused cognitive impairment in mice, but the combination of the two methods induced hippocampus-dependent cognitive dysfunction. Furthermore, hippocampal microglia of mice with 12 h of preoperative REM-SD were polarized to the M1-type, accompanied by increased interleukin-6 and decreased interleukin-10 at the mRNA level.</div></div><div><h3>Conclusions</h3><div>We successfully established an adult mouse model of postoperative dNCR based on preoperative REM-SD, which provides an alternative model to explore the pathogenesis and therapeutic measures of dNCR<!--> <!-->.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"153 ","pages":"Article 114508"},"PeriodicalIF":4.8,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143706278","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":"Metformin-mediated protection against Immunosenescence in diabetic cardiomyopathy: The potential roles of GDF-15 and klotho proteins","authors":"Ghada M. Almohaimeed ,&nbsp;Asma S. Alonazi ,&nbsp;Tahani K. Alshammari ,&nbsp;Anfal F. Bin Dayel ,&nbsp;Hanan K. Alghibiwi ,&nbsp;Maha A. Alamin ,&nbsp;Ahmad R. Almotairi ,&nbsp;Nasser A. Aldawsari ,&nbsp;Dalal A. Alkhelb ,&nbsp;Nawal M. Alrasheed ,&nbsp;Wedad S. Sarawi ,&nbsp;Nouf M. Alrasheed","doi":"10.1016/j.intimp.2025.114530","DOIUrl":"10.1016/j.intimp.2025.114530","url":null,"abstract":"<div><div>Diabetic cardiomyopathy (DCM) is a global health concern. However, studies examining the effect of metformin on diabetes-induced cardiac myocyte aging are lacking. This study aimed to investigate the protective effect of metformin against DCM involving modulation of macrophage phenotypes, growth differentiation factor-15 (GDF-15), and the anti-aging protein Klotho. Diabetes was induced in male Wistar rats using streptozotocin. Diabetic and nondiabetic rats were treated with metformin (200 mg/kg/day) and saline (control). DCM, inflammation, adhesion molecules, immunometabolic, and GDF-15 biomarkers were assessed using immunoassays. Western blotting was used to analyze Klotho expression. Macrophage phenotypes, senescence-associated-galactosidase (SA-β-gal), and p16^INK4a were examined using immunohistochemistry, whereas the heart sections were histologically examined. The untreated diabetic rats showed increased serum troponin I and creatine kinase-MB levels, reflecting cardiac damage, which was confirmed via morphological changes and senescence. Klotho expression was decreased, indicating cardiac aging. Treatment with metformin reduced the heart weight-body weight ratio and lowered cardiac injury, inflammation, and adhesion molecule biomarker levels. It also reversed the histopathological changes induced by diabetes. It shifted macrophage polarization toward the M2 phenotype, decreased p16^INK4a and SA-β-gal expression, and enhanced Klotho and GDF-15 expression. These findings revealed that diabetes induces cardiac aging by increasing senescence markers and decreasing the expression of Klotho. Metformin treatment protects against DCM by modulating macrophage phenotypes, attenuating immunosenescence-related dysregulation, and enhancing GDF-15 and Klotho expressions. Thus, metformin has potential clinical implications in alleviating DCM.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"153 ","pages":"Article 114530"},"PeriodicalIF":4.8,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143706323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}