European journal of pharmacology最新文献

Impact of neonatal hyperoxia on adult cardiac autonomic function in rats: Role of angiotensin II type 1 receptor activation 新生儿高氧对大鼠成年心脏自主神经功能的影响：血管紧张素 II 1 型受体激活的作用

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-10-11 DOI: 10.1016/j.ejphar.2024.177026

Individuals born preterm present altered cardiac autonomic function, a risk factor to heart diseases. Neonatal renin-angiotensin-system activation contributes to adult cardiomyopathy in rats exposed to neonatal hyperoxia, a well-established model of preterm birth-related conditions. Central angiotensin II receptor activation is a key modulator of the autonomic drive to the heart. Whether neonatal hyperoxia leads to alteration of the cardiac autonomic function through activation of the angiotensin II receptor type 1 (AT1) is unknown and was examined in the present study.

Sprague-Dawley pups were exposed to hyperoxia or room air from postnatal days 3–10. AT1 antagonist losartan or water was given orally postnatal days 8–10. Blood pressure, autonomic function, left ventricular sympathetic innervation, β-adrenergic-receptors expression, and AT1 expression in the solitary-tract-nucleus were examined in adult rats.

Neonatal hyperoxia led to loss of day-night blood pressure variation, decreased heart rate variability, increased sympathovagal balance, increased AT1 expression in the solitary-tract, decreased left ventricle sympathetic innervation, and increased β1-adrenergic-receptor protein expression. Losartan prevented the autonomic changes and AT1 expression in the solitary-tract but did not impact the loss of circadian blood pressure variation nor the changes in sympathetic innervation and in β1-adrenergic-receptor expression.

In conclusion, neonatal hyperoxia leads to both central autonomic and cardiac sympathetic changes, partly programmed by neonatal activation of the renin-angiotensin system.

早产儿的心脏自主神经功能会发生改变，这是导致心脏病的一个危险因素。新生儿肾素-血管紧张素系统活化是导致大鼠患上成人心肌病的原因。中枢血管紧张素 II 受体激活是心脏自律神经驱动的一个关键调节器。新生儿高氧是否会通过激活血管紧张素 II 受体 1 型（AT1）而导致心脏自主神经功能的改变尚不清楚，本研究对此进行了研究。出生后第 8-10 天口服 AT1 拮抗剂洛沙坦或水。对成年大鼠的血压、自律神经功能、左心室交感神经支配、β肾上腺素能受体表达以及孤束核中AT1的表达进行了检测。新生儿高氧导致昼夜血压变化消失、心率变异性降低、交感-迷走平衡增加、孤束核中AT1表达增加、左心室交感神经支配减少以及β1肾上腺素能受体蛋白表达增加。总之，新生儿高氧会导致中枢自律神经和心脏交感神经的变化，其中部分原因是新生儿肾素-血管紧张素系统的激活。

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引用次数: 0

Anti-nociceptive effects of non-antibiotic derivatives of demeclocycline and doxycycline against formalin-induced pain stimulation 去甲环素和强力霉素的非抗生素衍生物对福尔马林引起的疼痛刺激的抗痛觉作用。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-10-10 DOI: 10.1016/j.ejphar.2024.177054

In previous studies, some tetracycline (TC) antibiotics showed potential as analgesic. We investigated here the analgesic activity of new non-antibiotic TC derivatives using the formalin-induced nociceptive pain model in adult C57BL/6 mice. Specifically, we tested the effects of i.p. injections of DDMC (5, 10, 20 mg kg⁻¹) and DDOX (10, 20, 40 mg kg⁻¹), which are non-antibiotic derivatives of demeclocycline and doxycycline, respectively. Repeated treatments with DDMC remarkably reduced nociceptive pain in both phases of the test, at 10 mg kg⁻¹ its efficacy was comparable to that of 10 mg kg⁻¹ of morphine. DDOX was also effective in this paradigm but intrinsically less potent than DDMC, exerting analgesic effects between 20 and 40 mg kg⁻¹. Interestingly, a single injection of DDMC (10 mg kg⁻¹) was sufficient to produce a robust anti-nociceptive effect similar to that of morphine. A single injection of DDOX (40 mg kg⁻¹) also produced anti-nociceptive effects but only in the second phase of the test. Noticeably, male mice exhibited a better analgesic response to DDMC (10 mg kg⁻¹) than females. A single injection of DDMC (10 mg kg⁻¹) and morphine but not of DDOX (40 mg kg⁻¹), powerfully inhibited formalin-induced spinal cord c-Fos expression whereas both TC derivatives restrained the activation of Iba-1-immunoreactive cells, indicating a potential indirect effect on inflamed microglial cells. In summary, the non-antibiotic TCs, DDMC and DDOX, demonstrated notable analgesic efficacy against formalin-induced pain, suggesting their potential as alternatives for analgesic treatment.

在以前的研究中，一些四环素（TC）抗生素显示出镇痛潜力。在此，我们利用福尔马林诱导的成年 C57BL/6 小鼠痛觉模型，研究了新型非抗生素 TC 衍生物的镇痛活性。具体来说，我们测试了静注 DDMC（5、10、20 mg.kg-1）和 DDOX（10、20、40 mg.kg-1）的效果，它们分别是去甲环素和多西环素的非抗生素衍生物。在两个阶段的试验中，重复使用 DDMC 都能显著减轻痛觉疼痛，10 毫克/千克的疗效与 10 毫克/千克吗啡相当。DDOX 在这一范例中也有效，但内在效力低于 DDMC，其镇痛效果介于 20 至 40 毫克/千克-1 之间。有趣的是，单次注射 DDMC（10 毫克/千克）足以产生与吗啡相似的强效抗痛觉效应。单次注射 DDOX（40 毫克/千克-1）也能产生抗痛觉作用，但只在试验的第二阶段。值得注意的是，雄性小鼠对 DDMC（10 毫克/千克）的镇痛反应优于雌性小鼠。单次注射 DDMC（10 毫克/千克-1）和吗啡（而不是 DDOX（40 毫克/千克-1））可有效抑制福尔马林诱导的脊髓 c-Fos 表达，而这两种 TC 衍生物都能抑制 Iba-1 免疫反应细胞的活化，这表明它们对发炎的小胶质细胞有潜在的间接影响。总之，DDMC 和 DDOX 这两种非抗生素类三氯乙酸对福尔马林引起的疼痛具有显著的镇痛效果，表明它们有可能成为镇痛治疗的替代品。

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引用次数: 0

PHARMACOLOGICAL INHIBITION REVEALS PARTICIPATION OF THE ENDOCYTIC COMPARTMENT IN POSITIVE FEEDBACK IL-6 SECRETION IN HUMAN SKELETAL MYOTUBES 药理抑制揭示了内细胞区参与人类骨骼肌管中 IL-6 正反馈分泌的过程

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-10-10 DOI: 10.1016/j.ejphar.2024.177055

IL-6 is an important cytokine involved in metabolic, immunological, and cell-fate responses. It is released upon stimulation by skeletal muscle cells through partially characterized mechanisms. In some cell types, IL-6 has been reported to activate a positive feedback loop involving endocytic vesicles, but evidence is mostly based on transcription and signal transduction mechanisms and is very scarce in muscle cells. Our aim was to directly demonstrate the presence of positive feedback in the ATP-induced release of IL-6 into the supernatant of human skeletal muscle cultures. The total release (production) of IL-6 was reduced for higher volumes of supernatant, when the secreted IL-6 molecules are more diluted, and enhanced when the supernatant volume was lower. In addition, secretion was impaired both by tocilizumab, a blocker of human IL-6 receptors, and by the soluble form of the receptor. The secretion in response to ATP was also inhibited by treatment with the endocytosis inhibitor dynasore, and by disruption of the acidic gradient of the endocytic compartment using different methods (chloroquine, NH4Cl or monensin). IL-6 secretion was also impaired by NED-19, a specific inhibitor of the two pore channels receptor mediating Ca2+ release from the endolysosomal compartment. IL-6 and ATP increased IL-6 mRNA levels, an effect blocked by tocilizumab. Altogether, our results demonstrate that ATP-secreted IL-6 activates a positive loop based on IL-6 receptors, endocytosis, two pore channels and IL-6 transcription. Given the importance of muscle IL-6 as a systemic regulator and as an inflammatory mediator, our study can help to understand muscle pathophysiology.

IL-6 是一种重要的细胞因子，参与新陈代谢、免疫和细胞命运反应。它在骨骼肌细胞受到刺激时通过部分特征机制释放出来。据报道，在某些细胞类型中，IL-6 可激活涉及内吞泡的正反馈回路，但证据大多基于转录和信号转导机制，在肌肉细胞中非常缺乏。我们的目的是直接证明在 ATP 诱导的 IL-6 释放到人体骨骼肌培养物的上清液中存在正反馈。上清液体积越大，分泌的 IL-6 分子越稀释，IL-6 的总释放量（产量）就越低；上清液体积越小，IL-6 的总释放量（产量）就越高。此外，人 IL-6 受体阻断剂托西珠单抗和可溶性形式的受体都会影响分泌。使用内吞抑制剂 dynasore 和使用不同方法（氯喹、NH4Cl 或莫能菌素）破坏内吞室的酸性梯度也会抑制对 ATP 反应的分泌。NED-19也会影响IL-6的分泌，NED-19是介导内溶酶体释放Ca2+的两个孔道受体的特异性抑制剂。IL-6和ATP增加了IL-6 mRNA水平，而托珠单抗阻断了这种效应。总之，我们的研究结果表明，ATP 分泌的 IL-6 激活了基于 IL-6 受体、内吞、两个孔道和 IL-6 转录的正向循环。鉴于肌肉 IL-6 作为系统调节因子和炎症介质的重要性，我们的研究有助于了解肌肉的病理生理学。

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引用次数: 0

Anti-arthritic effect of spirocyclopiperazinium bromide DXL-A-24 in CFA-induced arthritic rats and its mechanism 螺环哌嗪溴化物 DXL-A-24 对 CFA 诱导的关节炎大鼠的抗关节炎作用及其机制

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-10-10 DOI: 10.1016/j.ejphar.2024.177051

This study aimed to investigate the effect of spirocyclopiperazinium bromide DXL-A-24 on complete Freund's adjuvant (CFA)-induced arthritis and its underlying mechanism in rats. A rheumatoid arthritis model was established by the intradermal injection of CFA into the paws of rats. Mechanical withdrawal threshold (MWT), thermal withdrawal latency (TWL), ankle swelling and paw edema were used to evaluate the effects of DXL-A-24. Bone erosion and bone mineral density (BMD) were observed using micro-computed tomography. Receptor blocking test, western blotting, and enzyme-linked immunosorbent assay were performed to explore the mechanisms. Administration of DXL-A-24 (1, 0.5, 0.25 mg/kg, i.g.) dose-dependently increased the MWT and TWL, while alleviating ankle and paw swelling in CFA rats. The effects were blocked by peripheral α7 nicotinic or M4 muscarinic receptor antagonists. DXL-A-24 improved bone erosion and BMD, as well as downregulated the overexpression of Cav3.2, pJAK2, pSTAT3, pIκBα, pNF-κB p65, c-Fos and TNF-α proteins that were induced by CFA. In conclusion, this study shows, for the first time, that DXL-A-24 improves bone erosion and BMD and exhibits obvious anti-arthritic effects in CFA rats. The mechanism may be related to activating the peripheral α7 nicotinic and M4 muscarinic receptors, reducing Cav3.2 expression, and suppressing JAK2/STAT3 and IκBα/NF-κB p65 inflammatory signaling pathways, ultimately inhibiting inflammation-related proteins TNF-α and c-Fos.

本研究旨在探讨螺环哌嗪溴化物 DXL-A-24 对完全弗氏佐剂（CFA）诱导的大鼠关节炎的影响及其内在机制。通过向大鼠爪部皮内注射 CFA，建立了类风湿性关节炎模型。用机械退缩阈值（MWT）、热退缩潜伏期（TWL）、踝关节肿胀和爪水肿来评估 DXL-A-24 的作用。使用微型计算机断层扫描观察骨侵蚀和骨矿物质密度（BMD）。为探究其作用机制，还进行了受体阻断试验、Western 印迹和酶联免疫吸附试验。DXL-A-24（1、0.5、0.25 毫克/千克，静脉注射）剂量依赖性地增加了 CFA 大鼠的 MWT 和 TWL，同时缓解了脚踝和脚掌肿胀。外周α7烟碱或 M4毒蕈碱受体拮抗剂可阻断这些效应。DXL-A-24 改善了骨侵蚀和 BMD，并降低了 CFA 诱导的 Cav3.2、pJAK2、pSTAT3、pIκBα、pNF-κB p65、c-Fos 和 TNF-α 蛋白的过度表达。总之，本研究首次表明，DXL-A-24 可改善 CFA 大鼠的骨侵蚀和 BMD，并具有明显的抗关节炎作用。其机制可能与激活外周α7烟碱受体和M4毒蕈碱受体，降低Cav3.2表达，抑制JAK2/STAT3和IκBα/NF-κB p65炎症信号通路，最终抑制炎症相关蛋白TNF-α和c-Fos有关。

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引用次数: 0

P2X3 and P2X2/3 receptors inhibition produces a consistent analgesic efficacy: A systematic review and meta-analysis of preclinical studies 抑制 P2X3 和 P2X2/3 受体可产生一致的镇痛效果：临床前研究的系统回顾和元分析》。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-10-10 DOI: 10.1016/j.ejphar.2024.177052

Background

P2X3 and P2X2/3 receptors are promising therapeutic targets for pain treatment and selective inhibitors are under evaluation in ongoing clinical trials. Here we aim to consolidate and quantitatively evaluate the preclinical evidence on P2X3 and P2X2/3 receptors inhibitors for pain treatment.

Methods

A literature search was conducted in PubMed, Scopus and Web-of-Science on August 5, 2023. Data was extracted and meta-analyzed using a random-effects model to estimate the analgesic efficacy of the intervention; then several subgroup analyses were performed.

Results

67 articles were included. The intervention induced a consistent pain reduction (66.5 [CI95% = 58.5, 74.5]; p < 0.0001), which was highest for visceral pain (114.3), followed by muscle (79.8) and neuropathic pain (71.1), but lower for cancer (64.1), joint (57.5) and inflammatory pain (49.0). Further analysis showed a greater effect for mechanical hypersensitivity (70.4) compared to heat hypersensitivity (64.5) and pain-related behavior (54.1). Sex (male or female) or interspecies (mice or rats) differences were not appreciated (p > 0.05). The most used molecule was A-317491, but other such as gefapixant or eliapixant were also effective (p < 0.0001 for all). The analgesic effect was higher for systemic or peripheral administration than for intrathecal administration. Conversely, intracerebroventricular administration was not analgesic, but potentiated pain.

Conclusion

P2X3 and P2X2/3 receptor inhibitors showed a good analgesic efficacy in preclinical studies, which was dependent on the pain etiology, pain outcome measured, the drug used and its route of administration. Further research is needed to assess the clinical utility of these preclinical findings.

Protocol registration

PROSPERO ID CRD42023450685.

背景：P2X3和P2X2/3受体是很有希望的疼痛治疗靶点，目前正在临床试验中评估选择性抑制剂。在此，我们旨在整合并定量评估有关 P2X3 和 P2X2/3 受体抑制剂治疗疼痛的临床前证据：方法：2023 年 8 月 5 日，我们在 PubMed、Scopus 和 Web-of-Science 上进行了文献检索。采用随机效应模型提取数据并进行荟萃分析，以估算干预措施的镇痛疗效；然后进行了几项亚组分析：结果：共纳入 67 篇文章。干预对疼痛的减轻效果一致（66.5 [CI95% = 58.5, 74.5]; p < 0.0001），其中内脏痛的减轻效果最高（114.3），其次是肌肉痛（79.8）和神经痛（71.1），但癌症痛（64.1）、关节痛（57.5）和炎症痛（49.0）的减轻效果较低。进一步分析表明，与热过敏（64.5）和疼痛相关行为（54.1）相比，机械过敏（70.4）的影响更大。性别（雄性或雌性）或种间（小鼠或大鼠）差异不明显（P > 0.05）。使用最多的分子是 A-317491，但其他分子如吉法酯或艾利匹酯也有效（所有分子的 p < 0.0001）。全身或外周给药的镇痛效果高于鞘内给药。相反，脑室内给药不仅没有镇痛作用，反而会加剧疼痛：结论：P2X3 和 P2X2/3 受体抑制剂在临床前研究中表现出良好的镇痛效果，这取决于疼痛的病因、疼痛的测量结果、所用药物及其给药途径。要评估这些临床前研究结果的临床实用性，还需要进一步的研究：PROCMPERO.ID：CRD42023450685。

{"title":"P2X3 and P2X2/3 receptors inhibition produces a consistent analgesic efficacy: A systematic review and meta-analysis of preclinical studies","authors":"","doi":"10.1016/j.ejphar.2024.177052","DOIUrl":"10.1016/j.ejphar.2024.177052","url":null,"abstract":"<div><h3>Background</h3><div>P2X3 and P2X2/3 receptors are promising therapeutic targets for pain treatment and selective inhibitors are under evaluation in ongoing clinical trials. Here we aim to consolidate and quantitatively evaluate the preclinical evidence on P2X3 and P2X2/3 receptors inhibitors for pain treatment.</div></div><div><h3>Methods</h3><div>A literature search was conducted in PubMed, Scopus and Web-of-Science on August 5, 2023. Data was extracted and meta-analyzed using a random-effects model to estimate the analgesic efficacy of the intervention; then several subgroup analyses were performed.</div></div><div><h3>Results</h3><div>67 articles were included. The intervention induced a consistent pain reduction (66.5 [CI95% = 58.5, 74.5]; <em>p</em> < 0.0001), which was highest for visceral pain (114.3), followed by muscle (79.8) and neuropathic pain (71.1), but lower for cancer (64.1), joint (57.5) and inflammatory pain (49.0). Further analysis showed a greater effect for mechanical hypersensitivity (70.4) compared to heat hypersensitivity (64.5) and pain-related behavior (54.1). Sex (male or female) or interspecies (mice or rats) differences were not appreciated (<em>p</em> > 0.05). The most used molecule was A-317491, but other such as gefapixant or eliapixant were also effective (<em>p</em> < 0.0001 for all). The analgesic effect was higher for systemic or peripheral administration than for intrathecal administration. Conversely, intracerebroventricular administration was not analgesic, but potentiated pain.</div></div><div><h3>Conclusion</h3><div>P2X3 and P2X2/3 receptor inhibitors showed a good analgesic efficacy in preclinical studies, which was dependent on the pain etiology, pain outcome measured, the drug used and its route of administration. Further research is needed to assess the clinical utility of these preclinical findings.</div></div><div><h3>Protocol registration</h3><div>PROSPERO ID CRD42023450685.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Protective effects of licofelone on scopolamine-induced spatial learning and memory impairment by enhancing parkin-dependent mitophagy and promotion of neural regeneration and in adult mice 通过增强帕金依赖性有丝分裂和促进神经再生，利可非酮对东莨菪碱诱导的成年小鼠空间学习和记忆损伤具有保护作用

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-10-10 DOI: 10.1016/j.ejphar.2024.177025

Inhibition of COX and LOX could contribute to memory formation and prevention of neurodegeneration, by alleviation of neuroinflammation and improvement of mitochondrial homeostasis. We aimed to assess the effect of licofelone, a dual COX and 5-LOX inhibitor on memory formation, neural apoptosis, neural regeneration, and mitophagy in acute and chronic dosages, given that licofelone could regulate nitric oxide levels. Y-maze and Passive Avoidance tests were used to evaluate memory function in NMRI mice using the EthoVision setting, following scopolamine administration (1 mg/kg, i.p.) as an acute amnestic drug. Hippocampi were used to evaluate the levels of apoptosis via TUNEL assay, neural regeneration via immunohistochemistry method detecting doublecortin and nestin, and mitophagy via Western blot of mitophagy proteins Parkin and ATG5. While acute high-dose licofelone (20 mg/kg) could reverse amnestic effects of scopolamine in passive avoidance test (p = 0.0001), Chronic licofelone (10 mg/kg for 10 consecutive days) could improve performance in Y-maze (p = 0.0007). Molecular analysis revealed that the chronic form of the drug could enhance neural regeneration in CA1 and SGZ regions, reset mitophagy levels as much as the healthy state, and reduce apoptosis rate. Licofelone appears to show a desirable anti-amnestic profile in a low dose chronically; it is hence recommended for future clinical studies on the prevention of neuroinflammation and memory deficit.

通过减轻神经炎症和改善线粒体平衡，抑制 COX 和 LOX 有助于记忆形成和预防神经退行性变。我们的目的是评估利可非龙（一种 COX 和 5-LOX 双重抑制剂）在急性和慢性剂量下对记忆形成、神经凋亡、神经再生和有丝分裂的影响，因为利可非龙能调节一氧化氮水平。在使用东莨菪碱（1 毫克/千克，静脉注射）作为急性失忆药物后，使用 EthoVision 设置的 Y 迷宫和被动回避测试来评估 NMRI 小鼠的记忆功能。海马通过TUNEL检测法评估细胞凋亡水平，通过免疫组化法检测双皮质素和巢蛋白评估神经再生水平，通过Western印迹检测有丝分裂蛋白Parkin和ATG5评估有丝分裂水平。急性大剂量利可非龙（20毫克/千克）可逆转东莨菪碱在被动回避试验中的失忆效应（p = 0.0001），而慢性利可非龙（10毫克/千克，连续10天）可改善Y迷宫中的表现（p = 0.0007）。分子分析表明，慢性利可非龙能促进CA1和SGZ区域的神经再生，重置有丝分裂水平与健康状态相同，并降低细胞凋亡率。利考非龙似乎在低剂量的慢性治疗中表现出了理想的抗失忆特性，因此推荐用于未来预防神经炎症和记忆缺失的临床研究。

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引用次数: 0

Differential MRGPRX2-dependent activation of human mast cells by polymyxins and octapeptins 多粘菌素和八肽对人类肥大细胞的不同 MRGPRX2 依赖性激活作用

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-10-09 DOI: 10.1016/j.ejphar.2024.177050

The emergence of multi-drug resistant Gram-negative bacteria has led to renewed interest in the antimicrobial activity of polymyxins and novel polymyxin analogues (e.g. nonapeptides and octapeptin). In some individuals, clinically used polymyxins can cause acute hypersensitivity reactions through mast cell activation, with a recent study attributing this effect to activation of the MAS-related G protein-coupled receptor X2 (MRGPRX2). In the present study, HEK293 cells expressing human MRGPRX2 and the human mast cell line LAD2 were used to characterize the activity of the broader family of polymyxins. Octapeptin C4, polymyxin B and colistin produced concentration-dependent calcium mobilization, degranulation, and CCL-2 (MCP-1) release in LAD2 mast cells, with the former being highly potent. CRISPR-Cas9 knockdown of MRGPRX2 in LAD2 cells and a MRGPRX2 inverse agonist caused a significant reduction in calcium mobilization, degranulation, and CCL-2 release, demonstrating dependency on MRGPRX2 expression. In contrast, polymyxin nonapeptides were far less potent calcium mobilisers and failed to induce functional degranulation in LAD2 cells. Our results confirm that activation of mast cells induced by polymyxin-related antibiotics is MRGPRX2-dependent and reveal that octapeptin C4 might be more liable, whilst nonapeptides are less liable, to trigger immediate hypersensitivity reactions clinically. The mechanism underpinning the difference in MRGPRX2 activation between polymyxin-related antibiotics is important to better understand as it may help design new, safer polymyxins and guide the optimal clinical use of existing polymyxin drugs.

多重耐药革兰氏阴性菌的出现使人们对多粘菌素和新型多粘菌素类似物（如壬肽和八肽）的抗菌活性重新产生了兴趣。在某些人体内，临床使用的多粘菌素可通过激活肥大细胞引起急性超敏反应，最近的一项研究将这种效应归因于激活 MAS 相关 G 蛋白偶联受体 X2（MRGPRX2）。在本研究中，我们使用了表达人类 MRGPRX2 的 HEK293 细胞和人类肥大细胞系 LAD2 来鉴定更广泛的多粘菌素家族的活性。八肽 C4、多粘菌素 B 和大肠杆菌素能在 LAD2 肥大细胞中产生浓度依赖性的钙动员、脱颗粒和 CCL-2（MCP-1）释放，其中前者的效力很强。CRISPR-Cas9 敲除 LAD2 细胞中的 MRGPRX2 和新的 MRGPRX2 反激动剂可显著降低钙动员、脱颗粒和 CCL-2 释放，这表明 MRGPRX2 的表达具有依赖性。相比之下，多粘菌素非肽的钙动员作用要弱得多，而且不能诱导 LAD2 细胞的功能性脱颗粒。我们的研究结果证实，多粘菌素相关抗生素诱导的肥大细胞活化是依赖于 MRGPRX2 的，并揭示了八肽 C4 可能更容易在临床上引发即刻超敏反应，而非肽类则不那么容易。更好地了解多粘菌素相关抗生素之间 MRGPRX2 激活差异的机制非常重要，因为这有助于设计更安全的新型多粘菌素，并指导现有多粘菌素药物的最佳临床使用。

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引用次数: 0

Unveiling Novel Molecules and Therapeutic Targets in Hypertension - A Narrative Review. 揭示高血压的新分子和治疗靶点 - 综述。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-10-09 DOI: 10.1016/j.ejphar.2024.177053

Jefry Winner G, Surbhi Jain, Dimpy Gupta

Hypertension is a prevalent non-communicable disease with serious cardiovascular complications, including heart failure, myocardial infarction, and stroke, often resulting from uncontrolled hypertension. While current treatments primarily target the renin-angiotensin-aldosterone pathway, the therapeutic response remains modest in many patients, with some developing resistant hypertension. Newer therapeutic approaches aim to address hypertension from various aspects beyond conventional drugs, including targeting central nervous system pathways, inflammatory pathways, vascular smooth muscle function, and baroreceptors. Despite these advancements, each therapy faces unique clinical and mechanistic challenges that influence its clinical translatability and long-term viability. This review explores the mechanisms of novel molecules in preclinical and clinical development, highlights potential therapeutic targets, and discusses the challenges and ethical considerations related to hypertension therapeutics and their development.

高血压是一种普遍存在的非传染性疾病，其严重的心血管并发症包括心力衰竭、心肌梗死和中风，而这些并发症往往都是由未得到控制的高血压引起的。虽然目前的治疗方法主要针对肾素-血管紧张素-醛固酮通路，但许多患者的治疗反应仍不明显，有些患者还会出现耐药性高血压。新的治疗方法旨在从传统药物之外的多个方面解决高血压问题，包括针对中枢神经系统通路、炎症通路、血管平滑肌功能和巴氏感受器。尽管取得了这些进展，但每种疗法都面临着独特的临床和机理挑战，影响着其临床转化能力和长期可行性。本综述探讨了临床前和临床开发中新型分子的机理，强调了潜在的治疗靶点，并讨论了与高血压疗法及其开发相关的挑战和伦理考虑。

引用次数: 0

Rhoifolin, baicalein 5,6-dimethyl ether and agathisflavone prevent amnesia induced in scopolamine zebrafish (Danio rerio) model by increasing the mRNA expression of bdnf, npy, egr-1, nfr2α, and creb1 genes Rhoifolin、黄芩素 5,6-二甲醚和龙葵黄酮通过增加 bdnf、nyy、egr-1、nfr2α 和 creb1 基因的 mRNA 表达，防止东莨菪碱诱导的斑马鱼（Danio rerio）模型失忆。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-10-06 DOI: 10.1016/j.ejphar.2024.177013

The increasing attention towards age-related diseases has generated significant interest in the concept of cognitive dysfunction associated with Alzheimer's disease (AD). Certain limitations are associated with the current therapies, and flavonoids have been reported to exhibit multiple biological activities and anti-AD effects in several AD models owing to their antioxidative, anti-inflammatory, and anti-amyloidogenic properties. In this study, we performed an initial in silico predictions of the pharmacokinetic properties of three flavonoids (rhoifolin, baicalein 5,6-dimethyl ether and agathisflavone). Subsequently, we evaluated the antiamnesic and antioxidant potential of flavonoids in concentrations of 1, 3, and 5 μg/L in scopolamine (100 μM)-induced amnesic zebrafish (Danio rerio) model. Zebrafish behavior was analyzed by novel tank diving test (NTT), Y-maze, and novel object recognition test (NOR). Acetylcholinesterase (AChE) activity, brain antioxidant status and the expression of bdnf, npy, egr1, nrf2α, creb1 genes, and CREB-1 protein level was measured to elucidate the underlying mechanism of action. Our flavonoids improved memory and decreased anxiety-like behavior of scopolamine-induced amnesia in zebrafish. Also, the studied flavonoids reduced AChE activity and brain oxidative stress and upregulated the gene expression, collectively contributing to neuroprotective properties. The results of our study add new perspectives on the properties of flavonoids to regulate the evolution of neurodegenerative diseases, especially AD, by modulating the expression of genes involved in the regulation of synaptic plasticity, axonal growth, and guidance, sympathetic and vagal transmission, the antioxidant response and cell proliferation and growth.

随着人们对老年相关疾病的关注与日俱增，与阿尔茨海默病（AD）相关的认知功能障碍这一概念也引起了人们的极大兴趣。据报道，黄酮类化合物由于其抗氧化、抗炎和抗淀粉样蛋白生成的特性，在几种阿尔茨海默病模型中表现出多种生物活性和抗阿尔茨海默病的作用。在本研究中，我们对三种类黄酮（荷叶黄素、黄芩素 5,6-二甲醚和龙葵黄酮）的药代动力学特性进行了初步的硅学预测。随后，我们评估了黄酮类化合物在东莨菪碱（100 μM）诱导的失忆斑马鱼（Danio rerio）模型中1、3和5 μg/L浓度的抗失忆和抗氧化潜力。斑马鱼的行为分析包括新颖水槽潜水试验（NTT）、Y迷宫和新颖物体识别试验（NOR）。研究还测定了乙酰胆碱酯酶（AChE）活性、大脑抗氧化状态以及bdnf、nyy、egr1、nrf2α、creb1基因的表达和CREB-1蛋白水平，以阐明其潜在的作用机制。我们的黄酮类化合物改善了斑马鱼的记忆力，并减少了东莨菪碱诱导的失忆的焦虑行为。此外，所研究的黄酮类化合物还降低了乙酰胆碱酯酶活性和脑氧化应激，并上调了基因表达，这些共同促成了黄酮类化合物的神经保护特性。我们的研究结果为黄酮类化合物通过调节参与突触可塑性、轴突生长和引导、交感神经和迷走神经传导、抗氧化反应以及细胞增殖和生长调控的基因表达来调控神经退行性疾病（尤其是老年痴呆症）的演变提供了新的视角。

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引用次数: 0

The NF-κB pathway: Key players in neurocognitive functions and related disorders NF-κB 通路：神经认知功能及相关疾病的关键角色

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-10-05 DOI: 10.1016/j.ejphar.2024.177038

Perioperative neurocognitive disorder (PND) is a common complication of surgical anesthesia, yet its precise etiology remains unclear. Neuroinflammation is a key feature of PND, influenced by both patient -related and surgical variables. The nuclear factor-κB (NF-κB) transcription factor family plays a critical role in regulating the body's immunological proinflammatory response, which is pivotal in the development of PND. Surgery and anesthesia trigger the activation of the NF-κB signaling pathway, leading to the initiation of inflammatory cascades, disruption of the blood-brain barrier, and neuronal injury. Immune cells and glial cells are central to these pathological processes in PND. Furthermore, this study explores the interactions between NF-κB and various signaling molecules, including Tlr4, P2X, α7-nAChR, ROS, HIF-1α, PI3K/Ak, MicroRNA, Circular RNA, and histone deacetylases, within the context of PND. Targeting NF-κB as a therapeutic approach for PND shows promise as a potential treatment strategy.

围手术期神经认知障碍（PND）是手术麻醉的常见并发症，但其确切病因仍不清楚。神经炎症是 PND 的一个主要特征，受患者相关变量和手术变量的影响。核因子-κB（NF-κB）转录因子家族在调节机体的免疫促炎反应中起着关键作用，而免疫促炎反应在 PND 的发生发展中起着举足轻重的作用。手术和麻醉会触发 NF-κB 信号通路的激活，导致炎症级联的启动、血脑屏障的破坏和神经元的损伤。免疫细胞和神经胶质细胞是 PND 这些病理过程的核心。此外，本研究还探讨了在 PND 的背景下，NF-κB 与各种信号分子（包括 Tlr4、P2X、α7-nAChR、ROS、HIF-1α、PI3K/Ak、MicroRNA、环状 RNA 和组蛋白去乙酰化酶）之间的相互作用。以 NF-κB 为靶点作为 PND 的治疗方法有望成为一种潜在的治疗策略。

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