Biochemical pharmacology最新文献_第3页

Targeting DOT1L-mediated histone methylation by hesperetin alleviates retinal microvascular endothelial cell dysfunction and diabetic retinopathy. 橙皮苷靶向dot1l介导的组蛋白甲基化可减轻视网膜微血管内皮细胞功能障碍和糖尿病视网膜病变。

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2025-10-03 DOI: 10.1016/j.bcp.2025.117402

Zhu-Jun Mao, Shi-Yu Liu, Tian Lan, Xi-Xi Zeng, Ling-Lin Zhou, Ping Li, Yu-Hua Tong, Si-Wei Wang

{"title":"Targeting DOT1L-mediated histone methylation by hesperetin alleviates retinal microvascular endothelial cell dysfunction and diabetic retinopathy.","authors":"Zhu-Jun Mao, Shi-Yu Liu, Tian Lan, Xi-Xi Zeng, Ling-Lin Zhou, Ping Li, Yu-Hua Tong, Si-Wei Wang","doi":"10.1016/j.bcp.2025.117402","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.117402","url":null,"abstract":"<p><p>The role of disruptor of telomeric silencing-1 like (DOT1L) mediated histone methylation in the pathophysiology of diabetic retinopathy (DR) and retinal microvascular endothelial (RME) cell dysfunction remains inadequately elucidated. In this study, we demonstrate that the attenuation of RME cell dysfunction was observed upon either knockdown or inhibition of DOT1L, which was correlated with a downregulation of fatty acid synthase (FASN) and sterol regulatory element-binding protein 1 (SREBF1) expression through histone methylation-dependent mechanisms. Furthermore, targeted knockdown of DOT1L was found to alleviate the progression of DR in diabetic murine models. Importantly, the flavonoid hesperetin (Hes) demonstrated the ability to directly interact with DOT1L, thereby inhibiting its enzymatic activity, which in turn ameliorated RME cell dysfunction and decreased FASN and SREBF1 expression via histone methylation mechanisms. These findings not only position DOT1L as a novel therapeutic target for intervention in DR but also identify Hes as a promising lead compound for future DR therapeutic strategies.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"117402"},"PeriodicalIF":5.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231591","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}

引用次数: 0

ACOD1/Itaconate regulates trophoblast function through the PI3K/Akt/FOLR1 axis to participate in the pathogenesis of recurrent spontaneous abortion. ACOD1/Itaconate通过PI3K/Akt/FOLR1轴调控滋养细胞功能参与复发性自然流产的发病机制。

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2025-10-03 DOI: 10.1016/j.bcp.2025.117405

Tingting Feng, Shujuan Wu, Jianye Fang, Jinli Ding, Fujin Shen, Jing Yang

{"title":"ACOD1/Itaconate regulates trophoblast function through the PI3K/Akt/FOLR1 axis to participate in the pathogenesis of recurrent spontaneous abortion.","authors":"Tingting Feng, Shujuan Wu, Jianye Fang, Jinli Ding, Fujin Shen, Jing Yang","doi":"10.1016/j.bcp.2025.117405","DOIUrl":"10.1016/j.bcp.2025.117405","url":null,"abstract":"<p><p>The pathogenesis of recurrent spontaneous abortion (RSA) remains unclear. Our research focused on Aconitate decarboxylase 1 (Acod1) and discovered its role in RSA. Western blotting, qPCR, and immunohistochemistry results indicated that Acod1 was markedly upregulated in villous tissues of RSA patients. On one hand, overexpression of Acod1 inhibited the invasion and migration abilities of trophoblast cell lines. Screening for differentially expressed genes related to cell migration, folate receptor 1 (FOLR1) was significantly downregulated after Acod1 overexpression. Overexpression of FOLR1 restored the invasion and migration abilities of trophoblast cells. On the other hand, when trophoblast cells were co-cultured with macrophages, trophoblast cells overexpressing Acod1 promoted the polarization of macrophages towards the M1 phenotype. Acod1 mainly exerted its function by catalyzing the production of excessive itaconate (ITA). Further analysis of KEGG results revealed that PI3K/Akt was the main mechanism of Acod1/Itaconate action. Overexpression of Acod1 or addition of exogenous itaconate inhibited the phosphorylation of PI3K and Akt. We also found that Acod1 was abnormally elevated in decidual macrophages, and macrophages overexpressing Acod1 further impaired the invasion and migration abilities of trophoblast cells. Injecting itaconate into pregnant mice increased the embryo resorption rate in mice. Exploring the mechanism of itaconate's action revealed that PI3K did not directly interact with itaconate. Itaconate might regulate the signal transduction by alkylating cysteine residues of upstream proteins such as IL21R or Oncostatin M receptor. Our research revealed the possible role of Acod1/Itaconate in RSA, and it may become a target for future intervention and treatment.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"117405"},"PeriodicalIF":5.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231457","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}

引用次数: 0

Tyrphostin AG538 inhibits platelet activation and thrombosis via TREM2 agonism. Tyrphostin AG538通过TREM2激动作用抑制血小板活化和血栓形成。

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2025-10-02 DOI: 10.1016/j.bcp.2025.117379

Qian Liu, Qingyuan Yang, Yixian Wang, Changran Liu, Meina Jin, Dongxing Chen, Zhongren Ding

{"title":"Tyrphostin AG538 inhibits platelet activation and thrombosis via TREM2 agonism.","authors":"Qian Liu, Qingyuan Yang, Yixian Wang, Changran Liu, Meina Jin, Dongxing Chen, Zhongren Ding","doi":"10.1016/j.bcp.2025.117379","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.117379","url":null,"abstract":"<p><p>Arterial thrombotic diseases remain a major threat to human health. Given the critical role of platelets in thrombus formation, dysregulated platelet activity can result in either hemorrhagic or ischemic complications. Although current antiplatelet therapies are effective, their use is often limited by bleeding risks, highlighting the need for novel antiplatelet agents that can prevent thrombosis with minimal hemostatic disruption. We recently reported that TREM2 (triggering receptor expressed on myeloid cells 2) as a negative regulator of platelet activation and thrombosis. In this study, we demonstrate that Tyrphostin AG538 functions as a platelet TREM2 receptor agonist. Molecular docking, SPR (surface plasmon resonance) assay, and experiments using platelets from TREM2 knockout mice confirm that AG538 directly binds TREM2. AG538 inhibited platelet aggregation, dense granule release of human and mouse platelets, and impaired platelet spreading and clot retraction. Oral administration of AG538 suppressed collagen-induced platelet activation in mice. Moreover, AG538 significantly reduced arterial thrombus formation in mesenteric arteriole injury model and alleviated pulmonary embolism, without increasing bleeding. Mechanistically, as a TREM2 agonist, AG538 inhibits the downstream SHIP1 (Src homology 2 (SH2) domain-containing inositol 5-phosphatase 1)-Akt pathway. These findings suggest that AG538 may be a promising antiplatelet antithrombotic agent with a favorable safety profile.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"117379"},"PeriodicalIF":5.6,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228416","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}

引用次数: 0

Ex vivo study of the vasorelaxant activity induced by cannabigerol in human pulmonary artery- the role of endothelium, sex and selected clinical factors. 大麻酚诱导人肺动脉血管舒张活性的体外研究——内皮、性别和选定临床因素的作用。

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2025-10-02 DOI: 10.1016/j.bcp.2025.117383

Anna Krzyżewska, Monika Kloza, Mirosław Kozłowski, Anna Galicka, Hanna Kozłowska

{"title":"Ex vivo study of the vasorelaxant activity induced by cannabigerol in human pulmonary artery- the role of endothelium, sex and selected clinical factors.","authors":"Anna Krzyżewska, Monika Kloza, Mirosław Kozłowski, Anna Galicka, Hanna Kozłowska","doi":"10.1016/j.bcp.2025.117383","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.117383","url":null,"abstract":"<p><p>Cannabigerol (CBG) is a non-psychoactive phytocannabinoid with an antioxidant and anti-inflammatory properties. Because CBG has a promising pharmacological profile involving activation of α<sub>2</sub>adrenergic and peroxisome proliferator-activated γ (PPARγ) receptors it may have relevance in the pharmacotherapy of cardiovascular diseases. Cannabigerol was also effective in lowering blood pressure in normotensive mice. In addition, it has been shown that cannabinoids can exhibit vasorelaxant effects in various vascular beds, and another plant cannabinoid-cannabidiol-has been shown to be effective in attenuating the development of pulmonary arterial hypertension. In view of these reports, the aims of our study were to investigate whether CBG, exhibits a vasorelaxant effect on human pulmonary arteries (hPAs), to determine the mechanisms of CBG's potentiating effects and to assess the influence the selected clinical factors and patients' comorbidities on the vascular response induced by CBG. Our study reports that CBG relaxes hPAs, and post-hoc analysis has shown that this response can be modified by hypertension and hypercholesterolaemia. We showed that the vasorelaxant effect of CBG depends on the vascular endothelium and the following mechanisms are involved: 1) cyclooxygenase-dependent pathway, 2) nitric oxide-dependent pathway, 3) voltage- and calcium-dependent K<sup>+</sup> channels and 4) probably cannabinoid type 1 and 2, PPARγ, G-protein-coupled 55 and transient receptor potential vanilloid 1 receptors. At all, CBG appears to be a possible vasorelaxant agent, but its therapeutic efficacy may vary based on the patient's condition and comorbidities. CBG's mild vasorelaxant property may provide an added benefit in addition to its anti-inflammatory and antioxidant properties in hemp preparations.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"117383"},"PeriodicalIF":5.6,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228372","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}

引用次数: 0

Exon 13 skipping mediated by HNRNPL facilitates truncated SLK-induced metastasis in hepatocellular carcinoma. HNRNPL介导的外显子13跳变促进了slk诱导的肝细胞癌的截断转移。

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2025-10-02 DOI: 10.1016/j.bcp.2025.117390

Zhongxue Guo, Peining Yu, Liu Yu, Mengzhen Huang, Zhiwei Wu, Aime Gael Yaya Traore, Zhen Sun, Ziyou Bai, Wei Wu, Tongzheng Liu, Qiang Li, Feng Wang

{"title":"Exon 13 skipping mediated by HNRNPL facilitates truncated SLK-induced metastasis in hepatocellular carcinoma.","authors":"Zhongxue Guo, Peining Yu, Liu Yu, Mengzhen Huang, Zhiwei Wu, Aime Gael Yaya Traore, Zhen Sun, Ziyou Bai, Wei Wu, Tongzheng Liu, Qiang Li, Feng Wang","doi":"10.1016/j.bcp.2025.117390","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.117390","url":null,"abstract":"<p><p>The STE20-like serine/threonine-protein kinase (SLK), a key regulator of cellular signaling, exhibits remarkable functional heterogeneity through alternative splicing in various cancers. This study investigates the splicing regulation of SLK in hepatocellular carcinoma (HCC), revealing that exon 13 skipping generates functionally antagonistic isoforms: the long isoform (SLK-L, containing exon 13) acts as a tumor suppressor, whereas the short isoform (SLK-S, lacking exon 13) displays oncogenic properties. This splicing imbalance is particularly prominent during HCC metastasis, underscoring the critical role of SLK splicing regulation in tumor progression. Mechanistically, the RNA-binding protein Heterogeneous Nuclear Ribonucleoprotein L (HNRNPL) functions as a \"molecular scissor\" that specifically recognizes introns 12 and 13 of SLK pre-mRNA to precisely promote SLK-S production. Functional assays demonstrate that SLK-S enhances HCC cell invasion and metastasis by activating the Extracellular signal-Regulated Kinase (ERK) signaling pathway, while SLK-L suppresses these effects through pathway inhibition. Notably, in vivo targeting of the HNRNPL/SLK-S/Rac family small GTPase 1 (Rac1)/ERK axis effectively inhibits HCC metastasis. These findings not only elucidate a novel RNA splicing regulatory mechanism in HCC metastasis but also provide a theoretical foundation and potential therapeutic targets for developing precision treatments based on SLK splicing modulation.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"117390"},"PeriodicalIF":5.6,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228378","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}

引用次数: 0

Cancer-associated transporters: Molecular drivers and drug delivery gateways. 癌症相关转运蛋白：分子驱动和药物传递通道。

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2025-10-02 DOI: 10.1016/j.bcp.2025.117376

Aqsa Khan, Subhrajit Biswas, Manoj Garg, Shinjinee Sengupta

{"title":"Cancer-associated transporters: Molecular drivers and drug delivery gateways.","authors":"Aqsa Khan, Subhrajit Biswas, Manoj Garg, Shinjinee Sengupta","doi":"10.1016/j.bcp.2025.117376","DOIUrl":"10.1016/j.bcp.2025.117376","url":null,"abstract":"<p><p>Membrane transporters are critical regulators of cellular homeostasis, mediating the uptake and efflux of nutrients, ions, and drugs. In cancer, their expression is frequently reprogrammed to support enhanced growth, survival, metabolic rewiring, invasiveness, and therapy resistance. Among these several solute carrier (SLC) transporters such as glucose transporters (GLUTs), monocarboxylate transporters (MCTs), and the sodium/iodine symporter (NIS) also facilitate selective delivery of radiopharmaceuticals, making them attractive therapeutic targets. The tumor suppressor p53 known for its central role in genome stability and apoptosis, also regulates a broad spectrum of membrane transporters. However, oncogenic mutations or structural conversion into amyloids can disrupt this regulatory network, leading to altered transporter expression and multidrug resistance. Despite growing interest, the transcriptional and post-transcriptional control of transporters by wt, mutant, and amyloid forms of p53 remains underexplored. In this review, we systematically characterize the p53-mediated regulation of diverse transporter classes involved in the transport of sugar, amino acids, metal ions, lipids along with ABC transporter functions and multidrug resistance. We highlight how cancer cells exploit transporters such as P-glycoprotein (P-gp), LAT1, GLUT1, MCTs, and NIS for metabolic advantage and survival. We also examine therapeutic strategies aimed at modulating transporter function using CRISPR/Cas9, small-molecule inhibitors, siRNA, and nanoparticle-based co-delivery systems. In particular, LAT1 inhibition demonstrates potential to starve tumors of essential nutrients. Ultimately, we propose that dual targeting of p53 aberrations and membrane transporters through synthetic biology and precision delivery approaches could restore chemosensitivity and suppress tumor progression, offering promising avenues for personalized cancer therapy.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"117376"},"PeriodicalIF":5.6,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228361","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}

引用次数: 0

The MyD88 inhibitor TJ-M2010-5 protects against obesity in mice by suppressing macrophage-induced metabolic inflammation MyD88抑制剂TJ-M2010-5通过抑制巨噬细胞诱导的代谢性炎症来预防小鼠肥胖。

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2025-10-01 DOI: 10.1016/j.bcp.2025.117378

Xi Yang , Fu-rong Liang , Yi-chi Wu , Fu-cheng Meng , Huan-yu Wang , Ling Hou , Ping Zhou , Cai Zhang , Xiao-ping Luo

{"title":"The MyD88 inhibitor TJ-M2010-5 protects against obesity in mice by suppressing macrophage-induced metabolic inflammation","authors":"Xi Yang , Fu-rong Liang , Yi-chi Wu , Fu-cheng Meng , Huan-yu Wang , Ling Hou , Ping Zhou , Cai Zhang , Xiao-ping Luo","doi":"10.1016/j.bcp.2025.117378","DOIUrl":"10.1016/j.bcp.2025.117378","url":null,"abstract":"<div><div>Metabolic inflammation is an important link in exacerbating obesity and insulin resistance, and the M1 polarization of macrophages is the key to the generation and maintenance of metabolic inflammation. As an inflammatory regulator, the toll-like receptor 4 (TLR4) / myeloid differentiation factor 88 (MyD88) signaling pathway plays an important role in the M1 polarization of macrophages. We previously proved that TJ-M2010-5 is a novel MyD88 inhibitor. However, the protective effect and underlying mechanisms of the MyD88 inhibitor TJ-M2010-5 against obesity induced by high fat diet (HFD) have not been reported. This study revealed that TJ-M2010-5 significantly improved the body weight, blood glucose and lipid levels of HFD mice. Histologically, TJ-M2010-5 alleviated lipid deposition in liver and adipose tissue. The proportion of M1 macrophages and the protein levels of TLR4, MyD88 and the phosphorylation ratio of nuclear factor-κB (NF-κB) in liver and epididymis adipose tissue of HFD mice were decreased after TJ-M2010-5 intervention. In vitro, TJ-M2010-5 inhibited the activation of TLR4 and MyD88 in bone marrow-derived macrophage (BMDM), significantly reduced the proportion of M1 polarization of BMDM. TJ-M2010-5 can improve obesity and its related glucose and lipid metabolism abnormalities induced by HFD through alleviating M1 polarization of macrophages and metabolic inflammation via inhibiting TLR4/MyD88 pathway.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117378"},"PeriodicalIF":5.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145224616","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}

引用次数: 0

Tauroursodeoxycholic acid ameliorates palmitic acid induced endoplasmic reticulum stress and impaired autophagy via IRE1- XBP1-FoxO1 pathway in KGN cells. 牛磺酸去氧胆酸通过IRE1- XBP1-FoxO1通路改善棕榈酸诱导的KGN细胞内质网应激和自噬受损。

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2025-10-01 DOI: 10.1016/j.bcp.2025.117377

Maosheng Cao, Fengxin Qiao, Qingwei Wang, Jinhong Luo, Yonghong Ju, Xiaodong Wang, Xiang Chen

{"title":"Tauroursodeoxycholic acid ameliorates palmitic acid induced endoplasmic reticulum stress and impaired autophagy via IRE1- XBP1-FoxO1 pathway in KGN cells.","authors":"Maosheng Cao, Fengxin Qiao, Qingwei Wang, Jinhong Luo, Yonghong Ju, Xiaodong Wang, Xiang Chen","doi":"10.1016/j.bcp.2025.117377","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.117377","url":null,"abstract":"<p><p>Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder among women of childbearing age. Patients with PCOS often have elevated levels of palmitic acid (PA) in their blood and follicular fluid. Granulosa cells (GCs) play crucial roles in follicular development and oocyte maturation. Whether the development of PCOS is related to an increase in PA, which affects GC function, and the underlying mechanisms remain unclear. Tauroursodeoxycholic acid is important for the treatment of metabolic diseases; however, whether it protects GCs remains unknown. In this study, KGN human GCs were treated with PA for 24 h to determine the effects of PA on GCs and elucidate the underlying mechanisms. PA treatment activated the inositol-requiring enzyme 1 pathway and promoted the expression of X-box binding protein 1, which interacted with forkhead box protein O1 and promoted its ubiquitination and degradation. This decreased the levels of autophagy-related gene 7 and inhibited cellular autophagy, leading to impaired mitochondrial function. However, tauroursodeoxycholic acid application reduced inositol-requiring enzyme 1 phosphorylation and promoted autophagy in KGN cells via the X-box binding protein 1-forkhead box protein O1 pathway, thereby restoring the mitochondrial function. Overall, these findings enhance our understanding of the molecular basis of GC impairment in patients with PCOS and provide potential therapeutic targets for their treatment.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"117377"},"PeriodicalIF":5.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145224621","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}

引用次数: 0

Roles and therapeutic potential of PARP-1 in neurodegenerative diseases PARP-1在神经退行性疾病中的作用和治疗潜力。

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2025-09-27 DOI: 10.1016/j.bcp.2025.117373

Chang Liu , Fei-fan Lai , Ting Zhang , Kun-jun Mao , Hai-tong Wan , Yu He

{"title":"Roles and therapeutic potential of PARP-1 in neurodegenerative diseases","authors":"Chang Liu , Fei-fan Lai , Ting Zhang , Kun-jun Mao , Hai-tong Wan , Yu He","doi":"10.1016/j.bcp.2025.117373","DOIUrl":"10.1016/j.bcp.2025.117373","url":null,"abstract":"<div><div>Poly(ADP-ribose) polymerase 1 (PARP-1) was first discovered in the 1960 s, and over the past few decades, there has been growing evidence that PARP-1 plays a key role in neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. With DNA damage detection and repair as its main function, PARP-1 is activated by regulation in the early stages of neurodegenerative diseases, quickly and effectively repairs mild DNA damage, and protects nerve cells from death. However, as the disease progresses, severe DNA damage causes PARP-1 to overactivate, resulting in neuronal cell death, including apoptosis, necrosis, and parthanatos, further exacerbating the disease progression. PARP-1 is also involved in the pathological process of neurodegenerative diseases, such as pathological protein aggregation, neuroinflammation, mitochondrial dysfunction, autophagy disorder, and damage to the blood–brain barrier. According to a large number of studies, PARP-1 inhibition has shown great therapeutic potential for neurodegenerative diseases, and the development of PARP-1 inhibitors has received increasing attention. Here, we review the role of PARP-1 in the process of neurodegenerative diseases and summarize the latest research progress and application of PARP-1 inhibitors in neurodegenerative diseases.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117373"},"PeriodicalIF":5.6,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145190703","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}

引用次数: 0

Dual activation of PPARα/γ by bezafibrate triggers PINK1/Parkin-Mediated mitophagy to enhance lenvatinib sensitivity in hepatocellular carcinoma 贝扎贝特双重激活PPARα/γ触发PINK1/帕金森介导的线粒体自噬，增强lenvatinib在肝癌中的敏感性。

IF 5.6 2区医学

Biochemical pharmacology Pub Date : 2025-09-26 DOI: 10.1016/j.bcp.2025.117367

Jian Wang , Lu Chen , Li Jiang , Yuteng Wang , Wenqian Xue , Xinyan Cai , Hui Li , Tianxiao Wang

{"title":"Dual activation of PPARα/γ by bezafibrate triggers PINK1/Parkin-Mediated mitophagy to enhance lenvatinib sensitivity in hepatocellular carcinoma","authors":"Jian Wang , Lu Chen , Li Jiang , Yuteng Wang , Wenqian Xue , Xinyan Cai , Hui Li , Tianxiao Wang","doi":"10.1016/j.bcp.2025.117367","DOIUrl":"10.1016/j.bcp.2025.117367","url":null,"abstract":"<div><div>Lenvatinib resistance, driven by metabolic adaptation and angiogenic escape, poses a major challenge in hepatocellular carcinoma (HCC) therapy. This study explores bezafibrate, a clinically approved Peroxisome Proliferator-Activated Receptor Alpha or Gamma (PPARα/γ) dual agonist, to enhance lenvatinib sensitivity by inducing PTEN-Induced Putative Kinase 1(PINK1)/ Parkin-mediated mitophagy. Using SNU-739/HepG2 cells, we investigated bezafibrate’s anti-tumor efficacy alone and in combination with lenvatinib. The results demonstrated that bezafibrate alone exhibits anti-tumor efficacy in HCC and enhances the anti-HCC efficacy of lenvatinib. It was observed that bezafibrate activated PPARα, increasing fatty acid oxidation (FAO) via Carnitine Palmitoyltransferase IA (CPT1A)/ Acyl-CoA Oxidase 1(ACOX1) upregulation, leading to elevated ROS and reduced mitochondrial membrane potential (ΔΨm). It also activated PPARγ, which bound to PINK1 with high affinity (ΔG = −64.6 kcal/mol). Dual PPARα/γ activation by bezafibrate enhanced Parkin recruitment and promoted mitophagic cell death, characterized by reduced p62 and Translocase of Outer Mitochondrial Membrane 20 (TOM20), increased LC3-II, decreased ATP, and elevated Annexin V-positive cells. This approach demonstrated efficacy, inducing PINK1/Parklin-mediated mitophagy and reducing VEGF-A/C and EGFR in vitro, and decreasing tumor volume and weight in a syngeneic H22 mouse model compared to lenvatinib alone, without significant toxicity. In conclusion, bezafibrate, through PPARα/γ-mediated PINK1/Parkin activation and angiogenic suppression, complements lenvatinib’s therapeutic effects in HCC, providing a rationale for clinical evaluation to address treatment resistance.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117367"},"PeriodicalIF":5.6,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184712","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}

引用次数: 0