Biochemical pharmacology最新文献_第3页

CircCramp1l targets the miR-532-3p/HMGB1/Drp1 axis to regulate allergic rhinitis. CircCramp1l靶向miR-532-3p/HMGB1/Drp1轴调控变应性鼻炎。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-08 DOI: 10.1016/j.bcp.2026.117699

Yalin Zhang, Jiangang Wang, Yilan Song, Jingmei Chai, Liangchang Li, Hainan Jin, Yi Yang, Chongyang Wang, Yongde Jin, Guanghai Yan

The pathogenesis of allergic rhinitis (AR) remains incompletely understood, and the role of circular RNAs (circRNAs) in its progression warrants further investigation. This study aimed to elucidate the underlying mechanisms of circRNA-mediated regulation in AR and identify potential therapeutic targets. By collecting nasal mucosa specimens from AR patients, establishing house dust mite(HDM)-induced AR mouse models and human nasal epithelial cell(HNEpCs) models, and combining circRNA/miRNA sequencing with GEO data analysis, it was found that HDM triggers a significant upregulation of circCramp1l in AR. Mechanistically, circCramp1l acts as a ceRNA to sponge miR-532-3p, thereby relieving the suppression of HMGB1, an response-related DAMP molecule. Further validation through dual-luciferase reporter(DLR)assays, Co-IP combined with mass spectrometry, and molecular dynamics(MD) simulations demonstrated that HMGB1 directly binds to Drp1(binding free energy ΔG = -480.02 kcal/mol; key domain: amino acids 86-164 of HMGB1), driving Drp1 Ser616 phosphorylation. This leads to excessive mitochondrial fission, ROS accumulation, P2X7R/TLR4/NLRP3 axis. This signaling cascade induces Th2 polarization(elevated IL-4/IL-5/IL-13), eosinophil infiltration, and epithelial damage. Intervention experiments showed that conditional knockout of HMGB1, silencing of circCramp1l, administration of miR-532-3p mimics, or treatment with the Drp1 inhibitor Mdivi-1 all reversed mitochondrial dysfunction and significantly alleviated AR symptoms. This study reveals that the circCramp1l/miR-532-3p/HMGB1/Drp1 signaling axis contributes to AR pathogenesis by modulating mitochondrial dynamics and P2X7R/TLR4/NLRP3 axis. These results offer a novel target for the diagnosis and treatment of AR.

变应性鼻炎（AR）的发病机制尚不完全清楚，环状rna （circRNAs）在其进展中的作用有待进一步研究。本研究旨在阐明环状rna介导的AR调控的潜在机制，并确定潜在的治疗靶点。通过收集AR患者鼻黏膜标本，建立屋尘螨（HDM）诱导的AR小鼠模型和人鼻上皮细胞（HNEpCs）模型，结合circRNA/miRNA测序和GEO数据分析，发现HDM可触发AR中circrp1l的显著上调。从机制上说，circrp1l作为ceRNA海绵miR-532-3p，从而缓解对反应相关的DAMP分子HMGB1的抑制。通过双荧光素酶报告基因（DLR）测定、Co-IP结合质谱和分子动力学（MD）模拟进一步验证，HMGB1直接结合Drp1（结合自由能ΔG = -480.02 kcal/mol；关键结构域：HMGB1的86-164个氨基酸），驱动Drp1 Ser616磷酸化。这导致线粒体分裂过度，ROS积累，P2X7R/TLR4/NLRP3轴。这种信号级联诱导Th2极化（IL-4/IL-5/IL-13升高）、嗜酸性粒细胞浸润和上皮损伤。干预实验表明，有条件敲除HMGB1、沉默circCramp1l、给予miR-532-3p模拟物或使用Drp1抑制剂mdii -1治疗均可逆转线粒体功能障碍并显著缓解AR症状。本研究表明circCramp1l/miR-532-3p/HMGB1/Drp1信号轴通过调节线粒体动力学和P2X7R/TLR4/NLRP3轴参与AR发病。这些结果为AR的诊断和治疗提供了新的靶点。

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引用次数: 0

Recent advances in understanding the pathogenesis, diagnosis, and treatment of tuberous sclerosis complex (TSC)-associated Lymphangioleiomyomatosis 结节性硬化症（TSC）相关淋巴管平滑肌瘤病的发病机制、诊断和治疗的最新进展

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-08 DOI: 10.1016/j.bcp.2026.117697

Zhongchao Gai , Yujiao He , Quanjian Zhao , Xinran Du , Jieqiong Zhao

Lymphangioleiomyomatosis (LAM) is a rare, slowly progressive lung disorder that predominantly affects women of childbearing age. LAM is classified into two subtypes: tuberous sclerosis complex (TSC)-associated LAM (TSC-LAM) and sporadic LAM. Mutations in the TSC1 or TSC2 genes are the underlying cause of both forms. Over the past decade, research and clinical practice in managing LAM have advanced significantly, with breakthroughs in the understanding of disease pathogenesis, biomarker discovery, targeted therapies, and new therapeutic technologies. This article presents a review of the progress in understanding the pathobiology, diagnosis, and treatment of LAM, based on PubMed-indexed studies published from 2015 to 2024. According to the current literature, the activation of mechanistic target of rapamycin (mTOR) signaling is the leading cause of LAM, while other mTOR-independent pathways, such as the sphingosine kinase 1 (SPHK1)/sphingosine-1-phosphate (S1P) and cyclooxygenase 2 (COX2)/prostaglandin E2 (PGE2) pathways, have been hypothesized to play roles in the pathogenesis. The literature suggests that LAM might originate in the uterine and/or pulmonary mesenchymal cells. Advanced imaging methods such as chest high-resolution CT (HRCT) and newly identified LAM biomarkers can aid in improving the diagnostic of LAM. mTOR inhibitors, such as sirolimus, remain the cornerstone therapy, but variable treatment responses highlight the need for personalized approaches. Nevertheless, more studies are needed to better understand LAM, develop more powerful diagnostic, prognostic, and predictive biomarkers, and optimize the current treatments of LAM while developing novel therapeutic approaches.

淋巴管平滑肌瘤病（LAM）是一种罕见的，缓慢进展的肺部疾病，主要影响育龄妇女。LAM分为两种亚型：结节性硬化症（TSC）相关LAM （TSC-LAM）和散发性LAM。TSC1或TSC2基因的突变是这两种形式的潜在原因。在过去的十年中，LAM的研究和临床实践取得了显著进展，在疾病发病机制的理解、生物标志物的发现、靶向治疗和新的治疗技术方面取得了突破。本文基于2015年至2024年发表的pubmed索引研究，综述了LAM在病理生物学、诊断和治疗方面的进展。根据目前的文献，雷帕霉素（rapamycin, mTOR）信号的机制靶点的激活是LAM的主要原因，而其他与mTOR无关的途径，如鞘氨醇激酶1 (SPHK1)/鞘氨醇-1-磷酸（S1P）和环氧化酶2 (COX2)/前列腺素E2 （PGE2）途径，也被假设在发病机制中发挥作用。文献提示LAM可能起源于子宫和/或肺间充质细胞。先进的成像方法，如胸部高分辨率CT （HRCT）和新发现的LAM生物标志物可以帮助提高LAM的诊断。mTOR抑制剂，如西罗莫司，仍然是治疗的基础，但不同的治疗反应强调需要个性化的方法。然而，需要更多的研究来更好地了解LAM，开发更强大的诊断、预后和预测生物标志物，优化LAM的现有治疗方法，同时开发新的治疗方法。

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引用次数: 0

Deciphering the role of zinc in prostate health: From mechanism to therapeutic application 解读锌在前列腺健康中的作用：从机制到治疗应用

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-07 DOI: 10.1016/j.bcp.2026.117689

Ziang Li , Yifan Hou , Zhenhua Zhao , Wenbo Zhang , Jianhua Zhang , Song Li , Xiaobo Nie , Junqing Hou

Zinc is an essential trace element crucial for human health. The prostate contains the highest concentration of zinc in the male body, making it the organ most affected by zinc disturbances. Zinc plays a critical role in maintaining normal prostate structure and function by modulating energy metabolism and secretory processes in prostate cells, regulating androgen balance, and exerting antibacterial effects. Disturbances in zinc homeostasis are closely associated with the pathogenesis of common prostatic diseases, including prostatitis, benign prostatic hyperplasia (BPH), and prostate cancer (PCa). Consequently, zinc supplementation has emerged as a potential strategy for managing certain prostatic diseases. However, its efficacy and safety remain controversial. This review presents a comprehensive overview of zinc metabolism and mechanisms of action, with a focus on its role in the pathogenesis of common prostatic diseases, and analyzes recent advancements and current challenges in the clinical application of zinc supplementations.

锌是人体必需的微量元素，对人体健康至关重要。前列腺是男性体内锌含量最高的器官，也是受锌干扰影响最大的器官。锌通过调节前列腺细胞的能量代谢和分泌过程，调节雄激素平衡，发挥抗菌作用，在维持正常前列腺结构和功能中起着至关重要的作用。锌稳态紊乱与前列腺炎、良性前列腺增生（BPH）和前列腺癌（PCa）等常见前列腺疾病的发病密切相关。因此，锌补充剂已成为治疗某些前列腺疾病的潜在策略。然而，其有效性和安全性仍存在争议。本文综述了锌的代谢和作用机制，重点介绍了锌在常见前列腺疾病的发病机制中的作用，并分析了锌补充剂在临床应用中的最新进展和面临的挑战。

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引用次数: 0

Transient receptor potential channels as emerging therapeutic targets: mechanisms and therapeutic insights in inflammatory bowel disease 瞬时受体电位通道作为新兴的治疗靶点：炎症性肠病的机制和治疗见解

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-07 DOI: 10.1016/j.bcp.2026.117693

Ying Jiang , Xi Wang , Yinwei Zhou , Yuting Feng, Han Gu, Xingjun Liu, Lin Luo

Transient Receptor Potential channels (TRPs) are a family of non-selective cation channels widely distributed across diverse tissues and cells in mammals. They participate in numerous physiological processes, including environmental stimulus perception, signal transduction, neurotransmitter release, and insulin secretion. The involvement of TRPs in pain syndromes, neurodegenerative diseases, metabolic disorders, and tumorigenesis has established them as prominent targets in translational medicine. Inflammatory Bowel Disease (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic and relapsing inflammatory disorder of the intestine. Its pathogenesis involves complex interactions among genetic susceptibility, gut microbiota dysbiosis, immune system dysregulation, and neuroimmunomodulatory disturbances. Although the precise etiology of IBD remains incompletely elucidated, substantial evidence indicates that TRPs sense and respond to diverse intestinal luminal stimuli (e.g., bacteria, viruses, and food antigens). They participate in IBD pathophysiology by modulating inflammatory signaling, immune responses, and visceral nociception, thereby contributing to neurogenic inflammation, disruption of the intestinal barrier function, immune and metabolic dysregulation, visceral hypersensitivity, and intestinal fibrosis. Given the pivotal role of TRPs in IBD progression, this review comprehensively elaborates on the structure and function of TRPs associated with IBD, their mechanisms in disease pathology, and recent advances in TRP-targeted therapy for IBD. This article aims to provide insights into the development of innovative treatment strategies for IBD.

瞬态受体电位通道（Transient Receptor Potential channels, TRPs）是一类非选择性阳离子通道，广泛分布于哺乳动物的多种组织和细胞中。它们参与许多生理过程，包括环境刺激感知、信号转导、神经递质释放和胰岛素分泌。TRPs在疼痛综合征、神经退行性疾病、代谢紊乱和肿瘤发生中的作用使其成为转化医学的重要靶点。炎症性肠病（IBD），包括克罗恩病（CD）和溃疡性结肠炎（UC），是一种慢性和复发性肠道炎症性疾病。其发病机制涉及遗传易感性、肠道菌群失调、免疫系统失调和神经免疫调节紊乱等复杂的相互作用。尽管IBD的确切病因尚不完全清楚，但有大量证据表明，TRPs能感知并响应各种肠道刺激（如细菌、病毒和食物抗原）。它们通过调节炎症信号、免疫反应和内脏伤害感受参与IBD病理生理，从而导致神经源性炎症、肠屏障功能破坏、免疫和代谢失调、内脏过敏和肠纤维化。鉴于TRPs在IBD进展中的关键作用，本文全面阐述了与IBD相关的TRPs的结构和功能、它们在疾病病理中的机制以及trp靶向IBD治疗的最新进展。本文旨在为IBD的创新治疗策略的发展提供见解。

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引用次数: 0

Advances in melanoma immunotherapy: harnessing vaccination as a potential novel immunotherapeutic strategy 黑色素瘤免疫治疗的进展：利用疫苗接种作为一种潜在的新型免疫治疗策略。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-07 DOI: 10.1016/j.bcp.2026.117687

Dima Saleem Abuelainain , Amal Kamal Abdel-Aziz , Mona Kamal Saadeldin

Melanoma, an aggressive form of skin cancer, demands innovative immunotherapeutic strategies to improve patient outcomes. This review explores recent advances in melanoma immunotherapy, with a particular focus on vaccination as a promising approach. It examines diverse vaccine platforms aimed at eliciting robust immune responses against melanoma-specific antigens, emphasizing the role of adjuvants in enhancing efficacy and overcoming resistance. The use of model organisms—especially murine models—is highlighted for their critical role in elucidating vaccine mechanisms, identifying novel antigens, and optimizing delivery systems. The review also discusses ongoing clinical trials targeting improved response rates and overall survival. Looking ahead, the integration of artificial intelligence and personalized medicine is proposed as a transformative direction, leveraging individual genetic, immunologic, and environmental factors to address current challenges. By summarizing key progress and outlining future research avenues, this review aims to inspire continued innovation in the development of safe, effective, and durable immunotherapeutic strategies for melanoma patients.

黑色素瘤是一种侵袭性皮肤癌，需要创新的免疫治疗策略来改善患者的预后。本综述探讨了黑色素瘤免疫治疗的最新进展，特别关注疫苗接种作为一种有前途的方法。它研究了多种疫苗平台，旨在激发针对黑色素瘤特异性抗原的强大免疫反应，强调佐剂在增强疗效和克服耐药性方面的作用。模型生物（尤其是小鼠模型）的使用因其在阐明疫苗机制、识别新抗原和优化递送系统方面的关键作用而得到强调。本综述还讨论了正在进行的旨在提高反应率和总生存率的临床试验。展望未来，人工智能和个性化医疗的整合被认为是一个变革方向，利用个体遗传、免疫和环境因素来应对当前的挑战。通过总结关键进展和概述未来的研究途径，本综述旨在激发持续创新，开发安全、有效和持久的黑色素瘤患者免疫治疗策略。

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引用次数: 0

Chlorogenic acid attenuates endometrial senescence via mTOR modulation: A combined network pharmacology, in vitro, and in vivo study 绿原酸通过mTOR调节减缓子宫内膜衰老：一项联合网络药理学，体外和体内研究

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-07 DOI: 10.1016/j.bcp.2026.117672

Woonghee Lee , Gwonhwa Song , Hyocheol Bae

Advanced maternal age is correlated with increased infertility, often due to impaired decidualization and placentation. This study elucidated the senotherapeutic potential of chlorogenic acid (CGA), a phenylacrylate polyphenol as major compound of coffee, in endometrial stromal cells (ESCs). Using a passage number-induced senescence model, CGA reduced senescence markers (P16, P21), promoted proliferation, and upregulated decidualization markers (PRL, IGFBP1, FOXO1). In aged hTERT-immortalized ESCs, CGA enhanced mitochondrial biogenesis by upregulating mitochondrial complex genes and restoring mitochondrial function. Docking and molecular dynamics analyses demonstrated a high binding affinity of CGA toward mTOR (−8.29 kcal/mol), with stabilizing interactions at key residues. CGA treatment decreased mTOR expression in uterine tissue of aged mice in vivo. By modulating the mTOR/AMPK/SIRT1 pathway, CGA attenuates senescence and supports decidualization. These findings suggest CGA as a promising senotherapeutic candidate for improving endometrial function and addressing infertility related to advanced maternal age.

高龄产妇与不孕症增加相关，通常是由于去个体化和胎盘受损。这项研究阐明了绿原酸（CGA）对子宫内膜间质细胞（ESCs）的衰老治疗潜力，绿原酸是咖啡的主要化合物，是苯基丙烯酸酯多酚。通过传代数诱导的衰老模型，CGA降低了衰老标记（P16, P21），促进了增殖，上调了去个化标记（PRL, IGFBP1, FOXO1）。在衰老的htert永生化ESCs中，CGA通过上调线粒体复合物基因和恢复线粒体功能来增强线粒体生物发生。对接和分子动力学分析表明，CGA对mTOR具有较高的结合亲和力（−8.29 kcal/mol），在关键残基上具有稳定的相互作用。CGA处理可降低老龄小鼠子宫组织中mTOR的表达。CGA通过调节mTOR/AMPK/SIRT1通路，减缓衰老并支持去个体化。这些发现表明，CGA作为一种有希望的老年治疗候选者，可以改善子宫内膜功能和解决与高龄产妇相关的不孕症。

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引用次数: 0

Natural polycyclic aromatic naphthodianthrone compound S3273 calms cytokine storm to restore acute lung injury via modulating CD39-P2X7R-IL-17A route 天然多环芳香族萘醌化合物S3273通过调节CD39-P2X7R-IL-17A途径平息细胞因子风暴，恢复急性肺损伤。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-06 DOI: 10.1016/j.bcp.2026.117691

Jiasi Wu , Yuejia Lan , Mengzhen Wu , Lingyao Han , Hongkai Huang , Xiao Deng , Yafei Zhao , Xianli Meng

CD39 participates in the process of ATP hydrolyzing into AMP, ADP and adenosine, and ATP mediates the channel-opening of P2X7 which further induces the downstream pyroptotic cell death. Current announced small-molecule CD39 enhancer are limited and to develop novel CD39 enhancer will be meaningful for inflammation-associated disorders treatment. CD39 enzymic screening assay was conducted to detect CD39 enhancing effect among a library of 424 FDA-approval small-molecule compounds. CETSA and SPR assay were arranged to assess the direct interaction between S3273 and CD39. Multiple techniques like YO-PRO-1 assay and patch clamp were employed to evaluate diverse CD39-P2X7 route modulators. RNA-Seq experiment was thereafter employed to fish potential targets in LPS-challenged mice. A polycyclic aromatic naphthodianthrone compound, S3273, was the most potent CD39 enhancer with EC₅₀ value of 5.66 μM. S3273 restored LPS-induced ALI via blocking NLRP3/GSDMD signaling to calm cytokine storm. In vitro, S3273 rescued pyroptosis via inhibiting the ROS accumulation, inflammasome assembly, as well as pyroptosis in a range types of macrophages. Mechanically, S3273 affected purinergic modulators including CD39, CD73, A2b and P2X7R to facilitate the formation and function of CD39-P2X7-dominated purinergic brake. IL-17 was a key pathway responsible for the protective effect of S3273 on LPS-induced ALI. S3273 directly binds to IL-17 and prevented the up-regulation of IL-17. S3273 calms cytokine storm to reverse lung damage in LPS-challenged mice, and these effects are at least partly through the modulation on CD39-P2X7R-IL-17A route.

CD39参与ATP水解成AMP、ADP和腺苷的过程，ATP介导P2X7的通道开通，进而诱导下游热腐细胞死亡。目前已宣布的小分子CD39增强剂有限，开发新的CD39增强剂对炎症相关疾病的治疗具有重要意义。采用CD39酶促筛选法检测424种fda批准的小分子化合物对CD39的增强作用。采用CETSA法和SPR法评估S3273与CD39的直接相互作用。采用YO-PRO-1法、膜片钳法等多种技术评价不同CD39-P2X7通路调节剂。随后采用RNA-Seq实验寻找lps致毒小鼠的潜在靶点。多环芳香族萘醌化合物S3273是最有效的CD39增强剂，EC50值为5.66 μM。S3273通过阻断NLRP3/GSDMD信号，平息细胞因子风暴，恢复lps诱导的ALI。在体外实验中，S3273通过抑制ROS积累、炎性体组装和巨噬细胞的焦亡来挽救焦亡。机械上，S3273影响嘌呤能调节剂包括CD39、CD73、A2b和P2X7R，促进CD39- p2x7主导的嘌呤能制动器的形成和功能。IL-17是S3273对lps诱导的ALI起保护作用的关键途径。S3273直接结合IL-17，阻止IL-17的上调。S3273可以平息细胞因子风暴，逆转lps挑战小鼠的肺损伤，这些作用至少部分是通过调节CD39-P2X7R-IL-17A途径实现的。

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引用次数: 0

Imperatorin induces ferroptosis via mediating lipid peroxidation and SLC7A11/ACSL4/GPX4 signaling for inhibition and therapeutics of prostate cancer 欧前胡素通过介导脂质过氧化和SLC7A11/ACSL4/GPX4信号通路诱导铁下垂，抑制和治疗前列腺癌。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-06 DOI: 10.1016/j.bcp.2026.117683

Jingang Jian , Haodong Xu , Xiaofeng Shi , Jun Zhang , He Wang , Yuefan Xu , Yuhua Huang , Jianquan Hou , Xuedong Wei , Yuxin Lin

Prostate cancer (PCa) remains a leading cause of cancer-related death among males worldwide. Targeting ferroptosis has now emerged as a promising strategy against cancer. This study aims to deciphering the anti-tumor role of imperatorin, a natural furanocoumarin, in mediating ferroptosis-induced mechanisms for PCa inhibition and treatment. Cell-based assays, including CCK-8, EdU, colony formation, migration, and invasion assays, were used to evaluate the effects of imperatorin on cellular malignant phenotypes. RNA sequencing and bioinformatics analyses identified ferroptosis-related marker signatures, i.e., SLC7A11, ACSL4 and GPX4, were key targets of imperatorin, which were functionally validated using experimental approaches to establish its binding role of ferroptosis, clarify drug specificity, and support translational relevance. It is showed that imperatorin inhibited proliferation, migration, and invasion of PCa cells in a dose-dependent manner by triggering ferroptosis with a potential mechanism of inducing lipid peroxidation via downregulating SLC7A11/GPX4 and upregulating ACSL4. In particular, a significant decreased level of TRIM21-mediated ubiquitination was detected in ACSL4 after imperatorin treatment. Moreover, imperatorin exhibited a synergistic effect with Enzalutamide in vitro, highlighting it as a latent medication strategy for combination therapy. In vivo characterization further demonstrated that imperatorin reduced tumor growth and altered the expression of ferroptosis marker signatures with favorable safety on vital organs from toxicity. This study revealed the ferroptosis-induced power of imperatorin, indicating it as a novel therapeutic candidate against PCa resistance. Future pharmacological and clinical analyses will be conducted for translational understanding of the findings to personalized PCa management.

前列腺癌（PCa）仍然是全球男性癌症相关死亡的主要原因。靶向铁下垂现已成为一种有希望的抗癌策略。本研究旨在揭示欧前胡素（一种天然呋喃香豆素）的抗肿瘤作用，通过介导凋亡诱导的PCa抑制和治疗机制。基于细胞的测定，包括CCK-8、EdU、菌落形成、迁移和侵袭测定，用于评估欧前胡素对细胞恶性表型的影响。RNA测序和生物信息学分析发现，与铁下垂相关的标记特征，即SLC7A11、ACSL4和GPX4是欧前胡素的关键靶点，并通过实验方法对其进行功能验证，以确定其对铁下垂的结合作用，阐明药物特异性，并支持翻译相关性。研究表明，欧前胡素通过下调SLC7A11/GPX4和上调ACSL4诱导铁下垂，以剂量依赖性的方式抑制PCa细胞的增殖、迁移和侵袭。特别是，经欧前胡素处理后，在ACSL4中检测到trim21介导的泛素化水平显著降低。此外，欧前胡素在体外表现出与恩杂鲁胺的协同作用，突出了它作为联合治疗的潜在药物策略。体内实验进一步证明，欧前胡素能降低肿瘤生长，改变铁下垂标志物的表达，对重要器官具有良好的毒性。这项研究揭示了欧前胡素诱导铁中毒的能力，表明它是一种新的抗PCa抗性的候选药物。未来将进行药理学和临床分析，以将研究结果转化为个性化的PCa管理。

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引用次数: 0

Agonism of FFA4/GPR120 activates tyrosine hydroxylase and confers neuroprotection from 6-OHDA-induced cytotoxicity in PC12 cells and in a rat 6-OHDA model of Parkinson’s disease FFA4/GPR120的激动作用激活酪氨酸羟化酶，在PC12细胞和6-OHDA帕金森病大鼠模型中对6-OHDA诱导的细胞毒性具有神经保护作用。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-06 DOI: 10.1016/j.bcp.2026.117685

Farnoosh Moghaddam , Monika Binwal , Andrea J. Green , Kalyn M. Rambacher , Bo Jarrett Wood , Kevin S. Murnane , Nader H. Moniri

Free-fatty acid receptor 4 (FFA4/GPR120), a G-protein-coupled receptor activated by medium to long-chain free-fatty acids (FFA) including ω-3 polyunsaturated fatty acids, regulates many metabolic and anti-inflammatory processes, and has also been linked to diverse neurophysiological functions. Here, we investigated the expression and functional role of FFA4 in dopaminergic systems using PC12 cells, rat striatal tissue, and an in vivo 6-hydroxydopamine (6-OHDA) model of Parkinson’s disease (PD). FFA4 mRNA and protein were expressed in rat caudate-putamen and colocalized with tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine biosynthesis. Agonism of FFA4 by the endogenous agonist docosahexaenoic acid (DHA) or the selective synthetic agonist TUG-891 significantly increased phosphorylation of TH-Ser⁴⁰ in PC12 cells and rat striatal minces, without elevating cAMP, suggesting non-canonical signaling of FFA4 to TH. In PC12 cells, TUG-891 attenuated 6-OHDA-induced cytotoxicity in a concentration-dependent manner, concomitant with reductions in reactive oxygen species (ROS) generation and NF-κB transcriptional activity, effects that were reversed by the FFA4 antagonist AH-7614. In an in vivo rat 6-OHDA model of PD, TUG-891 administration significantly mitigated apomorphine-induced rotational asymmetry and motor deficits in 6-OHDA-lesioned rats, while preserving striatal TH immunoreactivity. These findings identify FFA4 as a novel modulator of dopaminergic neuron integrity that may operate through antioxidant and anti-inflammatory signals to preserve cell function, warranting further exploration of FFA4 in dopaminergic degeneration and PD.

游离脂肪酸受体4 （FFA4/GPR120）是一种由中至长链游离脂肪酸（FFA）激活的g蛋白偶联受体，包括ω-3多不饱和脂肪酸，调节许多代谢和抗炎过程，并与多种神经生理功能有关。本研究利用PC12细胞、大鼠纹状体组织和帕金森病（PD）体内6-羟多巴胺（6-OHDA）模型研究FFA4在多巴胺能系统中的表达和功能作用。FFA4 mRNA和蛋白在大鼠尾壳核中表达，并与多巴胺生物合成的限速酶酪氨酸羟化酶（TH）共定位。内源性激动剂二十二碳六烯酸（DHA）或选择性合成激动剂TUG-891对FFA4的激动作用可显著增加PC12细胞和大鼠纹状体中TH- ser40的磷酸化，而不升高cAMP，提示FFA4对TH的非典型信号传导。在PC12细胞中，TUG-891以浓度依赖的方式减弱6- ohda诱导的细胞毒性，同时降低活性氧（ROS）的产生和NF-κB转录活性，这种作用被FFA4拮抗剂AH-7614逆转。在体内大鼠6-OHDA PD模型中，给予TUG-891可显著减轻阿帕吗啡诱导的6-OHDA损伤大鼠旋转不对称和运动缺陷，同时保持纹状体TH免疫反应性。这些发现表明FFA4是一种新的多巴胺能神经元完整性调节剂，可能通过抗氧化和抗炎信号来维持细胞功能，值得进一步探索FFA4在多巴胺能变性和PD中的作用。

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引用次数: 0

Targeting the FBXW7-AKAP13-YAP axis suppresses gliomagenesis by dual inhibition of tumor invasion and macrophage recruitment 靶向FBXW7-AKAP13-YAP轴通过双重抑制肿瘤侵袭和巨噬细胞募集来抑制胶质瘤形成。

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2026-01-06 DOI: 10.1016/j.bcp.2026.117677

Changfu Zhang, Haichun Li, Yushuai Gao, Kaiyuan Deng, Rongjun Qian

Glioma, a highly lethal and common malignant tumor of the central nervous system, is characterized by its aggressive invasive behavior. Tumor-associated macrophage (TAM) represent the most abundant infiltrating immune cell population in the glioma microenvironment and play a critical role in gliomagenesis and progression. Although A-kinase anchoring protein 13 (AKAP13) has been implicated in other cancers, its specific role in glioma progression and TAM infiltration remains unclear. In this study, we identify AKAP13 is significantly upregulated in glioma tissues and associated with poor patient survival. Functionally, AKAP13 silencing inhibited glioma cell invasion and TAM recruitment in both in vitro and in vivo models. Mechanistically, AKAP13 drives tumor progression by enhancing YAP expression and nuclear translocation, which subsequently upregulates the TAM-recruiting chemokines CSF1 and CCL2. We further identified F-box and WD repeat domain-containing 7 (FBXW7) as an upstream regulator that promotes ubiquitin-mediated degradation of AKAP13. Together, our findings reveal a novel FBXW7/AKAP13/YAP/chemokine signaling axis that promotes glioma pathogenesis through both tumor-autonomous invasion and TAM recruitment, highlighting a promising therapeutic target for this lethal malignancy.

胶质瘤是一种高致死率的常见中枢神经系统恶性肿瘤，其特点是具有侵袭性。肿瘤相关巨噬细胞（Tumor-associated macrophage， TAM）是胶质瘤微环境中最丰富的浸润性免疫细胞群，在胶质瘤的发生和发展中起着至关重要的作用。尽管a激酶锚定蛋白13 （AKAP13）与其他癌症有关，但其在胶质瘤进展和TAM浸润中的具体作用尚不清楚。在这项研究中，我们发现AKAP13在胶质瘤组织中显著上调，并与患者生存率低相关。在功能上，在体外和体内模型中，AKAP13沉默抑制胶质瘤细胞的侵袭和TAM的募集。从机制上讲，AKAP13通过增强YAP表达和核易位来驱动肿瘤进展，进而上调tam募集趋化因子CSF1和CCL2。我们进一步发现F-box和WD重复结构域7 （FBXW7）是促进泛素介导的AKAP13降解的上游调节因子。总之，我们的研究结果揭示了一种新的FBXW7/AKAP13/YAP/趋化因子信号轴，通过肿瘤自主侵袭和TAM募集促进胶质瘤的发病，突出了这种致命恶性肿瘤的有希望的治疗靶点。

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