Pharmacological research最新文献

英文中文

New insights in the mechanisms of opioid analgesia and tolerance: Ultramicronized palmitoylethanolamide down-modulates vascular endothelial growth factor-A in the nervous system 阿片类镇痛和耐受机制的新发现：超微粒化棕榈酰乙醇酰胺可降低神经系统中的血管内皮生长因子-A。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-11-01 DOI: 10.1016/j.phrs.2024.107472

Laura Micheli, Stefania Nobili, Elena Lucarini, Alessandra Toti, Francesco Margiotta, Clara Ciampi, Daniel Venturi, Lorenzo Di Cesare Mannelli, Carla Ghelardini

Growing evidence suggests that opioid analgesics modulate angiogenesis during pathophysiological processes. Vascular endothelial growth factor-A (VEGF-A) was recently proposed to be involved in pain development. To date, no anti-angiogenic drug is used for pain management. When administered in a bioavailable formulation, (i.e., ultramicronized) N-palmitoylethanolamine (PEA) delays the onset of morphine tolerance, improves morphine analgesic activity and reduces angiogenesis in in vivo models. This study aimed at investigating whether VEGF-A is involved in PEA-induced delay of morphine tolerance. The anti-VEGF-A monoclonal antibody bevacizumab was used as a reference drug. Preemptive and concomitant treatment with ultramicronized PEA delayed morphine tolerance and potentiated the analgesic effect of morphine, while counteracting morphine-induced increase of VEGF-A in the nervous system. Similar results were obtained when bevacizumab was administered together with morphine. Of note, bevacizumab showed an analgesic effect per se. In equianalgesic treatment regimens (obtained through increasing morphine doses and associating PEA), PEA resulted in lower expression of VEGF-A in dorsal root ganglia (DRG) and spinal cord compared to morphine alone. Similar results were observed for plasma levels of the soluble VEGF receptor 1 (sFLT-1). Moreover, in morphine-treated animals, two pain-related genes (i.e., Serpina3n and Eaat2) showed a more than 3-fold increase in their expression at spinal cord and DRG level, with the increase being significantly counteracted by PEA treatment. This study supports the hypothesis that the effects of PEA on morphine analgesia and tolerance may be mediated by the down-modulation of VEGF-A and sFLT-1 in the nervous system and plasma, respectively.

越来越多的证据表明，阿片类镇痛药可在病理生理过程中调节血管生成。血管内皮生长因子-A（VEGF-A）最近被认为参与了疼痛的发展。迄今为止，还没有抗血管生成药物用于疼痛治疗。以生物可利用制剂（即超微粒化）给药时，N-棕榈酰乙醇胺（PEA）可延缓吗啡耐受性的发生，改善吗啡镇痛活性，并减少体内模型的血管生成。本研究旨在探讨血管内皮生长因子-A是否参与了 PEA 诱导的吗啡耐受性延迟。研究以抗血管内皮生长因子-A单克隆抗体贝伐珠单抗作为参考药物。超微粒子化PEA的先期治疗和同时治疗延迟了吗啡耐受性并增强了吗啡的镇痛效果，同时抵消了吗啡诱导的神经系统中血管内皮生长因子-A的增加。当贝伐单抗与吗啡同时使用时，也获得了类似的结果。值得注意的是，贝伐单抗本身具有镇痛作用。在等效镇痛治疗方案中（通过增加吗啡剂量并同时使用 PEA），PEA 在背根神经节（DRG）和脊髓中的 VEGF-A 表达量低于单独使用吗啡时的表达量。可溶性血管内皮生长因子受体 1（sFLT-1）的血浆水平也出现了类似的结果。此外，在接受吗啡治疗的动物中，两个与疼痛相关的基因（即 Serpina3n 和 Eaat2）在脊髓和 DRG 水平的表达量增加了 3 倍多，而 PEA 治疗则显著抵消了这一增加。这项研究支持了一个假设，即 PEA 对吗啡镇痛和耐受性的影响可能是通过下调神经系统和血浆中的 VEGF-A 和 sFLT-1 而介导的。

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引用次数: 0

Simultaneously blocking ANGPTL3 and CD47 prevents the progression of atherosclerosis through regulating lipid metabolism, macrophagic efferocytosis and lipid peroxidation 同时阻断 ANGPTL3 和 CD47 可通过调节脂质代谢、巨噬细胞排泄和脂质过氧化防止动脉粥样硬化的发展。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-10-31 DOI: 10.1016/j.phrs.2024.107486

Xiaozhi Hu , Yanyang Nan , Yuting Zhang , Jiajun Fan , Hanqi Wang , Yu Bai , Yuanzhen Zhang , Xuyao Zhang , Zeguo Zhu , Zhonglian Cao , Xiaomiao Ye , Tao Wu , Shuwen Xu , Zhengyu Wu , Wei Hu , Dianwen Ju

Atherosclerosis (AS) ultimately cause major adverse cardiovascular events (MACEs). While traditional strategies by lipid-reducing have reduced MACEs, many patients continue to face significant risks. It might attribute to the upregulation of CD47 expression in AS lesions, that mediated anti-efferocytosis of macrophages. Therefore, we propose simultaneously blocking ANGPTL3, a vital regulator of lipid metabolism, and CD47 might be a potential approach for AS therapy. Firstly, we investigate the role of a novel anti-ANGPTL3 nanobody-Fc (FD03) in AS. We found that FD03 treatment significantly decreased circulating lipids, plaque size, and lipid deposition in apoE^-/- mice compared to control Ab, but there was a twofold increase in plaque formation in comparison to baseline. However, immunofluorescence indicated the upregulation of CD47 expression in the plaques even after FD03 treatment compared to normal vascular tissue. Next, a bifunctional protein containing signal regulatory protein alpha (SIRPα) and FD03 (SIRPαD1-FD03) was constructed to block CD47 and ANGPTL3 concurrently, which had high purity, robust stability, and high affinity to CD47 and ANGPTL3 with biological activity in vitro. Furthermore, SIRPαD1-FD03 fusion protein exhibited the enhanced therapeutic effect on AS compared with SIRPαD1-Fc or FD03, regressing plaque contents and the necrotic core equal to baseline. Mechanistically, SIRPαD1-FD03 reduced serum lipids, augmented the efferocytosis rate and macrophage M2 polarization, and decreased the reactive oxygen species (ROS) and lipid peroxidation level in atherosclerotic plaques. Collectively, our project suggests an effective approach for AS by simultaneously blocking ANGPTL3 and CD47 to regulate lipid metabolism, macrophage activity and lipid peroxidation.

动脉粥样硬化（AS）最终会导致重大不良心血管事件（MACE）。虽然传统的降脂策略减少了心血管不良事件的发生，但许多患者仍面临巨大风险。这可能是由于AS病变中CD47表达上调，介导了巨噬细胞的抗吞噬作用。因此，我们提出同时阻断脂质代谢的重要调节因子ANGPTL3和CD47可能是治疗强直性脊柱炎的一种潜在方法。首先，我们研究了一种新型抗ANGPTL3纳米抗体-Fc（FD03）在强直性脊柱炎中的作用。我们发现，与对照Ab相比，FD03治疗可明显降低apoE-/-小鼠的循环脂质、斑块大小和脂质沉积，但斑块的形成与基线相比增加了两倍。不过，免疫荧光显示，与正常血管组织相比，即使经过 FD03 处理，斑块中 CD47 的表达也会上调。接下来，研究人员构建了一种包含信号调节蛋白α（SIRPα）和 FD03（SIRPαD1-FD03）的双功能蛋白，用于同时阻断 CD47 和 ANGPTL3，该蛋白纯度高、稳定性强，与 CD47 和 ANGPTL3 的亲和力高，在体外具有生物活性。此外，与SIRPαD1-Fc或FD03相比，SIRPαD1-FD03融合蛋白对强直性脊柱炎的治疗效果更强，可使斑块内容物和坏死核心消退至基线水平。从机理上讲，SIRPαD1-FD03能降低血清脂质，提高巨噬细胞的流出率和M2极化，降低动脉粥样硬化斑块中的活性氧（ROS）和脂质过氧化水平。总之，我们的项目提出了一种同时阻断ANGPTL3和CD47以调节脂质代谢、巨噬细胞活性和脂质过氧化的治疗强直性脊柱炎的有效方法。

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引用次数: 0

Global and Chinese trends in oligonucleotide drug clinical development: A comparative analysis 全球和中国的寡核苷酸药物临床开发趋势：比较分析。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-10-31 DOI: 10.1016/j.phrs.2024.107487

Xiaofei Wu , Shupeng Liu , Dan Liu , Xiuqi Li , Hongyun Wang , Xiaohong Han

Oligonucleotide drugs are anticipated to mark the new wave of pharmaceutical innovation, succeeding the eras of small molecule drugs and monoclonal antibodies. This review assessed a decade of global and Chinese clinical advancements in this field. Since 2013, there has been a notable surge in the development of oligonucleotide drugs, although a considerable majority of these candidates are still in the nascent stages of clinical trials. Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) represent two pivotal classes both on global scale and within China. Rare diseases have been the main therapeutic target for oligonucleotide drugs, with a less pronounced focus in China's pipeline relative to the global trend. Concurrently, these drugs are broadening their scope to encompass a variety of indications, potentially revolutionizing treatment approaches for chronic conditions. While China's clinical development in this sector is in its infancy compared to the global stage, technological progress and favorable policies are expected to foster a new landscape of oligonucleotide drug development in the future.

继小分子药物和单克隆抗体时代之后，寡核苷酸药物有望成为医药创新的新浪潮。本综述评估了十年来全球和中国在这一领域取得的临床进展。自2013年以来，寡核苷酸药物的开发明显激增，尽管其中相当多的候选药物仍处于临床试验的初级阶段。反义寡核苷酸（ASOs）和小干扰RNAs（siRNAs）是全球和中国两大举足轻重的寡核苷酸类药物。罕见病一直是寡核苷酸类药物的主要治疗靶点，与全球趋势相比，中国的研发管线对这类药物的关注较少。与此同时，这类药物的适应症范围也在不断扩大，有可能彻底改变慢性病的治疗方法。虽然与全球相比，中国在这一领域的临床开发尚处于起步阶段，但技术进步和政策利好有望促进未来寡核苷酸药物开发的新格局。

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引用次数: 0

The mysteries of LETM1 pleiotropy LETM1 多态性之谜

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-10-30 DOI: 10.1016/j.phrs.2024.107485

Sami E.M. Mohammed, Karin Nowikovsky

LETM1 is a nuclear-encoded protein located in the inner mitochondrial membrane, playing a critical role in regulating mitochondrial cation and volume homeostasis. However, numerous studies on functional features, molecular interactions, and disease-associated effects of LETM1 revealed that LETM1 is also involved in other metabolic functions including glucose utilization, mitochondrial DNA and ribosome organization, cristae architecture and respiratory complex stability. Undisputedly, osmoregulatory processes are essential for mitochondrial functionality, but the pleiotropic aspects of LETM1 challenges us to understand the core function of LETM1, which still remains elusive. In this review, we provide an overview of the current knowledge and latest developments regarding the activities involving LETM1. We highlight various findings that offer different functional perspectives and ideas on the core function of LETM1. Specifically, we emphasize data supporting LETM1's role as a mitochondrial translational factor, K⁺/H⁺ exchanger, or Ca²⁺/H⁺ exchanger, along with recent findings on its interaction with ATAD3A and TMBIM5. We also present the severe clinical implications of LETM1 deficiency. Finally, we discuss emerging questions raised by the different views on LETM1, which need to be addressed to guide future research directions and ultimately resolve the function of this essential protein and develop targeted therapeutic strategies.

LETM1 是一种位于线粒体内膜的核编码蛋白，在调节线粒体阳离子和容积平衡方面发挥着关键作用。然而，对 LETM1 的功能特征、分子相互作用和疾病相关效应的大量研究表明，LETM1 还参与其他代谢功能，包括葡萄糖利用、线粒体 DNA 和核糖体组织、嵴结构和呼吸复合体稳定性。毋庸置疑，渗透调节过程对线粒体的功能至关重要，但 LETM1 的多效性对我们了解 LETM1 的核心功能提出了挑战，而这一功能至今仍难以确定。在这篇综述中，我们概述了有关 LETM1 活动的现有知识和最新进展。我们强调了各种研究结果，这些结果为 LETM1 的核心功能提供了不同的功能视角和观点。具体来说，我们强调了支持 LETM1 作为线粒体翻译因子、K+/H+ 交换子或 Ca2+/H+ 交换子的数据，以及其与 ATAD3A 和 TMBIM5 相互作用的最新发现。我们还介绍了 LETM1 缺乏症的严重临床影响。最后，我们讨论了关于 LETM1 的不同观点所引发的新问题，这些问题亟待解决，以指导未来的研究方向，并最终解决这一重要蛋白的功能问题和开发有针对性的治疗策略。

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引用次数: 0

Correspondence: Reply to commentary on "Omega-3 PUFAs slow organ aging through promoting energy metabolism". 通讯：回复关于 "Omega-3 PUFAs 通过促进能量代谢延缓器官衰老 "的评论。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-10-30 DOI: 10.1016/j.phrs.2024.107479

Yabing Xiong, Lili Zhou

引用次数: 0

USP14 inhibition enhances Parkin-independent mitophagy in iNeurons USP14 抑制会增强 iNeurons 中与 Parkin 无关的有丝分裂。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-10-30 DOI: 10.1016/j.phrs.2024.107484

Greta Bernardo , Miguel A. Prado , Anna Roshani Dashtmian , Mariavittoria Favaro , Sofia Mauri , Alice Borsetto , Elena Marchesan , Joao A. Paulo , Steve P. Gygi , Daniel J. Finley , Elena Ziviani

Loss of proteostasis is well documented during physiological aging and depends on the progressive decline in the activity of two major degradative mechanisms: the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway. This decline in proteostasis is exacerbated in age-associated neurodegenerative diseases, such as Parkinson’s Disease (PD). In PD, patients develop an accumulation of aggregated proteins and dysfunctional mitochondria, which leads to ROS production, neuroinflammation and neurodegeneration. We recently reported that inhibition of the deubiquitinating enzyme USP14, which is known to enhance both the UPS and autophagy, increases lifespan and rescues the pathological phenotype of two Drosophila models of PD. Studies on the effects of USP14 inhibition in mammalian neurons have not yet been conducted. To close this gap, we exploited iNeurons differentiated from human embryonic stem cells (hESCs), and investigated the effect of inhibiting USP14 in these cultured neurons. Quantitative global proteomics analysis performed following genetic ablation or pharmacological inhibition of USP14 demonstrated that USP14 loss of function specifically promotes mitochondrial autophagy in iNeurons. Biochemical and imaging data also showed that USP14 inhibition enhances mitophagy. The mitophagic effect of USP14 inhibition proved to be PINK1/Parkin- independent, instead relying on expression of the mitochondrial E3 Ubiquitin Ligase MITOL/MARCH5. Notably, USP14 inhibition normalized the mitochondrial defects of Parkin KO human neurons.

在生理衰老过程中，蛋白稳态的丧失是有据可查的，它取决于两种主要降解机制活性的逐步下降：泛素-蛋白酶体系统（UPS）和自噬-溶酶体途径。在帕金森病（PD）等与年龄相关的神经退行性疾病中，蛋白稳态的衰退会加剧。帕金森病患者体内聚集的蛋白质和线粒体功能失调，导致 ROS 生成、神经炎症和神经退行性变。我们最近报告说，已知去泛素化酶 USP14 能增强 UPS 和自噬作用，抑制 USP14 能延长果蝇的寿命并挽救两种 PD 果蝇模型的病理表型。目前尚未研究抑制 USP14 对哺乳动物神经元的影响。为了填补这一空白，我们利用从人类胚胎干细胞（hESCs）分化出的iNeurons，研究了抑制USP14对这些培养神经元的影响。在对 USP14 进行基因消减或药物抑制后进行的定量全局蛋白质组学分析表明，USP14 的功能缺失会特异性地促进 iNeurons 中线粒体的自噬。生化和成像数据还显示，抑制 USP14 能增强有丝分裂。事实证明，USP14抑制的有丝分裂效应与PINK1/Parkin无关，而是依赖于线粒体E3泛素连接酶MITOL/MARCH5的表达。值得注意的是，USP14抑制能使Parkin KO人类神经元的线粒体缺陷正常化。

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引用次数: 0

Methodological considerations in assessing GLP-1 receptor agonists and gastrointestinal cancer risk 评估 GLP-1 受体激动剂和胃肠道癌症风险的方法学考虑因素。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-10-28 DOI: 10.1016/j.phrs.2024.107481

Cheng-Hsien Hung , Chun-Ting Lin , James Cheng-Chung Wei

引用次数: 0

Clarifying methodological approaches in the assessment of GLP-1 RAs and gastrointestinal cancer risk 明确评估 GLP-1 RA 与胃肠道癌症风险的方法。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-10-28 DOI: 10.1016/j.phrs.2024.107482

Gisella Figlioli, Daniele Piovani, Spyros Peppas, Nicola Pugliese, Cesare Hassan, Alessandro Repici, Ana Lleo, Alessio Aghemo, Stefanos Bonovas

引用次数: 0

Irisin in degenerative musculoskeletal diseases: Functions in system and potential in therapy 退行性肌肉骨骼疾病中的鸢尾素：系统功能和治疗潜力

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-10-25 DOI: 10.1016/j.phrs.2024.107480

Yu-tong Wang , Sheng-yuan Zheng , Shi-de Jiang , Yan Luo , Yu-xiang Wu , Shinen Naranmandakh , Yu-sheng Li , Shu-guang Liu , Wen-feng Xiao

Degenerative musculoskeletal diseases are a class of diseases related to the gradual structural and functional deterioration of muscles, joints, and bones, including osteoarthritis (OA), osteoporosis (OP), sarcopenia (SP), and intervertebral disc degeneration (IDD). As the proportion of aging people around the world increases, degenerative musculoskeletal diseases not only have a multifaceted impact on patients, but also impose a huge burden on the medical industry in various countries. Therefore, it is crucial to find key regulatory factors and potential therapeutic targets. Recent studies have shown that irisin plays an important role in degenerative musculoskeletal diseases, suggesting that it may become a key molecule in the prevention and treatment of degenerative diseases of the musculoskeletal system. Therefore, this review provides a comprehensive description of the release and basic functions of irisin, and summarizes the role of irisin in OA, OP, SP, and IDD from a cellular and tissue perspective, providing comprehensive basis for clinical application. In addition, we summarized the many roles of irisin as a key information molecule in bone-muscle-adipose crosstalk and a regulatory molecule involved in inflammation, senescence, and cell death, and proposed the interesting possibility of irisin in degenerative musculoskeletal diseases.

肌肉骨骼退行性疾病是指肌肉、关节和骨骼的结构和功能逐渐退化的一类疾病，包括骨关节炎（OA）、骨质疏松症（OP）、肌肉疏松症（SP）和椎间盘退行性变（IDD）。随着全球老龄化人口比例的增加，退行性肌肉骨骼疾病不仅对患者造成了多方面的影响，也给各国的医疗行业带来了巨大的负担。因此，寻找关键调控因子和潜在治疗靶点至关重要。最近的研究表明，鸢尾素在退行性肌肉骨骼疾病中发挥着重要作用，这表明它可能成为预防和治疗肌肉骨骼系统退行性疾病的关键分子。因此，本综述全面阐述了鸢尾素的释放和基本功能，并从细胞和组织的角度总结了鸢尾素在 OA、OP、SP 和 IDD 中的作用，为临床应用提供了全面的依据。此外，我们还总结了鸢尾素作为骨-肌肉-脂肪串联过程中的关键信息分子以及参与炎症、衰老和细胞死亡的调控分子的多种作用，并提出了鸢尾素在退行性肌肉骨骼疾病中的有趣可能性。

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引用次数: 0

Omega-3 PUFAs slow organ aging through promoting energy metabolism. 通讯：奥米加-3 脂肪酸通过促进能量代谢延缓器官衰老。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-10-23 DOI: 10.1016/j.phrs.2024.107477

Da-Jyun Yan, Chi-Shan Huang, Chi-Ya Yang, Su-Boon Yong, Chin-Yuan Yii

引用次数: 0

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