British Journal of Pharmacology最新文献_第10页

Disruption of survivin protein expression by treatment with YM155 accelerates the resolution of neutrophilic inflammation 用 YM155 治疗可破坏存活素蛋白的表达，从而加速中性粒细胞炎症的消退。

IF 6.8 2区医学 Q1 PHARMACOLOGY & PHARMACY

British Journal of Pharmacology

Pub Date : 2024-11-20 DOI: 10.1111/bph.17375

Débora de Oliveira Fernandes, Jessica Rayssa Machado, Vinicius Amorim Beltrami, Anna Clara Paiva Menezes Dos Santos, Celso Martins Queiroz-Junior, Juliana Priscila Vago, Frederico Marianetti Soriani, Flávio Almeida Amaral, Mauro Martins Teixeira, Franciel Batista Felix, Vanessa Pinho

Background and Purpose

Prolonged survival of neutrophils is essential for determining the progression and severity of inflammatory and immune-mediated disorders, including gouty arthritis. Survivin, an anti-apoptotic molecule, has been described as a regulator of cell survival. This study aims to examine the effects of YM155 treatment, a survivin selective suppressant, in maintaining neutrophil survival in vitro and in vivo experimental settings of neutrophilic inflammation.

Experimental approach

BALB/c mice were injected with monosodium urate (MSU) crystals and treated with YM155 (intra-articularly) at the peak of inflammatory response. Leukocyte recruitment, apoptosis neutrophil and efferocytosis were determined by knee joint wash cell morphology counting and flow cytometry. Resolution interval (Ri) was quantified by neutrophil infiltration, monitoring the amplitude and duration of the inflammation. Cytokine production was measured by ELISA. Mechanical hypernociception was assessed using an electronic von Frey aesthesiometer. Efferocytosis was evaluated in zymosan-induced neutrophilic peritonitis. Survivin and cleaved caspase-3 expression was determined in human neutrophils by flow cytometry.

Key Results

Survivin was expressed in neutrophils during MSU-induced gout, and the treatment with YM155 reduced survivin expression and shortened Ri from ∼8 h observed in vehicle-treated mice to ∼5.5 h, effect accompanied by increased neutrophil apoptosis and efferocytosis, both crucial for the inflammation resolution. Reduced IL-1β and CXCL1 levels were also observed in periarticular tissue. YM155 reduced histopathological score and hypernociceptive response. In human neutrophils, lipopolysaccharide (LPS) increased survivin expression, whereas survivin inhibition with YM155 induced neutrophil apoptosis, with activation of caspase-3.

Conclusions and Implications

Survivin may be a promising therapeutic target to control neutrophilic inflammation.

背景和目的：中性粒细胞的长期存活对于决定包括痛风性关节炎在内的炎症和免疫介导疾病的进展和严重程度至关重要。Survivin 是一种抗凋亡分子，已被描述为细胞存活的调节因子。本研究旨在考察 YM155（一种存活素选择性抑制剂）在体外和体内中性粒细胞炎症实验环境中维持中性粒细胞存活的效果：实验方法：给 BALB/c 小鼠注射单钠尿酸盐（MSU）结晶，并在炎症反应高峰期用 YM155（关节内）治疗。通过膝关节冲洗细胞形态计数和流式细胞术测定白细胞募集、中性粒细胞凋亡和流出。通过中性粒细胞浸润量化分辨间期（Ri），监测炎症的幅度和持续时间。细胞因子的产生是通过酶联免疫吸附法测定的。机械性痛觉减退是通过电子冯-弗雷痛觉计进行评估的。在紫霉素诱导的嗜中性粒细胞腹膜炎中评估了排泄功能。通过流式细胞术测定了人中性粒细胞中 Survivin 和裂解 Caspase-3 的表达：用YM155治疗可减少Survivin的表达，并将Ri从药物治疗小鼠的8小时缩短至5.5小时。在关节周围组织中也观察到了 IL-1β 和 CXCL1 水平的降低。YM155 降低了组织病理学评分和痛觉反应。在人中性粒细胞中，脂多糖（LPS）会增加存活素的表达，而用 YM155 抑制存活素会诱导中性粒细胞凋亡，并激活 caspase-3：Survivin 可能是控制中性粒细胞炎症的一个有前途的治疗靶点。

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引用次数: 0

GraphCPP: The new state-of-the-art method for cell-penetrating peptide prediction via graph neural networks GraphCPP：通过图神经网络预测细胞穿透肽的最新方法。

IF 6.8 2区医学 Q1 PHARMACOLOGY & PHARMACY

British Journal of Pharmacology

Pub Date : 2024-11-20 DOI: 10.1111/bph.17388

Attila Imre, Balázs Balogh, István Mándity

Background and Purpose

Cell-penetrating peptides (CPPs) are short amino acid sequences that can penetrate cell membranes and deliver molecules into cells. Several models have been developed for their discovery, yet these models often face challenges in accurately predicting membrane penetration due to the complex nature of peptide–cell interactions. Hence, there is a need for innovative approaches that can enhance predictive performance.

Experimental Approach

In this study, we present the application GraphCPP, a novel graph neural network (GNN) for the prediction of membrane penetration capability of peptides.

Key Results

A new comprehensive dataset—dubbed CPP1708—was constructed resulting in the largest reliable database of CPPs to date. Comparative analyses with previous methods, such as MLCPP2, C2Pred, CellPPD and CellPPD-Mod, demonstrated the superior predictive performance of our model. Upon testing against other published methods, GraphCPP performs exceptionally, achieving 0.5787 Matthews correlation coefficient and 0.8459 area under the curve (AUC) values on one dataset. This means a 92.8% and 23.3% improvement in Matthews correlation coefficient and AUC measures respectively compared with the next best model. The capability of the model to effectively learn peptide representations was demonstrated through t-distributed stochastic neighbour embedding plots. Additionally, the uncertainty analysis revealed that GraphCPP maintains high confidence in predictions for peptides shorter than 40 amino acids. The source code is available at https://github.com/attilaimre99/GraphCPP.

Conclusion and Implications

These findings indicate the potential of GNN-based models to improve CPP penetration prediction and it may contribute towards the development of more efficient drug delivery systems.

背景和目的：细胞穿透肽（CPPs）是一种能穿透细胞膜并将分子送入细胞的短氨基酸序列。目前已开发出多种用于发现它们的模型，但由于肽与细胞间相互作用的复杂性，这些模型在准确预测膜穿透性方面往往面临挑战。因此，我们需要能提高预测性能的创新方法：在本研究中，我们介绍了 GraphCPP 的应用，这是一种新型图神经网络（GNN），用于预测多肽的膜穿透能力：我们构建了一个新的综合数据集，称为 CPP1708，这是迄今为止最大的可靠 CPP 数据库。与以往方法（如 MLCPP2、C2Pred、CellPPD 和 CellPPD-Mod）的比较分析表明，我们的模型具有更优越的预测性能。在与其他已发布方法的对比测试中，GraphCPP 表现优异，在一个数据集上实现了 0.5787 的马修斯相关系数和 0.8459 的曲线下面积（AUC）值。这意味着与次佳模型相比，马修斯相关系数和 AUC 值分别提高了 92.8% 和 23.3%。该模型有效学习多肽表征的能力通过 t 分布随机相邻嵌入图得到了证明。此外，不确定性分析表明，GraphCPP 对短于 40 个氨基酸的肽的预测保持了很高的置信度。源代码见 https://github.com/attilaimre99/GraphCPP.Conclusion 和 implications：这些研究结果表明，基于 GNN 的模型具有改进 CPP 穿透预测的潜力，它可能有助于开发更高效的给药系统。

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引用次数: 0

NaHS alters synaptic plasticity proteins and enhances dendritic arborization to improve cognitive and motor deficits after traumatic brain injury in mice NaHS 可改变突触可塑性蛋白并增强树突树轴化，从而改善小鼠脑外伤后的认知和运动障碍。

IF 6.8 2区医学 Q1 PHARMACOLOGY & PHARMACY

British Journal of Pharmacology

Pub Date : 2024-11-19 DOI: 10.1111/bph.17386

Farheen Nasir, Priyanka Yadav, Thamil Mani Sivanandam

Background and Purpose

Traumatic brain injury (TBI) is a complex medical condition affecting people globally. Hydrogen sulfide (H₂S) is a recently discovered gaseous mediator and is dysregulated in the brain after TBI. Sodium hydrogen sulfide (NaHS), a known donor of H₂S, is beneficial in various biological processes involving aging and diseases, including injury. It is neuroprotective against oxidative stress, neuroinflammation, and other secondary injury processes. However, the NaHS-H₂S system has not been investigated as a regulator of injury-mediated synaptic plasticity proteins and the underlying mechanisms after TBI.

Experimental approach

We developed a model of TBI in Swiss albino mice to study the effects of exogenous H₂S, administered as NaHS. We assessed cognitive function (Barnes maze and novel object recognition) and motor function (rotarod). Brain tissue was analysed with ELISA, qRT-PCR, immunoblotting, Golgi-cox staining, and immunofluorescence.

Key results

NaHS administration restored the injury-caused decline in H₂S levels. Injury-mediated oxidative stress parameters were improved following NaHS. It down-regulated TBI biomarkers, ameliorated the synaptic marker proteins, and improved cognitive and motor deficits. These changes were accompanied by enhanced dendritic arborization and spine number. Restoration of N-methyl D-aspartate receptor subunits and diminished glutamate and calcium levels, along with marked changes in microtubule-associated protein 2 A and calcium/calmodulin-dependent protein kinase II, formed the basis of the underlying mechanism(s).

Conclusion and Implications

Our findings suggest that NaHS could have therapeutic activity against TBI, as it ameliorated cognitive and motor deficits caused by changes in synaptic plasticity proteins and dendritic arborisation, in our model.

背景和目的：创伤性脑损伤（TBI）是一种复杂的医疗状况，影响着全球各地的人们。硫化氢（H2S）是最近发现的一种气体介质，在创伤性脑损伤后会在大脑中失调。硫化氢钠（NaHS）是一种已知的 H2S 供体，在涉及衰老和疾病（包括损伤）的各种生物过程中都有益处。它对氧化应激、神经炎症和其他继发性损伤过程具有神经保护作用。然而，NaHS-H2S 系统作为损伤介导的突触可塑性蛋白的调控因子及其在创伤性脑损伤后的内在机制尚未得到研究：我们在瑞士白化小鼠中建立了创伤性脑损伤模型，以研究外源 H2S（以 NaHS 的形式给药）的影响。我们评估了认知功能（巴恩斯迷宫和新物体识别）和运动功能（旋转木马）。通过酶联免疫吸附试验、qRT-PCR、免疫印迹、高尔基体-细胞毒染色和免疫荧光对脑组织进行了分析：主要结果：服用 NaHS 可恢复损伤导致的 H2S 水平下降。服用 NaHS 后，损伤介导的氧化应激参数得到改善。它下调了创伤性脑损伤生物标志物，改善了突触标志蛋白，并改善了认知和运动障碍。伴随这些变化的是树突轴化和脊柱数量的增加。N 甲基 D-天冬氨酸受体亚单位的恢复、谷氨酸和钙水平的降低，以及微管相关蛋白 2 A 和钙/钙调蛋白依赖性蛋白激酶 II 的明显变化，构成了潜在机制的基础：我们的研究结果表明，NaHS 对创伤性脑损伤具有治疗活性，因为在我们的模型中，NaHS 可改善因突触可塑性蛋白和树突轴化的变化而导致的认知和运动障碍。

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引用次数: 0

The endocannabinoid anandamide mediates anti-inflammatory effects through activation of NR4A nuclear receptors 内源性大麻酰胺通过激活 NR4A 核受体介导抗炎作用。

IF 6.8 2区医学 Q1 PHARMACOLOGY & PHARMACY

British Journal of Pharmacology

Pub Date : 2024-11-19 DOI: 10.1111/bph.17366

Tom Teichmann, Beatrice Pflüger-Müller, Virna Margarita Martín Giménez, Fiona Sailer, Henrik Dirks, Simonida Zehr, Timothy Warwick, Felix Brettner, Paola Munoz-Tello, Andreas Zimmer, Irmgard Tegeder, Dominique Thomas, Robert Gurke, Stefan Günther, Jan Heering, Ewgenij Proschak, Gerd Geisslinger, Iris-S. Bibli, Dagmar Meyer zu Heringdorf, Walter Manucha, Maike Windbergs, Stefan Knapp, Andreas Weigert, Matthias S. Leisegang, Douglas Kojetin, Ralf P. Brandes

Background and purpose

Endocannabinoids are lipid mediators, which elicit complex biological effects that extend beyond the central nervous system. Tissue concentrations of endocannabinoids increase in atherosclerosis, and for the endocannabinoid N-arachidonoyl-ethanolamine (anandamide, AEA), this has been linked to an anti-inflammatory function. In this study, we set out to determine the anti-inflammatory mechanism of action of AEA, specifically focusing on vascular smooth muscle cells.

Experimental approach

RNA-sequencing, RT-qPCR, LC-MS/MS, NanoBit, ChIP, microscale thermophoresis, NMR structural footprinting, Gal4 reporter gene assays and loss of function approaches in cell and ex vivo organ culture were used.

Key results

AEA pretreatment attenuated the cytokine-mediated induction of inflammatory gene expression such as CCL2. This effect was also observed in preparations obtained from cannabinoid receptor knockout mice and after pertussis toxin treatment. The anti-inflammatory effect of AEA required preincubation, suggesting an effect through gene induction. AEA increased the expression of the nuclear receptors NR4A1 and NR4A2. Knockdown and knockout of these receptors blocked the AEA-mediated anti-inflammatory effect in cell culture and aortic organ culture, respectively. Conversely, NR4A agonists (CsnB, C-DIM12) attenuated inflammatory gene expression. AEA binds to NR4A, and mutations in NR4A attenuated this effect. The interaction of AEA with NR4A caused recruitment of the nuclear corepressor NCoR1 to the CCL2 promoter, resulting in gene suppression.

Conclusion and implications

By binding to NR4A, AEA elicits an anti-inflammatory response in vascular smooth muscle cells. NR4A-binding by AEA analogues may represent novel anti-inflammatory agents.

背景和目的：内源性大麻素是一种脂质介质，它所产生的复杂生物效应超出了中枢神经系统的范围。动脉粥样硬化时，组织中的内源性大麻素浓度会增加，而内源性大麻素 N-丙烯酰乙醇胺（anandamide，AEA）与抗炎功能有关。在这项研究中，我们试图确定 AEA 的抗炎作用机制，特别是针对血管平滑肌细胞：实验方法：采用 RNA 序列测定、RT-qPCR、LC-MS/MS、NanoBit、ChIP、微尺度热泳、核磁共振结构足迹分析、Gal4 报告基因测定以及细胞和体外器官培养中的功能缺失方法：AEA 预处理可减轻细胞因子介导的炎症基因（如 CCL2）表达。在大麻素受体剔除小鼠的制备物中和百日咳毒素处理后也观察到了这种效果。AEA 的抗炎作用需要预孵育，这表明其作用是通过基因诱导产生的。AEA 增加了核受体 NR4A1 和 NR4A2 的表达。在细胞培养和主动脉器官培养中，敲除和剔除这些受体分别阻断了 AEA 介导的抗炎作用。相反，NR4A 激动剂（CsnB、C-DIM12）可减轻炎症基因的表达。AEA 与 NR4A 结合，而 NR4A 的突变会减弱这种效应。AEA 与 NR4A 的相互作用导致核核心抑制因子 NCoR1 募集到 CCL2 启动子，从而导致基因抑制：通过与 NR4A 结合，AEA 在血管平滑肌细胞中引起抗炎反应。与 NR4A 结合的 AEA 类似物可能是新型抗炎药物。

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引用次数: 0

RETRACTION: Cloricromene, a Coumarine Derivative, Protects Against Collagen-induced Arthritis in Lewis Rats 回放：香豆素衍生物氯克罗孟能保护路易斯大鼠免受胶原蛋白诱发的关节炎。

IF 6.8 2区医学 Q1 PHARMACOLOGY & PHARMACY

British Journal of Pharmacology

Pub Date : 2024-11-17 DOI: 10.1111/bph.17417

RETRACTION: S. Cuzzocrea, E. Mazzon, C. Bevilaqua, G. Costantino, D. Britti, G. Mazzullo, A. De Sarro, and A. P. Caputi, “Cloricromene, a Coumarine Derivative, Protects Against Collagen-induced Arthritis in Lewis Rats,” British Journal of Pharmacology 131, no. 7 (2000): 1399–1407, https://doi.org/10.1038/sj.bjp.0703695.

The above article, published online on 29 January 2009 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Péter Ferdinandy; the British Pharmacological Society; and John Wiley & Sons Ltd. The retraction has been agreed due to concerns raised by third parties on the data presented in the article. Specifically, image elements of Figure 7 were found to have been published in a different article with at least one common author and in a different scientific context. Further investigation by the journal team revealed that also Figure 4B was published in the same article to represent a different treatment. Due to the significant time elapsed since publication, the authors were unable to retrieve the full set of original data, and the data provided was found insufficient to address the concerns. As the editors have lost trust in the accuracy and integrity of the overall body of data presented in the article and consider the conclusions invalid, the article must be retracted.

撤回：S. Cuzzocrea， E. Mazzon， C. Bevilaqua， G. Costantino， D. Britti， G. Mazzullo, a . De Sarro, a . P. Caputi，“Cloricromene， Coumarine衍生物，对胶原蛋白诱导的Lewis大鼠关节炎的保护作用”，英国药理学杂志，第131期。7 (2000): 1399-1407, https://doi.org/10.1038/sj.bjp.0703695.The上述文章于2009年1月29日在线发表在Wiley在线图书馆（wileyonlinelibrary.com）上，经该杂志总编辑p·费迪南迪同意撤回；英国药理学会；约翰·威利&；子有限公司由于第三方对文章中提供的数据提出了担忧，已同意撤回。具体来说，图7的图像元素被发现发表在不同的文章中，至少有一个共同的作者，并且在不同的科学背景下。该期刊团队的进一步调查显示，图4B也发表在同一篇文章中，代表了不同的处理方法。由于论文发表已经过了很长时间，作者无法检索到完整的原始数据集，所提供的数据也不足以解决这些问题。由于编辑已经对文章中呈现的整体数据的准确性和完整性失去了信任，并认为结论无效，文章必须撤回。

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引用次数: 0

RETRACTION: Pyrrolidine Dithiocarbamate Attenuates the Development of Acute and Chronic Inflammation 回放：吡咯烷二硫代氨基甲酸盐可减轻急性和慢性炎症的发展。

IF 6.8 2区医学 Q1 PHARMACOLOGY & PHARMACY

British Journal of Pharmacology

Pub Date : 2024-11-17 DOI: 10.1111/bph.17418

RETRACTION: S. Cuzzocrea, P. K. Chatterjee, E. Mazzon, L. Dugo, I. Serraino, D. Britti, G. Mazzullo, A. P. Caputi, and C. Thiemermann, “Pyrrolidine Dithiocarbamate Attenuates the Development of Acute and Chronic Inflammation,” British Journal of Pharmacology 135, no. 2 (2002): 496–510, https://doi.org/10.1038/sj.bjp.0704463.

The above article, published online on 2 February 2009 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Péter Ferdinandy; the British Pharmacological Society; and John Wiley & Sons Ltd. The retraction has been agreed due to concerns raised by third parties on the data presented in the article.

Specifically, the Western Blot presented in Figure 6 was found to have been presented in multiple previous publications with at least one common author and in a different scientific context. Furthermore, duplication has been detected within Figure 3. Due to the significant time elapsed since publication, the authors were unable to retrieve the full set of original data, and the data provided was found insufficient to address the concerns. As the editors have lost trust in the accuracy and integrity of the overall body of data presented in the article and consider the conclusions invalid, the article must be retracted.

撤回：S. Cuzzocrea， P. K. Chatterjee， E. Mazzon， L. Dugo， I. Serraino， D. Britti， G. Mazzullo， A. P. Caputi， C. Thiemermann，“吡啶二硫代氨基甲酸酯减轻急性和慢性炎症的发展”，《英国药理学杂志》第135期。2 (2002): 496-510, https://doi.org/10.1038/sj.bjp.0704463.The上述文章于2009年2月2日在线发表在Wiley在线图书馆（wileyonlinelibrary.com）上，经该杂志总编辑psamter Ferdinandy同意撤回；英国药理学会；约翰·威利&；子有限公司由于第三方对文章中提供的数据提出了担忧，已同意撤回。具体来说，图6所示的Western Blot被发现在多个先前的出版物中出现过，至少有一个共同的作者，并且在不同的科学背景下。此外，在图3中还检测到了重复。由于论文发表已经过了很长时间，作者无法检索到完整的原始数据集，所提供的数据也不足以解决这些问题。由于编辑已经对文章中呈现的整体数据的准确性和完整性失去了信任，并认为结论无效，文章必须撤回。

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引用次数: 0

Combined therapy with pirfenidone and nintedanib counteracts fibrotic silicosis in mice 吡非尼酮和宁替尼联合疗法可对抗小鼠的纤维性矽肺。

IF 6.8 2区医学 Q1 PHARMACOLOGY & PHARMACY

British Journal of Pharmacology

Pub Date : 2024-11-15 DOI: 10.1111/bph.17390

Lu Bai, Jiaxin Wang, Xue Wang, Jixin Wang, Wei Zeng, Junling Pang, Tiantian Zhang, Shengxi Li, Meiyue Song, Yiwei Shi, Jing Wang, Chen Wang

Background and Purpose

Pneumoconiosis, especially silicosis, is a prevalent occupational disease with substantial global economic implications and lacks a definitive cure. Both pneumoconiosis and idiopathic pulmonary fibrosis (IPF) are interstitial lung diseases, which share many common physiological characteristics. Because pirfenidone and nintedanib are approved to treat IPF, their potential efficacy as antifibrotic agents in advanced silicosis deserves further exploration. Thus, we aimed to evaluate the individual and combined effects of pirfenidone and nintedanib in treating advanced silicosis mice and elucidate the underlying mechanisms of their therapeutic actions via multiomics.

Experimental Approach

We administered monotherapy or combined therapy of pirfenidone and nintedanib, with low and high doses, in silicosis established after 6 weeks and evaluated lung function, inflammatory responses and fibrotic status. Additionally, we employed transcriptomic and metabolomic analyses to uncover the mechanisms underlying different therapeutic strategies.

Key Results

Both pirfenidone and nintedanib were effective in treating advanced silicosis, with superior outcomes observed in combination therapy. Transcriptomic and metabolomic analyses revealed that pirfenidone and nintedanib primarily exerted their therapeutic effects by modulating immune responses, signalling cascades and metabolic processes involving lipids, nucleotides and carbohydrates. Furthermore, we experimentally validated both monotherapy and combined therapy yielded therapeutic benefits through two common signalling pathways: steroid biosynthesis and purine metabolism.

Conclusion and Implications

In conclusion, pirfenidone and nintedanib, either individually or in combination, demonstrate substantial potential in advanced silicosis. Furthermore, combined therapy outperformed monotherapy, even at low doses. These therapeutic benefits are attributed to their influence on diverse signalling pathways and metabolic processes.

背景和目的：尘肺病，尤其是矽肺病，是一种普遍存在的职业病，对全球经济造成了重大影响，而且缺乏根治方法。尘肺病和特发性肺纤维化（IPF）都属于间质性肺部疾病，具有许多共同的生理特征。由于吡非尼酮（pirfenidone）和宁替达尼（nintedanib）已被批准用于治疗 IPF，它们作为抗纤维化药物在晚期矽肺中的潜在疗效值得进一步探索。因此，我们旨在评估吡非尼酮和宁替尼治疗晚期矽肺小鼠的单独和联合作用，并通过多组学阐明其治疗作用的潜在机制：实验方法：我们对矽肺小鼠进行单药治疗或联合治疗，分别使用低剂量和高剂量的吡非尼酮和宁替尼，6周后评估肺功能、炎症反应和纤维化状态。此外，我们还采用了转录组学和代谢组学分析来揭示不同治疗策略的内在机制：主要结果：吡非尼酮和宁替达尼都能有效治疗晚期矽肺，联合治疗效果更佳。转录组和代谢组分析显示，吡非尼酮和宁替尼主要通过调节免疫反应、信号级联以及涉及脂质、核苷酸和碳水化合物的代谢过程来发挥治疗效果。此外，我们通过实验验证了单药治疗和联合治疗都能通过两个共同的信号通路产生治疗效果：类固醇生物合成和嘌呤代谢：总之，吡非尼酮和宁替尼单独或联合治疗晚期矽肺都具有巨大的潜力。此外，联合疗法的疗效优于单一疗法，即使剂量较低。这些治疗效果归功于它们对不同信号通路和代谢过程的影响。

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引用次数: 0

Optical control of cardiac electrophysiology by the photochromic ligand azobupivacaine 2 光致变色配体偶氮布卡因 2 对心脏电生理学的光学控制。

IF 6.8 2区医学 Q1 PHARMACOLOGY & PHARMACY

British Journal of Pharmacology

Pub Date : 2024-11-14 DOI: 10.1111/bph.17394

Timm Fehrentz, Ehsan Amin, Nicole Görldt, Tobias Strasdeit, Seyed-Erfan Moussavi-Torshizi, Philipp Leippe, Dirk Trauner, Christian Meyer, Norbert Frey, Philipp Sasse, Nikolaj Klöcker

Background and Purpose

Patients suffering from ischaemic heart disease and heart failure are at high risk of recurrent ventricular arrhythmias (VAs), eventually leading to sudden cardiac death. While high-voltage shocks delivered by an implantable defibrillator may prevent sudden cardiac death, these interventions themselves impair quality of life and raise both morbidity and mortality, which accentuates the need for developing novel defibrillation techniques.

Experimental Approach

Photopharmacology allows for reversible control of biological processes by light. When relying on synthetic and externally applied chromophores, it renders genetic modification of target cells dispensable and may hence be advantageous over optogenetic approaches. Here, the photochromic ligand azobupivacaine 2 (AB2) was probed as a modulator of cardiac electrophysiology in an ex vivo intact mouse heart model.

Key Results

By reversibly blocking voltage-gated Na⁺ and K⁺ channels, photoswitching of AB2 modulated both the ventricular effective refractory period and the conduction velocity in native heart tissue. Moreover, photoswitching of AB2 was able to convert VA into sinus rhythm.

Conclusion and Implications

The present study provides the first proof of concept that AB2 enables gradual control of cardiac electrophysiology by light. AB2 may hence open the door to the development of an optical defibrillator based on photopharmacology.

背景和目的：缺血性心脏病和心力衰竭患者极易反复发生室性心律失常（VAs），最终导致心脏性猝死。虽然植入式除颤器发出的高压电击可以预防心脏性猝死，但这些干预措施本身会损害患者的生活质量，并增加发病率和死亡率，因此更有必要开发新型除颤技术：光药理学可通过光对生物过程进行可逆控制。依靠合成和外部应用的发色团，它无需对靶细胞进行基因修饰，因此可能比光遗传学方法更具优势。在此，研究人员在活体小鼠心脏模型中研究了光致变色配体偶氮布比卡因2（AB2）对心脏电生理学的调节作用：主要结果：通过可逆性阻断电压门控的Na+和K+通道，AB2的光开关调节了原生心脏组织中心室的有效折返期和传导速度。此外，AB2 的光开关还能将 VA 转为窦性心律：本研究首次证明了 AB2 能够通过光逐渐控制心脏电生理学的概念。因此，AB2 可为开发基于光药理学的光学除颤器打开大门。

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引用次数: 0

The expression of contextual fear conditioning involves the dorsal hippocampus TRPV1 receptor interacting with the NMDA/NO/cGMP signalling pathway 情境恐惧条件反射的表达涉及海马背侧 TRPV1 受体与 NMDA/NO/cGMP 信号通路的相互作用。

IF 6.8 2区医学 Q1 PHARMACOLOGY & PHARMACY

British Journal of Pharmacology

Pub Date : 2024-11-12 DOI: 10.1111/bph.17384

Gabriela L. Bertacchini, Andreza B. Sonego, Sabrina F. Lisboa, Davi C. Lagatta, Leonardo B. M. Resstel

Background and Purpose

The dorsal hippocampus (dHIP) is pivotal for learning, memory, and defensive responses. Transient receptor potential vanilloid type 1 (TRPV1) receptors in the dHIP modulate contextual fear conditioning by triggering a cascade involving glutamate release, nitric oxide (NO) formation and cyclic guanosine monophosphate (cGMP) production. The present study investigated the involvement of dHIP TRPV1 receptors and their interaction with the glutamate/NO/cGMP signalling pathway in modulating the expression of contextual fear conditioning (CFC).

Experimental Approach

Male Wistar rats were submitted to an aversive contextual conditioning session and, 48 h later, were re-introduced to the same aversive environment where the freezing response and autonomic activity (evidenced by increased arterial pressure and heart rate and a decrease in tail temperature) were measured.

Key Results

The results demonstrated that the TRPV1 antagonist 6-I-CPS in dHIP reduced the expression of CFC, whereas the agonist capsaicin had the opposite effect. Furthermore, dHIP pre-treatment with an NMDA receptor antagonist (AP7), neuronal NO synthase inhibitor (N-propyl-L-arginine), NO scavenger (c-PTIO) or guanylate cyclase inhibitor (ODQ) attenuated capsaicin-induced increases in CFC. Finally, we observed that re-exposure to the aversive chamber increased dHIP NO levels in conditioned animals compared with a non-conditioned group, which was prevented by the administration of the TRPV1 antagonist, 6-I-CPS.

Conclusion and Implications

Our study revealed that TRPV1 receptors in the dHIP play a crucial role in modulating contextual fear expression by acting through the NMDA receptor/NO/cGMP signalling pathway, providing important insights into the underlying mechanisms and potential therapeutic avenues associated with these pathways.

背景和目的：背侧海马（dHIP）对学习、记忆和防御反应至关重要。dHIP中的瞬时受体电位类香草素1型（TRPV1）受体通过触发涉及谷氨酸释放、一氧化氮（NO）形成和环磷酸鸟苷（cGMP）产生的级联反应来调节情境恐惧条件反射。本研究调查了 dHIP TRPV1 受体及其与谷氨酸/一氧化氮/cGMP 信号通路的相互作用在调节情境恐惧条件反射（CFC）表达中的参与情况：实验方法：对雄性 Wistar 大鼠进行厌恶性情境条件反射训练，48 小时后将其再次置于相同的厌恶环境中，测量其冻结反应和自律神经活动（表现为动脉压和心率升高以及尾温降低）：结果表明，在dHIP中TRPV1拮抗剂6-I-CPS可减少CFC的表达，而激动剂辣椒素则有相反的效果。此外，用 NMDA 受体拮抗剂（AP7）、神经元 NO 合酶抑制剂（N-丙基-L-精氨酸）、NO 清除剂（c-PTIO）或鸟苷酸环化酶抑制剂（ODQ）预处理 dHIP 可减轻辣椒素诱导的 CFC 的增加。最后，我们观察到，与非条件组相比，再次暴露于厌恶室会增加条件组动物的 dHIP NO 水平，而给予 TRPV1 拮抗剂 6-I-CPS 则可防止这种情况的发生：我们的研究揭示了 dHIP 中的 TRPV1 受体通过 NMDA 受体/NO/cGMP 信号通路在调节情境性恐惧表达中起着至关重要的作用，为了解与这些通路相关的内在机制和潜在治疗途径提供了重要依据。

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引用次数: 0

Compound 4a induces paraptosis in liver cancer through endoplasmic reticulum stress mediated by the calreticulin protein. 化合物 4a 通过钙网蛋白介导的内质网应激诱导肝癌的凋亡。

IF 6.8 2区医学 Q1 PHARMACOLOGY & PHARMACY

British Journal of Pharmacology

Pub Date : 2024-11-12 DOI: 10.1111/bph.17385

Chunmiao Wang, Dandan Liang, Xiaoyan Shen, Xuyang Chen, Linfang Lai, Huaxin Hou

Background and purpose: Emerging evidence has highlighted that paraptosis may be an effective strategy for treating liver cancer. In our previous studies, Compound 4a induced paraptosis in cancer cells. Here, the characteristics of Compound 4a-induced paraptosis were further revealed and, for the first time, the target and related molecular mechanisms of Compound 4a-induced paraptosis in liver cancer were defined.

Experimental approach: The effects and mechanism of Compound 4a in liver cancer cells were studied in in vitro and in vivo (BALB/c-nude xenograft model) experiments, and the targets of Compound 4a that trigger paraptosis were identified and confirmed via mass spectrometry-based drug affinity responsive target stability (DARTS) analyses, siRNA experiments and a cellular thermal shift assay (CETSA). The function and distribution of calreticulin (CRT) protein were detected via Cal-520 AM and immunofluorescence staining, respectively.

Key results: Compound 4a effectively induced paraptosis-like cell death in liver cancer, both in vitro and in vivo, and its effect was comparable with the first-line anti-liver cancer drug oxaliplatin but with a higher safety profile. We identified the CRT protein as a target of Compound 4a, which caused cellular endoplasmic reticulum stress (ERS) and calcium overload. CRT knockdown weakened the anti-liver cancer activity of Compound 4a, which may be related to the inhibition of paraptosis.

Conclusion: Compound 4a represents a potentially safe and effective agent for the treatment of liver cancer. The characteristics of Compound 4a-triggered paraptosis was clarified and a unique function of CRT in paraptosis was revealed.

背景和目的：新的证据表明，副aptosis 可能是治疗肝癌的一种有效策略。在我们之前的研究中，化合物 4a 诱导了癌细胞的副aptosis。在此，我们进一步揭示了化合物 4a 诱导副aptosis 的特征，并首次明确了化合物 4a 诱导肝癌副aptosis 的靶点及相关分子机制：实验方法：通过体外和体内（BALB/裸鼠异种移植模型）实验研究了化合物4a在肝癌细胞中的作用和机制，并通过基于质谱的药物亲和力反应靶点稳定性（DARTS）分析、siRNA实验和细胞热转移实验（CETSA）确定和证实了化合物4a引发副aptosis的靶点。通过Cal-520 AM和免疫荧光染色分别检测了钙网蛋白（CRT）的功能和分布：主要结果：化合物4a在体外和体内均能有效诱导肝癌细胞的凋亡，其效果与一线抗肝癌药物奥沙利铂相当，但安全性更高。我们发现CRT蛋白是化合物4a的靶点，它能引起细胞内质网应激（ERS）和钙超载。CRT基因敲除削弱了化合物4a的抗肝癌活性，这可能与抑制paraptosis有关：结论：化合物 4a 是一种潜在的安全有效的肝癌治疗药物。结论：化合物 4a 是一种潜在的治疗肝癌的安全有效的药物，它明确了化合物 4a 触发副aptosis 的特征，并揭示了 CRT 在副aptosis 中的独特功能。

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引用次数: 0