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A p75 neurotrophin receptor-sparing nerve growth factor protects retinal ganglion cells from neurodegeneration by targeting microglia 一种p75神经营养素受体稀释神经生长因子通过靶向小胶质细胞保护视网膜神经节细胞免于神经退化
IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-09 DOI: 10.1111/bph.17316
Laura Latini, Daniel Souza Monteiro De Araujo, Rosario Amato, Alessio Canovai, Lucia Buccarello, Francesco De Logu, Elena Novelli, Anastasiia Vlasiuk, Francesca Malerba, Ivan Arisi, Rita Florio, Hiroki Asari, Simona Capsoni, Enrica Strettoi, Gino Villetti, Bruno Pietro Imbimbo, Massimo Dal Monte, Romina Nassini, Pierangelo Geppetti, Silvia Marinelli, Antonino Cattaneo

Background and Purpose

Retinal ganglion cells (RGCs) are the output stage of retinal information processing, via their axons forming the optic nerve (ON). ON damage leads to axonal degeneration and death of RGCs, and results in vision impairment. Nerve growth factor (NGF) signalling is crucial for RGC operations and visual functions. Here, we investigate a new neuroprotective mechanism of a novel therapeutic candidate, a p75-less, TrkA-biased NGF agonist (hNGFp) in rat RGC degeneration, in comparison with wild type human NGF (hNGFwt).

Experimental Approach

Both neonate and adult rats, whether subjected or not to ON lesion, were treated with intravitreal injections or eye drops containing either hNGFp or hNGFwt. Different doses of the drugs were administered at days 1, 4 or 7 after injury for a maximum of 10 days, when immunofluorescence, electrophysiology, cellular morphology, cytokine array and behaviour studies were carried out. Pharmacokinetic evaluation was performed on rabbits treated with hNGFp ocular drops.

Results

hNGFp exerted a potent RGC neuroprotection by acting on microglia cells, and outperformed hNGFwt in rescuing RGC degeneration and reducing inflammatory molecules. Delayed use of hNGFp after ON lesion resulted in better outcomes compared with treatment with hNGFwt. Moreover, hNGFp-based ocular drops were less algogenic than hNGFwt. Pharmacokinetic measurements revealed that biologically relevant quantities of hNGFp were found in the rabbit retina.

Conclusions and Implications

Our data point to microglia as a new cell target through which NGF-induced TrkA signalling exerts neuroprotection of the RGC, emphasizing hNGFp as a powerful treatment to tackle retinal degeneration.

背景和目的视网膜神经节细胞(RGC)通过轴突形成视神经(ON),是视网膜信息处理的输出阶段。视神经轴突受损会导致轴突变性和 RGC 死亡,从而导致视力受损。神经生长因子(NGF)信号对 RGC 的运行和视觉功能至关重要。实验方法新生大鼠和成年大鼠,无论是否发生视网膜损伤,均接受含有 hNGFp 或 hNGFwt 的玻璃体内注射或滴眼液治疗。在损伤后第1天、第4天或第7天给予不同剂量的药物,最长持续10天,然后进行免疫荧光、电生理学、细胞形态学、细胞因子阵列和行为研究。结果hNGFp通过作用于小胶质细胞对RGC神经起到了有效的保护作用,在挽救RGC变性和减少炎症分子方面优于hNGFwt。与使用 hNGFwt 治疗相比,在 ON 病变后延迟使用 hNGFp 可获得更好的疗效。此外,基于 hNGFp 的滴眼液比 hNGFwt 的致藻性更低。结论与启示我们的数据表明,小胶质细胞是一个新的细胞靶点,NGF诱导的TrkA信号可通过它对RGC发挥神经保护作用,这强调了hNGFp是一种治疗视网膜变性的有效药物。
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引用次数: 0
Serotonergic transmission plays differentiated roles in the rapid and sustained antidepressant-like effects of ketamine 羟色胺能传导在氯胺酮快速和持续的抗抑郁样作用中发挥着不同的作用。
IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-05 DOI: 10.1111/bph.17324
Yong-Yu Yin, Jiao-Zhao Yan, Qian-Qian Wei, Si-Rui Sun, Yu-Qiang Ding, Li-Ming Zhang, Yun-Feng Li

Background and Purpose

The emerging antidepressant effects of ketamine have inspired tremendous interest in its underlying neurobiological mechanisms, although the involvement of 5-HT in the antidepressant effects of ketamine remains unclear.

Experimental approach

The chronic restraint stress procedure was performed to induce depression-like behaviours in mice. OFT, FST, TST, and NSFT tests were used to evaluate the antidepressant-like effects of ketamine. Tph2 knockout or depletion of 5-HT by PCPA and 5,7-DHT were used to manipulate the brain 5-HT system. ELISA and fibre photometry recordings were used to measure extracellular 5-HT levels in the brain.

Key Results

60 min after injection, ketamine (10 mg·kg−1, i.p.) produced rapid antidepressant-like effects and increased brain 5-HT levels. After 24 h, ketamine significantly reduced immobility time in TST and FST tests and increased brain 5-HT levels, as measured by ELISA and fibre photometry recordings. The sustained (24 h) but not rapid (60 min) antidepressant-like effects of ketamine were abrogated by PCPA and 5,7-DHT, or by Tph2 knockout. Importantly, NBQX (10 mg·kg−1, i.p.), an AMPA receptor antagonist, significantly inhibited the effect of ketamine on brain 5-HT levels and abolished the sustained antidepressant-like effects of ketamine in naïve or CRS-treated mice.

Conclusion and Implications

This study confirms the requirement of serotonergic neurotransmission for the sustained antidepressant-like effects of ketamine, which appears to involve AMPA receptors, and provides avenues to search for antidepressant pharmacological targets.

背景和目的:氯胺酮新出现的抗抑郁作用激发了人们对其潜在神经生物学机制的极大兴趣,但5-羟色胺参与氯胺酮抗抑郁作用的情况仍不清楚:实验方法:采用慢性束缚应激程序诱导小鼠出现类似抑郁的行为。实验方法:采用慢性束缚应激程序诱导小鼠抑郁样行为,并使用OFT、FST、TST和NSFT测试评估氯胺酮的抗抑郁样作用。Tph2基因敲除或通过PCPA和5,7-DHT消耗5-羟色胺被用来操纵大脑5-羟色胺系统。ELISA和纤维光度记录用于测量脑细胞外5-羟色胺的水平:注射氯胺酮(10 毫克-千克-1,静脉注射)60 分钟后,氯胺酮迅速产生类似抗抑郁的作用,并增加大脑 5-HT 的水平。24小时后,氯胺酮可明显缩短TST和FST试验中的静止时间,并通过酶联免疫吸附试验和纤维光度记录测量,提高大脑5-羟色胺水平。氯胺酮的持续(24小时)而非快速(60分钟)抗抑郁作用会被PCPA和5,7-DHT或Tph2基因敲除所减弱。重要的是,AMPA受体拮抗剂NBQX(10 mg-kg-1,i.p.)可显著抑制氯胺酮对大脑5-羟色胺水平的影响,并消除氯胺酮对天真或CRS处理小鼠的持续抗抑郁样作用:本研究证实了氯胺酮的持续抗抑郁样作用需要5-羟色胺能神经递质的参与,这似乎涉及AMPA受体,并为寻找抗抑郁药理靶点提供了途径。
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引用次数: 0
Schwann cell transient receptor potential ankyrin 1 (TRPA1) ortholog in zebrafish larvae mediates chemotherapy-induced peripheral neuropathy 斑马鱼幼体中的许旺细胞瞬时受体电位蛋白1(TRPA1)同源物介导化疗引起的周围神经病变
IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-05 DOI: 10.1111/bph.17318
Elisa Bellantoni, Matilde Marini, Martina Chieca, Chiara Gabellini, Erica Lucia Crapanzano, Daniel Souza Monteiro de Araujo, Daniele Nosi, Lorenzo Roschi, Lorenzo Landini, Gaetano De Siena, Pasquale Pensieri, Alessandra Mastricci, Irene Scuffi, Pierangelo Geppetti, Romina Nassini, Francesco De Logu

Background and Purpose

The oxidant sensor transient receptor potential ankyrin 1 (TRPA1) channel expressed by Schwann cells (SCs) has recently been implicated in several models of neuropathic pain in rodents. Here we investigate whether the pro-algesic function of Schwann cell TRPA1 is not limited to mammals by exploring the role of TRPA1 in a model of chemotherapy-induced peripheral neuropathy (CIPN) in zebrafish larvae.

Experimental Approach

We used zebrafish larvae and a mouse model to test oxaliplatin-evoked nociceptive behaviours. We also performed a TRPA1 selective silencing in Schwann cells both in zebrafish larvae and mice to study their contribution in oxaliplatin-induced CIPN model.

Key Results

We found that zebrafish larvae and zebrafish TRPA1 (zTRPA1)-transfected HEK293T cells respond to reactive oxygen species (ROS) with nociceptive behaviours and intracellular calcium increases, respectively. TRPA1 was found to be co-expressed with the Schwann cell marker, SOX10, in zebrafish larvae. Oxaliplatin caused nociceptive behaviours in zebrafish larvae that were attenuated by a TRPA1 antagonist and a ROS scavenger. Oxaliplatin failed to produce mechanical allodynia in mice with Schwann cell TRPA1 selective silencing (Plp1+-Trpa1 mice). Comparable results were observed in zebrafish larvae where TRPA1 selective silencing in Schwann cells, using the specific Schwann cell promoter myelin basic protein (MBP), attenuated oxaliplatin-evoked nociceptive behaviours.

Conclusion and Implications

These results indicate that the contribution of the oxidative stress/Schwann cell/TRPA1 pro-allodynic pathway to neuropathic pain models seems to be conserved across the animal kingdom.

背景和目的:最近,许旺细胞(SC)表达的氧化剂传感器瞬时受体电位蛋白1(TRPA1)通道与啮齿类动物的几种神经病理性疼痛模型有关。在此,我们通过探索 TRPA1 在斑马鱼幼体化疗诱导周围神经病变(CIPN)模型中的作用,研究许旺细胞 TRPA1 的促痛觉功能是否不仅限于哺乳动物:实验方法:我们使用斑马鱼幼体和小鼠模型来测试奥沙利铂诱发的痛觉行为。我们还在斑马鱼幼体和小鼠的许旺细胞中进行了 TRPA1 选择性沉默,以研究它们在奥沙利铂诱导的 CIPN 模型中的贡献:我们发现斑马鱼幼体和斑马鱼TRPA1(zTRPA1)转染的HEK293T细胞对活性氧(ROS)的反应分别是痛觉行为和细胞内钙增加。研究发现,在斑马鱼幼体中,TRPA1与许旺细胞标记物SOX10共同表达。奥沙利铂在斑马鱼幼体中引起痛觉行为,TRPA1拮抗剂和ROS清除剂可减轻这种行为。在许旺细胞 TRPA1 选择性沉默的小鼠(Plp1+-Trpa1 小鼠)中,奥沙利铂不能产生机械异感。在斑马鱼幼体中也观察到了类似的结果,使用特定的许旺细胞启动子髓鞘碱性蛋白(MBP)选择性沉默许旺细胞中的TRPA1,可减轻奥沙利铂诱发的痛觉行为:这些结果表明,氧化应激/许旺细胞/TRPA1 促变态反应途径对神经病理性疼痛模型的作用似乎在整个动物界都是一致的。
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引用次数: 0
Deficiency of 5-HT2B receptors alleviates atherosclerosis by regulating macrophage phenotype through inhibiting interferon signalling. 缺乏 5-HT2B 受体可通过抑制干扰素信号调节巨噬细胞表型,从而缓解动脉粥样硬化。
IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-04 DOI: 10.1111/bph.17315
Yahan Liu, Zhipeng Wang, Li Fang, Yaohua Xu, Beilei Zhao, Xuya Kang, Yanqing Zhao, Jintao Han, Yan Zhang, Erdan Dong, Nanping Wang

Background and purpose: Elevated levels of 5-HT have been correlated with coronary artery disease and cardiac events, suggesting 5-HT is a potential novel factor in the development of atherosclerotic cardiovascular disease. However, the underlying pathological mechanisms of the 5-HT system in atherosclerosis remain unclear. The 5-HT2B receptor (5-HT2BR), which establishes a positive feedback loop with 5-HT, has been identified as a contributor to pathophysiological processes in various vascular disorders. In this study, we investigated the immunological impact of 5-HT2BR in atherosclerosis-prone apolipoprotein E-deficient (ApoE-/-) mice.

Experimental approach: Plasma levels of 5-HT were measured in mice using an ELISA kit. Atherosclerotic plaque formation, macrophage infiltration and inflammatory signalling were assessed in ApoE-/- mice by employing both pharmacological inhibition and genetic deficiency of 5-HT2BR. Inflammasome activation was elucidated using peritoneal macrophages isolated from 5-HT2BR-deficient mice.

Key results: An upregulation of 5-HT2BR expression was observed in the aortas of ApoE-/- mice, exhibiting a strong correlation with the presence of macrophages in plaques. Atherosclerosis was attenuated in mice through pharmacological inhibition and genetic deficiency of 5-HT2BR. Additionally, a significant reduction in atherosclerotic plaque size was achieved through bone marrow reconstitution with 5-HT2BR-deficient cells. 5-HT2BR-deficient macrophages showed attenuated interferon (IFN) signalling, NLRP3 inflammasome activation, and interleukin-1β release. Moreover, macrophages primed with 5-HT2BR deficiency displayed an anti-inflammatory phenotype.

Conclusion and implications: These findings support the hypothesis that 5-HT2BR in macrophages plays a causal role in the development of atherosclerosis, revealing a novel perspective for potential therapeutic strategies in atherosclerosis-related diseases.

背景和目的:5-羟色胺水平的升高与冠状动脉疾病和心脏事件相关,这表明 5-HT 是动脉粥样硬化性心血管疾病发生发展的潜在新因素。然而,5-HT 系统在动脉粥样硬化中的潜在病理机制仍不清楚。5-HT2B受体(5-HT2BR)与5-HT建立了正反馈环路,已被确定为各种血管疾病病理生理过程的促成因素。在这项研究中,我们研究了 5-HT2BR 对易患动脉粥样硬化的载脂蛋白 E 缺失(ApoE-/-)小鼠的免疫学影响:实验方法:使用ELISA试剂盒测定小鼠血浆中5-HT的水平。通过药物抑制和遗传性5-HT2BR缺失,评估载脂蛋白E-/-小鼠动脉粥样硬化斑块的形成、巨噬细胞浸润和炎症信号传导。利用从5-HT2BR缺陷小鼠体内分离的腹腔巨噬细胞阐明了炎症体的激活:主要结果:在载脂蛋白E-/-小鼠的主动脉中观察到5-HT2BR表达上调,这与斑块中巨噬细胞的存在密切相关。通过药物抑制和基因缺失 5-HT2BR 可减轻小鼠的动脉粥样硬化。此外,通过用5-HT2BR缺陷细胞进行骨髓重组,动脉粥样硬化斑块的大小也明显缩小。5-HT2BR缺陷型巨噬细胞的干扰素(IFN)信号、NLRP3炎性体激活和白细胞介素-1β释放均有所减弱。此外,缺乏 5-HT2BR 的巨噬细胞显示出抗炎表型:这些发现支持了巨噬细胞中的 5-HT2BR 在动脉粥样硬化的发展中起着因果作用的假设,为动脉粥样硬化相关疾病的潜在治疗策略提供了新的视角。
{"title":"Deficiency of 5-HT<sub>2B</sub> receptors alleviates atherosclerosis by regulating macrophage phenotype through inhibiting interferon signalling.","authors":"Yahan Liu, Zhipeng Wang, Li Fang, Yaohua Xu, Beilei Zhao, Xuya Kang, Yanqing Zhao, Jintao Han, Yan Zhang, Erdan Dong, Nanping Wang","doi":"10.1111/bph.17315","DOIUrl":"https://doi.org/10.1111/bph.17315","url":null,"abstract":"<p><strong>Background and purpose: </strong>Elevated levels of 5-HT have been correlated with coronary artery disease and cardiac events, suggesting 5-HT is a potential novel factor in the development of atherosclerotic cardiovascular disease. However, the underlying pathological mechanisms of the 5-HT system in atherosclerosis remain unclear. The 5-HT<sub>2B</sub> receptor (5-HT2BR), which establishes a positive feedback loop with 5-HT, has been identified as a contributor to pathophysiological processes in various vascular disorders. In this study, we investigated the immunological impact of 5-HT2BR in atherosclerosis-prone apolipoprotein E-deficient (ApoE<sup>-/-</sup>) mice.</p><p><strong>Experimental approach: </strong>Plasma levels of 5-HT were measured in mice using an ELISA kit. Atherosclerotic plaque formation, macrophage infiltration and inflammatory signalling were assessed in ApoE<sup>-/-</sup> mice by employing both pharmacological inhibition and genetic deficiency of 5-HT2BR. Inflammasome activation was elucidated using peritoneal macrophages isolated from 5-HT2BR-deficient mice.</p><p><strong>Key results: </strong>An upregulation of 5-HT2BR expression was observed in the aortas of ApoE<sup>-/-</sup> mice, exhibiting a strong correlation with the presence of macrophages in plaques. Atherosclerosis was attenuated in mice through pharmacological inhibition and genetic deficiency of 5-HT2BR. Additionally, a significant reduction in atherosclerotic plaque size was achieved through bone marrow reconstitution with 5-HT2BR-deficient cells. 5-HT2BR-deficient macrophages showed attenuated interferon (IFN) signalling, NLRP3 inflammasome activation, and interleukin-1β release. Moreover, macrophages primed with 5-HT2BR deficiency displayed an anti-inflammatory phenotype.</p><p><strong>Conclusion and implications: </strong>These findings support the hypothesis that 5-HT2BR in macrophages plays a causal role in the development of atherosclerosis, revealing a novel perspective for potential therapeutic strategies in atherosclerosis-related diseases.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131897","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
Tert-butylhydroquinone promotes skin flap survival by inhibiting oxidative stress mediated by the Nrf2/HO-1 signalling pathway 叔丁基对苯二酚通过抑制 Nrf2/HO-1 信号通路介导的氧化应激促进皮瓣存活。
IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-04 DOI: 10.1111/bph.17321
Kaitao Wang, An Wang, Jiapeng Deng, Jialong Yang, Guodong Chen, Qingyu Chen, Minle Ye, Dingsheng Lin

Background and Purpose

Skin flaps are among the most important means of wound repair in clinical settings. However, partial or even total distal necrosis may occur after a flap operation, with severe consequences for both patients and doctors. This study investigated whether tert-butylhydroquinone (TBHQ), a known agonist of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), and an antioxidant, could promote skin flap survival.

Experimental Approach

McFarlane skin flap models were established in male Sprague–Dawley rats and then randomly divided into control, low-dose TBHQ, and high-dose TBHQ treatment groups. On postoperative day 7, the survival and blood flow of the skin flaps were assessed. Using flap tissue samples, angiogenesis, inflammation, apoptosis, autophagy, and Nrf2/haem oxygenase 1 (HO-1) signalling pathway activity were measured with immunohistochemical techniques and western blotting.

Key Results

TBHQ dose-dependently stimulated the Nrf2/HO-1 signalling pathway, inducing autophagy through the up-regulation of LC3B and beclin 1 and concurrently suppressing p62 expression. Additionally, TBHQ hindered apoptosis by enhancing Bcl-2 expression while inhibiting the expression of Bax. It suppressed inflammation by inhibiting the expression of interleukin 1β, interleukin 6, and tumour necrosis factor-α and enhanced angiogenesis by promoting the expression of vascular endothelial growth factor.

Conclusion and Implications

In summary, TBHQ promoted flap survival in rats by up-regulating the Nrf2/HO-1 signalling pathway. As TBHQ is already widely used as a food additive, it could offer an acceptable means of improving clinical outcomes following skin flap surgery in patients.

背景和目的:皮瓣是临床上最重要的伤口修复手段之一。然而,皮瓣手术后可能会出现部分甚至全部远端坏死,给患者和医生带来严重后果。本研究探讨了叔丁基对苯二酚(TBHQ)--一种已知的转录因子核因子红细胞2相关因子2(Nrf2)激动剂和抗氧化剂--能否促进皮瓣存活:实验方法:用雄性 Sprague-Dawley 大鼠建立麦克法兰皮瓣模型,然后将其随机分为对照组、低剂量 TBHQ 治疗组和高浓度 TBHQ 治疗组。术后第 7 天,对皮瓣的存活率和血流量进行评估。利用皮瓣组织样本,采用免疫组化技术和 Western 印迹法测定血管生成、炎症、细胞凋亡、自噬和 Nrf2/ 血氧合酶 1(HO-1)信号通路的活性:主要结果:TBHQ剂量依赖性地刺激Nrf2/HO-1信号通路,通过上调LC3B和beclin 1诱导自噬,同时抑制p62的表达。此外,TBHQ 还能提高 Bcl-2 的表达,同时抑制 Bax 的表达,从而阻碍细胞凋亡。它通过抑制白细胞介素 1β、白细胞介素 6 和肿瘤坏死因子-α的表达来抑制炎症,并通过促进血管内皮生长因子的表达来增强血管生成:总之,TBHQ 通过上调 Nrf2/HO-1 信号通路促进了大鼠皮瓣的存活。由于 TBHQ 已被广泛用作食品添加剂,因此它可以为改善患者皮瓣手术后的临床疗效提供一种可接受的方法。
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引用次数: 0
Advancing the field of viroporins—Structure, function and pharmacology: IUPHAR Review 39 推进 viroporins 领域--结构、功能和药理学:IUPHAR Review X.
IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-03 DOI: 10.1111/bph.17317
Kira Devantier, Viktoria M. S. Kjær, Stephen Griffin, Birthe B. Kragelund, Mette M. Rosenkilde

Viroporins possess important potential as antiviral targets due to their critical roles during virus life cycles, spanning from virus entry to egress. Although the antiviral amantadine targets the M2 viroporin of influenza A virus, successful progression of other viroporin inhibitors into clinical use remains challenging. These challenges relate in varying proportions to a lack of reliable full-length 3D-structures, difficulties in functionally characterising individual viroporins, and absence of verifiable direct binding between inhibitor and viroporin. This review offers perspectives to help overcome these challenges. We provide a comprehensive overview of the viroporin family, including their structural and functional features, highlighting the moldability of their energy landscapes and actions. To advance the field, we suggest a list of best practices to aspire towards unambiguous viroporin identification and characterisation, along with considerations of potential pitfalls. Finally, we present current and future scenarios of, and prospects for, viroporin targeting drugs.

病毒蛋白在病毒生命周期(从病毒进入到排出)中发挥着关键作用,因此具有作为抗病毒靶点的重要潜力。虽然抗病毒药物金刚烷胺针对的是甲型流感病毒的 M2 病毒蛋白,但其他病毒蛋白抑制剂能否成功进入临床应用仍面临挑战。这些挑战在不同程度上与缺乏可靠的全长三维结构、难以对单个病毒蛋白进行功能表征以及抑制剂与病毒蛋白之间缺乏可验证的直接结合有关。本综述提出了有助于克服这些挑战的观点。我们全面概述了病毒蛋白家族,包括其结构和功能特征,强调了其能量景观和作用的可塑性。为了推动该领域的发展,我们提出了一份最佳实践清单,以实现明确的病毒蛋白鉴定和表征,同时考虑到潜在的陷阱。最后,我们介绍了病毒蛋白靶向药物目前和未来的发展前景。
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引用次数: 0
Targeting RNA with small molecules, from RNA structures to precision medicines: IUPHAR review: 40 用小分子靶向 RNA,从 RNA 结构到精准药物:IUPHAR review:40.
IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-03 DOI: 10.1111/bph.17308
Yuquan Tong, Jessica L. Childs-Disney, Matthew D. Disney

RNA plays important roles in regulating both health and disease biology in all kingdoms of life. Notably, RNA can form intricate three-dimensional structures, and their biological functions are dependent on these structures. Targeting the structured regions of RNA with small molecules has gained increasing attention over the past decade, because it provides both chemical probes to study fundamental biology processes and lead medicines for diseases with unmet medical needs. Recent advances in RNA structure prediction and determination and RNA biology have accelerated the rational design and development of RNA-targeted small molecules to modulate disease pathology. However, challenges remain in advancing RNA-targeted small molecules towards clinical applications. This review summarizes strategies to study RNA structures, to identify small molecules recognizing these structures, and to augment the functionality of RNA-binding small molecules. We focus on recent advances in developing RNA-targeted small molecules as potential therapeutics in a variety of diseases, encompassing different modes of actions and targeting strategies. Furthermore, we present the current gaps between early-stage discovery of RNA-binding small molecules and their clinical applications, as well as a roadmap to overcome these challenges in the near future.

RNA 在调节所有生命体的健康和疾病生物学方面都发挥着重要作用。值得注意的是,RNA 可以形成复杂的三维结构,其生物功能取决于这些结构。过去十年来,用小分子靶向 RNA 结构区的研究越来越受到关注,因为它既能提供化学探针来研究基本生物学过程,又能提供先导药物来治疗医疗需求未得到满足的疾病。最近在 RNA 结构预测和确定以及 RNA 生物学方面取得的进展,加速了 RNA 靶向小分子的合理设计和开发,以调节疾病病理。然而,将 RNA 靶向小分子推向临床应用仍面临挑战。本综述总结了研究 RNA 结构、识别这些结构的小分子以及增强 RNA 结合型小分子功能的策略。我们重点介绍了开发 RNA 靶向小分子作为各种疾病潜在疗法的最新进展,包括不同的作用模式和靶向策略。此外,我们还介绍了目前 RNA 结合小分子的早期发现与其临床应用之间的差距,以及在不久的将来克服这些挑战的路线图。
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引用次数: 0
The plant extract PNS mitigates atherosclerosis via promoting Nrf2-mediated inhibition of ferroptosis through reducing USP2-mediated Keap1 deubiquitination 植物提取物PNS通过减少USP2介导的Keap1去泛素化,促进Nrf2介导的铁变态反应抑制,从而减轻动脉粥样硬化。
IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-03 DOI: 10.1111/bph.17311
Yun Zhao, Guobin Zheng, Shu Yang, Shangjing Liu, Yifan Wu, Yaodong Miao, Zhen Liang, Yunqing Hua, Jing Zhang, Jia Shi, Dan Li, Yanfei Cheng, Yunsha Zhang, Yuanli Chen, Guanwei Fan, Chuanrui Ma

Background and purpose

Atherosclerosis is the basis of cardiovascular disease. Ferroptosis is a form of programmed cell death characterized by lipid peroxidation, which contributes to atherogenesis. The plant extract PNS (Panax notoginseng saponins), containing the main active ingredients of Panax notoginseng, exhibits anti-atherogenic properties. Herein, we determined whether PNS and its major components could attenuate atherosclerosis by suppressing ferroptosis and revealed the underlying mechanism(s).

Experimental approach

The anti-atherogenic effects of PNS and their association with inhibition of ferroptosis was determined in apoE−/− mice. In vitro, the anti-ferroptotic effect and mechanism(s) of PNS components were demonstrated in the presence of ferroptosis inducers. Expression of ferroptosis markers and the ubiquitination of Keap1 were evaluated in USP2−/− macrophages. Finally, the anti-atherogenic effect of USP2 knockout was determined by using USP2−/− mice treated with high-fat diet (HFD) and AAV-PCSK9.

Key results

PNS inhibited ferroptosis and atherosclerosis in vivo. PNS suppressed ferroptosis and ferroptosis-aggravated foam cell formation and inflammation in vitro. Mechanistically, PNS and its components activated Nrf2 by antagonizing Keap1, which was attributed to the inhibition of USP2 expression. USP2 knockout antagonized ferroptosis and ferroptosis-aggravated foam cell formation and inflammation, thus mitigating atherosclerosis. USP2 knockout abolished inhibitory effects of PNS on foam cell formation and inflammation in vitro.

Conclusion and implications

PNS reduced USP2-mediated Keap1 de-ubiquitination and promoted Keap1 degradation, thereby activating Nrf2, improving iron metabolism and reducing lipid peroxidation, thus contributing to an anti-atherosclerotic outcome. Our study revealed the mechanism(s) underlying inhibition of ferroptosis and atherosclerosis by PNS.

背景和目的:动脉粥样硬化是心血管疾病的基础。铁变态反应是一种以脂质过氧化为特征的程序性细胞死亡,它是动脉粥样硬化的诱因。植物提取物 PNS(三七皂苷)含有三七的主要活性成分,具有抗动脉粥样硬化的特性。在此,我们确定了三七皂苷及其主要成分是否能通过抑制铁变态反应来减轻动脉粥样硬化,并揭示了其潜在机制:实验方法:在载脂蛋白E-/-小鼠体内测定PNS的抗动脉粥样硬化作用及其与抑制铁蛋白沉积的关系。实验方法:在载脂蛋白E-/-小鼠体内测定 PNS 的抗动脉粥样硬化作用及其与抑制铁蛋白沉积的关系。评估了 USP2-/-巨噬细胞中铁败标志物的表达和 Keap1 的泛素化。最后,通过使用高脂饮食(HFD)和AAV-PCSK9处理USP2-/-小鼠,确定了USP2基因敲除的抗动脉粥样硬化作用:PNS抑制了体内的铁蛋白沉积和动脉粥样硬化。PNS 在体外抑制了铁蛋白沉积和铁蛋白沉积加重的泡沫细胞形成和炎症。从机理上讲,PNS 及其成分通过拮抗 Keap1 激活了 Nrf2,这归因于对 USP2 表达的抑制。USP2 基因敲除可拮抗铁蛋白沉积和铁蛋白沉积加重的泡沫细胞形成和炎症,从而减轻动脉粥样硬化。USP2 基因敲除消除了 PNS 对体外泡沫细胞形成和炎症的抑制作用:PNS减少了USP2介导的Keap1去泛素化,促进了Keap1降解,从而激活了Nrf2,改善了铁代谢,减少了脂质过氧化,从而有助于抗动脉粥样硬化。我们的研究揭示了 PNS 抑制铁代谢和动脉粥样硬化的机制。
{"title":"The plant extract PNS mitigates atherosclerosis via promoting Nrf2-mediated inhibition of ferroptosis through reducing USP2-mediated Keap1 deubiquitination","authors":"Yun Zhao,&nbsp;Guobin Zheng,&nbsp;Shu Yang,&nbsp;Shangjing Liu,&nbsp;Yifan Wu,&nbsp;Yaodong Miao,&nbsp;Zhen Liang,&nbsp;Yunqing Hua,&nbsp;Jing Zhang,&nbsp;Jia Shi,&nbsp;Dan Li,&nbsp;Yanfei Cheng,&nbsp;Yunsha Zhang,&nbsp;Yuanli Chen,&nbsp;Guanwei Fan,&nbsp;Chuanrui Ma","doi":"10.1111/bph.17311","DOIUrl":"10.1111/bph.17311","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and purpose</h3>\u0000 \u0000 <p>Atherosclerosis is the basis of cardiovascular disease. Ferroptosis is a form of programmed cell death characterized by lipid peroxidation, which contributes to atherogenesis. The plant extract PNS (<i>Panax notoginseng saponins</i>), containing the main active ingredients of <i>Panax notoginseng</i>, exhibits anti-atherogenic properties. Herein, we determined whether PNS and its major components could attenuate atherosclerosis by suppressing ferroptosis and revealed the underlying mechanism(s).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental approach</h3>\u0000 \u0000 <p>The anti-atherogenic effects of PNS and their association with inhibition of ferroptosis was determined in apoE<sup>−/−</sup> mice. In vitro, the anti-ferroptotic effect and mechanism(s) of PNS components were demonstrated in the presence of ferroptosis inducers. Expression of ferroptosis markers and the ubiquitination of Keap1 were evaluated in USP2<sup>−/−</sup> macrophages. Finally, the anti-atherogenic effect of USP2 knockout was determined by using USP2<sup>−/−</sup> mice treated with high-fat diet (HFD) and AAV-PCSK9.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key results</h3>\u0000 \u0000 <p>PNS inhibited ferroptosis and atherosclerosis in vivo. PNS suppressed ferroptosis and ferroptosis-aggravated foam cell formation and inflammation in vitro. Mechanistically, PNS and its components activated Nrf2 by antagonizing Keap1, which was attributed to the inhibition of USP2 expression. USP2 knockout antagonized ferroptosis and ferroptosis-aggravated foam cell formation and inflammation, thus mitigating atherosclerosis. USP2 knockout abolished inhibitory effects of PNS on foam cell formation and inflammation in vitro.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and implications</h3>\u0000 \u0000 <p>PNS reduced USP2-mediated Keap1 de-ubiquitination and promoted Keap1 degradation, thereby activating Nrf2, improving iron metabolism and reducing lipid peroxidation, thus contributing to an anti-atherosclerotic outcome. Our study revealed the mechanism(s) underlying inhibition of ferroptosis and atherosclerosis by PNS.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142124879","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 inhibitor of class IIa histone deacetylases attenuates collagen-induced arthritis 一种新型 IIa 类组蛋白去乙酰化酶抑制剂可减轻胶原蛋白诱发的关节炎。
IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-02 DOI: 10.1111/bph.17306
Eunice K. Poon, Ligong Liu, Kai-Chen Wu, Junxian Lim, Matthew J. Sweet, Rink-Jan Lohman, Abishek Iyer, David P. Fairlie

Background and Purpose

Most inhibitors of histone deacetylases (HDACs) are not selective and are cytotoxic. Some have anti-inflammatory activity in disease models, but cytotoxicity prevents long-term uses in non-fatal diseases. Inhibitors selective for class IIa HDACs are much less cytotoxic and may have applications in management of chronic inflammatory diseases.

Experimental Approach

LL87 is a novel HDAC inhibitor examined here for HDAC enzyme selectivity. It was also investigated in macrophages for cytotoxicity and for inhibition of lipopolysaccharide (LPS)-stimulated cytokine secretion. In a rat model of collagen-induced arthritis, LL87 was investigated for effects on joint inflammation in Dark Agouti rats. Histological, immunohistochemical, micro-computed tomography and molecular analyses characterise developing arthritis and anti-inflammatory efficacy.

Key Results

LL87 was significantly more inhibitory against class IIa than class I or IIb HDAC enzymes. In macrophages, LL87 was not cytotoxic and reduced both LPS-induced secretion of pro-inflammatory cytokines, and IL6-induced class IIa HDAC activity. In rats, LL87 attenuated paw swelling and clinical signs of arthritis, reducing collagen loss and histological damage in ankle joints. LL87 decreased immune cell infiltration, especially pro-inflammatory macrophages and osteoclasts, into synovial joints and significantly reduced expression of pro-inflammatory cytokines and tissue-degrading proteases.

Conclusion and Implications

A novel inhibitor of class IIa HDACs has been shown to have an anti-inflammatory and anti-arthritic profile distinct from current therapies. It is efficacious in reducing macrophage infiltration and joint inflammation in a chronic model of rat arthritis.

背景和目的:大多数组蛋白去乙酰化酶(HDACs)抑制剂都没有选择性,而且具有细胞毒性。有些抑制剂在疾病模型中具有抗炎活性,但细胞毒性阻碍了其在非致命性疾病中的长期应用。对 IIa 类 HDAC 具有选择性的抑制剂的细胞毒性要小得多,可用于慢性炎症性疾病的治疗:实验方法:LL87 是一种新型 HDAC 抑制剂,本实验对其 HDAC 酶选择性进行了研究。实验方法:LL87 是一种新型 HDAC 抑制剂,本文研究了它对 HDAC 酶的选择性,还研究了它在巨噬细胞中的细胞毒性和对脂多糖(LPS)刺激的细胞因子分泌的抑制作用。在胶原蛋白诱导的大鼠关节炎模型中,研究了 LL87 对 Dark Agouti 大鼠关节炎症的影响。组织学、免疫组化、微型计算机断层扫描和分子分析显示了关节炎发展和抗炎功效的特征:主要结果:LL87 对 IIa 类 HDAC 酶的抑制作用明显强于 I 类或 IIb 类 HDAC 酶。在巨噬细胞中,LL87 没有细胞毒性,并能减少 LPS 诱导的促炎细胞因子分泌和 IL6 诱导的 IIa 类 HDAC 活性。在大鼠身上,LL87 可减轻爪肿和关节炎的临床症状,减少胶原蛋白流失和踝关节的组织学损伤。LL87 可减少免疫细胞,尤其是促炎巨噬细胞和破骨细胞向滑膜关节的浸润,并显著降低促炎细胞因子和组织降解蛋白酶的表达:一种新型 IIa 类 HDAC 抑制剂具有不同于现有疗法的抗炎和抗关节炎特性。在慢性大鼠关节炎模型中,它能有效减少巨噬细胞浸润和关节炎症。
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引用次数: 0
Discovery of natural product derivative triptolidiol as a direct NLRP3 inhibitor by reducing K63-specific ubiquitination. 通过减少 K63 特异性泛素化,发现天然产物衍生物 triptolidiol 可直接作为 NLRP3 抑制剂。
IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-01 DOI: 10.1111/bph.17320
Mo-Yu Ding, Chengqing Ning, Shao-Ru Chen, Hao-Ran Yin, Jing Xu, Ying Wang

Background and purpose: NLRP3 is up-regulated in inflammatory and autoimmune diseases. The development of NLRP3 inhibitors is challenged by the identification of compounds with distinct mechanisms of action avoiding side effects and toxicity. Triptolide is a natural product with multiple anti-inflammatory activities, but a narrow therapeutic window.

Experimental approach: Natural product triptolide derivatives were screened for NLRP3 inhibitors in human THP-1 and mouse bone marrow-derived macrophages. The efficacy of potent NLRP3 inhibitors was evaluated in LPS-induced acute lung injury and septic shock models.

Key results: Triptolidiol was identified as a selective inhibitor of NLRP3 with high potency. Triptolidiol inactivated the NLRP3 inflammasome in human THP-1 and mouse primary macrophages primed with LPS. Triptolidiol specifically inhibited pro-caspase 1 cleavage downstream of NLRP3, but not AIM2 or NLRC4 inflammasomes. Based on the structure-activity relationship study, the C8-β-OH group was critical for its binding to NLRP3. Triptolidiol exhibited a submicromolar KD for NLRP3, binding to residue C280. This binding prevented the interaction of NLRP3 with NEK7, the key regulator of NLRP3 inflammasome oligomerization and assembly, but not with the inflammasome adaptor protein ASC. Triptolidiol decreased the K63-specific ubiquitination of NLRP3, leading NLRP3 to a "closed" inactive conformation. Intraperitoneal administration of triptolidiol significantly attenuated LPS-induced acute lung injury and lethal septic shock.

Conclusion and implications: Triptolidiol is a novel NLRP3 inhibitor that regulates inflammasome assembly and activation by decreasing K63-linked ubiquitination. Triptolidiol has novel structural features that make it distinct from reported NLRP3 inhibitors and represents a viable therapeutic lead for inflammatory diseases.

背景和目的:NLRP3 在炎症和自身免疫性疾病中上调。开发 NLRP3 抑制剂面临的挑战是找到具有独特作用机制、避免副作用和毒性的化合物。雷公藤内酯是一种天然产物,具有多种抗炎活性,但治疗窗口较窄:实验方法:在人类 THP-1 和小鼠骨髓衍生巨噬细胞中筛选天然产品曲托内酯衍生物作为 NLRP3 抑制剂。在 LPS 诱导的急性肺损伤和脓毒性休克模型中评估了强效 NLRP3 抑制剂的疗效:主要结果:经鉴定,Triptolidiol 是一种高效的 NLRP3 选择性抑制剂。Triptolidiol能使LPS诱导的人THP-1和小鼠原代巨噬细胞中的NLRP3炎性体失活。Triptolidiol 可特异性抑制 NLRP3 下游的促天冬酶 1 的裂解,但不能抑制 AIM2 或 NLRC4 炎症体。根据结构-活性关系研究,C8-β-OH基团是其与NLRP3结合的关键。Triptolidiol 与 NLRP3 的 KD 值为亚摩尔,与残基 C280 结合。这种结合阻止了 NLRP3 与 NEK7(NLRP3 炎症小体寡聚和组装的关键调节因子)的相互作用,但没有阻止 NLRP3 与炎症小体适配蛋白 ASC 的相互作用。Triptolidiol减少了NLRP3的K63特异性泛素化,导致NLRP3处于 "封闭 "的非活性构象。腹腔注射三唑醇能显著减轻LPS诱导的急性肺损伤和致死性脓毒性休克:Triptolidiol是一种新型NLRP3抑制剂,可通过减少K63连接的泛素化来调节炎性体的组装和激活。Triptolidiol 具有新颖的结构特征,使其有别于已报道的 NLRP3 抑制剂,是治疗炎症性疾病的可行药物。
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引用次数: 0
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