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Gpr55 deficiency crucially alters cardiomyocyte homeostasis and counteracts angiotensin II induced maladaption in female mice. Gpr55 缺乏症严重改变了雌性小鼠心肌细胞的稳态,并抵消了血管紧张素 II 诱导的适应不良。
IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-20 DOI: 10.1111/bph.17350
Brigitte Schopohl, Michael Kohlhaas, Alexander G Nickel, Anna-Florentine Schiuma, Sanne L Maas, Emiel P C van der Vorst, Yi Xuan Shia, Christoph Maack, Sabine Steffens, Sarah-Lena Puhl

Background and purpose: Cannabis stimulates several G-protein-coupled-receptors and causes bradycardia and hypotension upon sustained consumption. Moreover, in vitro studies suggest an interference of cannabinoid-signalling with cardiomyocyte contractility and hypertrophy. We aimed at revealing a functional contribution of the cannabinoid-sensitive receptor GPR55 to cardiomyocyte homeostasis and neurohumorally induced hypertrophy in vivo.

Experimental approach: Gpr55-/- and wild-type (WT) mice were characterized after 28-day angiotensin II (AngII; 1·μg·kg-1 min-1) or vehicle infusion. In isolated adult Gpr55-/- and WT cardiomyocytes, mitochondrial function was assessed under naïve conditions, while cytosolic Ca2+ handling was additionally determined following application of the selective GPR55 antagonist CID16020046.

Key results: Gpr55 deficiency did not affect angiotensin II (AngII) mediated hypertrophic growth, yet, especially in females, it alleviated maladaptive pro-hypertrophic and -inflammatory gene expression and improved inotropy and adrenergic responsiveness compared to WT. In-depth analyses implied increased cytosolic Ca2+ concentrations and transient amplitudes, and accelerated sarcomere contraction kinetics in Gpr55-/- myocytes, which could be mimicked by GPR55 blockade with CID16020046 in female WT cells. Moreover, Gpr55 deficiency up-regulated factors involved in glucose and fatty acid transport independent of the AngII challenge, accelerated basal mitochondrial respiration and reduced basal protein kinase (PK) A, G and C activity and phospholemman (PLM) phosphorylation.

Conclusions and implications: Our study suggests GPR55 as crucial regulator of cardiomyocyte hypertrophy and homeostasis presumably by regulating PKC/PKA-PLM and PKG signalling, and identifies the receptor as potential target to counteract maladaptation, adrenergic desensitization and metabolic shifts as unfavourable features of the hypertrophied heart in females.

背景和目的:大麻会刺激多个 G 蛋白偶联受体,持续吸食会导致心动过缓和低血压。此外,体外研究表明,大麻素信号会干扰心肌细胞的收缩力和肥大。我们的目的是揭示大麻素敏感受体 GPR55 对体内心肌细胞稳态和神经休克诱导的肥大的功能性贡献:实验方法:在输注血管紧张素 II(AngII;1-μg-kg-1 min-1)或药物 28 天后,对 Gpr55-/- 和野生型(WT)小鼠进行表征。在分离的成年 Gpr55-/- 和 WT 心肌细胞中,评估了线粒体在原始条件下的功能,并在应用选择性 GPR55 拮抗剂 CID16020046 后测定了细胞膜 Ca2+ 处理:主要结果:与 WT 相比,GPR55 缺乏并不影响血管紧张素 II(AngII)介导的肥厚性生长,但与 WT 相比,GPR55 缺乏可减轻不良的促肥厚性和炎症基因表达,并改善肌力和肾上腺素能反应性,尤其是在雌性中。深入分析表明,Gpr55-/-肌细胞的细胞膜Ca2+浓度和瞬时幅度增加,肌节收缩动力学加快,而在雌性WT细胞中,用CID16020046阻断GPR55可以模拟这种情况。此外,Gpr55 缺乏会上调参与葡萄糖和脂肪酸转运的因子,与 AngII 挑战无关,加速基础线粒体呼吸,降低基础蛋白激酶(PK)A、G 和 C 活性及磷脂酰亚胺(PLM)磷酸化:我们的研究表明,GPR55 可能通过调节 PKC/PKA-PLM 和 PKG 信号,成为心肌细胞肥大和稳态的关键调节因子,并将该受体确定为潜在靶点,以对抗女性肥大心脏的不利特征--适应不良、肾上腺素能脱敏和代谢转变。
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引用次数: 0
The activated caveolin-3/μ-opioid receptor complex drives morphine-induced rescue therapy in failing hearts. 激活的洞穴素-3/μ-阿片受体复合物推动了吗啡诱导的衰竭心脏抢救疗法。
IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-20 DOI: 10.1111/bph.17326
Chengxiao Guo, Xinxin Pan, Mengyun Dou, Juan Wu, Xinyu Chen, Baoli Wang, Rui Zhu, Shijin Xu, Wenyi Peng, Chao Wu, Shufang He, Sihe Zhang, Ye Zhang, Shiyun Jin

Background and purpose: Opioid analgesics can alleviate ischaemia/reperfusion (I/R) injury in chronic heart failure. However, the underlying mechanisms and targets remain unknown. Here, we investigate if caveolin-3 (Cav3) interacts with μ opioid receptors and if Cav3-μ receptor interactions play a role in morphine-induced cardioprotection in failing hearts.

Experimental approach: Cav3 and μ receptor proteins in human and rat heart tissue were determined by western blot, immunofluorescence and co-immunoprecipitation. Methyl-β-cyclodextrin (MβCD), a destroyer of caveolae, and AAV-Cav3 shRNA were used to reduce Cav3 expression in failing rat hearts. CTOP, a specific μ antagonist, was administrated before morphine preconditioning in perfused failing heart models of myocardial I/R injury.

Key results: Levels of Cav3 and μ receptor proteins were significantly higher in human and rat myocardial tissues with heart failure than in control tissues. Cav3 and μ receptor expression levels were positively correlated with disease severity. The signal of the cardiac Cav3 protein was colocalized with μ receptor in both the human and rat heart sections. Disruption of caveolae in the failing heart by either MβCD or AAV-Cav3 shRNA significantly inhibits morphine-induced phosphorylation of ERK1/2 and cardioprotection. Administration of CTOP substantially reduced Cav3 expression and morphine-induced cardioprotective effect in heart failure.

Conclusion and implications: Our data suggest that up-regulation of the Cav3/μ receptor complex is critical for morphine protection of the failing heart against I/R injury by regulating the ERK1/2 pathway. The activated Cav3/μ receptor complex is an understudied therapeutic target for opioid treatment of heart failure and ischaemic insult.

背景和目的:阿片类镇痛药可减轻慢性心力衰竭的缺血再灌注(I/R)损伤。然而,其潜在的机制和靶点仍然未知。在此,我们研究了洞穴素-3(Cav3)是否与μ阿片受体相互作用,以及Cav3-μ受体相互作用是否在吗啡诱导的心衰心脏保护中发挥作用:实验方法:通过Western印迹、免疫荧光和共免疫沉淀法测定人和大鼠心脏组织中的Cav3和μ受体蛋白。使用洞穴破坏剂甲基-β-环糊精(MβCD)和 AAV-Cav3 shRNA 减少衰竭大鼠心脏中 Cav3 的表达。在心肌I/R损伤的灌注衰竭心脏模型中,在吗啡预处理前给予特异性μ拮抗剂CTOP:主要结果:人和大鼠心力衰竭心肌组织中的Cav3和μ受体蛋白水平明显高于对照组织。Cav3和μ受体表达水平与疾病严重程度呈正相关。在人和大鼠的心脏切片中,心脏Cav3蛋白的信号与μ受体共定位。通过MβCD或AAV-Cav3 shRNA破坏衰竭心脏中的腔隙,可显著抑制吗啡诱导的ERK1/2磷酸化和心脏保护作用。CTOP可大幅降低Cav3的表达,并降低吗啡诱导的心衰患者心脏保护作用:我们的数据表明,Cav3/μ受体复合物的上调对于吗啡通过调节ERK1/2途径保护衰竭心脏免受I/R损伤至关重要。活化的Cav3/μ受体复合物是阿片类药物治疗心衰和缺血性损伤的一个未被充分研究的治疗靶点。
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引用次数: 0
QM107, a novel CD148 (RTP Type J) activating peptide therapy for treating neovascular age-related macular degeneration. 用于治疗新生血管性老年黄斑变性的新型 CD148(RTP J 型)激活肽疗法 QM107。
IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-20 DOI: 10.1111/bph.17362
Samantha Arokiasamy, Michaela J M Balderstone, Faheem Shaik, Enrico Cristante, Thomas C Moseley, Akshay Madoo, Matteo Rizzi, James W Bainbridge, Konstantin Tsoyi, Ivan O Rosas, James R Whiteford, Giulia De Rossi

Background and purpose: Angiogenesis is a pathological component of neovascular age-related macular degeneration. Current therapies, although successful, are prone to high levels of patient non-response and a loss of efficacy over time, indicating the need to explore other therapeutic avenues. We have shown that an interaction between syndecan-2 and the tyrosine phosphatase receptor CD148 (RTP Type J) results in the ablation of angiogenesis. Here we exploit this pathway to develop a peptide activator of CD148 as a therapy for neovascular age-related macular degeneration.

Experimental approach: We tested a peptide (QM107) derived from syndecan-2 in a variety of angiogenesis models and a pre-clinical model of neovascular age-related macular degeneration. We assessed the toxicological and inflammatory profiles of QM107 and its stability in vitreous humour.

Key results: QM107 inhibits angiogenesis in ex vivo sprouting assays and disrupts endothelial microcapillary formation via inhibition of cell migration. QM107 acts through CD148, leading to changes in GSK3A phosphorylation and β1 integrin activation. QM107 elicits a negligible inflammatory response and exhibits limited toxicity in cultured cells, and is stable in vitreous humour. Finally, we show proof of concept that QM107 blocks angiogenesis in vivo using a model of neovascular age-related macular degeneration.

Conclusion and implications: We have developed a CD148 activating peptide which shows promise in inhibiting angiogenesis in models of neovascular age-related macular degeneration. This treatment could either represent an alternative or augment existing therapies, and owing to its distinct mode of action be used in patients who do not respond to existing treatments.

背景和目的:血管生成是新生血管性老年黄斑变性的病理组成部分。目前的治疗方法虽然成功,但容易导致患者出现高水平的无应答,而且随着时间的推移,疗效会逐渐减弱,这表明有必要探索其他治疗途径。我们已经证明,辛迪加-2 和酪氨酸磷酸酶受体 CD148(RTP J 型)之间的相互作用会导致血管生成的消减。在此,我们利用这一途径开发了一种 CD148 多肽激活剂,用于治疗新生血管性老年黄斑变性:实验方法:我们在多种血管生成模型和新生血管性老年黄斑变性临床前模型中测试了一种源自辛迪加-2的多肽(QM107)。我们评估了QM107的毒理学和炎症特征及其在玻璃体液中的稳定性:主要结果:QM107在体外发芽试验中抑制血管生成,并通过抑制细胞迁移破坏内皮微毛细血管的形成。QM107通过CD148发挥作用,导致GSK3A磷酸化和β1整合素活化发生变化。QM107 在培养细胞中引起的炎症反应可忽略不计,毒性有限,在玻璃体液中也很稳定。最后,我们用一个新生血管性老年黄斑变性模型证明了 QM107 在体内阻断血管生成的概念:我们开发的 CD148 激活肽有望在新生血管性老年黄斑变性模型中抑制血管生成。这种疗法可以替代或增强现有疗法,而且由于其独特的作用模式,可用于对现有疗法无效的患者。
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引用次数: 0
Development of new Kir2.1 channel openers from propafenone analogues. 从普罗帕酮类似物中开发新的 Kir2.1 通道开启剂。
IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-17 DOI: 10.1111/bph.17377
Encan Li, Najla Boujeddaine, Marien J C Houtman, Renee G C Maas, Joost P G Sluijter, Gerhard F Ecker, Anna Stary-Weinzinger, Willem B van Ham, Marcel A G van der Heyden

Background and purposes: Reduced inward rectifier potassium channel (Kir2.1) functioning is associated with heart failure and may cause Andersen-Tawil Syndrome, among others characterized by ventricular arrhythmias. Most heart failure or Andersen-Tawil Syndrome patients are treated with β-adrenoceptor antagonists (β-blockers) or sodium channel blockers; however, these do not specifically address the inward rectifier current (IK1) nor aim to improve resting membrane potential stability. Consequently, additional pharmacotherapy for heart failure and Andersen-Tawil Syndrome treatment would be highly desirable. Acute propafenone treatment at low concentrations enhances IK1 current, but it also exerts many off-target effects. Therefore, discovering and exploring new IK1-channel openers is necessary.

Experimental approach: Effects of propafenone and 10 additional propafenone analogues were analysed. Currents were measured by single-cell patch-clamp electrophysiology. Kir2.1 protein expression levels were determined by western blot analysis and action potential characteristics were further validated in human-induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMCs). Molecular docking was performed to obtain detailed information on drug-channel interactions.

Key results: Analogues GPV0019, GPV0057 and GPV0576 strongly increased the outward component of IK1 while not affecting the Kir2.1 channel expression levels. GPV0057 did not block IKr at concentrations below 0.5 μmol L-1 nor NaV1.5 current below 1 μmol L-1. Moreover, hiPSC-CMC action potential duration was also not affected by GPV0057 at 0.5 and 1 μmol L-1. Structure analysis indicates a mechanism by which GPV0057 might enhance Kir2.1 channel activation.

Conclusion and implications: GPV0057 has a strong efficiency towards increasing IK1, which makes it a good candidate to address IK1 deficiency-associated diseases.

背景和目的:内向整流钾通道(Kir2.1)功能降低与心力衰竭有关,并可能导致以室性心律失常为特征的安德森-塔维尔综合征(Andersen-Tawil Syndrome)。大多数心力衰竭或安德森-塔维尔综合征患者都接受过β肾上腺素受体拮抗剂(β-受体阻滞剂)或钠通道阻滞剂治疗,但这些药物并不专门针对内向整流电流(IK1),也不旨在改善静息膜电位的稳定性。因此,针对心力衰竭和安德森-塔维尔综合征治疗的额外药物疗法是非常可取的。低浓度的急性普罗帕酮治疗可增强 IK1 电流,但也会产生许多脱靶效应。因此,有必要发现和探索新的 IK1 通道开放剂:实验方法:分析了普罗帕酮和另外 10 种普罗帕酮类似物的作用。电流通过单细胞膜片钳电生理学测量。通过Western印迹分析确定了Kir2.1蛋白的表达水平,并在人类诱导多能干细胞衍生的心肌细胞(hiPSC-CMCs)中进一步验证了动作电位特征。通过分子对接获得了药物与通道相互作用的详细信息:主要结果:类似物 GPV0019、GPV0057 和 GPV0576 能强烈增加 IK1 的外向成分,同时不影响 Kir2.1 通道的表达水平。GPV0057 在浓度低于 0.5 μmol L-1 时不会阻断 IKr,在浓度低于 1 μmol L-1 时也不会阻断 NaV1.5 电流。此外,在 0.5 和 1 μmol L-1 浓度下,hiPSC-CMC 的动作电位持续时间也不受 GPV0057 的影响。结构分析表明了 GPV0057 可增强 Kir2.1 通道活化的机制:GPV0057 对增加 IK1 有很强的效率,这使其成为解决 IK1 缺乏相关疾病的一个很好的候选药物。
{"title":"Development of new K<sub>ir</sub>2.1 channel openers from propafenone analogues.","authors":"Encan Li, Najla Boujeddaine, Marien J C Houtman, Renee G C Maas, Joost P G Sluijter, Gerhard F Ecker, Anna Stary-Weinzinger, Willem B van Ham, Marcel A G van der Heyden","doi":"10.1111/bph.17377","DOIUrl":"https://doi.org/10.1111/bph.17377","url":null,"abstract":"<p><strong>Background and purposes: </strong>Reduced inward rectifier potassium channel (K<sub>ir</sub>2.1) functioning is associated with heart failure and may cause Andersen-Tawil Syndrome, among others characterized by ventricular arrhythmias. Most heart failure or Andersen-Tawil Syndrome patients are treated with β-adrenoceptor antagonists (β-blockers) or sodium channel blockers; however, these do not specifically address the inward rectifier current (I<sub>K1</sub>) nor aim to improve resting membrane potential stability. Consequently, additional pharmacotherapy for heart failure and Andersen-Tawil Syndrome treatment would be highly desirable. Acute propafenone treatment at low concentrations enhances I<sub>K1</sub> current, but it also exerts many off-target effects. Therefore, discovering and exploring new I<sub>K1</sub>-channel openers is necessary.</p><p><strong>Experimental approach: </strong>Effects of propafenone and 10 additional propafenone analogues were analysed. Currents were measured by single-cell patch-clamp electrophysiology. K<sub>ir</sub>2.1 protein expression levels were determined by western blot analysis and action potential characteristics were further validated in human-induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMCs). Molecular docking was performed to obtain detailed information on drug-channel interactions.</p><p><strong>Key results: </strong>Analogues GPV0019, GPV0057 and GPV0576 strongly increased the outward component of I<sub>K1</sub> while not affecting the K<sub>ir</sub>2.1 channel expression levels. GPV0057 did not block I<sub>Kr</sub> at concentrations below 0.5 μmol L<sup>-1</sup> nor Na<sub>V</sub>1.5 current below 1 μmol L<sup>-1</sup>. Moreover, hiPSC-CMC action potential duration was also not affected by GPV0057 at 0.5 and 1 μmol L<sup>-1</sup>. Structure analysis indicates a mechanism by which GPV0057 might enhance K<sub>ir</sub>2.1 channel activation.</p><p><strong>Conclusion and implications: </strong>GPV0057 has a strong efficiency towards increasing I<sub>K1</sub>, which makes it a good candidate to address I<sub>K1</sub> deficiency-associated diseases.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458473","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
Site-specific m6A-miR-494-3p, not unmethylated miR-494-3p, compromises blood brain barrier by targeting tight junction protein 1 in intracranial atherosclerosis. 位点特异性 m6A-miR-494-3p 而非未甲基化的 miR-494-3p,通过靶向颅内动脉粥样硬化中的紧密连接蛋白 1 破坏血脑屏障。
IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-17 DOI: 10.1111/bph.17374
Tamar Woudenberg, M Leontien van der Bent, Veerle Kremer, Ingeborg S E Waas, Mat J A P Daemen, Reinier A Boon, Paul H A Quax, A Yaël Nossent

Background and purpose: Intracranial atherosclerosis is one of the most common causes of ischaemic stroke. However, there is a substantial knowledge gap on the development of intracranial atherosclerosis. Intracranial arteries are characterized by an upregulation of tight junctions between endothelial cells, which control endothelial permeability. We investigated the role of N6-methyladenosine (m6A), a common RNA modification, on endothelial integrity, focusing on the pro-atherogenic microRNA miR-494-3p and tight junction proteins TJP1 and PECAM1.

Experimental approach: We assessed the m6A landscape, along with the expression of miR-494-3p, TJP1 and PECAM1 in postmortem human vertebral arteries (VA), internal carotid arteries (ICA), and middle cerebral arteries (MCA) with various stages of intimal thickening and plaque formation. The interactions between m6A-modified miR-494-3p mimics, TJP1 and PECAM1, were investigated in vitro using primary human (brain) endothelial cells.

Key results: Increased m6A expression was observed in the luminal lining of atherosclerosis-affected VAs, accompanied by reduced TJP1 and PECAM1, but not VE-cadherin, expression. Colocalization of m6A and miR-494-3p in the luminal lining of VA plaques was confirmed, indicating m6A methylation of miR-494-3p in intracranial atherosclerosis. Moreover, site-specific m6A-modification of miR-494-3p led to repression specifically of TJP1 protein expression at cell-cell junctions of brain microvascular endothelial cells, while unmodified miR-494-3p showed no effect.

Conclusions and implications: This study highlights increasing m6A levels during intracranial atherogenesis. Increases in m6A-miR-494-3p contribute to the observed decreased TJP1 expression in endothelial cell-cell junctions. This is likely to have a negative effect on endothelial integrity and may thus accelerate intracranial atherosclerosis progression.

背景和目的:颅内动脉粥样硬化是缺血性脑卒中最常见的病因之一。然而,人们对颅内动脉粥样硬化的发展还缺乏足够的了解。颅内动脉的特点是内皮细胞之间的紧密连接上调,而紧密连接控制着内皮的通透性。我们研究了 N6-甲基腺苷(m6A)这种常见的 RNA 修饰对内皮完整性的作用,重点研究了促动脉粥样硬化的 microRNA miR-494-3p、紧密连接蛋白 TJP1 和 PECAM1:实验方法:我们评估了不同阶段内膜增厚和斑块形成的死后人类椎动脉(VA)、颈内动脉(ICA)和大脑中动脉(MCA)中的 m6A 情况以及 miR-494-3p、TJP1 和 PECAM1 的表达。利用原代人(脑)内皮细胞在体外研究了经 m6A 修饰的 miR-494-3p 模拟物、TJP1 和 PECAM1 之间的相互作用:主要结果:在受动脉粥样硬化影响的血管腔内膜中观察到 m6A 表达增加,同时 TJP1 和 PECAM1(而非 VE-cadherin)表达减少。m6A 和 miR-494-3p 在 VA 斑块管腔内壁的共定位被证实,这表明 miR-494-3p 在颅内动脉粥样硬化中的 m6A 甲基化。此外,miR-494-3p 的位点特异性 m6A 修饰导致脑微血管内皮细胞细胞-细胞连接处的 TJP1 蛋白表达受到特异性抑制,而未修饰的 miR-494-3p 则没有影响:本研究强调了颅内动脉粥样硬化发生过程中 m6A 水平的增加。m6A-miR-494-3p的增加导致了观察到的内皮细胞-细胞连接处TJP1表达的减少。这可能会对内皮完整性产生负面影响,从而加速颅内动脉粥样硬化的进展。
{"title":"Site-specific m6A-miR-494-3p, not unmethylated miR-494-3p, compromises blood brain barrier by targeting tight junction protein 1 in intracranial atherosclerosis.","authors":"Tamar Woudenberg, M Leontien van der Bent, Veerle Kremer, Ingeborg S E Waas, Mat J A P Daemen, Reinier A Boon, Paul H A Quax, A Yaël Nossent","doi":"10.1111/bph.17374","DOIUrl":"https://doi.org/10.1111/bph.17374","url":null,"abstract":"<p><strong>Background and purpose: </strong>Intracranial atherosclerosis is one of the most common causes of ischaemic stroke. However, there is a substantial knowledge gap on the development of intracranial atherosclerosis. Intracranial arteries are characterized by an upregulation of tight junctions between endothelial cells, which control endothelial permeability. We investigated the role of N6-methyladenosine (m6A), a common RNA modification, on endothelial integrity, focusing on the pro-atherogenic microRNA miR-494-3p and tight junction proteins TJP1 and PECAM1.</p><p><strong>Experimental approach: </strong>We assessed the m6A landscape, along with the expression of miR-494-3p, TJP1 and PECAM1 in postmortem human vertebral arteries (VA), internal carotid arteries (ICA), and middle cerebral arteries (MCA) with various stages of intimal thickening and plaque formation. The interactions between m6A-modified miR-494-3p mimics, TJP1 and PECAM1, were investigated in vitro using primary human (brain) endothelial cells.</p><p><strong>Key results: </strong>Increased m6A expression was observed in the luminal lining of atherosclerosis-affected VAs, accompanied by reduced TJP1 and PECAM1, but not VE-cadherin, expression. Colocalization of m6A and miR-494-3p in the luminal lining of VA plaques was confirmed, indicating m6A methylation of miR-494-3p in intracranial atherosclerosis. Moreover, site-specific m6A-modification of miR-494-3p led to repression specifically of TJP1 protein expression at cell-cell junctions of brain microvascular endothelial cells, while unmodified miR-494-3p showed no effect.</p><p><strong>Conclusions and implications: </strong>This study highlights increasing m6A levels during intracranial atherogenesis. Increases in m6A-miR-494-3p contribute to the observed decreased TJP1 expression in endothelial cell-cell junctions. This is likely to have a negative effect on endothelial integrity and may thus accelerate intracranial atherosclerosis progression.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458479","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
tiRNA-Gly-GCC-002 promotes epithelial-mesenchymal transition and fibrosis in lupus nephritis via FKBP5-mediated activation of Smad. tiRNA-Gly-GCC-002 通过 FKBP5 介导的 Smad 激活促进狼疮性肾炎的上皮-间质转化和纤维化。
IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-17 DOI: 10.1111/bph.17364
Xueting Liu, Ji Zhang, Yan Liang, Xuanwen Chen, Shungang Xu, Sishi Lin, Yuanting Dai, Xinxin Chen, Ying Zhou, Yongheng Bai, Chaosheng Chen

Background and purpose: Renal interstitial fibrosis is a frequent pathological manifestation of lupus nephritis (LN). tRNA halves (tiRNAs) are acquired from tRNA-derived small non-coding RNAs (sncRNAs) and are associated with fibrosis. Our previous study indicated enhanced tiRNA-Gly-GCC-002 (tiRNA002) levels in kidneys were positively related to LN-related fibrosis. However, the precise molecular mechanism remains unclear.

Experimental approach: The mimic and agomiR of tiRNA002 were introduced into tubular epithelial cells (TECs) and MRL/lpr mice by transfection. The levels of gene and protein expressions were quantified using real-time quantitative polymerase chain reaction (RT-qPCR), Western blot and immunofluorescence assays.

Key results: In TECs treated with LN serum, as well as in the kidneys of MRL/lpr mice, high levels of tiRNA002 directly influenced the epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) deposition. Furthermore, tiRNA002 overexpression promoted EMT in TECs and accelerated renal interstitial fibrosis in MRL/lpr mice via Smad signalling. The target gene of tiRNA002, FKBP prolyl isomerase 5 (FKBP5), improved Smad signalling by interacting with phosphorylated Smad2/3. Silencing FKBP5 alleviated LN serum- or tiRNA002-mimic-induced EMT in TECs. In addition, FKBP5 overexpression reversed the tiRNA002 knockdown-mediated reduction of EMT and ECM accumulation.

Conclusions and implications: These findings indicated that tiRNA002 is markedly increased in LN, which facilitates renal fibrosis by promoting EMT via FKBP5-mediated Smad signalling. Therefore, targeting tiRNA002 may be an innovative approach to treat renal interstitial fibrosis in LN.

背景和目的:肾间质纤维化是狼疮性肾炎(LN)的一种常见病理表现。tRNA半核酸(tiRNAs)是从tRNA衍生的小非编码RNA(sncRNAs)中获得的,与纤维化有关。我们之前的研究表明,肾脏中 tiRNA-Gly-GCC-002(tiRNA002)水平的升高与 LN 相关纤维化呈正相关。然而,确切的分子机制仍不清楚:实验方法:通过转染将tiRNA002的模拟物和agomiR引入肾小管上皮细胞(TECs)和MRL/lpr小鼠。采用实时定量聚合酶链反应(RT-qPCR)、Western 印迹和免疫荧光检测法对基因和蛋白质的表达水平进行量化:主要结果:在用LN血清处理的TEC以及MRL/lpr小鼠的肾脏中,高水平的tiRNA002直接影响上皮-间质转化(EMT)和细胞外基质(ECM)沉积。此外,tiRNA002 的过表达促进了 TEC 的 EMT,并通过 Smad 信号加速了 MRL/lpr 小鼠肾间质纤维化。tiRNA002的靶基因FKBP脯氨酰异构酶5(FKBP5)通过与磷酸化的Smad2/3相互作用改善了Smad信号传导。沉默FKBP5可减轻LN血清或tiRNA002模拟物诱导的TECs EMT。此外,FKBP5的过表达逆转了tiRNA002敲除介导的EMT和ECM积累的减少:这些研究结果表明,tiRNA002 在 LN 中明显增加,它通过 FKBP5 介导的 Smad 信号促进 EMT,从而促进肾纤维化。因此,靶向 tiRNA002 可能是治疗 LN 肾间质纤维化的一种创新方法。
{"title":"tiRNA-Gly-GCC-002 promotes epithelial-mesenchymal transition and fibrosis in lupus nephritis via FKBP5-mediated activation of Smad.","authors":"Xueting Liu, Ji Zhang, Yan Liang, Xuanwen Chen, Shungang Xu, Sishi Lin, Yuanting Dai, Xinxin Chen, Ying Zhou, Yongheng Bai, Chaosheng Chen","doi":"10.1111/bph.17364","DOIUrl":"https://doi.org/10.1111/bph.17364","url":null,"abstract":"<p><strong>Background and purpose: </strong>Renal interstitial fibrosis is a frequent pathological manifestation of lupus nephritis (LN). tRNA halves (tiRNAs) are acquired from tRNA-derived small non-coding RNAs (sncRNAs) and are associated with fibrosis. Our previous study indicated enhanced tiRNA-Gly-GCC-002 (tiRNA002) levels in kidneys were positively related to LN-related fibrosis. However, the precise molecular mechanism remains unclear.</p><p><strong>Experimental approach: </strong>The mimic and agomiR of tiRNA002 were introduced into tubular epithelial cells (TECs) and MRL/lpr mice by transfection. The levels of gene and protein expressions were quantified using real-time quantitative polymerase chain reaction (RT-qPCR), Western blot and immunofluorescence assays.</p><p><strong>Key results: </strong>In TECs treated with LN serum, as well as in the kidneys of MRL/lpr mice, high levels of tiRNA002 directly influenced the epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) deposition. Furthermore, tiRNA002 overexpression promoted EMT in TECs and accelerated renal interstitial fibrosis in MRL/lpr mice via Smad signalling. The target gene of tiRNA002, FKBP prolyl isomerase 5 (FKBP5), improved Smad signalling by interacting with phosphorylated Smad2/3. Silencing FKBP5 alleviated LN serum- or tiRNA002-mimic-induced EMT in TECs. In addition, FKBP5 overexpression reversed the tiRNA002 knockdown-mediated reduction of EMT and ECM accumulation.</p><p><strong>Conclusions and implications: </strong>These findings indicated that tiRNA002 is markedly increased in LN, which facilitates renal fibrosis by promoting EMT via FKBP5-mediated Smad signalling. Therefore, targeting tiRNA002 may be an innovative approach to treat renal interstitial fibrosis in LN.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458489","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
A novel hypothesis-generating computational workflow utilizing reverse pharmacophore mapping-A drug repurposing perspective of istradefylline towards major depressive disorder. 利用反向药理图谱的新型假设生成计算工作流程--从药物再利用的角度看重度抑郁障碍的异曲非林。
IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-15 DOI: 10.1111/bph.17346
Mietha Magdalena van der Walt, Arnold Petrus Smith

Background and purpose: Drug repurposing (DR) offers a compelling alternative to traditional drug discovery's lengthy, resource-intensive process. DR is the process of identifying alternative clinical applications for pre-approved drugs as a low-risk and low-cost strategy. Computational approaches are crucial during the early hypothesis-generating stage of DR. However, 'large-scale' data retrieval remains a significant challenge. A computational workflow addressing such limitations might improve hypothesis generation, ultimately benefit patients and advance DR research.

Experimental approach: We introduce a novel computational workflow (combining free-accessible computational platforms) to provide 'proof-of-concept' of the pre-approved drug's suitability for repurposing. Three key phases are included: target fishing (via reverse pharmacophore mapping), target identification (via disease- and drug-target pathway identification) and retrospective literature and drug-like analysis (via in silico ADMET properties determination). Istradefylline is a Parkinson's disease-approved drug with literature-attributed antidepressant properties remaining unclear. Practically applied, istradefylline's antidepressant activity was assessed in the context of major depressive disorder (MDD).

Key results: Data mining aided by target identification resulted in istradefylline potentially representing a novel antidepressant drug class. Retrieved drug targets (KYNU, MAO-B, ALOX12 and PLCB2) associated with selected MDD pathways (tryptophan metabolism and serotonergic synapse) generated a hypothesis that istradefylline increased extracellular 5-HT levels (MAO-B inhibition) and reduced inflammation (KYNU, ALOX12 and PLCB2 inhibition).

Conclusion and implications: The practically applied workflow's generated hypothesis aligns with known experimental data, validating the effectiveness of this novel computational workflow. It is a low-risk and low-cost DR computational tool providing a bird's-eye view for exploring alternative clinical applications of pre-approved drugs.

背景和目的:药物再利用(DR)为传统药物发现的漫长、资源密集型过程提供了一个令人信服的替代方案。药物再利用是一种低风险、低成本的策略,是为已获批准的药物确定替代临床应用的过程。在 DR 的早期假设生成阶段,计算方法至关重要。然而,"大规模 "数据检索仍然是一项重大挑战。解决这些局限性的计算工作流程可能会改善假设的生成,最终造福患者并推动 DR 研究:实验方法:我们介绍了一种新颖的计算工作流程(结合了可免费访问的计算平台),为预先批准的药物是否适合再利用提供 "概念证明"。其中包括三个关键阶段:靶点钓取(通过反向药效图谱)、靶点识别(通过疾病和药物靶点通路识别)以及文献和类药物回顾性分析(通过硅学 ADMET 特性测定)。伊斯替菲林是一种已获批准的帕金森病药物,但文献归因的抗抑郁特性尚不明确。在实际应用中,我们在重度抑郁症(MDD)的背景下评估了伊曲替菲林的抗抑郁活性:主要结果:通过靶点识别进行数据挖掘,发现异曲非林可能是一种新型抗抑郁药物。检索到的药物靶点(KYNU、MAO-B、ALOX12和PLCB2)与选定的MDD通路(色氨酸代谢和5-羟色胺能突触)相关,由此产生了一个假设:异曲飞林能提高细胞外5-羟色胺水平(抑制MAO-B)并减轻炎症(抑制KYNU、ALOX12和PLCB2):实际应用的工作流程生成的假设与已知实验数据一致,验证了这一新型计算工作流程的有效性。它是一种低风险、低成本的 DR 计算工具,可为探索已批准药物的其他临床应用提供鸟瞰图。
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引用次数: 0
miR-210 as a therapeutic target in diabetes-associated endothelial dysfunction. miR-210 作为糖尿病相关内皮功能障碍的治疗靶点。
IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-14 DOI: 10.1111/bph.17329
Aida Collado, Tong Jiao, Eftychia Kontidou, Lucas Rannier Ribeiro Antonino Carvalho, Ekaterina Chernogubova, Jiangning Yang, Germana Zaccagnini, Allan Zhao, John Tengbom, Xiaowei Zheng, Bence Rethi, Michael Alvarsson, Sergiu-Bogdan Catrina, Ali Mahdi, Mattias Carlström, Fabio Martelli, John Pernow, Zhichao Zhou

Background and purpose: MicroRNA (miR)-210 function in endothelial cells and its role in diabetes-associated endothelial dysfunction are not fully understood. We aimed to characterize the miR-210 function in endothelial cells and study its therapeutic potential in diabetes.

Experimental approach: Two different diabetic mouse models (db/db and Western diet-induced), miR-210 knockout and transgenic mice, isolated vessels and human endothelial cells were used.

Key results: miR-210 levels were lower in aortas isolated from db/db than in control mice. Endothelium-dependent relaxation (EDR) was impaired in aortas from miR-210 knockout mice, and this was restored by inhibiting miR-210 downstream protein tyrosine phosphatase 1B (PTP1B), mitochondrial glycerol-3-phosphate dehydrogenase 2 (GPD2), and mitochondrial oxidative stress. Inhibition of these pathways also improved EDR in both diabetic mouse models. High glucose reduced miR-210 levels in endothelial cells and impaired EDR in mouse aortas, effects that were reversed by overexpressing miR-210. However, plasma miR-210 levels were not affected in individuals with type 2 diabetes (T2D) following improved glycaemic status. Of note, genetic overexpression using miR-210 transgenic mice and pharmacological overexpression using miR-210 mimic in vivo ameliorated endothelial dysfunction in both diabetic mouse models by decreasing PTP1B, GPD2 and oxidative stress. Genetic overexpression of miR-210 altered the aortic transcriptome, decreasing genes in pathways involved in oxidative stress. miR-210 mimic restored decreased nitric oxide production by high glucose in endothelial cells.

Conclusion and implications: This study unravels the mechanisms by which down-regulated miR-210 by high glucose induces endothelial dysfunction in T2D and demonstrates that miR-210 serves as a novel therapeutic target.

背景和目的:微RNA(miR)-210在内皮细胞中的功能及其在糖尿病相关内皮功能障碍中的作用尚未完全清楚。我们旨在描述 miR-210 在内皮细胞中的功能,并研究其在糖尿病中的治疗潜力:实验方法:使用两种不同的糖尿病小鼠模型(db/db 和西方饮食诱导型)、miR-210 基因敲除和转基因小鼠、离体血管和人类内皮细胞。通过抑制 miR-210 下游蛋白酪氨酸磷酸酶 1B (PTP1B)、线粒体甘油-3-磷酸脱氢酶 2 (GPD2)和线粒体氧化应激,内皮依赖性松弛(EDR)在 miR-210 基因敲除小鼠的主动脉中受损。抑制这些通路也能改善两种糖尿病小鼠模型的 EDR。高血糖会降低内皮细胞中的 miR-210 水平,并损害小鼠主动脉的 EDR,而过表达 miR-210 则可逆转这种影响。然而,血糖状况改善后,2 型糖尿病(T2D)患者的血浆 miR-210 水平并不受影响。值得注意的是,利用 miR-210 转基因小鼠进行基因过表达,以及利用 miR-210 体内模拟物进行药理过表达,可通过降低 PTP1B、GPD2 和氧化应激,改善两种糖尿病小鼠模型的内皮功能障碍。基因过表达 miR-210 改变了主动脉转录组,减少了氧化应激通路中的基因:本研究揭示了高糖下调 miR-210 导致 T2D 内皮功能障碍的机制,并证明 miR-210 是一种新型治疗靶点。
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引用次数: 0
Pharmacology of PIEZO1 channels PIEZO1 通道的药理学。
IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-14 DOI: 10.1111/bph.17351
Jacob A. Kinsella, Marjolaine Debant, Gregory Parsonage, Lara C. Morley, Muath Bajarwan, Charlotte Revill, Richard Foster, David J. Beech

PIEZO1 is a eukaryotic membrane protein that assembles as trimers to form calcium-permeable, non-selective cation channels with exquisite capabilities for mechanical force sensing and transduction of force into effect in diverse cell types that include blood cells, endothelial cells, epithelial cells, fibroblasts and stem cells and diverse systems that include bone, lymphatics and muscle. The channel has wide-ranging roles and is considered as a target for novel therapeutics in ailments spanning cancers and cardiovascular, dental, gastrointestinal, hepatobiliary, infectious, musculoskeletal, nervous system, ocular, pregnancy, renal, respiratory and urological disorders. The identification of PIEZO1 modulators is in its infancy but useful experimental tools emerged for activating, and to a lesser extent inhibiting, the channels. Elementary structure–activity relationships are known for the Yoda series of small molecule agonists, which show the potential for diverse physicochemical and pharmacological properties. Intriguing effects of Yoda1 include the stimulated removal of excess cerebrospinal fluid. Despite PIEZO1's broad expression, opportunities are suggested for selective positive or negative modulation without intolerable adverse effects. Here we provide a focused, non-systematic, narrative review of progress with this pharmacology and discuss potential future directions for research in the area.

PIEZO1 是一种真核生物膜蛋白,它以三聚体的形式组装成具有钙渗透性的非选择性阳离子通道,在包括血细胞、内皮细胞、上皮细胞、成纤维细胞和干细胞在内的各种细胞类型以及包括骨骼、淋巴管和肌肉在内的各种系统中具有精湛的机械力感应和力传导能力。该通道具有广泛的作用,被认为是癌症、心血管、牙科、胃肠道、肝胆、感染、肌肉骨骼、神经系统、眼科、妊娠、肾脏、呼吸和泌尿系统疾病等各种疾病的新型疗法的靶点。PIEZO1 调制剂的鉴定工作尚处于起步阶段,但已经出现了一些有用的实验工具来激活或抑制该通道。目前已知的 Yoda 系列小分子激动剂具有基本的结构-活性关系,这些激动剂显示出多种物理化学和药理特性的潜力。Yoda1 令人感兴趣的作用包括刺激清除多余的脑脊液。尽管 PIEZO1 的表达范围很广,但仍有机会对其进行选择性的正向或负向调节,而不会产生难以忍受的不良反应。在此,我们对这一药理学的进展进行了集中、非系统的叙述性回顾,并讨论了该领域未来潜在的研究方向。
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引用次数: 0
A pH-sensitive opioid does not exhibit analgesic tolerance in a mouse model of colonic inflammation. 一种对 pH 值敏感的阿片类药物在小鼠结肠炎症模型中不会表现出镇痛耐受性。
IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-13 DOI: 10.1111/bph.17363
Claudius E Degro, Nestor Nivardo Jiménez-Vargas, Mabel Guzman-Rodriguez, Hailey Schincariol, Quentin Tsang, David E Reed, Alan E Lomax, Nigel W Bunnett, Christoph Stein, Stephen J Vanner

Background and purpose: Tolerance to the analgesic effects of opioids and resultant dose escalation is associated with worsening of side effects and greater addiction risk. Here, we compare the development of tolerance to the conventional opioid fentanyl with a novel pH-sensitive μ-opioid receptor (MOR) agonist, (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide (NFEPP) that is active only in acidic inflammatory microenvironments.

Experimental approach: An opioid tolerance model was developed in male C57BL/6 mice, with and without dextran sulphate sodium colitis, using increasing doses of either fentanyl or NFEPP over 5 days. Visceral nociception was assessed in vivo by measuring visceromotor responses (VMRs) to noxious colorectal distensions and in vitro measuring colonic afferent nerve activity of mesenteric nerves and performing patch-clamp recordings from isolated dorsal root ganglia neurons. Somatic thermal nociception was tested using a tail immersion assay. Cardiorespiratory effects were analysed by pulse oximeter experiments.

Key results: VMRs and tail immersion tests demonstrated tolerance to fentanyl, but not to NFEPP in colitis mice. Cross-tolerance also occurred to fentanyl, but not to NFEPP. The MOR agonist DAMGO inhibited colonic afferent nerve activity in colitis mice exposed to chronic NFEPP, but not those from fentanyl-treated mice. Similarly, in patch-clamp recordings from isolated dorsal root ganglia neurons, DAMGO inhibited neurons from NFEPP-, but not fentanyl-treated mice.

Conclusion and implications: NFEPP did not exhibit tolerance in an inflammatory pain model, unlike fentanyl. Consequently, dose escalation to maintain analgesia during an evolving inflammation could be avoided, mitigating the potential risk of side effects.

背景和目的:对阿片类药物镇痛效果的耐受性和由此导致的剂量升级与副作用恶化和更大的成瘾风险有关。在此,我们比较了传统阿片类药物芬太尼与新型 pH 值敏感型μ-阿片受体(MOR)激动剂 (±)-N-(3- 氟-1-苯乙基哌啶-4-基)-N-苯基丙酰胺(NFEPP)耐受性的发展情况,后者仅在酸性炎症微环境中具有活性:实验方法:在患有或未患有右旋糖酐硫酸钠结肠炎的雄性 C57BL/6 小鼠中建立阿片类药物耐受模型,在 5 天内使用递增剂量的芬太尼或 NFEPP。内脏痛觉的评估在体内是通过测量对有害结肠直肠胀气的内脏运动反应(VMRs)进行的,在体外是通过测量肠系膜神经的结肠传入神经活动和对离体背根神经节神经元进行贴片钳记录进行的。使用尾部浸入试验测试了体热痛觉。脉搏氧饱和度实验分析了对心肺功能的影响:主要结果:VMRs 和尾浸试验表明,结肠炎小鼠对芬太尼有耐受性,但对 NFEPP 没有耐受性。对芬太尼也有交叉耐受性,但对 NFEPP 没有。MOR 激动剂 DAMGO 可抑制长期接触 NFEPP 的结肠炎小鼠的结肠传入神经活动,但不能抑制经芬太尼处理的小鼠的结肠传入神经活动。同样,在离体背根神经节神经元的贴片钳记录中,DAMGO 可抑制 NFEPP 治疗小鼠的神经元,但不能抑制芬太尼治疗小鼠的神经元:与芬太尼不同,NFEPP 在炎性疼痛模型中不会表现出耐受性。因此,在炎症不断发展的过程中,可以避免通过剂量升级来维持镇痛,从而降低副作用的潜在风险。
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引用次数: 0
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British Journal of Pharmacology
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