International immunopharmacology最新文献

{"title":"Melatonin attenuates ischemia-reperfusion-induced acute kidney injury by regulating abnormal autophagy and pyroptosis through SIRT1-mediated p53 deacetylation","authors":"Chen Sun ,&nbsp;Jia Liu ,&nbsp;Hongjun Li ,&nbsp;Youyou Yan","doi":"10.1016/j.intimp.2025.115092","DOIUrl":"10.1016/j.intimp.2025.115092","url":null,"abstract":"<div><div>Ischemia-reperfusion (IR) injury is the leading cause of acute kidney injury (AKI), leading to deteriorated kidney function and high mortality. However, there are still no potent medications for IR-induced AKI. Pyroptosis is a type of inflammatory cell death that plays a significant role in IR-induced AKI, and inhibiting pyroptosis might be a promising therapeutic strategy. Melatonin has been reported to protect against IR-induced AKI and inhibit pyroptosis in various diseases. Moreover, Autophagy inhibits pyroptosis, which is affected by melatonin via up-regulation of SIRT1. SIRT1 mediates the p53 deacetylation, which can promote autophagy. However, the role of melatonin in regulating autophagy and pyroptosis through the SIRT1/p53 pathway in lessening IR-induced AKI is yet to be elucidated. Our data showed that melatonin significantly reduced IR or OGD/R-induced renal damage by inhibiting pyroptosis and promoting autophagy. Inhibition of autophagy by 3-methyladenine (3-MA) countered the protective effect of melatonin on inhibiting OGD/R-induced pyroptosis, ROS, and lactate dehydrogenase (LDH) productions in HK2 cells. In addition, SIRT1 was decreased by IR or OGD/R stimulation, which was significantly alleviated by melatonin treatment. Mechanistically, melatonin alleviates IR-induced AKI by activating autophagy to inhibit pyroptosis through SIRT1-mediated p53 deacetylation and nuclear translocation. Our data demonstrated the mechanism and potential therapeutics of melatonin in IR-induced AKI.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"162 ","pages":"Article 115092"},"PeriodicalIF":4.8,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144366182","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":"Dissecting the role of SPRY4-IT1 and TUG1 in modulating miR-425/TGF-β/ Smad signaling in mediating renal fibrosis and inflammation in lupus nephritis: Novel biomarkers and therapeutic targets","authors":"Mai A. Abd-Elmawla ,&nbsp;Mahmoud Zidan ,&nbsp;Yumn A. Elsabagh ,&nbsp;Nourhan Elfar ,&nbsp;Abdullah F. Radwan","doi":"10.1016/j.intimp.2025.115132","DOIUrl":"10.1016/j.intimp.2025.115132","url":null,"abstract":"<div><div>Lupus nephritis (LN), the severe complication of systemic lupus erythematosus (SLE), is driven by inflammation and fibrosis, often leading to chronic kidney diseases. The current study aimed to elucidate the roles of long non-coding RNAs (lncRNAs) <em>SPRY4-IT1</em> and <em>TUG1</em>, and <em>miR-425</em> in modulating the TGF-β/Smad signaling pathway and to assess their potential as biomarkers and therapeutic targets. A case-control study was conducted involving 100 participants, including LN patients (<em>n</em> = 35), SLE patients without LN (n = 35), and healthy controls (<em>n</em> = 30). Serum expression levels of <em>SPRY4-IT1</em>, <em>TUG1</em>, miR-425 and Smads were measured using qRT-PCR, while TGF-β, fibronectin,TNF-α and PIIINP were analyzed via ELISA. The results showed a significant upregulation of <em>SPRY4-IT1</em> and <em>TUG1</em> and a downregulation of <em>miR-425</em> in LN patients compared to controls (<em>p</em> &lt; 0.01). These ncRNAs demonstrated strong correlations with TGF-β, Smad2/3, and other fibrotic markers, while inversely correlating with miR-425. ROC curve analysis identified <em>SPRY4-IT1</em> as the most robust diagnostic marker (AUC = 0.85, sensitivity = 82 %, specificity = 70 %). Pathway analyses confirmed their involvement in inflammatory and fibrotic processes. These findings suggest that <em>SPRY4-IT1</em> and <em>TUG1</em> contribute to LN pathogenesis through the <em>miR-425</em>/TGF-β/Smad axis, underscoring their potential as novel diagnostic and therapeutic targets. Further research in larger cohorts is warranted to validate these findings and explore clinical applications.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"162 ","pages":"Article 115132"},"PeriodicalIF":4.8,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144366181","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":"Crocetin, a versatile carotenoid: Novel insights into pharmacological effects, molecular mechanisms, and therapeutic potential","authors":"Liping Liu ,&nbsp;Fan Qiu ,&nbsp;Dawei Wu ,&nbsp;Tingyu Ding ,&nbsp;Wenying Zhang ,&nbsp;Yuelei Mao ,&nbsp;Ke Xu ,&nbsp;Fengying Diao ,&nbsp;Huiying Yang ,&nbsp;Yunjia Wu ,&nbsp;Yuhang Zhang ,&nbsp;Lei Zhang ,&nbsp;Qin Wu","doi":"10.1016/j.intimp.2025.115125","DOIUrl":"10.1016/j.intimp.2025.115125","url":null,"abstract":"<div><div>Plant-derived natural products have emerged as indispensable resources in modern drug discovery, and demonstrated remarkable potential across diverse disease domains. As a representative bioactive carotenoid, crocetin features a unique polyunsaturated oleic acid structure, extracted from the stigma of <em>Crocus sativus</em> L. Recent studies have revealed that crocetin has multiple pharmacological effects and biological activities, including anti-tumor, hepatoprotective, analgesic, neuroprotective, cardioprotective, anti-radiation and other protective effects. The present comprehensive review synthesizes cutting-edge advances in crocetin research, systematically evaluating its multifaceted pharmacological actions, pharmacokinetic profiles and dose-dependent toxicity thresholds. Particularly noteworthy is our mechanistic elucidation of crocetin's disease-modulating capabilities, which offers promising research prospects for the development and utilization of the medicinal value of crocetin.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"162 ","pages":"Article 115125"},"PeriodicalIF":4.8,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144366289","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":"Kaempferol improves mitochondrial homeostasis via mitochondrial dynamics and mitophagy in diabetic kidney disease","authors":"Chenhui Xia ,&nbsp;Jiale Zhang ,&nbsp;Huixi Chen ,&nbsp;Weimin Jiang ,&nbsp;Shaofeng Zhou ,&nbsp;Huijuan Zheng ,&nbsp;Weiwei Sun","doi":"10.1016/j.intimp.2025.115121","DOIUrl":"10.1016/j.intimp.2025.115121","url":null,"abstract":"<div><div>Mitochondrial homeostasis imbalance plays an important role in the development of diabetic kidney disease (DKD). Kaempferol is a key bioactive compound widely present in the rhizomes of <em>Kaempferia</em> L. and vegetables. Its anti-inflammatory and antioxidant properties have gained increasing attention in treating various metabolic diseases. This study investigated whether kaempferol could improve mitochondrial structure and function by regulating mitochondrial dynamics and mitophagy in DKD. A DKD rat model was established <em>via</em> unilateral nephrectomy and streptozotocin injection. Renal function, histopathology, and inflammatory factors were assessed, along with fibrosis, apoptosis, mitochondrial dynamics, and mitophagy-related proteins. Meanwhile, an AGEs-induced HK-2 cell injury model was used to evaluate autophagic flux and mitochondrial function and morphology through ad-mCherry-GFP-LC3B transduction, JC-1 staining, and MitoTracker probes. <em>In vivo</em> results showed that kaempferol exhibited significant anti-inflammatory, anti-apoptotic, and anti-fibrotic effects in DKD rats. Moreover, kaempferol demonstrated good safety by alleviating hepatic fibrosis. It also restored mitochondrial dynamics by promoting the upregulation of mitochondrial fusion proteins (Mfn1, OPA1) and the downregulation of fission proteins (Drp1, Fis1). In addition, kaempferol enhanced mitochondrial biogenesis by upregulating PGC-1α and TFAM. Notably, kaempferol reactivated mitophagy, as evidenced by increased levels of PINK1, Parkin, LC3, Beclin1, and ATG5, along with a reduction in p62 levels. <em>In vitro</em>, kaempferol further demonstrated its antioxidative potential by increasing SOD levels and decreasing MDA levels. Additionally, it promoted autophagic induction and facilitated the fusion of autophagosomes with lysosomes. These combined effects led to the restoration of mitochondrial membrane potential and structural integrity, while reducing ROS production and enhancing ATP generation. In conclusion, kaempferol promotes mitochondrial fusion, restores mitophagy, enhances autophagy flux, and facilitates mitochondrial clearance, showing the potential to mitigate kidney injury and slow disease progression in DKD.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"162 ","pages":"Article 115121"},"PeriodicalIF":4.8,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144364880","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":"Kaempferol alleviates sepsis related acute lung injury by inhibiting the activation of alveolar macrophages mediated by extracellular vesicles from alveolar epithelial cells","authors":"Bailun Wang ,&nbsp;Angran Gu ,&nbsp;Jie Yan ,&nbsp;Yi Zhang,&nbsp;Jifa Liu,&nbsp;Chang Sun,&nbsp;Yi Wei,&nbsp;Changping Gu,&nbsp;Yuelan Wang","doi":"10.1016/j.intimp.2025.115130","DOIUrl":"10.1016/j.intimp.2025.115130","url":null,"abstract":"<div><div>Acute lung injury (ALI) is the most serious complication of sepsis, but there is currently a lack of effective treatment methods. Therefore, finding drugs to treat sepsis induced acute lung injury (SALI) is an urgent clinical problem that needs to be solved. Kaempferol has been proven to have therapeutic effects on various lung diseases. We used cecal ligation puncture (CLP) method to create a mouse model of sepsis. Mouse plasma exosomes and exosomes secreted by alveolar epithelial cells were injected into mice via tail vein, western blotting, PCR, flow cytometry, and other techniques were used to detect lung injury and macrophage activation in mice. Our research shows that the therapeutic effect of kaempferol in alleviating SALI partially depends on the extracellular vesicle mechanism. Compared with the Control group, the CLP group mice showed an increase in plasma exosome content, and these plasma exosomes gathered more in the lungs and promoted overactivation of alveolar macrophages. However, treatment with kaempferol reduced the levels of plasma exosomes in CLP mice and inhibited the harmful effects of exosomes on alveolar macrophages and lung tissue. Through biological information analysis and in vitro and in vivo experiments, we further discovered that the plasma exosomes affected by kaempferol exert their effects by inhibiting the MAPK signaling pathway, and these effects were amplified by MAPK inhibitors. And we found that the plasma exosomes affected by kaempferol come from alveolar epithelial cells. This study suggests that kaempferol can alleviate SALI by reducing the MAPK signaling pathway mediated by extracellular vesicles in alveolar epithelial cells and inhibiting macrophage activation.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"162 ","pages":"Article 115130"},"PeriodicalIF":4.8,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144366291","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":"Vitamin D against diabetic adipose tissue inflammation through SHP-1/STAT3 pathway","authors":"Xiaonuo Wei ,&nbsp;Yulin Wang ,&nbsp;Wenyi Liu ,&nbsp;Dongdong Zhang ,&nbsp;Chunyu Zhou ,&nbsp;Zhongyan Jiang ,&nbsp;Wenjie Li ,&nbsp;Xing Li ,&nbsp;Yufan Miao","doi":"10.1016/j.intimp.2025.115131","DOIUrl":"10.1016/j.intimp.2025.115131","url":null,"abstract":"<div><h3>Purpose</h3><div>This study aimed to investigate the anti-inflammatory effects of vitamin D (VD) on adipose tissue in type 2 diabetes mellitus (T2DM), with a particular focus on its regulation of macrophage polarization and the SHP-1/STAT3 signaling pathway.</div></div><div><h3>Methods</h3><div>A T2DM rat model was induced in 4-week-old Sprague-Dawley rats by feeding a high-fat diet followed by a low-dose streptozotocin injection. After successful model induction, the diabetic rats were treated with varying doses of vitamin D3 (VD3) for 10 weeks to evaluate its effects on adipose tissue inflammation associated with T2DM. To further elucidate the underlying mechanisms, high-glucose (HG)-stimulated RAW264.7 macrophages were employed as an in vitro model to investigate the anti-inflammatory effects of 1,25(OH)₂D₃, with particular emphasis on the SHP-1/STAT3 signaling pathway.</div></div><div><h3>Results</h3><div>VD3 treatment significantly improved body weight, reduced water intake and urine output, and alleviated hyperglycemia and dyslipidemia in T2DM rats (<em>P</em> &lt; 0.05). Histological analysis revealed restored adipocyte morphology and reduced expression of inflammatory cytokines (TNF-α, IL-6, TGF-β1, MCP-1; <em>P</em> &lt; 0.05). Immunofluorescence and protein analyses demonstrated that VD3 inhibited M1 macrophage polarization and enhanced the M2 phenotype. Moreover, VD3 upregulated SHP-1 expression while downregulating p-STAT3 in adipose tissue (<em>P</em> &lt; 0.05). In vitro, 1,25(OH)₂D₃ restored cell viability, suppressed pro-inflammatory cytokine production, and promoted M2 polarization under HG conditions (<em>P</em> &lt; 0.05). Inhibition of SHP-1 using TPI-1 abrogated these effects, whereas STAT3 inhibition with stattic further enhanced the anti-inflammatory responses (<em>P</em> &lt; 0.05).</div></div><div><h3>Conclusion</h3><div>VD mitigates adipose tissue inflammation and metabolic dysfunction in T2DM by regulating macrophage polarization via the SHP-1/STAT3 signaling pathway.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"162 ","pages":"Article 115131"},"PeriodicalIF":4.8,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144366290","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":"Unraveling the therapeutic mechanisms of Bufei Yiqi decoction in pulmonary fibrosis: Modulation of autophagy and glycolysis pathways","authors":"Huimin Chen ,&nbsp;Zhenzhen Zhang ,&nbsp;Yuanying Song ,&nbsp;Qing Hu ,&nbsp;Dexi Jin ,&nbsp;Shan Liu ,&nbsp;Jiayi Zu ,&nbsp;Lin Zhang ,&nbsp;Mengting Ke ,&nbsp;Longyun Chen ,&nbsp;Aiyue Hu","doi":"10.1016/j.intimp.2025.115030","DOIUrl":"10.1016/j.intimp.2025.115030","url":null,"abstract":"<div><div>Pulmonary fibrosis (PF) is a chronic, progressive lung disease marked by excessive collagen deposition and inflammation. Bufei Yiqi Decoction (BFYQD), a traditional Chinese herbal formula, has shown potential in treating PF, but its mechanisms remain unclear. This study aimed to explore BFYQD's therapeutic effects on PF, focusing on its regulation of glycolysis and autophagy via the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway, providing a foundation for its clinical application. A PF mouse model was established using bleomycin (BLM). Nontargeted metabolomics, network pharmacology, and transcriptomics were integrated to identify dysregulated pathways. Molecular docking assessed binding affinities between BFYQD compounds and targets. Western blot, biochemical assays, and histopathological staining validated findings. Serum metabolomics identified bioactive compounds. Multi-omics analysis revealed PI3K/Akt as a key regulator of glycolysis in PF. Quercetin, kaempferol, and glabridin were identified as bioactive compounds in BFYQD, showing strong binding to PI3K/Akt pathway proteins. BFYQD suppressed PI3K, Akt, mTOR, and HIF-1α phosphorylation, reducing glycolysis and enhancing autophagy. Histopathological analysis confirmed reduced fibrosis and epithelial-mesenchymal transition (EMT). BFYQD alleviates PF by modulating glycolysis and autophagy via the PI3K/Akt pathway. Its bioactive compounds, such as quercetin and kaempferol, offer a novel therapeutic strategy for PF.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"162 ","pages":"Article 115030"},"PeriodicalIF":4.8,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144364878","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":"Immune regulation of TLR4/MYD88/ NF-κB/AP1/IL-6 pathway and modulation of aldosterone/PPARα receptors by eplerenone and fenofibrate in ovarian ischemia reperfusion induced injury","authors":"Marwa Monier Mahmoud Refaie ,&nbsp;Elshymaa A. Abdel-Hakeem ,&nbsp;Sayed Shehata ,&nbsp;Shereen Mohammed Mohammed Elsaghir ,&nbsp;Sahar Ahmed Mokhemer ,&nbsp;Nagwa Zenhom Mustafa Ahmed ,&nbsp;Samar Hisham Elsayed ,&nbsp;Aya Aly Ashraf Abdel Mageed ,&nbsp;Heba Reda Mohamed ,&nbsp;Heba A. Shawky ,&nbsp;Doaa Mohamed Elroby Ali","doi":"10.1016/j.intimp.2025.115113","DOIUrl":"10.1016/j.intimp.2025.115113","url":null,"abstract":"<div><h3>Background</h3><div>The immune system is deeply involved in the pathogenesis of different gynecological disorders including ovarian torsion that commonly occurs during surgical manipulation or within ovarian masses, affecting not only the ovaries, but it has remote effect on different organs particularly cardiac tissue. Early intervention and proper medical treatment are so important to preserve the ovaries and prevent distant organ damage. Accordingly, the aim of this work was to evaluate the possible ameliorative role of eplerenone (EPL) or fenofibrate (FEN) on ovarian and cardiac affection in an experimental model of ovarian ischemia/reperfusion (OIR).</div></div><div><h3>Method</h3><div>Fifty female Wistar albino rats were divided into five groups (<em>n</em> = 10); control, OIR induced group, OIR plus EPL (100 mg/kg), OIR plus FEN (300 mg/kg), OIR plus EPL (100 mg/kg) plus FEN (300 mg/kg).</div></div><div><h3>Results</h3><div>OIR could induce ovarian injury with remote cardiac damage. Data of current study revealed significant increases of the cardiac enzymes, and malondialdehyde (MDA) levels but decreases of total anti-oxidant capacity (TAC) and reduced glutathione (GSH) levels. Moreover, there were increases in toll like receptor 4 (TLR4), myeloid differentiation primary response 88 (MYD88), activation protein 1 (AP1), interleukin 6 (IL-6), nuclear factor kappa b (NF-κB) and cleaved caspase-3 with abnormal histological features. However, EPL or FEN co-administration alone or in combination reversed OIR damaging effects by antagonizing aldosterone action by EPL, anti-inflammatory, anti-oxidant, and anti-apoptotic features with modulation of peroxisome proliferator activated receptor alpha (PPARα) by FEN and TLR4/MYD88/ NF-κB/AP1/IL-6 pathway. Interestingly, co-administration of both drugs showed more improvement than giving each one alone.</div></div><div><h3>Conclusion</h3><div>EPL and/or FEN had ameliorative properties against OIR induced harmful effects.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"162 ","pages":"Article 115113"},"PeriodicalIF":4.8,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144364698","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":"1,25-dihydroxyvitamin D3 attenuates type 1 diabetes-related myocardial apoptosis and fibrosis by influencing the interaction of FoxO1 and p-Smad3","authors":"Tiantian Zhang ,&nbsp;Junwei Hu ,&nbsp;Zhichi Li ,&nbsp;Tingting Tian ,&nbsp;Runnian Huang ,&nbsp;Na Li ,&nbsp;Difei Wang","doi":"10.1016/j.intimp.2025.115128","DOIUrl":"10.1016/j.intimp.2025.115128","url":null,"abstract":"<div><div>Diabetic cardiomyopathy (DCM) is one of the most important complications of diabetes. Vitamin D deficiency further increases the risk of heart failure (HF) and death in patients with diabetes. This study aimed at investigating the role of 1,25D3 in alleviating type 1 diabetes-related myocardial apoptosis and fibrosis by influencing the interaction of FoxO1 and p-Smad3. First, we found that vitamin D deficiency augments the risk of HF associated with elevated HbA1c in community-dwelling older adults. 1,25D3 partially ameliorated cardiac function and histological structural changes and reduced the expression levels of myocardial apoptosis and fibrosis proteins in streptozotocin-induced type 1 diabetes mouse model. In H9c2 cells, 1,25D3 treatment inhibited the expression of apoptosis and fibrosis marker proteins induced by high glucose (HG) in a dose-dependent manner. In addition, 1,25D3 treatment inhibited HG-stimulated FoxO1 and Smad3 signalling <em>in vivo</em> and <em>in vitro</em>. However, the cardioprotective effects of 1,25D3 were eliminated by FoxO1 overexpression. The co-immunoprecipitation experiments demonstrated that the interaction between p-Smad3 and FoxO1 proteins and 1,25D3 or FoxO1 inhibitor AS1842856 (AS) treatment could effectively suppress this association and the mRNA level of fibrotic gene Col-1. Our data suggest that 1,25D3 attenuates myocardial apoptosis and fibrosis in DCM by inhibiting the interaction between FoxO1 and p-Smad3. This study proposes a new mechanism and strongly supports the idea that 1,25D3 may be effective as a therapeutic agent for DCM.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"162 ","pages":"Article 115128"},"PeriodicalIF":4.8,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144364881","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":"Inhibition of phosphodiesterase-4 by rolipram alleviates anxiety-like behavior in mice with PTSD by modulating neuroinflammation and synaptic plasticity via cAMP signaling","authors":"Yuanyuan Lin ,&nbsp;Shengyao Ma ,&nbsp;Rongzhen Sun ,&nbsp;Mingcui Ruan,&nbsp;Fang Zhang,&nbsp;Han-Ting Zhang","doi":"10.1016/j.intimp.2025.115116","DOIUrl":"10.1016/j.intimp.2025.115116","url":null,"abstract":"<div><h3>Background</h3><div>Post-traumatic stress disorder (PTSD) is a mental disorder in which individuals exhibit fear and anxiety due to recurrent painful memories. Rolipram, a PDE4 inhibitor, exerts neuroprotective effects via anti-neuroinflammation, yet the role of PDE4 in PTSD pathogenesis remains unclear. This was addressed by exploring the molecular mechanisms through which rolipram exerts its therapeutic effects in PTSD.</div></div><div><h3>Methods</h3><div>The PTSD mouse model was established by a combined protocol of single prolonged stress and footshock (SPS&amp;FS). The activity of PDE4 in the brain was measured using high-performance liquid chromatography (HPLC). The behavioral effects of rolipram (1 mg/kg/d for 14 d) on the PTSD model were assessed by behavioral tests. Additionally, the impact of rolipram on neuroinflammation and synaptic deficits was evaluated in these mice using a combination of biochemical assays and morphological analyses.</div></div><div><h3>Results</h3><div>The PTSD mice showed abnormal behavioral changes, increased PDE4 activity, elevated levels of inflammation, and synaptic deficits. Administration of rolipram (1 mg/kg/d, i.p.) restored cAMP/PKA signaling, reduced the release of pro-inflammatory cytokines (IL-6 and IL-1β) and inhibited microglial activation in PTSD mice. Additionally, rolipram ameliorated PTSD-like behaviors and synaptic defects. The neuroprotective and anti-inflammatory effects of rolipram were abolished by co-treatment with the PKA inhibitor H89.</div></div><div><h3>Conclusion</h3><div>In summary, we demonstrated that rolipram ameliorated PTSD-like behavioral abnormalities, neuroinflammatory responses, and hippocampal synaptic deficits by activating the cAMP-PKA signaling pathway. These results suggest that PDE4 inhibition may serve as a promising therapeutic strategy for PTSD.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"162 ","pages":"Article 115116"},"PeriodicalIF":4.8,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144330895","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}