Pharmacological research最新文献_第10页

The development and therapeutic potential of classical and next-generation cannabinoid ligands 经典和新一代大麻素配体的发展和治疗潜力。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-01 Epub Date: 2025-11-03 DOI: 10.1016/j.phrs.2025.108022

Verónica Muñoz-Canales , Bellinda Benhamú , Mar Martín-Fontecha , Henar Vázquez-Villa , Silvia Ortega-Gutiérrez

The endogenous cannabinoid system (ECS) is a complex network that plays a crucial role in various physiological processes, and its modulation through cannabinoid ligands has garnered significant interest in pharmacological research. Cannabinoid receptors, primarily CB₁ and CB₂, are G-protein-coupled receptors that can interact with many different types of ligands, including orthosteric agonists and antagonists and allosteric and biased modulators. This review provides an updated perspective on cannabinoid receptor ligand development, beginning with natural ligands such as phytocannabinoids and endocannabinoids. These compounds provided the initial inspiration for the design of the first synthetic classical cannabinoids which were later refined into structurally distinct non-classical cannabinoids. Beyond these traditional orthosteric ligands, we explore the expanding field of allosteric and biased modulators, which offer refined control over receptor signaling and present opportunities to reduce side effects associated with direct receptor activation. We also highlight the significance of covalent ligands and labeled chemical probes in elucidating cannabinoid receptor structure, localization, and function. Advances in imaging and chemoproteomic techniques have further enhanced our ability to visualize receptor dynamics and identify novel interaction partners. Finally, we examine the clinical landscape of cannabinoid-based therapeutics, from approved drugs to ongoing clinical trials, and discuss the remaining challenges and future directions in ECS-targeted drug development. This review aims to provide a comprehensive overview of current trends and emerging strategies in cannabinoid ligand research.

内源性大麻素系统（ECS）是一个复杂的网络，在各种生理过程中起着至关重要的作用，其通过大麻素配体的调节已经引起了药理学研究的极大兴趣。大麻素受体，主要是CB1和CB2，是g蛋白偶联受体，可以与许多不同类型的配体相互作用，包括正构激动剂和拮抗剂以及变构和偏调剂。本文综述了大麻素受体配体的最新研究进展，从植物大麻素和内源性大麻素等天然配体开始。这些化合物为第一个合成经典大麻素的设计提供了最初的灵感，这些大麻素后来被提炼成结构独特的非经典大麻素。除了这些传统的正构配体之外，我们还探索了变构和偏置调节剂的扩展领域，这些调节剂提供了对受体信号传导的精细控制，并提供了减少与直接受体激活相关的副作用的机会。我们还强调了共价配体和标记化学探针在阐明大麻素受体结构，定位和功能方面的重要性。成像和化学蛋白质组学技术的进步进一步增强了我们可视化受体动态和识别新的相互作用伙伴的能力。最后，我们研究了基于大麻素的治疗方法的临床前景，从批准的药物到正在进行的临床试验，并讨论了ecs靶向药物开发的剩余挑战和未来方向。本综述旨在全面概述大麻素配体研究的当前趋势和新兴策略。

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引用次数: 0

Feeding difficulties, eating disorders and therapeutic approaches in autism spectrum disorder: An overview 自闭症谱系障碍的进食困难、进食障碍和治疗方法综述。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-01 Epub Date: 2025-11-17 DOI: 10.1016/j.phrs.2025.108040

Martina Siracusano , Lucrezia Arturi , Assia Riccioni , Alessandro Medoro , Rosa Savino , Giovanni Scapagnini , Sergio Davinelli , Luigi Mazzone

Feeding problems are highly prevalent in individuals with autism spectrum disorder (ASD) from early developmental stages. Difficulties during the transition to solid foods, limited dietary variety, and reluctance to try new foods since infancy, combined with gastrointestinal disorders, represent significant concerns for both parents and clinicians from diagnostic and, more importantly, therapeutic perspectives. The primary clinical link between atypical eating behaviors and core autistic symptoms lies in aberrant sensory processing and an insistence on sameness, which have important implications for intervention strategies. Additionally, the increased risk of gastrointestinal disorders and altered gut microbiome composition in individuals with ASD constitute another critical factor, opening avenues for novel therapeutic approaches. Therefore, the aim of this review is to summarize the existing literature on therapeutic approaches for feeding problems in ASD, with a focus on evidence-based practices across pharmacological, psychological, and nutritional domains.

进食问题在自闭症谱系障碍（ASD）的早期发育阶段非常普遍。从诊断和更重要的是，从治疗的角度来看，过渡到固体食物的困难，有限的饮食种类，以及自婴儿期以来不愿尝试新食物，都是父母和临床医生非常关注的问题。非典型饮食行为与核心自闭症症状之间的主要临床联系在于异常的感觉加工和对一致性的坚持，这对干预策略具有重要意义。此外，ASD患者胃肠道疾病风险的增加和肠道微生物组成的改变是另一个关键因素，为新的治疗方法开辟了道路。因此，本综述的目的是总结ASD喂养问题治疗方法的现有文献，重点关注药理学，心理学和营养领域的循证实践。

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引用次数: 0

The role of Chinese medicines in targeting non-coding RNAs to overcome cancer drug resistance: Mechanisms and clinical translation challenges 中药靶向非编码rna克服肿瘤耐药的作用：机制和临床翻译挑战

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-01 Epub Date: 2025-11-24 DOI: 10.1016/j.phrs.2025.108049

Guoming Chen , Qianhua He , Qili Xiao , Jiaqi Ai , Zhengya Qin , Zilan Zhong , Jiayi Zou , Bonan Chen , Cheng Zhang , Yibin Feng

As a major obstacle in cancer treatment, drug resistance is increasingly recognized that non-coding RNA (ncRNA) plays an important role in regulating cell plasticity. This review comprehensively explores how ncRNAs, including microRNAs, long non-coding RNAs, and circular RNAs, drive drug resistance by altering identity plasticity (epithelial-mesenchymal transition and stemness), state plasticity (cell fate selection and metabolic reprogramming), and communication plasticity in the tumor microenvironment. Due to the complexity of the ncRNA network, Chinese medicines (CMs) with multi-target properties have become a potential modulator. Preclinical evidence suggests that certain CMs and their bioactive compounds have been shown to inhibit therapeutic resistance by regulating various ncRNAs. For instance, curcumin upregulates miR-206 to inhibit the JAK/STAT3 pathway in colorectal cancer, while in gastric cancer, β-elemene inhibits miR-1323 to prevent EGFR-driven epithelial-mesenchymal transition. However, current clinical research is still in the preliminary exploration stage and lacks high-quality, large-scale, prospective randomized controlled trials.

Conclusions

From a mechanistic perspective, CMs targeting ncRNAs present a potential multi-target strategy against cancer drug resistance, but their clinical translation remains largely theoretical. Bridging this gap requires future research to prioritize in-depth mechanism studies, advanced delivery systems, and rigorous clinical validation related to ncRNA biomarkers.

Chemical Compounds in this article

Curcumin; Berberine; β-Elemene; Astragaloside IV; Icariin; Matrine; Toosendanin; Artesunate; Resveratrol; Cantharidin

非编码RNA （non-coding RNA, ncRNA）在调节细胞可塑性方面发挥着重要作用，这是肿瘤耐药治疗的一大障碍。这篇综述全面探讨了ncRNAs，包括microRNAs、长链非编码rna和环状rna，如何通过改变肿瘤微环境中的身份可塑性（上皮-间质转化和干性）、状态可塑性（细胞命运选择和代谢重编程）和通讯可塑性来驱动耐药。由于ncRNA网络的复杂性，具有多靶点特性的中药已成为一种潜在的调节剂。临床前证据表明，某些CMs及其生物活性化合物已被证明通过调节各种ncrna来抑制治疗耐药性。例如，在结直肠癌中，姜黄素上调miR-206抑制JAK/STAT3通路，而在胃癌中，β-榄香烯抑制miR-1323阻止egfr驱动的上皮-间质转化。但目前临床研究尚处于初步探索阶段，缺乏高质量、大规模、前瞻性的随机对照试验。从机制角度来看，靶向ncrna的CMs提供了一种潜在的抗癌多靶点策略，但其临床转化在很大程度上仍停留在理论阶段。弥合这一差距需要未来的研究优先考虑深入的机制研究，先进的递送系统，以及与ncRNA生物标志物相关的严格的临床验证。化学成分：姜黄素；小檗碱;β-Elemene;第四套;Icariin;苦参碱;川楝素;青蒿琥酯;白藜芦醇;斑蝥素

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引用次数: 0

Mdivi-1 promotes lipid droplets-mitochondria contact and ameliorates cardiac lipotoxicity in high-fat diet-fed mice Mdivi-1促进脂滴-线粒体接触并改善高脂饮食小鼠的心脏脂肪毒性

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-01 Epub Date: 2025-11-06 DOI: 10.1016/j.phrs.2025.108028

Zujie Xu , Zheying Ma , Huiqian Ren , Yaming Yang , Xiaoqin Zhao , Bing Zhang

Myocardial lipid overload triggers excessive mitochondrial fission and impairs lipid droplets (LDs)-mitochondrial contact, thereby contributing to the development of lipotoxic cardiomyopathy. This study aimed to investigate whether the mitochondrial fission inhibitor Mdivi-1 could alleviate cardiac lipotoxicity by restoring LDs-mitochondria contact in high-fat diet (HFD)-fed mice. In vivo, male C57BL/6 HFD-fed mice were intraperitoneally injected with the mitochondrial fission inhibitor Mdivi-1 for 8 weeks. In vitro, H9C2 cardiomyoblasts were exposed to palmitic acid (PA), followed by treatment with Mdivi-1. Comprehensive assessments of cardiac function, along with molecular, biochemical, histological, cellular, and morphological analyses were performed. Results showed that Mdivi-1 treatment exerted protective effects against metabolic disorder and cardiac dysfunction in HFD-fed mice. Mdivi-1 promoted LDs-mitochondria contact by upregulating Plin2 and Plin5 expression, thereby alleviating cardiac lipotoxicity. Furthermore, PA disrupted the LDs-mitochondrial contact and induced lipotoxicity in a dose-dependent manner in H9C2 cardiomyoblasts. Mdivi-1 effectively inhibited PA-induced mitochondrial fission, restored LDs-mitochondrial contact, and facilitated the transport of fatty acids from LDs to the mitochondria for fatty acid oxidation in H9C2 cells. In conclusion, our study identifies Mdivi-1 as a novel cardioprotective agent capable of ameliorating cardiac lipotoxicity and promoting LDs-mitochondria contact.

心肌脂质过载触发线粒体过度分裂，损害脂滴(ld)-线粒体接触，从而促进脂毒性心肌病的发展。本研究旨在探讨线粒体裂变抑制剂Mdivi-1是否可以通过恢复高脂饮食（HFD）喂养小鼠的lds -线粒体接触来减轻心脏脂肪毒性。在体内，雄性C57BL/6 hfd小鼠腹腔注射线粒体裂变抑制剂Mdivi-1 8周。在体外，H9C2成心肌细胞暴露于棕榈酸（PA），然后用Mdivi-1处理。全面评估心功能，以及分子、生化、组织学、细胞和形态学分析。结果表明，Mdivi-1对hfd喂养小鼠的代谢紊乱和心功能障碍具有保护作用。Mdivi-1通过上调Plin2和Plin5的表达促进lds与线粒体的接触，从而减轻心脏脂肪毒性。此外，PA在H9C2心肌细胞中破坏lds -线粒体接触并以剂量依赖的方式诱导脂肪毒性。在H9C2细胞中，Mdivi-1有效抑制pa诱导的线粒体分裂，恢复LDs-线粒体接触，促进脂肪酸从LDs转运到线粒体进行脂肪酸氧化。总之，我们的研究确定Mdivi-1是一种新型的心脏保护剂，能够改善心脏脂肪毒性并促进lds -线粒体接触。

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引用次数: 0

Crosstalk between lipid droplets and autophagy in cancer: A nexus for therapeutic targeting 肿瘤中脂滴与自噬之间的串扰：治疗靶向的联系。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-01 Epub Date: 2025-11-04 DOI: 10.1016/j.phrs.2025.108023

Xiaofen Li , Jiwen Zhang , Shiping Luo , Xiaoqin Yu , Chuangui Song

Metabolic reprogramming is a cornerstone of cancer cell adaptation to the demanding tumor microenvironment, requiring fine-tuned control over energy, lipid metabolism, and stress responses. Central to this adaptation is the profound and bidirectional interplay between two key cellular processes: lipid storage in lipid droplets (LDs) and cellular recycling via autophagy. LDs are dynamic organelles that have emerged as critical metabolic and signaling hubs, extending far beyond their role as simple lipid depots. Autophagy, a fundamental degradation system, supplies essential metabolites during stress by engulfing cellular material in autophagosomes. These pathways are deeply intertwined: LDs not only provide lipids and proteins for autophagosome formation but are also selectively targeted for degradation by autophagy in a process known as lipophagy. This degradation releases free fatty acids that fuel mitochondrial β-oxidation, enabling cancer cells to withstand hypoxic and nutrient-poor conditions. Moreover, lipophagy prevents lipotoxicity by eliminating excess lipids, thus maintaining cellular homeostasis. Here, we review the molecular mechanisms governing the LD-autophagy axis in cancer, discuss its pivotal roles in tumor progression, metastasis, and therapeutic resistance, and explore the promise of targeting this nexus for future cancer therapies. Unraveling this complex network provides not only a new paradigm for understanding cancer metabolism but also offers a compelling rationale for developing novel pharmacological agents to combat tumor metabolic plasticity and therapeutic resistance.

代谢重编程是癌细胞适应苛刻的肿瘤微环境的基石，需要对能量、脂质代谢和应激反应进行微调控制。这种适应的核心是两个关键细胞过程之间深刻的双向相互作用：脂滴中的脂储存（ld）和通过自噬进行的细胞循环。ld是一种动态细胞器，已成为关键的代谢和信号中枢，其作用远远超出了简单的脂质储存库。自噬是一种基本的降解系统，在应激时通过吞噬细胞物质提供必需的代谢物。这些途径是紧密交织在一起的：ld不仅为自噬体的形成提供脂质和蛋白质，而且在被称为脂噬的过程中被自噬选择性地降解。这种降解会释放游离脂肪酸，促进线粒体β氧化，使癌细胞能够承受缺氧和营养不良的条件。此外，脂噬通过消除多余的脂质来防止脂肪毒性，从而维持细胞稳态。在这里，我们回顾了在癌症中控制ld -自噬轴的分子机制，讨论了它在肿瘤进展、转移和治疗耐药中的关键作用，并探讨了针对这一联系的未来癌症治疗的前景。解开这个复杂的网络不仅为理解癌症代谢提供了一个新的范例，而且为开发新的药物来对抗肿瘤代谢可塑性和治疗耐药性提供了一个令人信服的理论基础。

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引用次数: 0

Poly (ADP-ribose) polymerase (PARP) inhibitors approved for the treatment of cancer 聚（adp -核糖）聚合酶（PARP）抑制剂被批准用于治疗癌症。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-01 Epub Date: 2025-12-03 DOI: 10.1016/j.phrs.2025.108058

Robert Roskoski Jr.

The human PARP enzyme family contains 17 members that are divided into five subfamilies, the chief one of which includes the DNA-dependent enzymes (PARP1/2/3). These enzymes participate, inter alia, in DNA repair, transcription, chromatin remodeling, and cells cycle progression. PARP 1/2 catalyze both the mono-ADP ribosylation (MARylation) and poly-ADP ribosylation (PARylation) of its various substrates including itself. PARP1/2 catalyze the formation of large (200 units) linear and branched ADP-ribosyl polymer chains. When the PARP enzyme binds to DNA containing various lesions, it is activated. ADP ribosylated PARPs mark the sites of DNA damage and attract repair proteins. Back-of-the-envelope calculations suggest that the number of single-strand breaks and base loss or modification ranges from 10,000 to 100,000 per cell per day. To function properly, at least in proliferating and germline cells, the DNA lesions must be repaired. Otherwise, cell death may ensue or deleterious mutations that can cause cancer or cell senescence can occur. The FDA has approved four PARP inhibitors (olaparib, rucaparib, niraparib, and talazoparib) for the treatment of ovarian, breast, prostate, and pancreatic cancer. These agents are approved for cancers with homologous-recombination repair deficiencies including BRCA1/2 mutations. These inhibitors are approved agents used for neoadjuvant, adjuvant, and maintenance therapies. The Chinese NMPA has approved three PARP antagonists (fuzuloparib, pamiparib, senaparib) for the treatment of ovarian cancer. All seven of these drugs are orally bioavailable and fall within the criteria of Lipinski’s rule of five. Drug resistance develops in most PARP-inhibitor-treated cancer patients within one or two years.

人类PARP酶家族包含17个成员，分为5个亚家族，其中最主要的亚家族包括dna依赖性酶（PARP1/2/3）。这些酶参与DNA修复、转录、染色质重塑和细胞周期进程。parp1 /2催化包括自身在内的各种底物的单adp核糖基化（MARylation）和多adp核糖基化（PARylation）。PARP1/2催化形成大的（200单位）线性和支化的adp -核糖基聚合物链。当PARP酶与含有各种病变的DNA结合时，它被激活。ADP核糖化的parp标记DNA损伤位点并吸引修复蛋白。粗略计算表明，每个细胞每天单链断裂和碱基丢失或修饰的数量在1万到10万之间。至少在增殖细胞和生殖细胞中，为了正常工作，DNA损伤必须修复。否则，细胞死亡或有害突变可能导致癌症或细胞衰老。FDA已批准4种PARP抑制剂（olaparib、rucaparib、niraparib和talazoparib）用于卵巢癌、乳腺癌、前列腺癌和胰腺癌的治疗。这些药物被批准用于同源重组修复缺陷的癌症，包括BRCA1/2突变。这些抑制剂被批准用于新辅助、辅助和维持治疗。中国国家药监局已批准三种PARP拮抗剂（fuzuloparib, pamiparib, senaparib）用于治疗卵巢癌。所有这七种药物都是口服生物可利用的，并且符合利平斯基五法则的标准。大多数parp抑制剂治疗的癌症患者在一到两年内出现耐药性。

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引用次数: 0

SLC transporters as metalloptotic gatekeepers in tumorigenesis: From molecular mechanisms to clinical potential SLC转运蛋白在肿瘤发生中的作用：从分子机制到临床潜力

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-01 Epub Date: 2025-12-04 DOI: 10.1016/j.phrs.2025.108061

Bingchen Pan , Tan Li , Na Deng , Xin Zhang , Yangjie Peng , Yanke Li , Jingjing Jing , Liping Sun

Solute carrier (SLC) transporters exert a crucial effect on metalloptosis in tumors via governing the translocation of ions and amino acids across cellular and organelle membranes. Disruptions in metal ion homeostasis mediated by SLC transporters, along with the subsequent induction of metalloptosis, are pivotal factors in tumor initiation and progression. However, the precise biological roles and clinical implications of SLC transporters in cancer remain incompletely interpreted. This review systematically summarizes the structural and functional features of SLC transporters in mediating metalloptosis and underscores their significant roles in cancer biology. We further delineate the regulatory mechanisms of SLC transporters in metal ion flux and amino acid metabolism, emphasizing their dynamic interplay in modulating metalloptosis during tumorigenesis. Furthermore, we provide a detailed overview of the complex crosstalk among SLC transporters, metal ions, and metalloptosis pathways, and highlight the role of SLC transporters in cancer, paving novel avenues for innovative anticancer strategies.

溶质载体（SLC）转运蛋白通过调控离子和氨基酸在细胞和细胞器膜上的易位，对肿瘤的金属凋亡起着至关重要的作用。SLC转运体介导的金属离子稳态破坏，以及随后的金属凋亡诱导，是肿瘤发生和发展的关键因素。然而，SLC转运体在癌症中的确切生物学作用和临床意义仍未完全解释。本文系统地综述了SLC转运体介导金属凋亡的结构和功能特点，并强调了它们在肿瘤生物学中的重要作用。我们进一步描述了SLC转运体在金属离子通量和氨基酸代谢中的调节机制，强调了它们在肿瘤发生过程中调节金属凋亡的动态相互作用。此外，我们详细概述了SLC转运体、金属离子和金属凋亡途径之间的复杂串话，并强调了SLC转运体在癌症中的作用，为创新的抗癌策略铺平了新的道路。

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引用次数: 0

Endolysosomes as a sorting hub for emerging viruses: Gatekeepers of cellular defense, viral fate and promising therapeutic target 内溶酶体作为新兴病毒的分选中心：细胞防御、病毒命运和有希望的治疗靶点的守门人。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-01 DOI: 10.1016/j.phrs.2025.108051

Sophie Post , Lena Rueschpler , Sebastian Schloer

Emerging viruses exploit the endolysosomal system to enter host cells, subvert immune defenses, and promote their replication, underscoring the need for a deeper understanding of this compartment at the host-pathogen interface. This review synthesizes current advances that position endolysosomes as central gatekeepers of cellular homeostasis and viral control. We illustrate how emerging viruses co-opt endolysosomal trafficking pathways for entry, uncoating, and propagation; how they manipulate autophagy and key signaling nodes such as mTORC1, TFEB, and the ESCRT machinery; and how they strategically disrupt innate immune signaling orchestrated from endolysosomal platforms. We further highlight recent discoveries revealing viral interference with endosomal pattern-recognition receptors, antigen presentation circuits, and downstream inflammatory signaling. Finally, we critically assess emerging therapeutic strategies that target endolysosomal functions to restrict viral infection. Together, these insights provide an integrated framework for understanding how endolysosomes shape host antiviral responses and how their dysregulation is exploited by diverse, rapidly evolving viral pathogens. Nevertheless, the clinical translation of endolysosome-targeted antiviral strategies remains constrained by pathway complexity, potential off-target effects, and the absence of reliable biomarkers to guide therapeutic precision, underscoring key limitations and opportunities for future investigation.

新出现的病毒利用内溶酶体系统进入宿主细胞，破坏免疫防御，并促进其复制，强调需要更深入地了解宿主-病原体界面上的这个隔室。本文综述了内溶酶体作为细胞稳态和病毒控制的中心守门人的最新研究进展。我们说明了新出现的病毒如何利用内溶酶体运输途径进入、脱壳和繁殖；它们如何操纵自噬和关键信号节点，如mTORC1、TFEB和ESCRT机制；以及它们是如何战略性地破坏由内溶酶体平台协调的先天免疫信号的。我们进一步强调了最近发现的病毒干扰内体模式识别受体、抗原递呈回路和下游炎症信号。最后，我们批判性地评估了针对内溶酶体功能限制病毒感染的新兴治疗策略。总之，这些见解为理解内溶酶体如何形成宿主抗病毒反应以及它们的失调如何被各种快速进化的病毒病原体利用提供了一个综合框架。然而，内溶酶体靶向抗病毒策略的临床翻译仍然受到途径复杂性、潜在脱靶效应和缺乏可靠的生物标志物来指导治疗精度的限制，强调了关键的局限性和未来研究的机会。

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引用次数: 0

Preference of short isoprene-repeat terpenes for Cx43 gap junctions compared with cardiac Na+ and Ca2+ channels: application for cardiac ephaptic transmission research 与心脏Na+和Ca2+通道相比，短异戊二烯重复萜烯对Cx43间隙连接的偏好：在心脏上皮传递研究中的应用。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-01 Epub Date: 2025-10-30 DOI: 10.1016/j.phrs.2025.108007

Vytautas Raškevičius , Rokas Mickus , Regina Mačianskienė , Jonas Jurevičius , Arslan Mamedov , Ieva Sarapinienė , Sergio Bordel , Vytenis Arvydas Skeberdis

Essential oils (EOs) from plants exhibit various biological activities. The major ingredients of EOs are terpenes composed of isoprene subunits. In our recent studies, we have determined several terpenes as new inhibitors of intercellular communication through gap junctions (GJ). Moreover, we showed that the potency of the monoterpene α-pinene depended on connexin 43 (Cx43) phosphorylation. In the current work, using molecular modeling, we selected terpenes composed of different number of isoprene subunits and having different number of cycles. Using patch-clamp techniques, we examined their potency to inhibit Cx43 GJ conductance. We found that the selected terpenes inhibited the Cx43 GJ conductance with IC₅₀ies ranging from 2.6 to 38 µM; the sesquiterpenes but not monoterpenes exhibited extremely long delay until the onset of GJ conductance recovery after their washout; the potency of sesquiterpenes to inhibit the membranous Na⁺ and L-type Ca²⁺ currents in human atrial myocytes was more than 10-fold lower. These properties of sesquiterpenes raised the idea of using them for verifying the controversial ephaptic excitation that we carried-out by microelectrode recording and optical mapping in Langendorff-perfused rabbit’s heart. High doses of farnesene that were supposed to completely block GJ intercellular communication did not block the spread of electrical excitation in the ventricles and only produced mild changes in action potential parameters comparable to farnesene impact on membranous Na⁺ and Ca²⁺ currents. Our findings suggest that ephaptic transmission may play a major role in cardiac excitation.

植物精油具有多种生物活性。EOs的主要成分是由异戊二烯亚基组成的萜烯。在我们最近的研究中，我们已经确定了几种萜烯作为通过间隙连接（GJ）的细胞间通讯的新抑制剂。此外，我们发现单萜α-蒎烯的效价依赖于连接蛋白43 （Cx43）的磷酸化。在目前的工作中，我们采用分子模拟的方法，选择了由不同数目的异戊二烯亚基组成，具有不同环数的萜烯。使用膜片钳技术，我们检测了它们抑制Cx43 GJ电导的效力。结果表明，所选萜烯抑制Cx43 GJ电导的ic50值在2.6 ~ 38µM之间；倍半萜类而非单萜类在冲洗后GJ电导恢复的时间延迟极长；倍半萜素抑制人心房肌细胞膜性Na+和l型Ca2+电流的效力降低了10倍以上。倍半萜的这些性质提出了用它们来验证我们在langendorff灌注兔心脏中通过微电极记录和光学成像进行的有争议的触觉激发的想法。高剂量的法脂烯被认为可以完全阻断GJ细胞间通讯，但它并没有阻断脑室电兴奋的传播，只产生了与法脂烯对膜Na+和Ca2+电流的影响相当的动作电位参数的轻微变化。我们的研究结果表明，触觉传递可能在心脏兴奋中起主要作用。

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引用次数: 0

The saga of the guidelines on hypertension: Focus on the 2025 ACC/AHA document 高血压指南的传奇：关注2025年acc / aha文件。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-01 Epub Date: 2025-10-28 DOI: 10.1016/j.phrs.2025.108014

Guido Grassi

引用次数: 0