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Mu-opioid receptors in tachykinin-1-positive cells mediate the respiratory and antinociceptive effects of the opioid fentanyl. 速激肽-1阳性细胞中的缪阿片受体介导了阿片类药物芬太尼的呼吸和抗痛觉效应。
IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-06 DOI: 10.1111/bph.17369
Andreea Furdui, Carolina da Silveira Scarpellini, Gaspard Montandon

Background and purpose: Opioid drugs are potent analgesics that carry the risk of respiratory side effects due to actions on μ-opioid receptors (MORs) in brainstem regions that control respiration. Substance P is encoded by the Tac1 gene and is expressed in neurons regulating breathing, nociception, and locomotion. Tac1-positive cells also express MORs in brainstem regions mediating opioid-induced respiratory depression. We determined the role of Tac1-positive cells in mediating the respiratory effects of opioid drugs.

Experimental approach: In situ hybridization was used to determine Oprm1 mRNA expression (gene encoding MORs) in Tac1-positive cells in regions regulating respiratory depression by opioid drugs. Conditional knockout mice lacking functional MORs in Tac1-positive cells were produced and the respiratory and locomotor responses to the opioid analgesic fentanyl were assessed using whole-body plethysmography. A tail immersion assay was used to assess the antinociceptive response to fentanyl.

Key results: Oprm1 mRNA was highly expressed (>80%) in subpopulations of Tac1-positive cells in the preBötzinger Complex, nucleus tractus solitarius, and Kölliker-Fuse/lateral parabrachial region. Conditionally knocking out MORs in Tac1-positive cells abolished the effects of fentanyl on respiratory rate, relative tidal volume, and relative minute ventilation compared with control mice. Importantly, the antinociceptive response of fentanyl was eliminated in mice lacking functional MORs in Tac1-positive cells, whereas locomotor effects induced by fentanyl were preserved.

Conclusions and implications: Our findings suggest that Tac1-positive cells mediate the respiratory depressive and antinociceptive effects of the opioid fentanyl, providing important insights for the development of pain therapies with reduced risk of respiratory side effects.

背景和目的:阿片类药物是一种强效镇痛药,由于作用于控制呼吸的脑干区域的μ-阿片受体(MORs),因此有可能对呼吸系统产生副作用。P 物质由 Tac1 基因编码,在调节呼吸、痛觉和运动的神经元中表达。Tac1 阳性细胞还在脑干区域表达 MORs,介导阿片类药物诱导的呼吸抑制。我们确定了 Tac1 阳性细胞在介导阿片类药物呼吸效应中的作用:实验方法:采用原位杂交法测定阿片类药物呼吸抑制调节区 Tac1 阳性细胞中 Oprm1 mRNA(编码 MORs 的基因)的表达。制备了在 Tac1 阳性细胞中缺乏功能性 MORs 的条件基因剔除小鼠,并使用全身褶压计评估了小鼠对阿片类镇痛药芬太尼的呼吸和运动反应。使用尾部浸泡试验评估对芬太尼的抗痛觉反应:主要结果:Oprm1 mRNA在前伯丁格复合体、孤束核和Kölliker-Fuse/外侧腕旁区域的Tac1阳性细胞亚群中高度表达(>80%)。与对照组小鼠相比,有条件地敲除 Tac1 阳性细胞中的 MORs 可消除芬太尼对呼吸频率、相对潮气量和相对分钟通气量的影响。重要的是,在 Tac1 阳性细胞中缺乏功能性 MORs 的小鼠中,芬太尼的抗痛觉反应被消除,而芬太尼诱导的运动效应却得以保留:我们的研究结果表明,Tac1 阳性细胞介导了阿片类药物芬太尼的呼吸抑制和抗痛觉效应,为开发可降低呼吸副作用风险的疼痛疗法提供了重要启示。
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引用次数: 0
Sex influence on serotonergic modulation of the vascular noradrenergic drive in rats. 性别对血清素能调节大鼠血管去甲肾上腺素能驱动力的影响
IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-03 DOI: 10.1111/bph.17380
Anaïs Clara Terol-Úbeda, Juan Francisco Fernández-González, Carlos Andrés Roldán-Hernández, María Luisa Martín, Asunción Morán, Mónica García-Domingo, José Ángel García-Pedraza

Background and purpose: In male rats, the serotonergic system modulates sympathetic outflow at vascular levels, causing sympatho-inhibition and sympatho-excitation, mainly via 5-HT1D/1A and 5-HT3 receptors, respectively. However, sex influence on vascular serotonergic regulation has not yet been elucidated. This study aimed to analyse the 5-HT sympatho-modulatory role in female rats, characterising the 5-HT receptors involved.

Experimental approach: Female Wistar (14- to 16-week-old) rats were prepared for sympathetic stimulation. Mean blood pressure (MBP) and heart rate (HR) were continuously measured. Vasopressor responses were obtained by electrical stimulation of the sympathetic outflow (0.1-5 Hz) or i.v. noradrenaline (0.01-0.5 μg·kg-1). 5-HT-related drug effects on adrenergic system were determined. Age-matched male rats were used as control.

Key results: Basal MBP in females was lower than in male rats, whereas electrical-induced increases in MBP were similar. In females, 5-HT exerted a dose-dependent inhibition on the sympathetic-evoked vasoconstrictions, that was reproduced by some agonists; 5-CT (5-HT1/5/7) and L-694,247 (5-HT1D), whereas the selective 5-HT2A/2B/2C (α-methyl-5-HT) and 5-HT3 agonist (1-PBG) increased the electrically-produced vasopressor responses. None of the other drugs tested (targeting 5-HT1A/1B/1F, 5-HT2B/2C, 5-HT4, 5-HT5A or 5-HT7) modified these vasoconstrictions. Only 1-PBG (5-HT3) modified the vasoconstrictions induced by exogenous noradrenaline.

Conclusions and implications: In female rats, vascular serotonergic sympatholytic effects are due to prejunctional 5-HT1D receptor activation, whereas pre and/or postjunctional 5-HT3 and prejunctional 5-HT2A receptor activation is involved in the potentiating effect of vascular sympathetic neurotransmission. These findings may open novel sex-differential therapeutic strategies for treating cardiovascular conditions.

背景和目的:在雄性大鼠体内,5-羟色胺能系统主要通过 5-HT1D/1A 和 5-HT3 受体调节血管水平的交感神经外流,引起交感抑制和交感兴奋。然而,性别对血管血清素能调节的影响尚未阐明。本研究旨在分析 5-HT 对雌性大鼠交感神经的调节作用,并确定参与其中的 5-HT 受体的特征:实验方法:准备对雌性 Wistar(14 至 16 周大)大鼠进行交感神经刺激。连续测量平均血压(MBP)和心率(HR)。通过电刺激交感神经外流(0.1-5 Hz)或静脉注射去甲肾上腺素(0.01-0.5 μg-kg-1)获得血管加压反应。测定5-HT相关药物对肾上腺素能系统的影响。将年龄匹配的雄性大鼠作为对照:主要结果:雌性大鼠的基础 MBP 低于雄性大鼠,而电诱导的 MBP 升高与雄性大鼠相似。在雌性大鼠中,5-HT 对交感神经诱发的血管收缩有剂量依赖性抑制作用,一些激动剂(5-CT(5-HT1/5/7)和 L-694,247(5-HT1D))可再现这种作用,而选择性 5-HT2A/2B/2C(α-甲基-5-HT)和 5-HT3 激动剂(1-PBG)可增加电引起的血管加压反应。其他测试药物(靶向 5-HT1A/1B/1F、5-HT2B/2C、5-HT4、5-HT5A 或 5-HT7)均未改变这些血管收缩反应。只有 1-PBG(5-HT3)能改变外源性去甲肾上腺素诱导的血管收缩:在雌性大鼠中,血管5-羟色胺能交感神经溶解作用是由功能前5-HT1D受体激活引起的,而功能前和/或功能后5-HT3和功能前5-HT2A受体激活参与了血管交感神经传递的增效作用。这些发现可能为治疗心血管疾病开辟新的性别差异治疗策略。
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引用次数: 0
Cognitive improvement via cortical cannabinoid receptors and choline-containing lipids. 通过大脑皮层大麻素受体和含胆碱脂质改善认知。
IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-03 DOI: 10.1111/bph.17381
Marta Moreno-Rodríguez, Jonatan Martínez-Gardeazabal, Iker Bengoetxea de Tena, Alberto Llorente-Ovejero, Laura Lombardero, Estibaliz González de San Román, Lydia Giménez-Llort, Iván Manuel, Rafael Rodríguez-Puertas

Background and purpose: Recent research linking choline-containing lipids to degeneration of basal forebrain cholinergic neurons in neuropathological states illustrates the challenge of balancing lipid integrity with optimal acetylcholine levels, essential for memory preservation. The endocannabinoid system influences learning and memory processes regulated by cholinergic neurotransmission. Therefore, we hypothesised that activation of the endocannabinoid system may confer neuroprotection against cholinergic degeneration.

Experimental approach: We examined the neuroprotective potential of sub-chronic treatments with the cannabinoid agonist WIN55,212-2, using ex vivo organotypic tissue cultures including nucleus basalis magnocellularis and cortex and in vivo rat models of specific cholinergic damage induced by 192IgG-saporin. Levels of lipids, choline and acetylcholine were measured with histochemical and immunofluorescence assays, along with [35S]GTPγS autoradiography of cannabinoid and muscarinic GPCRs and MALDI-mass spectrometry imaging analysis. Learning and memory were assessed by the Barnes maze and the novel object recognition test in rats and in the 3xTg-AD mouse model.

Key results: Degeneration, induced by 192IgG-saporin, of baso-cortical cholinergic pathways resulted in memory deficits and decreased cortical levels of lysophosphatidylcholines (LPC). WIN55,212-2 restored cortical cholinergic transmission and LPC levels via activation of cannabinoid receptors. This activation altered cortical lipid homeostasis mainly by reducing sphingomyelins in lesioned animals. These modifications were crucial for memory recovery.

Conclusion and implications: We hypothesise that WIN55,212-2 facilitates an alternative choline source by breaking down sphingomyelins, leading to elevated cortical acetylcholine levels and LPCs. These results imply that altering choline-containing lipids via activation of cannabinoid receptors presents a promising therapeutic approach for dementia linked to cholinergic dysfunction.

背景和目的:最近的研究表明,在神经病理状态下,含胆碱的脂质与基底前脑胆碱能神经元的变性有关,这说明了在脂质完整性与最佳乙酰胆碱水平之间取得平衡所面临的挑战,而乙酰胆碱对记忆的保存至关重要。内源性大麻素系统影响着由胆碱能神经传递调节的学习和记忆过程。因此,我们假设,激活内源性大麻素系统可能会对胆碱能退化产生神经保护作用:实验方法:我们利用包括大细胞基底核和皮层在内的体外器官组织培养物以及 192IgG-saporin 诱导的特定胆碱能损伤体内大鼠模型,研究了亚慢性大麻素激动剂 WIN55,212-2 治疗的神经保护潜力。脂质、胆碱和乙酰胆碱的水平是通过组织化学和免疫荧光测定法,以及大麻素和毒蕈碱类 GPCR 的 [35S]GTPγS 自显影和 MALDI 质谱成像分析来测量的。对大鼠和 3xTg-AD 小鼠模型的学习和记忆进行了巴恩斯迷宫和新物体识别测试评估:主要结果:192IgG-saporin诱导的皮层基底胆碱能通路退化导致记忆缺陷和皮层溶血磷脂酰胆碱(LPC)水平下降。WIN55,212-2通过激活大麻素受体恢复了大脑皮层的胆碱能传导和LPC水平。这种激活主要通过减少病变动物的鞘磷脂来改变大脑皮层的脂质平衡。这些改变对记忆恢复至关重要:我们假设,WIN55,212-2 可通过分解鞘磷脂促进胆碱替代来源,从而导致皮质乙酰胆碱水平和 LPCs 的升高。这些结果表明,通过激活大麻素受体来改变含胆碱脂质,是治疗与胆碱能功能障碍有关的痴呆症的一种很有前景的方法。
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引用次数: 0
Have plastic culture models prevented the discovery of effective cancer therapeutics? 塑料培养模型是否阻碍了有效癌症疗法的发现?
IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-03 DOI: 10.1111/bph.17387
Kevin M Tharp

Conventional cell culture techniques generally fail to recapitulate the expression profiles or functional phenotypes of the in vivo equivalents they are meant to model. These cell culture models are indispensable for preclinical drug discovery and mechanistic studies. However, if our goal is to develop effective therapies that work as intended in the human body, we must revise our cell culture models to recapitulate normal and disease physiology to ensure that we identify compounds that are useful and effective beyond our in vitro models.

传统的细胞培养技术通常无法再现其所要模拟的体内等效物的表达谱或功能表型。这些细胞培养模型对于临床前药物发现和机理研究是不可或缺的。但是,如果我们的目标是开发能在人体中发挥预期作用的有效疗法,我们就必须修改细胞培养模型,以再现正常和疾病的生理学,从而确保我们所发现的化合物在体外模型之外也是有用和有效的。
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引用次数: 0
Pharmacokinetics and cardioprotective efficacy of intravenous miR-125b* microRNA mimic in a mouse model of acute myocardial infarction. 急性心肌梗死小鼠模型中静脉注射 miR-125b* 微核糖核酸模拟物的药代动力学和心脏保护功效。
IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-29 DOI: 10.1111/bph.17345
Tamara Szabados, András Makkos, Bence Ágg, Bettina Benczik, Gábor G Brenner, Márta Szabó, Barnabás Váradi, Imre Vörös, Kamilla Gömöri, Zoltán V Varga, Anikó Görbe, Péter Bencsik, Péter Ferdinandy

Background and purpose: MicroRNA (miRNA) therapy is a promising approach to induce cardioprotection. We have previously identified cardiac microRNA-125b* (microRNA-125b-2-3p; miR-125b*) as a potential cardioprotective miRNA, termed ProtectomiR. We aimed to characterize the pharmacokinetics and pharmacodynamics, and the effect of miR-125b* mimic on infarct size using an in vivo mouse model.

Experimental approach: To characterize the pharmacokinetics properties of miR-125b* mimic, a single injection of 10-μg miR-125b* mimic or its scramble miRNA control, or vehicle i.v. was given to C57BL/6 mice. MiR-125b* expression was measured from plasma, heart, kidney and liver samples. Effect of miR-125b* on area at risk and infarct size was assessed after 45-min coronary occlusion, followed by 24-h reperfusion; 10-μg miR-125b* mimic or 10-μg non-targeting miRNA mimic control or vehicle were administered via the right jugular vein at 10th mins of coronary occlusion. To assess molecular mechanism involved in cardioprotection, expression of mRNA targets of miR-125b* were measured from ventricular myocardium at 1, 2, 4, 8 or 24 h post-treatment using quantitative real time polymerase chain reaction.

Key results: MiR-125b* expression was markedly increased in plasma and myocardium 1 h, and in the liver 2h after treatment. Infarct size was significantly reduced after miR-125b* mimic treatment when compared to the vehicle. The expression of Ccna2, Eef2k and Cacnb2 target mRNAs was significantly reduced 8 h after injection of miR-125b* mimic.

Conclusion and implications: This is the first demonstration of pharmacokinetic and molecular pharmacodynamic properties as well as the cardioprotective effect of miR-125b* mimic in vivo.

背景和目的:微RNA(miRNA)疗法是诱导心脏保护的一种很有前景的方法。我们之前已发现心脏微RNA-125b*(microRNA-125b-2-3p;miR-125b*)是一种潜在的心脏保护性miRNA,被称为ProtectomiR。我们的目的是利用体内小鼠模型,研究miR-125b*的药代动力学和药效学特征,以及miR-125b*模拟物对梗死面积的影响:为了鉴定 miR-125b* mimic 的药代动力学特性,给 C57BL/6 小鼠静脉注射一次 10-μg miR-125b* mimic 或其扰乱 miRNA 对照或载体。测量血浆、心脏、肾脏和肝脏样本中 MiR-125b* 的表达。在冠状动脉闭塞 45 分钟、再灌注 24 小时后,评估 miR-125b* 对危险面积和梗死面积的影响;在冠状动脉闭塞 10 分钟后,通过右颈静脉注射 10μg miR-125b* mimic 或 10μg 非靶向 miRNA mimic 对照组或载体。为了评估参与心脏保护的分子机制,使用定量实时聚合酶链反应法测定了治疗后 1、2、4、8 或 24 小时心室心肌中 miR-125b* 靶标 mRNA 的表达:主要结果:治疗后 1 小时,血浆和心肌中的 MiR-125b* 表达明显增加,2 小时后肝脏中的表达也明显增加。与药物相比,miR-125b*模拟物治疗后梗死面积明显缩小。注射 miR-125b* mimic 8 小时后,Ccna2、Eef2k 和 Cacnb2 靶 mRNA 的表达明显减少:这是首次证明 miR-125b* mimic 在体内的药代动力学和分子药效学特性以及对心脏的保护作用。
{"title":"Pharmacokinetics and cardioprotective efficacy of intravenous miR-125b* microRNA mimic in a mouse model of acute myocardial infarction.","authors":"Tamara Szabados, András Makkos, Bence Ágg, Bettina Benczik, Gábor G Brenner, Márta Szabó, Barnabás Váradi, Imre Vörös, Kamilla Gömöri, Zoltán V Varga, Anikó Görbe, Péter Bencsik, Péter Ferdinandy","doi":"10.1111/bph.17345","DOIUrl":"https://doi.org/10.1111/bph.17345","url":null,"abstract":"<p><strong>Background and purpose: </strong>MicroRNA (miRNA) therapy is a promising approach to induce cardioprotection. We have previously identified cardiac microRNA-125b* (microRNA-125b-2-3p; miR-125b*) as a potential cardioprotective miRNA, termed ProtectomiR. We aimed to characterize the pharmacokinetics and pharmacodynamics, and the effect of miR-125b* mimic on infarct size using an in vivo mouse model.</p><p><strong>Experimental approach: </strong>To characterize the pharmacokinetics properties of miR-125b* mimic, a single injection of 10-μg miR-125b* mimic or its scramble miRNA control, or vehicle i.v. was given to C57BL/6 mice. MiR-125b* expression was measured from plasma, heart, kidney and liver samples. Effect of miR-125b* on area at risk and infarct size was assessed after 45-min coronary occlusion, followed by 24-h reperfusion; 10-μg miR-125b* mimic or 10-μg non-targeting miRNA mimic control or vehicle were administered via the right jugular vein at 10th mins of coronary occlusion. To assess molecular mechanism involved in cardioprotection, expression of mRNA targets of miR-125b* were measured from ventricular myocardium at 1, 2, 4, 8 or 24 h post-treatment using quantitative real time polymerase chain reaction.</p><p><strong>Key results: </strong>MiR-125b* expression was markedly increased in plasma and myocardium 1 h, and in the liver 2h after treatment. Infarct size was significantly reduced after miR-125b* mimic treatment when compared to the vehicle. The expression of Ccna2, Eef2k and Cacnb2 target mRNAs was significantly reduced 8 h after injection of miR-125b* mimic.</p><p><strong>Conclusion and implications: </strong>This is the first demonstration of pharmacokinetic and molecular pharmacodynamic properties as well as the cardioprotective effect of miR-125b* mimic in vivo.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543847","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
Preclinical models for evaluating psychedelics in the treatment of major depressive disorder. 评估治疗重度抑郁症的迷幻剂的临床前模型。
IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-28 DOI: 10.1111/bph.17370
Laith Alexander, Dasha Anderson, Luke Baxter, Matthew Claydon, James Rucker, Emma S J Robinson

Psychedelic drugs have seen a resurgence in interest as a next generation of psychiatric medicines with potential as rapid-acting antidepressants (RAADs). Despite promising early clinical trials, the mechanisms which underlie the effects of psychedelics are poorly understood. For example, key questions such as whether antidepressant and psychedelic effects involve related or independent mechanisms are unresolved. Preclinical studies in relevant animal models are key to understanding the pharmacology of psychedelics and translating these findings to explain efficacy and safety in patients. Understanding the mechanisms of action associated with the behavioural effects of psychedelic drugs can also support the identification of novel drug targets and more effective treatments. Here we review the behavioural approaches currently used to quantify the psychedelic and antidepressant effects of psychedelic drugs. We discuss conceptual and methodological issues, the importance of using clinically relevant doses and the need to consider possible sex differences in preclinical psychedelic studies.

迷幻药作为新一代精神科药物,具有作为速效抗抑郁药(RAAD)的潜力,再次引起了人们的兴趣。尽管早期的临床试验前景看好,但人们对迷幻药的作用机制仍知之甚少。例如,抗抑郁和迷幻药的作用是涉及相关机制还是独立机制等关键问题尚未解决。相关动物模型的临床前研究是了解迷幻药药理学并将这些发现转化为解释对患者的疗效和安全性的关键。了解与迷幻药行为效应相关的作用机制也有助于确定新的药物靶点和更有效的治疗方法。在此,我们回顾了目前用于量化迷幻药的迷幻和抗抑郁作用的行为学方法。我们讨论了概念和方法问题、使用临床相关剂量的重要性以及在临床前迷幻药研究中考虑可能的性别差异的必要性。
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引用次数: 0
Dihydro-resveratrol ameliorates NLRP3 inflammasome-mediated neuroinflammation via Bnip3-dependent mitophagy in Alzheimer's disease. 二氢白藜芦醇通过 Bnip3 依赖性有丝分裂改善阿尔茨海默病中 NLRP3 炎症体介导的神经炎症
IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-28 DOI: 10.1111/bph.17373
Guorong Tao, Xuebao Wang, Jian Wang, Yiru Ye, Minxue Zhang, Yan Lang, Saidan Ding

Background and purpose: Dihydro-resveratrol (DHR), a polyphenol derivative, that has been demonstrated to suppress inflammation-mediated injury. However, it is still unknown whether it has anti-neuroinflammatory and neuroprotective effects, and a therapeutic action in Alzheimer's disease (AD).

Experimental approach: The anti-inflammatory and anti-Alzheimer's disease actions of dihydro-resveratrol were investigated using lipopolysaccharide (LPS) and AD mice models, and primary microglial cells. The changes in behaviour in mice were detected by the Morris water maze test and open-field test. Flow cytometry assay, western blotting, immunofluorescence assays and co-immunoprecipitation were used to investigate the changes in the NLRP3 inflammasome activation and mitophagy.

Key results: In this study, in vivo observations indicated that the administration of dihydro-resveratrol (DHR) dramatically restored spatial learning, memory ability, autophagy and mitophagy, attenuated NLRP3 inflammasome activation, neuroinflammation and amyloid precursor protein pathology in LPS mice and AD mice. In addition, the inhibition of autophagy and mitophagy, or the activation of NLRP3 in vivo greatly abolished DHR-generated therapeutic efficacy on neuroinflammation, amyloid precursor protein pathology and cognitive loss. Further examination indicated that the application of DHR after the LPS and ATP exposure significantly inhibited the NLRP3 inflammasome activation, neuroinflammation and enhanced autophagic and mitophagic activation in microglia. Additionally, in vitro results show that DHR protects microglial cells against LPS and ATP-induced cytotoxicity by inhibiting NLRP3 inflammasome through activating Bnip3-dependent mitophagy and ULK phosphorylation.

Conclusions and implications: In summary, these findings suggest that dihydro-resveratrol (DHR) possesses potent anti-neuroinflammatory property and can act as a potential therapeutic agent for the treatment of AD.

背景和目的:二氢白藜芦醇(DHR)是一种多酚衍生物,已被证实可以抑制炎症介导的损伤。然而,它是否具有抗神经炎症和神经保护作用,以及对阿尔茨海默病(AD)的治疗作用仍是未知数:实验方法:使用脂多糖(LPS)和阿氏痴呆症小鼠模型以及原代小胶质细胞研究了二氢白藜芦醇的抗炎和抗阿尔茨海默病作用。通过莫里斯水迷宫试验和开阔地试验检测了小鼠行为的变化。流式细胞仪测定、Western 印迹、免疫荧光测定和共免疫沉淀被用来研究 NLRP3 炎性体激活和有丝分裂的变化:本研究的体内观察结果表明,服用二氢白藜芦醇(DHR)能显著恢复LPS小鼠和AD小鼠的空间学习能力、记忆能力、自噬和有丝分裂,减轻NLRP3炎性体的激活、神经炎症和淀粉样前体蛋白的病理变化。此外,在体内抑制自噬和有丝分裂或激活 NLRP3 会大大降低 DHR 对神经炎症、淀粉样前体蛋白病理学和认知功能丧失的疗效。进一步的研究表明,在 LPS 和 ATP 暴露后应用 DHR 能显著抑制 NLRP3 炎性体的激活和神经炎症,并增强小胶质细胞的自噬和有丝分裂活化。此外,体外研究结果表明,DHR通过激活依赖于Bnip3的有丝分裂和ULK磷酸化来抑制NLRP3炎症体,从而保护小胶质细胞免受LPS和ATP诱导的细胞毒性的伤害:综上所述,这些研究结果表明,二氢白藜芦醇(DHR)具有强效的抗神经炎症特性,可作为一种潜在的治疗药物用于AD的治疗。
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引用次数: 0
Immunoglobin attenuates fulminant myocarditis by inhibiting overactivated innate immune response. 免疫球蛋白通过抑制过度激活的先天性免疫反应减轻暴发性心肌炎的病情
IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-23 DOI: 10.1111/bph.17372
Jianpei Wen, Huihui Li, Yufei Zhou, Hengzhi Du, Guo Hu, Zheng Wen, Du Tang, Yanwen Wang, Xinwu Cui, Zhou Zhou, Dao Wen Wang, Chen Chen

Background and purpose: Fulminant myocarditis (FM) is a myocardial inflammatory disease that can result from either viral diseases or autoimmune diseases. In this study, we have determined the treatment effects of immunomodulatory drugs on FM.

Experimental approach: FM was induced in A/JGpt mice by intraperitoneal administration of coxsackievirus B3, after which immunoglobins were administered daily by intraperitoneal injection. On the seventh day, the cardiac structure and function were determined using echocardiography and cardiac catheterisation. Single-cell RNA sequencing (scRNA-seq) was performed to evaluate CD45+ cells in the heart.

Key results: Immunoglobin, a typical immunomodulatory drug, dramatically reduced mortality and significantly improved cardiac function in mice with FM. ScRNA-seq revealed that immunoglobin treatment effectively modulated cardiac immune homeostasis, particularly by attenuating overactivated innate immune responses. At the cellular level, immunoglobin predominantly targeted Plac8+ monocytes and S100a8+ neutrophils, suppressing their proinflammatory activities, and enhancing antigen processing and presentation capabilities, thereby amplifying the efficiency and potency of the immune response against the virus. Immunoglobin benefits are mediated by the modulation of multiple signalling pathways, including relevant receptors on immune cells, direction of inflammatory cell chemotaxis, antigen presentation and anti-viral effects. Subsequently, Bst2-ILT7 ligand-receptor-mediated cellular interactions manipulated by immunoglobin were further confirmed in vivo.

Conclusions and implications: Immunoglobin treatment significantly attenuated FM-induced cardiac inflammation and improved cardiac function by inhibiting overactivated innate immune responses.

背景和目的:暴发性心肌炎(FM)是一种心肌炎性疾病,可由病毒性疾病或自身免疫性疾病引起。本研究确定了免疫调节药物对 FM 的治疗效果:实验方法:通过腹腔注射柯萨奇病毒B3诱导A/JGpt小鼠发生FM,然后每天腹腔注射免疫球蛋白。第七天,通过超声心动图和心导管检查确定心脏结构和功能。进行了单细胞 RNA 测序(scRNA-seq)以评估心脏中的 CD45+ 细胞:免疫球蛋白是一种典型的免疫调节药物,它能显著降低FM小鼠的死亡率并明显改善其心脏功能。SCRNA-seq显示,免疫球蛋白治疗能有效调节心脏免疫平衡,尤其是通过减轻过度激活的先天性免疫反应。在细胞水平上,免疫球蛋白主要靶向 Plac8+ 单核细胞和 S100a8+ 中性粒细胞,抑制它们的促炎活性,增强抗原处理和呈递能力,从而提高抗病毒免疫反应的效率和效力。免疫球蛋白的益处是通过调节多种信号通路介导的,包括免疫细胞上的相关受体、炎症细胞趋化方向、抗原递呈和抗病毒作用。随后,由免疫球蛋白操纵的Bst2-ILT7配体-受体介导的细胞相互作用在体内得到了进一步证实:免疫球蛋白治疗通过抑制过度激活的先天性免疫反应,明显减轻了调频诱导的心脏炎症并改善了心脏功能。
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引用次数: 0
Salvianolic acid B improves the microcirculation in a mouse model of sepsis through a mechanism involving the platelet receptor CD226. 丹酚酸 B 通过涉及血小板受体 CD226 的机制改善脓毒症小鼠模型的微循环。
IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-23 DOI: 10.1111/bph.17371
Xuemei Li, Shanshou Liu, Jiangang Xie, Lin Liu, Chujun Duan, Lu Yang, Yuling Wang, Yilin Wu, Niqi Shan, Yun Zhang, Yuan Zhang, Ran Zhuang

Background and purpose: Salvianolic acid B (SalB) demonstrates diverse clinical applications, particularly in cardiovascular and cerebral protection. This study primarily investigated the effects of SalB on sepsis.

Experimental approach: The model of sepsis via caecal ligation puncture (CLP) was established in male C57BL/6 mice. Therapeutic effects of SalB on hepatic and pulmonary injury, inflammatory responses and microcirculatory disturbances in sepsis were evaluated. Platelet aggregation and adhesion were measured via flow cytometry and an adhesion test. After overexpression of platelet-related activating molecules by 293T cells, the efficient binding of SalB and platelet CD226 molecules was further evaluated. Finally, neutralizing antibody experiments were used to assess the mechanism of SalB in alleviating the progression of sepsis.

Key results: SalB mitigated hepatic and pulmonary impairments, reduced inflammatory cytokine levels and enhanced mesenteric microvascular blood flow in septic mice. SalB enhanced CLP-induced reduction of platelet count and platelet pressure cumulative volume. SalB reduced platelet adhesion to endothelial cells and platelet aggregation to leukocytes. A high binding efficiency was observed between SalB and the platelet adhesion molecule CD226. Ex vivo, interactions between SalB and platelets from CD226-knockout mice were markedly decreased. In vivo administration of CD226 neutralizing antibodies significantly delayed disease progression and enhanced mesenteric microcirculation in septic mice.

Conclusion and implications: In our murine model of sepsis, treatment with SalB improved the microcirculatory disturbance and hindered the progression of sepsis by inhibiting platelet CD226 function. Our results suggest SalB is a promising therapeutic approach to the treatment of sepsis.

背景和目的:丹酚酸 B(SalB)具有多种临床应用,尤其是在心血管和大脑保护方面。本研究主要探讨丹酚酸 B 对败血症的影响:实验方法:以雄性 C57BL/6 小鼠为实验对象,通过盲肠结扎术(CLP)建立败血症模型。实验方法:在雄性 C57BL/6 小鼠中建立了通过盲肠穿刺(CLP)的败血症模型,评估了 SalB 对败血症中肝和肺损伤、炎症反应和微循环障碍的治疗效果。血小板聚集和粘附是通过流式细胞术和粘附试验测量的。在 293T 细胞过量表达血小板相关激活分子后,进一步评估了 SalB 与血小板 CD226 分子的有效结合。最后,通过中和抗体实验评估了 SalB 缓解败血症恶化的机制:主要结果:SalB 可减轻脓毒症小鼠的肝、肺功能损伤,降低炎性细胞因子水平,增强肠系膜微血管血流量。SalB 可增强 CLP 诱导的血小板数量和血小板压力累积体积的减少。SalB 可减少血小板与内皮细胞的粘附以及血小板与白细胞的聚集。观察到 SalB 与血小板粘附分子 CD226 的结合效率很高。在体内,SalB 与来自 CD226 基因敲除小鼠的血小板之间的相互作用明显减少。体内注射 CD226 中和抗体可显著延缓脓毒症小鼠的疾病进展并增强肠系膜微循环:在我们的脓毒症小鼠模型中,SalB 通过抑制血小板 CD226 功能改善了微循环障碍并阻碍了脓毒症的进展。我们的研究结果表明,SalB 是一种治疗脓毒症的有前途的方法。
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引用次数: 0
Insight into structural properties of viral G protein-coupled receptors and their role in the viral infection: IUPHAR Review 41. 洞察病毒 G 蛋白偶联受体的结构特性及其在病毒感染中的作用:IUPHAR Review 41.
IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-23 DOI: 10.1111/bph.17379
Naotaka Tsutsumi, Dagmar Fæster Kildedal, Olivia Kramer Hansen, Qianqian Kong, Dominique Schols, Tom Van Loy, Mette Marie Rosenkilde

G protein-coupled receptors (GPCRs) are pivotal in cellular signalling and drug targeting. Herpesviruses encode GPCRs (vGPCRs) to manipulate cellular signalling, thereby regulating various aspects of the virus life cycle, such as viral spreading and immune evasion. vGPCRs mimic host chemokine receptors, often with broader signalling and high constitutive activity. This review focuses on the recent advancements in structural knowledge about vGPCRs, with an emphasis on molecular mechanisms of action and ligand binding. The structures of US27 and US28 from human cytomegalovirus (HCMV) are compared to their closest human homologue, CX3CR1. Contrasting US27 and US28, the homotrimeric UL78 structure (HCMV) reveals more distance to chemokine receptors. Open reading frame 74 (ORF74; Kaposi's sarcoma-associated herpesvirus) is compared to CXCRs, whereas BILF1 (Epstein-Barr virus) is discussed as a putative lipid receptor. Furthermore, the roles of vGPCRs in latency and lytic replication, reactivation, dissemination and immune evasion are reviewed, together with their potential as drug targets for virus infections and virus-related diseases.

G 蛋白偶联受体(GPCR)在细胞信号传导和药物靶向中起着关键作用。疱疹病毒编码 GPCRs(vGPCRs)来操纵细胞信号,从而调节病毒生命周期的各个方面,如病毒传播和免疫逃避。vGPCRs 模仿宿主趋化因子受体,通常具有更广泛的信号传导和高组成活性。本综述重点介绍 vGPCR 结构知识的最新进展,重点是分子作用机制和配体结合。本文将人类巨细胞病毒(HCMV)中的 US27 和 US28 的结构与其最接近的人类同源物 CX3CR1 进行了比较。与 US27 和 US28 相比,同源三聚体 UL78 结构(HCMV)更接近趋化因子受体。开放阅读框 74(ORF74;卡波西肉瘤相关疱疹病毒)与 CXCR 进行了比较,而 BILF1(Epstein-Barr 病毒)被认为是一种假定的脂质受体。此外,还综述了 vGPCR 在潜伏和溶解复制、再活化、传播和免疫逃避中的作用,以及它们作为病毒感染和病毒相关疾病药物靶点的潜力。
{"title":"Insight into structural properties of viral G protein-coupled receptors and their role in the viral infection: IUPHAR Review 41.","authors":"Naotaka Tsutsumi, Dagmar Fæster Kildedal, Olivia Kramer Hansen, Qianqian Kong, Dominique Schols, Tom Van Loy, Mette Marie Rosenkilde","doi":"10.1111/bph.17379","DOIUrl":"https://doi.org/10.1111/bph.17379","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) are pivotal in cellular signalling and drug targeting. Herpesviruses encode GPCRs (vGPCRs) to manipulate cellular signalling, thereby regulating various aspects of the virus life cycle, such as viral spreading and immune evasion. vGPCRs mimic host chemokine receptors, often with broader signalling and high constitutive activity. This review focuses on the recent advancements in structural knowledge about vGPCRs, with an emphasis on molecular mechanisms of action and ligand binding. The structures of US27 and US28 from human cytomegalovirus (HCMV) are compared to their closest human homologue, CX<sub>3</sub>CR1. Contrasting US27 and US28, the homotrimeric UL78 structure (HCMV) reveals more distance to chemokine receptors. Open reading frame 74 (ORF74; Kaposi's sarcoma-associated herpesvirus) is compared to CXCRs, whereas BILF1 (Epstein-Barr virus) is discussed as a putative lipid receptor. Furthermore, the roles of vGPCRs in latency and lytic replication, reactivation, dissemination and immune evasion are reviewed, together with their potential as drug targets for virus infections and virus-related diseases.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495520","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
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British Journal of Pharmacology
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