European journal of pharmacology最新文献_第4页

Neuroprotective potential of Epigenetic modulators, its regulation and therapeutic approaches for the management of Parkinson's disease 表观遗传调节剂的神经保护潜力、对帕金森病的调控和治疗方法。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-11-12 DOI: 10.1016/j.ejphar.2024.177123

Shobha Kumari , Sakshi Gupta , Rajesh Sukhija , Shaifali Gurjar , Sunil Kumar Dubey , Rajeev Taliyan

The progressive degeneration of dopaminergic neurons in the substantia nigra region of the brain leads to a deficiency of dopamine and, ultimately, the onset of Parkinson's disease (PD). Since there is currently no cure for PD, patients all around the world are dealing with symptomatic management. PD progression is influenced by multiple elements, such as environmental, biological, chemical, genetic, and epigenetic factors. Epigenetics is gaining increased attention due to its role in controlling the expression of genes that contribute to PD. Recent advancements in our understanding of the brain network and its related conditions have shown that alterations in gene expression may occur independently of genetic abnormalities. Therefore, a thorough investigation has been carried out to explore the significance of epigenetics in all degenerative disorders. Epigenetic modifications are essential for regulating cellular homeostasis. Therefore, a deeper understanding of these modifications might provide valuable insights into many diseases and potentially serve as targets for therapeutic interventions. This review article focuses on diverse epigenetic alterations linked to the progression of PD. These abnormalities are supported by numerous research on the control of gene expression and encompass all the epigenetic processes. The beginning of PD is intricately associated with aberrant DNA methylation mechanisms. DNA methyltransferases are the enzymes that create and preserve various DNA methylation patterns. Integrating epigenetic data with existing clinical methods for diagnosing PD may aid in discovering potential curative medicines and novel drug development approaches. This article solely addresses the importance of epigenetic modulators in PD, primarily the mechanisms of DNMTs, their roles in the development of PD, and their therapeutic approaches; it bypasses other PD therapies.

大脑黑质区域的多巴胺能神经元逐渐退化，导致多巴胺缺乏，最终引发帕金森病（PD）。由于帕金森病目前尚无根治方法，全世界的帕金森病患者都在接受对症治疗。帕金森病的进展受多种因素的影响，如环境、生物、化学、遗传和表观遗传因素。表观遗传学在控制导致帕金森病的基因表达方面的作用日益受到关注。最近，我们对大脑网络及其相关情况的了解取得了进展，这表明基因表达的改变可能与遗传异常无关。因此，我们对表观遗传学在所有退行性疾病中的重要性进行了深入研究。表观遗传修饰对调节细胞的平衡至关重要。因此，深入了解这些修饰可能会为许多疾病提供有价值的见解，并有可能成为治疗干预的靶点。这篇综述文章重点探讨了与帕金森病进展相关的各种表观遗传学改变。这些异常得到了大量关于基因表达控制的研究的支持，并涵盖了所有的表观遗传过程。帕金森病的发病与异常的DNA甲基化机制密切相关。DNA 甲基转移酶是创建和保存各种 DNA 甲基化模式的酶。将表观遗传学数据与诊断帕金森病的现有临床方法相结合，有助于发现潜在的治疗药物和新型药物开发方法。本文仅讨论表观遗传调节剂在帕金森病中的重要性，主要是 DNMTs 的机制、它们在帕金森病发展中的作用及其治疗方法；本文绕过了其他帕金森病疗法。

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引用次数: 0

Intracellular delivery of a phospholamban-targeting aptamer using cardiomyocyte-internalizing aptamers 使用心肌细胞内化适配体在细胞内输送磷脂酰胆碱靶向适配体。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-11-12 DOI: 10.1016/j.ejphar.2024.177130

Takeshi Honda , Hiroki Sakai , Makoto Inui

The sarco (endo)plasmic reticulum Ca²⁺-ATPase 2a (SERCA2a)–phospholamban (PLN) system within the sarcoplasmic reticulum is crucial for regulating intracellular Ca²⁺ cycling in ventricular cardiomyocytes. Given that impaired Ca²⁺ cycling is associated with heart failure, modulating SERCA2a activity represents a promising therapeutic strategy. Previously, we engineered an RNA aptamer (Apt30) that binds to PLN, thereby activating SERCA2a by alleviating PLN's inhibitory effect. However, Apt30 alone cannot reach intracellular PLN, necessitating the development of a mechanism for its specific internalization into cardiomyocytes.

Using the systematic evolution of ligands by exponential enrichment (SELEX) method, we isolated RNA aptamers capable of internalizing into cardiomyocytes. These aptamers demonstrated sub-micromolar EC₅₀ values for cardiomyocyte internalization and exhibited significantly reduced activity against various non-myocardial cells, highlighting their specificity for cardiomyocytes. Moreover, some of these cardiomyocyte-internalizing aptamers could be linked to Apt30 as a single RNA strand without compromising their internalization efficacy. Supplementing the culture medium with these hybrid aptamers enhanced Ca²⁺ transients and contractile function in rat cardiomyocytes. These findings provide critical insights for developing novel therapeutics directly acting on PLN in cardiomyocytes, potentially compensating for the disadvantages of conventional methods that involve viral vector-mediated intracellular transduction or alterations in endogenous protein expression.

肌质网内的肌质网 Ca2+-ATPase 2a（SERCA2a）-磷脂澜班（PLN）系统对于调节心室心肌细胞内的 Ca2+ 循环至关重要。鉴于 Ca2+ 循环受损与心力衰竭有关，调节 SERCA2a 的活性是一种很有前景的治疗策略。此前，我们设计了一种能与 PLN 结合的 RNA 合体（Apt30），从而通过减轻 PLN 的抑制作用来激活 SERCA2a。然而，单靠 Apt30 无法到达细胞内的 PLN，因此有必要开发一种机制，使其特异性地内化到心肌细胞中。利用指数富集配体的系统进化（SELEX）方法，我们分离出了能够内化到心肌细胞中的 RNA 合体。这些适配体对心肌细胞内化的 EC50 值达到亚微摩级，对各种非心肌细胞的活性明显降低，突出了它们对心肌细胞的特异性。此外，其中一些心肌细胞内化适配体可以作为单条 RNA 链与 Apt30 连接，而不会影响其内化功效。在培养基中添加这些混合适配体能增强大鼠心肌细胞的钙离子瞬态和收缩功能。这些发现为开发直接作用于心肌细胞中 PLN 的新型疗法提供了重要启示，有可能弥补病毒载体介导的细胞内转导或改变内源性蛋白表达的传统方法的缺点。

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引用次数: 0

Biochanin A inhibits excitotoxicity-triggered ferroptosis in hippocampal neurons 生物变色素 A 可抑制兴奋毒性触发的海马神经元铁突变。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-11-10 DOI: 10.1016/j.ejphar.2024.177104

Jun Pil Won, Han Jun Yoon, Hyuk Gyoon Lee, Han Geuk Seo

Excitatory neurotransmitter-induced neuronal ferroptosis has been implicated in multiple neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Although there are several reports pertaining to the pharmacological activities of biochanin A, the effects of this isoflavone on excitotoxicity-triggered neuronal ferroptosis remain unclear. In this study, we demonstrate that biochanin A inhibits ferroptosis of mouse hippocampal neurons induced by glutamate or the glutamate analog, kainic acid. Biochanin A significantly inhibited accumulation of intracellular iron and lipid peroxidation in glutamate- or kainic acid-treated mouse hippocampal neurons. Furthermore, biochanin A regulated the level of glutathione peroxidase 4, a master regulator of ferroptosis, by modulating its autophagy-dependent degradation. We observed that biochanin A reduced the glutamate-induced accumulation of intracellular iron by regulating expression of iron metabolism-related proteins including ferroportin-1, divalent metal transferase 1, and transferrin receptor 1. Taken together, these results indicate that biochanin A effectively inhibits hippocampal neuronal death triggered by glutamate or kainic acid. Our study is the first to report that biochanin A has therapeutic potential for the treatment of diseases associated with hippocampal neuronal death, particularly ferroptosis induced by excitatory neurotransmitter.

兴奋性神经递质诱导的神经元铁氧化与多种神经退行性疾病（如阿尔茨海默病和帕金森病）有关。虽然有一些关于生物黄酮 A 药理活性的报道，但这种异黄酮对兴奋性毒性诱导的神经元铁氧化的影响仍不清楚。在这项研究中，我们证明生物黄酮 A 能抑制谷氨酸或谷氨酸类似物凯尼酸诱导的小鼠海马神经元的铁突变。生物变色素 A 能明显抑制谷氨酸或凯尼酸处理的小鼠海马神经元细胞内铁的积累和脂质过氧化。此外，生物变色素 A 还能通过调节谷胱甘肽过氧化物酶 4 的自噬依赖性降解来调节其水平，而谷胱甘肽过氧化物酶 4 是铁变态反应的主要调节因子。我们观察到，生物变色素 A 通过调节铁代谢相关蛋白（包括铁转运蛋白-1、二价金属转移酶 1 和转铁蛋白受体 1）的表达，减少了谷氨酸诱导的细胞内铁积累。综上所述，这些结果表明，生物变色素 A 能有效抑制谷氨酸或凯尼酸引发的海马神经元死亡。我们的研究首次报道了生物变色素 A 具有治疗与海马神经元死亡相关疾病的潜力，特别是兴奋性神经递质诱导的铁中毒。

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引用次数: 0

4-Octyl itaconate inhibits vascular calcification partially via modulation of HMOX-1 signaling 衣康酸 4-辛酯部分通过调节 HMOX-1 信号抑制血管钙化。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-11-10 DOI: 10.1016/j.ejphar.2024.177122

Qianqian Dong , Fang Liu , Jiahui Zhu , Mingxi Li , An Chen , Liyun Feng , Zirong Lan , Yuanzhi Ye , Lihe Lu , Qingchun Liang , Jianyun Yan

Vascular calcification frequently occurs in patients with chronic conditions such as chronic kidney disease (CKD), diabetes, and hypertension and represents a significant cause of cardiovascular events. Thus, identifying effective therapeutic targets to inhibit the progression of vascular calcification is essential. 4-Octyl itaconate (4-OI), a derivative of itaconate, exhibits anti-inflammatory and antioxidant activity, both of which play an essential role in the progression of vascular calcification. However, the role and molecular mechanisms of 4-OI in vascular calcification have not yet been elucidated. In this study, we investigated the effects of exogenous 4-OI on vascular calcification using vascular smooth muscle cells (VSMCs), arterial rings, and mice. Alizarin red staining and western blot revealed that 4-OI inhibited calcification and osteogenic differentiation of human VSMCs. Similarly, 4-OI inhibited calcification of rat and human arterial rings and VitD₃-overloaded mouse aortas. Mechanistically, RNA sequencing analysis revealed that 4-OI treatment is most likely to affect heme oxygenase 1 (HMOX-1) mRNA expression. The study demonstrated that 4-OI treatment increased HMOX-1 mRNA and protein levels, but suppressed inflammation and oxidative stress in VSMCs under osteogenic conditions. Moreover, HMOX-1 knockdown by siRNA or treatment with the HMOX-1 inhibitor ZnPP9 significantly reversed the suppression effect on calcification of VSMCs and aortas of VitD₃-overloaded mice by 4-OI. Furthermore, HMOX-1 knockdown by siRNA markedly abrogated the inhibitory effect of 4-OI on inflammation in VSMCs. These findings suggest that 4-OI alleviates vascular calcification and inhibits oxidative stress and inflammation through modulation of HMOX-1, indicating its potential as a therapeutic target for vascular calcification.

血管钙化经常发生在慢性肾病（CKD）、糖尿病和高血压等慢性病患者身上，是导致心血管事件的重要原因之一。因此，找到有效的治疗靶点来抑制血管钙化的进展至关重要。伊塔康酸 4-辛酯（4-OI）是伊塔康酸的一种衍生物，具有抗炎和抗氧化活性，这两种活性在血管钙化的进展过程中起着至关重要的作用。然而，4-OI 在血管钙化中的作用和分子机制尚未阐明。在这项研究中，我们利用血管平滑肌细胞（VSMC）、动脉环和小鼠研究了外源性 4-OI 对血管钙化的影响。茜素红染色和 Western 印迹显示，4-OI 可抑制人血管平滑肌细胞的钙化和成骨分化。同样，4-OI 也抑制了大鼠动脉环和 VitD3 负载的小鼠主动脉的钙化。从机理上讲，RNA 测序分析表明，4-OI 处理最有可能影响血红素加氧酶 1 (HMOX-1) mRNA 的表达。研究表明，4-OI 处理可提高 HMOX-1 mRNA 和蛋白水平，但会抑制成骨条件下 VSMC 的炎症和氧化应激。此外，4-OI通过 siRNA 敲除 HMOX-1，或使用 HMOX-1 抑制剂 ZnPP9 可显著逆转 4-OI 对 VitD3 负载小鼠 VSMC 和主动脉钙化的抑制作用。此外，通过 siRNA 敲除 HMOX-1 能明显减弱 4-OI 对血管内皮细胞炎症的抑制作用。这些研究结果表明，4-OI能缓解血管钙化，并通过调节HMOX-1抑制氧化应激和炎症，表明其有可能成为血管钙化的治疗靶点。

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引用次数: 0

Protective effects and mechanism of quercetin from Rhododendron dauricum against cerebral ischemia-reperfusion injury 杜鹃花槲皮素对脑缺血再灌注损伤的保护作用及其机制

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-11-10 DOI: 10.1016/j.ejphar.2024.177126

Fang Fang , Siwei Bao , Danxia Chen , Xiaofeng Duan , Yuefen Zhao , Yabin Ma

Methods

This study seeks to identify the bioactive compounds within Rhododendron dauricum and explore potential mechanisms for treating cerebral I/R injury through a comprehensive analysis employing network pharmacology, complemented by experimental validation.

Results

The core targets associated with quercetin in the treatment of cerebral I/R injury are TNF-α, IL-6, IL-1β, and AKT1. Notably, we propose for the first time that its mode of action primarily involves the inhibition of the TNF-α/RhoA/ROCK2 pathway.

Conclusion

Our findings reveal that quercetin emerges as a pivotal bioactive component of Rhododendron dauricum in the context of cerebral I/R injury treatment.

方法：本研究旨在通过网络药理学的综合分析，并辅以实验验证，确定杜鹃花中的生物活性化合物，并探索治疗脑I/R损伤的潜在机制：结果：槲皮素治疗脑I/R损伤的核心靶点是TNF-α、IL-6、IL-1β和AKT1。值得注意的是，我们首次提出槲皮素的作用模式主要涉及抑制 TNF-α/RhoA/ROCK2 通路：我们的研究结果表明，槲皮素是杜鹃花中治疗脑 I/R 损伤的关键生物活性成分。

引用次数: 0

A combination of peripherally restricted CB1 and CB2 cannabinoid receptor agonists reduces bladder afferent sensitisation in cystitis 外周限制性 CB1 和 CB2 大麻受体激动剂组合可降低膀胱炎的膀胱传入敏感性。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-11-10 DOI: 10.1016/j.ejphar.2024.177078

Stewart Ramsay, Wai Ping Yew, Simon Brookes, Vladimir Zagorodnyuk

Cannabinoid agonists can potentially ameliorate lower urinary tract symptoms (LUTS), including pain associated with interstitial cystitis/bladder pain syndrome (IC/BPS). This study aims to determine the contributions of the cannabinoid 1 receptors (CB₁Rs) and CB₂Rs in regulating the activity of different functional classes of afferents, comparing normal healthy bladder with bladders from guinea pigs with protamine/zymosan-induced cystitis. The mechanosensitivity of different functional afferent classes was determined by ex vivo single-unit extracellular recordings.

Peripherally restricted CB₁R preferential agonists, ACEA and PrNMI and peripherally restricted CB₂R selective agonists, 4Q3C and olorinab all reduced the mechanosensitivity of mucosal bladder afferents. The potency and efficacy of these synthetic cannabinoid agonists were significantly increased in cystitis compared to controls. Combined application of CB₁R agonists, ACEA or PrNMI with the CB₂R agonist, 4Q3C produced additive inhibitory effects. ACEA and PrNMI also inhibited the stretch-induced firing of high-threshold muscular bladder afferents in animals with cystitis. In contrast, low- and high-threshold muscular-mucosal bladder afferents were unaffected by the CB₁R and CB₂R agonists in control and cystitis. Our data indicated that peripherally restricted CB₁R and CB₂R agonists effectively reduce the sensitisation of probable nociceptive afferents in the bladder in cystitis. The findings also suggest a potential benefit of simultaneously targeting both the CB₁Rs and CB₂Rs to ameliorate LUTS in cystitis.

大麻素激动剂有可能改善下尿路症状（LUTS），包括与间质性膀胱炎/膀胱疼痛综合征（IC/BPS）相关的疼痛。本研究旨在通过比较正常健康膀胱与原胺/zymosan诱发膀胱炎的豚鼠膀胱，确定大麻素1受体（CB1Rs）和CB2Rs在调节不同功能类别传入神经活动中的贡献。通过体外单体胞外记录确定了不同功能传入类的机械敏感性。外周限制性 CB1R 首选激动剂 ACEA 和 PrNMI 以及外周限制性 CB2R 选择性激动剂 4Q3C 和 olorinab 都降低了膀胱粘膜传入的机械敏感性。与对照组相比，这些合成大麻素激动剂在膀胱炎患者中的效力和疗效显著提高。将 CB1R 激动剂 ACEA 或 PrNMI 与 CB2R 激动剂 4Q3C 联合应用可产生相加的抑制作用。ACEA 和 PrNMI 还能抑制膀胱炎动物高阈值膀胱肌肉传入的拉伸诱发点燃。相比之下，在对照组和膀胱炎动物中，低阈值和高阈值的膀胱粘膜肌肉传入神经不受 CB1R 和 CB2R 激动剂的影响。我们的数据表明，外周限制性 CB1R 和 CB2R 激动剂能有效降低膀胱炎患者膀胱中可能的痛觉传入的敏感性。研究结果还表明，同时靶向 CB1R 和 CB2R 有助于改善膀胱炎患者的尿失禁症状。

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引用次数: 0

Metformin inhibits migration and epithelial-to-mesenchymal transition in non-small cell lung cancer cells through AMPK-mediated GDF15 induction 二甲双胍通过AMPK介导的GDF15诱导作用抑制非小细胞肺癌细胞的迁移和上皮细胞向间质转化。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-11-09 DOI: 10.1016/j.ejphar.2024.177127

Hongyu Zhou , Jun Xiao , Qi Cheng, Wen Wang, He Peng, Xiaojian Lin, Jiajun Chen, Xingya Wang

The growth differentiation factor 15 (GDF15) may serve as a biomarker of metformin, which mediates the bodyweight lowering effect of metformin. However, whether GDF15 also serves as a molecular target of metformin to inhibit carcinogenesis remains largely unknown. This study examined the role and molecular mechanisms of GDF15 in the anticancer effects of metformin in non-small cell lung cancer (NSCLC) cells, which has never been reported before. We found that metformin significantly inhibited the migration of NSCLC A549 and NCI-H460 cells and reduced the expression of epithelial-to-mesenchymal transition (EMT)-related molecules, including neuro-cadherin (N-cadherin), matrix metalloproteinase 2 (MMP2), and the zinc finger transcription factor Snail, but increased epithelial cadherin (E-cadherin) expression. Furthermore, metformin increased GDF15 and its upstream transcription factors activated transcription factor 4 (ATF4) and C/EBP-homologous protein (CHOP) expressions and increased AMP-activated protein kinase (AMPK) phosphorylation in NSCLC cells. GDF15 siRNA partially reverses the inhibitory effect of metformin on NSCLC cell migration. Moreover, metformin-induced increases in GDF15, CHOP, and ATF4 expression and the inhibition of migration were partially reversed by treatment with Compound C, a specific AMPK inhibitor. Meanwhile, metformin significantly inhibited NCI-H460 xenograft tumor growth in nude mice, increased GDF15 expression, and regulated EMT- and migration-related protein expression in xenograft tumors. In conclusion, our results provide novel insights into revealing that GDF15 can serve as a potential molecular target of metformin owing to its anti-cancer effect in NSCLC, which is mediated by AMPK activation.

生长分化因子15（GDF15）可作为二甲双胍的生物标志物，它介导二甲双胍的减重作用。然而，GDF15是否也是二甲双胍抑制癌变的分子靶点，目前仍是一个未知数。本研究探讨了GDF15在二甲双胍对非小细胞肺癌（NSCLC）细胞的抗癌作用中的作用和分子机制。我们发现，二甲双胍能显著抑制NSCLC A549和NCI-H460细胞的迁移，并减少上皮细胞向间质转化（EMT）相关分子的表达，包括神经粘附素（N-cadherin）、基质金属蛋白酶2（MMP2）和锌指转录因子Snail，但增加了上皮粘附素（E-cadherin）的表达。此外，二甲双胍增加了GDF15及其上游转录因子活化转录因子4（ATF4）和C/EBP同源蛋白（CHOP）的表达，并增加了NSCLC细胞中AMP激活蛋白激酶（AMPK）的磷酸化。GDF15 siRNA能部分逆转二甲双胍对NSCLC细胞迁移的抑制作用。此外，二甲双胍诱导的GDF15、CHOP和ATF4表达的增加以及迁移的抑制在使用特异性AMPK抑制剂化合物C处理后被部分逆转。同时，二甲双胍能显著抑制裸鼠体内 NCI-H460 异种移植瘤的生长，增加 GDF15 的表达，并调节异种移植瘤中 EMT 和迁移相关蛋白的表达。总之，我们的研究结果提供了新的见解，揭示了二甲双胍对NSCLC的抗癌作用是由AMPK激活介导的，因此GDF15可以作为二甲双胍的潜在分子靶点。

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引用次数: 0

Leukemia inhibitory factor receptor inhibition by EC359 reduces atherosclerotic stenosis grade in Ldlr−/− mice EC359 对白血病抑制因子受体的抑制可降低 Ldlr-/- 小鼠动脉粥样硬化性狭窄的等级。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-11-09 DOI: 10.1016/j.ejphar.2024.177121

Esmeralda Hemme , Marie A.C. Depuydt , Peter J. van Santbrink , Anouk Wezel , Harm J. Smeets , Amanda C. Foks , Johan Kuiper , Ilze Bot

Cytokines are involved in all stages of atherosclerosis, generally contributing to disease progression. Previously, members of the Interleukin (IL)-6 cytokine family, such as IL-6, oncostatin M, and cardiotrophin-1, have been extensively studied in atherosclerosis. However, the role of leukemia inhibitory factor (LIF), member of the IL-6 family, and its receptor (LIFR), remains to be further elucidated. Therefore, the aim of this study is to provide insight in LIF receptor signalling in atherosclerosis development.

Single-cell RNA sequencing analysis of human carotid artery plaques revealed that mast cells highly express LIF, whereas LIFR was specifically expressed on activated endothelial cells. A similar expression pattern of Lifr was observed in mouse atherosclerotic plaques. Next, female Western-type diet fed Ldlr^−/− mice were treated with LIF receptor inhibitor EC359 (5 mg/kg s.c., n = 15) or control solvent (n = 15) three times per week for eight weeks. Stenosis grade was reduced in the aortic root of EC359 treated mice compared to control mice, but treatment did not affect plaque composition. Serum cholesterol levels were significantly reduced in EC359 treated mice, likely attributed to a reduction in VLDL cholesterol levels. Furthermore, LIF receptor inhibition reduced Pecam1 and Vcam1 expression in the aorta. Consequently, immune cell infiltration was reduced in aortic plaques of EC359 treated mice compared to control mice.

Conclusively, we demonstrated that LIF receptor is a potential therapeutic target in atherosclerosis by reducing plaque size, attributed to lower serum cholesterol levels, reduced endothelial activation and less immune cell infiltration in the plaque.

细胞因子参与了动脉粥样硬化的各个阶段，通常会导致疾病进展。此前，白细胞介素-6、oncostatin M 和心脏营养素-1 等 IL-6 细胞因子家族成员在动脉粥样硬化中的作用已被广泛研究。然而，IL-6 家族中的白血病抑制因子（LIF）及其受体（LIFR）在动脉粥样硬化中的作用仍有待进一步阐明。因此，本研究旨在深入了解 LIF 受体信号在动脉粥样硬化发展过程中的作用。对人类颈动脉斑块进行的单细胞 RNA 测序分析表明，肥大细胞高度表达 LIF，而 LIFR 则在活化的内皮细胞上特异性表达。在小鼠动脉粥样硬化斑块中也观察到了类似的 Lifr 表达模式。接下来，用 LIF 受体抑制剂 EC359（5 mg/kg s.c.，n=15）或对照溶剂（n=15）治疗雌性西式饮食喂养的 Ldlr-/- 小鼠，每周三次，连续八周。与对照组小鼠相比，接受EC359治疗的小鼠主动脉根部狭窄等级降低，但治疗并不影响斑块的组成。经 EC359 治疗的小鼠血清胆固醇水平明显降低，这可能是由于 VLDL 胆固醇水平降低所致。此外，LIF 受体抑制降低了主动脉中 Pecam1 和 Vcam1 的表达。因此，与对照组小鼠相比，EC359 治疗小鼠主动脉斑块中的免疫细胞浸润减少了。最后，我们证明了 LIF 受体是动脉粥样硬化的潜在治疗靶点，它能缩小斑块，降低血清胆固醇水平，减少内皮活化和免疫细胞在斑块中的浸润。

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引用次数: 0

Inhibition of lysophosphatidic acid receptor 2 attenuates neonatal chronic lung disease in mice by preserving vascular and alveolar development 抑制溶血磷脂酸受体2可保护血管和肺泡发育，从而减轻小鼠新生儿慢性肺病。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-11-09 DOI: 10.1016/j.ejphar.2024.177120

Xueyu Chen , Dongshan Han , Yali Zeng , Huitao Li , Xuan Wang , Zilu Huang , Lingling Yang , Gerry T.M. Wagenaar , Bingchun Lin , Chuanzhong Yang

Aim

Bronchopulmonary dysplasia (BPD) is a common morbidity in extremely premature infants. Previous studies demonstrated the important role of lysophosphatidic acid (LPA) in inflammation in BPD. However, the role of LPA and its receptors in hyperoxia-induced vascular malformations in BPD remains to be elucidated.

Methods and results

Elevated plasma LPA levels were observed in mice with BPD compared to controls (792 vs. 607 ng/mL, p < 0.05). Inhibition of LPA signaling protected against hyperoxia-induced lung injury in neonatal mice, demonstrated by a 2.8-fold increase in pulmonary vascular density and a 14% reduction in alveolar enlargement. In vitro studies showed that LPA suppressed tube formation in human umbilical vein endothelial cells (HUVECs) by approximately 50%. LPA receptor 2 (LPA₂) was identified as a functional LPA receptor in primary endothelial cells from the lungs of hyperoxic mice and in HUVECs under hyperoxic conditions. The LPA₂ antagonist H2L5186303 enhanced the tube formation ability of HUVECs exposed to LPA, both under normoxia (4-fold) and hyperoxia (5-fold). Moreover, H2L5186303 significantly protected against hyperoxia-induced vascular malformation (2-fold) and improved alveolarization in neonatal mice (12% decrease in mean linear intercept, MLI). Early growth response 1 (EGR1) was characterized as a downstream target of LPA₂, silencing EGR1 restored tube formation in HUVECs exposed to LPA and hyperoxia.

Conclusions

Our in vitro and in vivo findings demonstrate that the inhibition of LPA/LPA₂ signaling mitigates hyperoxia-induced pulmonary vascular malformations, suggesting the LPA/LPA₂-dependent signaling pathway has therapeutic potential for extremely premature infants with BPD.

目的：支气管肺发育不良（BPD）是极早产儿的常见病。以往的研究表明，溶血磷脂酸（LPA）在 BPD 的炎症中起着重要作用。然而，LPA及其受体在高氧诱导的BPD血管畸形中的作用仍有待阐明：与对照组相比，BPD 小鼠血浆中的 LPA 水平升高（792 vs. 607 ng/mL，p < 0.05）。抑制 LPA 信号传导可保护新生小鼠免受高氧诱导的肺损伤，肺血管密度增加了 2.8 倍，肺泡增大减少了 14%。体外研究表明，LPA 可抑制人脐静脉内皮细胞（HUVECs）中管的形成约 50%。在高氧小鼠肺部的原代内皮细胞和高氧条件下的 HUVECs 中，LPA 受体 2（LPA2）被确定为一种功能性 LPA 受体。LPA2 拮抗剂 H2L5186303 能增强暴露于 LPA 的 HUVECs 在常氧（4 倍）和高氧（5 倍）条件下的管形成能力。此外，H2L5186303 还能显著防止高氧引起的血管畸形（2 倍），并改善新生小鼠的肺泡化（平均线截距减少 12%）。早期生长反应 1（EGR1）是 LPA2 的下游靶标，沉默 EGR1 可恢复暴露于 LPA 和高氧条件下的 HUVECs 的血管形成：我们的体外和体内研究结果表明，抑制 LPA/LPA2 信号传导可减轻高氧诱导的肺血管畸形，这表明 LPA/LPA2 依赖性信号传导途径对患有 BPD 的极早产儿具有治疗潜力。

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引用次数: 0

Effect of GB1107, a novel galectin-3 inhibitor on pro-fibrotic signalling in the liver 新型 galectin-3 抑制剂 GB1107 对肝脏促纤维化信号的影响

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology

Pub Date : 2024-11-09 DOI: 10.1016/j.ejphar.2024.177077

Alison C. MacKinnon , Duncan C. Humphries , Kimberley Herman , James A. Roper , Ian Holyer , Joseph Mabbitt , Ross Mills , Ulf J. Nilsson , Hakon Leffler , Anders Pedersen , Hans Schambye , Fredrik Zetterberg , Robert J. Slack

Background and purpose

Galectin-3 (Gal-3) is a pro-fibrotic β-galactoside binding lectin highly expressed in fibrotic liver and implicated in hepatic fibrosis. GB1107 is a novel orally active Gal-3 small molecule inhibitor that has high affinity for Gal-3 >1000-fold selectively over other galectins. The aim of this study was to characterise GB1107 and galectin-3 in vitro and in vivo in the context of fibrosis signalling and liver disease.

Experimental approach

Liver fibrosis was induced by administration of CCl₄ twice weekly by intraperitoneal injection in mice for 8 weeks. GB1107 was orally administered once daily (10 mg/kg) for the last 4 weeks of CCl₄ treatment. Fibrosis was assessed by picrosirius red staining of FFPE sections. Liver enzymes, Gal-3 and downstream biomarkers were assessed in liver and plasma. Paired-end sequencing was performed on the Nextseq 2000 platform. Pathway enrichment analysis was performed to determine enrichment of differentially expressed genes (DEGs) within Reactome pathways and Gene Ontology (GO) terms.

Key results

GB1107 significantly reduced plasma transaminases and liver Gal-3 and reduced liver fibrosis. RNAseq analysis of whole liver showed that 1659 DEGs were identified with CCl₄ treatment compared to control. Pathways enriched in up-regulated genes in the CCl₄ group included those related to the extracellular matrix, collagen biosynthesis and assembly, cell cycle and the immune system. Comparing GB1107 treatment with CCl₄ control 1147 DEGs were identified. GB1107 effectively reversed the majority of the CCl₄ induced gene changes.

Conclusions and implications

GB1107 attenuated liver fibrosis and highlights Gal-3 as a therapeutic target for hepatic fibrosis.

背景和目的：Galectin-3（Gal-3）是一种促纤维化的β-半乳糖苷结合凝集素，在纤维化肝脏中高度表达，与肝纤维化有关。GB1107 是一种新型口服活性 Gal-3 小分子抑制剂，与其他半凝集素相比，它对 Gal-3 的亲和力高出 1000 倍。本研究的目的是结合肝纤维化信号传导和肝脏疾病，对 GB1107 和 Galectin-3 在体外和体内的特性进行研究：实验方法：小鼠腹腔注射 CCl4，每周两次，连续 8 周，诱发肝纤维化。在CCl4治疗的最后4周，每天口服一次GB1107（10 mg/kg）。FFPE切片的纤维化通过吡啶红染色进行评估。评估肝脏和血浆中的肝酶、Gal-3和下游生物标记物。在 NextSeq 2000 平台上进行了成对测序。进行了通路富集分析，以确定 Reactome 通路和基因本体（Gene Ontology，GO）术语中差异表达基因（DEGs）的富集情况：GB1107能明显降低血浆转氨酶和肝脏Gal-3，减轻肝纤维化。全肝 RNAseq 分析显示，与对照组相比，在 CCl4 处理中发现了 1,659 个 DEGs。在CCl4组中，上调基因丰富的通路包括与细胞外基质、胶原生物合成和组装、细胞周期和免疫系统有关的通路。将 GB1107 治疗与 CCl4 对照组进行比较，发现了 1147 个 DEGs。GB1107有效逆转了CCl4诱导的大部分基因变化：GB1107减轻了肝纤维化，突出了Gal-3作为肝纤维化治疗靶点的作用。

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