European journal of pharmacology最新文献

CircPhc3 promotes the repair of intestinal mucosa after burn injury through the TRIM28-mediated hnRNPK SUMOylation stability modification mechanism. CircPhc3通过trim28介导的hnRNPK SUMOylation稳定性修饰机制促进烧伤后肠黏膜的修复。

IF 4.7 3区医学

European journal of pharmacology Pub Date : 2025-10-15 Epub Date: 2025-08-05 DOI: 10.1016/j.ejphar.2025.178029

Xiaoqing Xu, Yiwen Wang, Simiao Chen, Fanze Meng, Ran Li, Hao Zhang, Chao Meng, Mengmeng Zhuang, Yong Sun

{"title":"CircPhc3 promotes the repair of intestinal mucosa after burn injury through the TRIM28-mediated hnRNPK SUMOylation stability modification mechanism.","authors":"Xiaoqing Xu, Yiwen Wang, Simiao Chen, Fanze Meng, Ran Li, Hao Zhang, Chao Meng, Mengmeng Zhuang, Yong Sun","doi":"10.1016/j.ejphar.2025.178029","DOIUrl":"10.1016/j.ejphar.2025.178029","url":null,"abstract":"This paper investigates the mechanism of action of circPhc3 in the repair of intestinal mucosa in mice with severe burn injuries. The expression of circPhc3 is decreased in the intestinal mucosal tissue of these mice, and its overexpression may aid in the reconstruction of the damaged mucosa. The effects of circPhc3 on cell proliferation and migration were studied in MC38 cells, with an initial assessment of its repair function in mouse intestinal mucosa. Next, trap and mass spectrometry were used to identify heterogeneous nuclear ribonucleoprotein K (hnRNPK) as a potential target. RNA immunoprecipitation experiments confirmed the binding of circPhc3 to hnRNPK.The study highlights that the intracellular level of circPhc3 plays a crucial role in regulating the degradation and stability of hnRNPK expression. It also demonstrates that the E3 SUMO ligase, trimeric domain-containing protein 28 (TRIM28), acts as a promoter of hnRNPK stability. CircPhc3 facilitates TRIM28's binding to hnRNPK, thereby promoting hnRNPK SUMOylation. This modification inhibits ubiquitination and subsequent protein degradation.These findings reveal that SUMOylation modulates cellular hnRNPK levels and plays a key role in the mechanism of intestinal mucosal injury and repair following severe burn injuries. Furthermore, the interaction between hnRNPK SUMOylation and ubiquitination is essential for understanding intestinal mucosal repair. This study is the first to report the role of circPhc3 in promoting intestinal mucosal repair.","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"178029"},"PeriodicalIF":4.7,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144793823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Concomitant use of low molecular weight heparin mitigates bortezomib-induced peripheral Neuropathy: Analysis of the FDA adverse event reporting system. 同时使用低分子肝素减轻硼替佐米诱导的周围神经病变：FDA不良事件报告系统的分析。

IF 4.7 3区医学

European journal of pharmacology Pub Date : 2025-10-15 Epub Date: 2025-08-06 DOI: 10.1016/j.ejphar.2025.177989

Yibei Zhao, Sha Zhang, Jing Huang, Yaji Yang, Dongzhi Ran, Long Meng

{"title":"Concomitant use of low molecular weight heparin mitigates bortezomib-induced peripheral Neuropathy: Analysis of the FDA adverse event reporting system.","authors":"Yibei Zhao, Sha Zhang, Jing Huang, Yaji Yang, Dongzhi Ran, Long Meng","doi":"10.1016/j.ejphar.2025.177989","DOIUrl":"10.1016/j.ejphar.2025.177989","url":null,"abstract":"The concurrent use of bortezomib and anticoagulants, including heparin and low molecular weight heparin (LMWH), is increasingly common in the standard clinical management of multiple myeloma. Peripheral neuropathy (PN) is a common and significant toxicity associated with bortezomib. This study aimed to identify and characterize interaction signals for the concomitant use of bortezomib with heparin/LMWH, resulting in PN, using data mining of the FDA Adverse Event Reporting System (FAERS). Adverse event (AE) reports to FAERS were analyzed. We conducted disproportionality analysis to detect PN signals associated with the combined use of bortezomib and heparin/LMWH by estimating reporting odds ratio (ROR) with 95 % confidence interval (CI). Adjusted odds ratios (ORs) were calculated using logistic regression analysis (adjusting for age, sex, and reporting year), and the Ω shrinkage measure method was used to further confirm the findings. Subset data analysis was performed based on the use of heparin and LMWH as a specific drug. From 84,428 AE reports, including 2805 PN reports, the combined use of bortezomib and heparin/LMWH was associated with a lower PN reporting (OR = 1.852, 95 % CI, 1.098-3.126) compared to bortezomib monotherapy (OR = 3.809, 95 % CI, 3.435-4.224), indicating a significant interaction signal. The results remained significant according to the Ω shrinkage measure method. In the subset analyses, an interaction signal was identified for enoxaparin but not for heparin. FAERS data suggest that combining bortezomib and LMWH, specifically enoxaparin, is associated with a reduced risk of PN reporting. No significant interaction was found between bortezomib and heparin.","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"177989"},"PeriodicalIF":4.7,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144803909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Effect of the mGlu₂ receptor positive allosteric modulator AZD8529 on L-DOPA-induced dyskinesia and psychosis-like behaviours in the parkinsonian marmoset. mGlu2受体阳性变构调节剂AZD8529对左旋多巴诱导的帕金森狨猴运动障碍和精神病样行为的影响

IF 4.7 3区医学

European journal of pharmacology Pub Date : 2025-10-15 Epub Date: 2025-08-05 DOI: 10.1016/j.ejphar.2025.178031

Judy Shaqfah, Dominique Bédard, Stephen G Nuara, Jim C Gourdon, Adjia Hamadjida, Fleur Gaudette, Francis Beaudry, Philippe Huot

{"title":"Effect of the mGlu2 receptor positive allosteric modulator AZD8529 on L-DOPA-induced dyskinesia and psychosis-like behaviours in the parkinsonian marmoset.","authors":"Judy Shaqfah, Dominique Bédard, Stephen G Nuara, Jim C Gourdon, Adjia Hamadjida, Fleur Gaudette, Francis Beaudry, Philippe Huot","doi":"10.1016/j.ejphar.2025.178031","DOIUrl":"10.1016/j.ejphar.2025.178031","url":null,"abstract":"AZD8529 is a highly selective metabotropic glutamate 2 (mGlu2) receptor positive allosteric modulator (PAM) that has undergone clinical trials for schizophrenia and smoking cessation. Previously, we demonstrated that the selective mGlu2 receptor PAMs LY-487,379, CBiPES, and biphenylindanone A (BINA) alleviated L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia and psychosis-like behaviours (PLBs) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset model of Parkinson's disease (PD). However, these drugs are not clinical candidates because of their pharmacological properties, contrary to AZD8529 which could be repurposed if pre-clinically efficacious. To assess the effect of AZD8529 on L-DOPA-induced dyskinesia and PLBs in the MPTP-lesioned marmoset, we first determined the pharmacokinetic (PK) profile of AZD8529 in this species to inform dose selection such that drug plasma levels were clinically relevant. Then, MPTP-lesioned animals were treated with L-DOPA with either vehicle or AZD8529 (0.1, 0.3, 1, and 10 mg/kg). The results showed a reduction in global dyskinesia severity (up to 70 %, P < 0.001), and in duration of on-time with disabling dyskinesia (up to 97 %, P < 0.001) when compared to L-DOPA/vehicle. Similarly, there was a reduction in global PLB severity (up to 64 %, P < 0.001), and in duration of on-time with disabling PLBs (up to 94 %, P < 0.001) when compared to L-DOPA/vehicle. Additionally, AZD8529 increased the duration of the anti-parkinsonian action of L-DOPA at doses of 0.3 mg/kg and above (up to 29 %, P < 0.05). Our results further demonstrate the potential of AZD8529 and mGlu2 receptor positive allosteric modulation for alleviating L-DOPA-induced dyskinesia and PLBs while amplifying the therapeutic efficacy of L-DOPA.","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"178031"},"PeriodicalIF":4.7,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Feasibility of galectin-3 as a diagnostic biomarker and therapeutic target for inflammatory bowel disease. 半乳糖凝集素-3作为炎症性肠病的诊断生物标志物和治疗靶点的可行性

IF 4.7 3区医学

European journal of pharmacology Pub Date : 2025-10-15 Epub Date: 2025-08-05 DOI: 10.1016/j.ejphar.2025.178041

Xianglin Pan, Li Luo, Minni Wang, Huifan Yu, Ziming Zheng

引用次数: 0

Captopril alleviates radiation-induced pulmonary fibrosis by suppressing PAI-1 expression and cytoskeleton-dependent epithelial-to-mesenchymal transition. 卡托普利通过抑制PAI-1表达和细胞骨架依赖的上皮-间质转化来减轻辐射诱导的肺纤维化。

IF 4.7 3区医学

European journal of pharmacology Pub Date : 2025-10-15 Epub Date: 2025-08-06 DOI: 10.1016/j.ejphar.2025.178045

Chengcheng Xia, Lihong Shao, Lixin Ma, Yan Gao, Yuning Xin, Kexin Chen, Lihua Dong

{"title":"Captopril alleviates radiation-induced pulmonary fibrosis by suppressing PAI-1 expression and cytoskeleton-dependent epithelial-to-mesenchymal transition.","authors":"Chengcheng Xia, Lihong Shao, Lixin Ma, Yan Gao, Yuning Xin, Kexin Chen, Lihua Dong","doi":"10.1016/j.ejphar.2025.178045","DOIUrl":"10.1016/j.ejphar.2025.178045","url":null,"abstract":"Radiation-induced lung injury (RILI) remains a significant complication of thoracic radiotherapy, with radiation-induced pulmonary fibrosis (RIPF) representing a serious and irreversible outcome. Epithelial-mesenchymal transition (EMT) has emerged as a critical contributor to RIPF progression; however, the underlying mechanisms remain poorly understood. Captopril (Cap), an angiotensin-converting enzyme inhibitor with established cardiovascular benefits, has been demonstrated to show protective effects against RILI. In this study, we investigated the role of Cap in facilitating RIPF using in vivo and in vitro models. A RIPF model was established by delivering a single 20 Gy dose of thoracic irradiation to male C57BL/6 mice using a Varian linear accelerator. A549 cells were exposed to 8 Gy of 6 MV X-ray radiation to mimic epithelial injury. Cap alleviated pulmonary edema, preserved alveolar structure, and reduced fibrosis in irradiated mice. In vitro, Cap suppressed radiation-induced changes in cellular morphology and multinucleation formation. Immunofluorescence analyses revealed that Cap reversed radiation-induced F-actin depolymerization, cytokinesis failure, and multinucleation. Network pharmacology identified PAI-1 as a potential target of Cap. Cap suppressed radiation-induced cell swelling and PAI-1 expression. For the mechanism, Cap downregulated the JNK/c-Jun signaling axis, a known regulator of PAI-1 transcription. Inhibition of JNK/c-Jun recapitulated the effects of Cap, leading to reduced multinucleation, lower PAI-1 levels, and downregulation of EMT markers. In summary, Cap prevented RIPF by down regulating PAI-1 to suppress EMT via JNK/c-Jun pathway. It provided a novel and potential therapeutic strategy for the clinical prevention and treatment of RIPF.","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"178045"},"PeriodicalIF":4.7,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144803907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The novel effects of the cardiovascular drug ranolazine on the alleviation of age-related cognitive decline and the underlying mechanisms. 心血管药物雷诺嗪对减轻年龄相关认知衰退的新作用及其潜在机制。

IF 4.7 3区医学

European journal of pharmacology Pub Date : 2025-10-15 Epub Date: 2025-07-30 DOI: 10.1016/j.ejphar.2025.178007

Xiaohua Yue, Shufen Wu, Yiru Yin, Xin Zhao, Enhui Li, Geliang Liu, Xiang Zan, Qi Yu, Peifeng He, Ce Zhang

{"title":"The novel effects of the cardiovascular drug ranolazine on the alleviation of age-related cognitive decline and the underlying mechanisms.","authors":"Xiaohua Yue, Shufen Wu, Yiru Yin, Xin Zhao, Enhui Li, Geliang Liu, Xiang Zan, Qi Yu, Peifeng He, Ce Zhang","doi":"10.1016/j.ejphar.2025.178007","DOIUrl":"10.1016/j.ejphar.2025.178007","url":null,"abstract":"The cognitive decline associated with ageing is the most critical health issue affecting elderly individuals, and there is still a lack of effective interventions available. This study was designed to identify a drug capable of ameliorating age-related cognitive decline and the underlying mechanisms. Utilizing data mining of multisource databases and drug repositioning approaches based on transcriptome similarity, the cardiovascular drug ranolazine (Ran), was identified as a potential candidate with similar effects to those of resveratrol (RSV). Network pharmacology analysis predicted that Ran's effects on cognitive decline through the PI3K/AKT/mTOR signalling pathway. These predictions were subsequently verified using a combination of molecular, cellular, and tissue experiments, animal models of ageing induced by D-galactose, and omics studies. The results revealed that Ran extended the lifespan of Caenorhabditis elegans (C. elegans), improved the head swinging ability of ageing C. elegans, and alleviated mitochondrial membrane potential (MMP) damage in ageing hippocampal neuronal cells (HT22). In ageing rats, Ran not only enhanced spatial memory, exploratory behaviors and motor ability, but also alleviated mitochondrial structural damage in hippocampus and medial prefrontal cortex (mPFC). Notably, Ran alleviated age-related cognitive decline by regulating mitochondrial autophagy in hippocampus and mPFC through the PI3K/AKT/mTOR signalling pathway, rather than through its conventional mechanism of regulating fatty acid metabolism. In summary, this study reveals Ran's previously unrecognized role in alleviating age-related cognitive decline for the first time. These findings provide new options for the treatment of age-related cognitive decline and broaden the potential clinical applications of Ran.","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"178007"},"PeriodicalIF":4.7,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The proline isomerase Pin1 inhibitors PiB and juglone protect rats against lipopolysaccharide-induced respiratory inflammation. 脯氨酸异构酶Pin1抑制剂PiB和核桃酮可保护大鼠免受脂多糖诱导的呼吸道炎症。

IF 4.7 3区医学

European journal of pharmacology Pub Date : 2025-10-15 Epub Date: 2025-07-31 DOI: 10.1016/j.ejphar.2025.178025

Ahmed Kouki, Abdelaziz Souli, Salwa Bouabdallah, Wafa Ferjani, Pham My-Chan Dang, Mossadok Ben-Attia, Jamel El-Benna

{"title":"The proline isomerase Pin1 inhibitors PiB and juglone protect rats against lipopolysaccharide-induced respiratory inflammation.","authors":"Ahmed Kouki, Abdelaziz Souli, Salwa Bouabdallah, Wafa Ferjani, Pham My-Chan Dang, Mossadok Ben-Attia, Jamel El-Benna","doi":"10.1016/j.ejphar.2025.178025","DOIUrl":"10.1016/j.ejphar.2025.178025","url":null,"abstract":"The peptidyl-prolyl cis/trans-isomerase, NIMA-interacting 1 (Pin1), is involved in several cellular functions by changing the conformation and activity of phosphorylated proteins. Its key role in cellular signalling makes Pin1 an appealing target for the development of pharmacological agents to treat diseases such as inflammation. Pulmonary inflammation is a major disease resulting from the activation of immune cells by microbes or pollutants. In this study, we examined the effects of two Pin1 inhibitors, PiB and juglone, on lipopolysaccharide (LPS)-induced pulmonary inflammation in rats. Our results demonstrate that the intraperitoneal (i.p.) administration of 3 mg/kg of PiB and juglone mitigates LPS-induced pulmonary inflammation by reducing haemorrhage, vascular injury, pulmonary oedema and immune cell accumulation in the airway region. Furthermore, these Pin1 inhibitors were found to protect rats against the overproduction of inflammatory markers by inhibiting myeloperoxidase (MPO) and lactate dehydrogenase (LDH) activities, as well as reducing plasma C-reactive protein (C-RP). Additionally, PiB and juglone protected the rats from nitric oxide synthase (NOS) hyperactivity, preventing oxidative stress by decreasing pro-oxidant markers and restoring the antioxidant enzymes such as catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPx). The use of juglone and PiB could therefore be an effective means of alleviating acute respiratory inflammation by modulating inflammatory and oxidant pathways and preserving lung microstructure.","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"178025"},"PeriodicalIF":4.7,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Overview of the effects of astaxanthin on the male reproductive system focusing on mechanism underling its action. 综述虾青素对男性生殖系统的影响，重点探讨其作用机制。

IF 4.7 3区医学

European journal of pharmacology Pub Date : 2025-10-15 Epub Date: 2025-08-05 DOI: 10.1016/j.ejphar.2025.178033

Taha Ghantabpour, Saba Parvaneh, Houman Parsaie, Tina Ramzanian Gilani, Marzieh Sadat Tabaei, Fardin Amidi

{"title":"Overview of the effects of astaxanthin on the male reproductive system focusing on mechanism underling its action.","authors":"Taha Ghantabpour, Saba Parvaneh, Houman Parsaie, Tina Ramzanian Gilani, Marzieh Sadat Tabaei, Fardin Amidi","doi":"10.1016/j.ejphar.2025.178033","DOIUrl":"10.1016/j.ejphar.2025.178033","url":null,"abstract":"Male infertility is a serious public health concern, affecting nearly half of infertile couples. Oxidative stress (OS) is a biological condition noted as a key factor related to male infertility. This condition arises from an imbalance between reactive oxygen species (ROS) and antioxidative potential. Astaxanthin (AXT) is a lipid-soluble pigment with the high antioxidant activity compared to vitamin E and beta-carotene. It has been mentioned that AXT functions through antioxidative, anti-inflammatory, anti-apoptotic features. Several studies reported that AXT improves sperm parameters such as motility, viability, and morphology in in vivo and in vitro studies. This carotenoid reduces testosterone in prostate but increases it in testis and serum. In acute conditions such as testicular torsion, AXT has reduced oxidative damage, which is critical for preserving testicular function following torsion. Activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is a main factor involved in these three mechanisms. This review explores the therapeutic role of AXT in male reproductive health in normal and pathological situations, focusing on its molecular mechanisms. Overall, the evidence we have so far suggests that AXT can be used as a therapeutic option for male reproductive dysfunctions, highlighting the necessity for future clinical studies to confirm its efficacy and safety in humans.","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"178033"},"PeriodicalIF":4.7,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144774952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Metformin activates autophagy and inhibits apoptosis and fetal heart abnormalities via the Dnmt3l/Usp18/STAT1 pathway. 二甲双胍通过dnmt31 /Usp18/STAT1通路激活自噬，抑制细胞凋亡和胎儿心脏异常。

IF 4.7 3区医学

European journal of pharmacology Pub Date : 2025-10-15 Epub Date: 2025-07-28 DOI: 10.1016/j.ejphar.2025.177997

Ying Wei, Rui Meng, Xiaofeng Chen, Lina Guan, Jiale Yu, Yifan Wu, Cuige Shi, Jialing He, Dongmei Su, Xu Ma, Lei Sun

{"title":"Metformin activates autophagy and inhibits apoptosis and fetal heart abnormalities via the Dnmt3l/Usp18/STAT1 pathway.","authors":"Ying Wei, Rui Meng, Xiaofeng Chen, Lina Guan, Jiale Yu, Yifan Wu, Cuige Shi, Jialing He, Dongmei Su, Xu Ma, Lei Sun","doi":"10.1016/j.ejphar.2025.177997","DOIUrl":"10.1016/j.ejphar.2025.177997","url":null,"abstract":"Gestational diabetes mellitus (GDM) is an important risk factor for developing congenital heart disease (CHD). It is urgent to find therapeutic drugs that reduce blood glucose and protect patients from CHD. In this study, rat models of type 1 (intraperitoneal injection with 50 mg/kg streptozocin) and type 2 (high fat/high sugar diet for 5 weeks plus 28 mg/kg streptozocin) gestational diabetes were established. Metformin (MET) had more beneficial effects on reducing maternal blood glucose levels and increasing the number of fetuses in the type 2 model than the type 1 model. The type 2 model was chosen for further study. Histological, apoptosis and western blotting analyses showed that MET activated autophagy and reduced apoptosis of cardiomyocytes in diabetic rats. After RNA-sequencing, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses, Dnmt3l was selected as a potential effector of MET. Western blotting, CCK8 and Hoechst 33342 staining analyses showed that Dnmt3l played an important role in the effects of MET on activating autophagy and inhibiting the excessive apoptosis induced by high glucose. 2-NP (STAT1 activator) counteracted the effects of MET. Further studies showed that Dnmt3l mediated the actions of MET by regulating STAT1(Y701) phosphorylation, and this process also required Usp18, which had decreased expression in fetal heart tissues exposed to hyperglycemia. These results demonstrate the effect of MET on reducing maternal blood glucose, reveal its new role in protecting fetal heart abnormalities via the Dnmt3l/Usp18/STAT1 pathway, and provide a theoretical basis for the treatment of MET on GDM and CHD.","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"177997"},"PeriodicalIF":4.7,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

SAP30BP aggravates mitochondrial-related ferroptosis in diabetic cardiomyopathy by regulating MFN2-ACSL4 axis. SAP30BP通过调节MFN2-ACSL4轴加重糖尿病心肌病线粒体相关性铁下垂。

IF 4.7 3区医学

European journal of pharmacology Pub Date : 2025-10-15 Epub Date: 2025-08-06 DOI: 10.1016/j.ejphar.2025.178046

Tong Zhao, Chen Chen, Wenjie Zhao, Jingjing Han, Mohammad Omar Jan, Han Lou, Zhouxiu Chen, Xin Liu, Shenhong Jing

{"title":"SAP30BP aggravates mitochondrial-related ferroptosis in diabetic cardiomyopathy by regulating MFN2-ACSL4 axis.","authors":"Tong Zhao, Chen Chen, Wenjie Zhao, Jingjing Han, Mohammad Omar Jan, Han Lou, Zhouxiu Chen, Xin Liu, Shenhong Jing","doi":"10.1016/j.ejphar.2025.178046","DOIUrl":"10.1016/j.ejphar.2025.178046","url":null,"abstract":"Ferroptosis is characterized by iron overload and uncontrolled lipid peroxidation, which plays a substantial role in the development of diabetic cardiomyopathy (DCM). However, the exact factor responsible for inducing ferroptosis in DCM has not been fully elucidated. SAP30 binding protein (SAP30BP), a member of the HCNGP family, functions as a transcription regulator. Our research reveals a significant increase in SAP30BP expression in the hearts of DCM mice and cardiomyocytes treated with high glucose (HG). Knockdown of SAP30BP ameliorated cardiac dysfunction and inhibited ferroptosis and mitochondrial damage in DCM hearts. At the cellular levels, transfection of si-SAP30BP suppressed ferroptosis, as evidenced by the reduced oxidative stress, iron overload and lipid peroxidation. RNA-seq and GEO database analysis suggested that mitochondrial dynamics contributed to SAP30BP induced ferroptosis. Mechanistically, SAP30BP inhibited the transcription of MFN2 through HDAC1-mediated histone deacetylation, leading to mitochondrial dynamic disruption and dysfunction. This process ultimately hindered the mitochondrial translocation of ACSL4 and mitochondria-associated ferroptosis. Collectively, our findings demonstrate the therapeutic benefits of SAP30BP knockdown in DCM by effectively suppressing mitochondria-associated ferroptosis through the MFN2-ACSL4 pathway. These results provide new mechanistic insights and a basis for developing mitochondria and ferroptosis targeting therapies for DCM.","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"178046"},"PeriodicalIF":4.7,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144798553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0