Pharmacological research最新文献

英文中文

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

Upregulation of ALOX12−12-HETE pathway impairs AMPK-dependent modulation of vascular metabolism in ApoE/LDLR−/− mice ALOX12-12-HETE 通路的上调会损害 AMPK 依赖性调节 ApoE/LDLR-/- 小鼠的血管代谢。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-10-22 DOI: 10.1016/j.phrs.2024.107478

Mariola Olkowicz , Agnieszka Karas , Piotr Berkowicz , Patrycja Kaczara , Agnieszka Jasztal , Zuzanna Kurylowicz , Filip Fedak , Hernando Rosales-Solano , Kanchan Sinha Roy , Agnieszka Kij , Elzbieta Buczek , Janusz Pawliszyn , Stefan Chlopicki

Mitochondrial dysfunction and 12-lipoxygenase (ALOX12)-derived 12(S)-HETE production have been associated with vascular inflammation and the pathogenesis of atherosclerosis. However, the role of ALOX12 in regulating vascular energy metabolism in vascular inflammation has not been studied to date. Using mitochondrial and glycolysis functional profiling with the Seahorse extracellular flux analyzer, metabolipidomics, and proteomic analysis (LC-MS/MS), we characterized alterations in vascular energy metabolism in 2- and 6-month-old ApoE/LDLR^−/− vs. control C57BL/6 mice. We identified that aorta of 6-month-old ApoE/LDLR^−/− mice displayed compromised mitochondrial metabolism manifested by the reduced expression of mitochondrial enzymes, impaired mitochondrial respiration, and consequently diminished respiratory reserve capacity. An increased flux through the glycolysis/lactate shuttle, the hexosamine biosynthetic pathway (HBP), and the pentose phosphate pathway (PPP) was also recognized. Interestingly, ALOX12−12-HETE was the most upregulated axis in eicosanoid metabolism and histological examinations indicated that ApoE/LDLR^−/− mice showed increased aortic expression of ALOX12, particularly in early atherosclerotic plaque areas. Remarkably, the joint blocking of ALOX12 and activation of AMPK, but not AMPK activation alone, resulted in the reprogramming of vascular metabolism, with improved mitochondrial respiration and suppressed auxiliary pathways (HBP, PPP, itaconate shunt). In conclusion, excessive activation of the ALOX12–12-HETE pathway in vascular inflammation in early atherosclerosis inhibits AMPK-dependent regulation of vascular metabolism. Consequently, ALOX12 may represent a novel target to boost impaired vascular mitochondrial function in pro-atherosclerotic vascular inflammation.

线粒体功能障碍和 12-脂氧合酶（ALOX12）产生的 12（S）-HETE 与血管炎症和动脉粥样硬化的发病机制有关。然而，迄今为止，人们尚未研究过 ALOX12 在血管炎症中调节血管能量代谢的作用。通过使用海马细胞外通量分析仪（Seahorse extraellular flux analyzer）进行线粒体和糖酵解功能分析、代谢脂质组学和蛋白质组学分析（LC-MS/MS），我们确定了 2 个月和 6 个月大载脂蛋白E/LDLR-/-小鼠与对照组 C57BL/6 小鼠血管能量代谢变化的特征。我们发现，6 个月大的载脂蛋白E/LDLR-/-小鼠的主动脉线粒体代谢受到影响，表现为线粒体酶的表达减少、线粒体呼吸受损，从而降低了呼吸储备能力。通过糖酵解/乳酸穿梭、己胺生物合成途径（HBP）和磷酸戊糖途径（PPP）的通量也有所增加。有趣的是，ALOX12-12-HETE 是类二十烷烃代谢中上调最多的轴，组织学检查显示，载脂蛋白E/LDLR-/小鼠主动脉中 ALOX12 的表达增加，尤其是在早期动脉粥样硬化斑块区域。值得注意的是，联合阻断 ALOX12 和激活 AMPK（而非单独激活 AMPK）可重新规划血管代谢，改善线粒体呼吸并抑制辅助途径（HBP、PPP、itaconate 分流）。总之，在动脉粥样硬化早期的血管炎症中，ALOX12-12-HETE 通路的过度激活抑制了 AMPK 对血管代谢的依赖性调节。因此，ALOX12 可能是促进动脉粥样硬化前血管炎症中受损血管线粒体功能的新靶点。

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引用次数: 0

Overcoming limitations and advancing the therapeutic potential of antibody-oligonucleotide conjugates (AOCs): Current status and future perspectives 克服抗体-寡核苷酸共轭物 (AOC) 的局限性并提高其治疗潜力：现状与未来展望》。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-10-19 DOI: 10.1016/j.phrs.2024.107469

Jinlan Jiao , Yun Qian , Yinhua Lv , Wenqian Wei , Yongxuan Long , Xiaoling Guo , Anya Buerliesi , Jiahui Ye , Hao Han , Jinbo Li , Yun Zhu , Weijie Zhang

As cancer incidence rises due to an aging population, the importance of precision medicine continues to grow. Antibody-drug conjugates (ADCs) exemplify targeted therapies by delivering cytotoxic agents to specific antigens. Building on this concept, researchers have developed antibody-oligonucleotide conjugates (AOCs), which combine antibodies with oligonucleotides to regulate gene expression. This review highlights the mechanism of AOCs, emphasizing their unique ability to selectively target and modulate disease-causing proteins. It also explores the components of AOCs and their application in tumor therapy while addressing key challenges such as manufacturing complexities, endosomal escape, and immune response. The article underscores the significance of AOCs in precision oncology and discusses future directions, highlighting their potential in treating cancers driven by genetic mutations and abnormal protein expression.

随着人口老龄化导致癌症发病率上升，精准医疗的重要性与日俱增。抗体-药物共轭物（ADCs）通过向特定抗原递送细胞毒剂，是靶向疗法的典范。在这一概念的基础上，研究人员开发出了抗体-寡核苷酸共轭物（AOCs），它将抗体与寡核苷酸结合起来以调节基因表达。本综述将重点介绍 AOCs 的作用机制，强调其选择性靶向和调节致病蛋白的独特能力。文章还探讨了 AOCs 的成分及其在肿瘤治疗中的应用，同时探讨了制造复杂性、内体逸出和免疫反应等关键挑战。文章强调了 AOCs 在精准肿瘤学中的重要意义，并讨论了未来的发展方向，突出了它们在治疗由基因突变和异常蛋白表达驱动的癌症方面的潜力。

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引用次数: 0

From exosomes to mitochondria and myocardial infarction: Molecular insight and therapeutic challenge 从外泌体到线粒体和心肌梗塞：分子洞察力和治疗挑战。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-10-18 DOI: 10.1016/j.phrs.2024.107468

Chang Liu , Dengwen Zhang , Kekao Long , Wensheng Qi , Lei Pang , Jia Li , Kenneth King-Yip Cheng , Yin Cai

Myocardial infarction (MI) remains a leading cause of mortality worldwide. Despite patients with MI benefit from timely reperfusion therapies, the rates of mortality and morbidity remain substantial, suggesting an enduring need for the development of new approaches. Molecular mechanisms underlying myocardial ischemic injury are associated with both cardiomyocytes and non-cardiomyocytes. Exosomes are nano-sized extracellular vesicles released by almost all eukaryotic cells. They facilitate the communication between various cells by transferring information via their cargo and altering different biological activities in recipient cells. Studies have created great prospects for therapeutic applications of exosomes in MI, as demonstrated through their beneficial effect on heart function and reducing ventricular remodeling in association with fibrosis, angiogenesis, apoptosis, and inflammation. Of note, myocardial ischemic injury is primarily due to restricted blood flow, reducing oxygen availability, and causing inefficient utilization of energy substrates. However, the impact of exosomes on cardiac energy metabolism has not been adequately investigated. Although exosomes have been engineered for targeted delivery to enhance clinical efficacy, challenges must be overcome to utilize them reliably in the clinic. In this review, we summarize the research progress of exosomes for MI with a focus on the known and unknown regarding the role of exosomes in energy metabolism in cardiomyocytes and non-cardiomyocytes; as well as potential research avenues of exosome-mitochondrial energy regulation as well as therapeutic challenges. We aim to help identify more efficient molecular targets that may promote the clinical application of exosomes.

心肌梗死（MI）仍然是全球死亡的主要原因。尽管心肌梗死患者可以从及时的再灌注疗法中获益，但死亡率和发病率仍然很高，这表明开发新方法的需求是持久的。心肌缺血损伤的分子机制既与心肌细胞有关，也与非心肌细胞有关。外泌体是几乎所有真核细胞释放的纳米级细胞外囊泡。它们通过货物传递信息，改变受体细胞的不同生物活性，从而促进不同细胞之间的交流。研究表明，外泌体对外心肌梗死的治疗应用前景广阔，因为外泌体对心脏功能有益，并能减少心室重塑与纤维化、血管生成、细胞凋亡和炎症的关联。值得注意的是，心肌缺血损伤的主要原因是血流受限，氧气供应减少，导致能量底物利用效率低下。然而，外泌体对心脏能量代谢的影响尚未得到充分研究。虽然外泌体已被设计用于定向输送以提高临床疗效，但要在临床中可靠地使用它们，还必须克服各种挑战。在这篇综述中，我们总结了外泌体用于心肌缺血的研究进展，重点关注外泌体在心肌细胞和非心肌细胞能量代谢中作用的已知和未知因素，以及外泌体-线粒体能量调节的潜在研究途径和治疗挑战。我们的目标是帮助确定更有效的分子靶点，从而促进外泌体的临床应用。

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引用次数: 0

USP9X-enriched MSC-sEV inhibits LSEC angiogenesis in MASH mice by downregulating the IκBα/NF-κB/Ang-2 pathway 富含 USP9X 的 MSC-sEV 通过下调 IκBα/NF-κB/Ang-2 通路抑制 MASH 小鼠 LSEC 血管生成。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-10-18 DOI: 10.1016/j.phrs.2024.107471

Yanjin Wang , Chen Wang , Fuji Yang , Yifei Chen , Yujie Shi , Ruizi Xu , Zhuan Zhang , Yongmin Yan

Pathological angiogenesis of liver sinusoidal endothelial cells (LSEC) plays a crucial role in the progression of metabolic dysfunction-associated steatohepatitis (MASH)-induced liver fibrosis. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEV) have shown promising therapeutic potential against MASH. This study aimed to investigate the impact of MSC-sEV on LSEC angiogenesis and elucidate the underlying molecular mechanisms. The effects of MSC-sEV on LSEC angiogenesis were evaluated in Tumor Necrosis Factor- alpha (TNF-α)-treated LSECs in vitro and in Methionine and Choline Deficient Diet (MCD)-induced MASH mice in vivo. Herein, we found that MSC-sEV effectively suppressed LSEC angiogenesis by targeting the angiogenesis marker Angiogenin 2 (Ang-2) in both TNF-α-treated LSECs and MASH mice. Gene manipulation experiments revealed that the primary mechanism by which MSC-sEV inhibited LSEC angiogenesis was through the modulation of nuclear factor kappa B inhibitor alpha (IκBα) / nuclear factor kappa B (NF-κB) / Ang-2 pathway. Additionally, mass spectrometry and co-immunoprecipitation (Co-IP) data suggested that MSC-sEV delivered the ubiquitin specific peptidase 9 X-linked (USP9X) protein to LSECs, leading to enhanced IκBα deubiquitination and NF-κB in activation, ultimately resulting in the inhibition of Ang-2-mediated LSEC angiogenesis. Knockdown of USP9X attenuated the regulatory effects of MSC-sEV on Ang-2 expression, LSEC angiogenesis, and the progression of MASH. In conclusion, our findings indicate that USP9X delivered via MSC-sEV can suppress LSEC angiogenesis and alleviate MASH-induced liver fibrosis through the IκBα/NF-κB/Ang-2 signaling pathway.

肝窦状内皮细胞（LSEC）病理性血管生成在代谢功能障碍相关性脂肪性肝炎（MASH）诱导的肝纤维化进展过程中起着至关重要的作用。间充质干细胞衍生的小细胞外囊泡（MSC-sEV）已显示出治疗MASH的巨大潜力。本研究旨在探讨间充质干细胞小泡对LSEC血管生成的影响，并阐明其潜在的分子机制。我们在体外肿瘤坏死因子-α（TNF-α）处理的LSEC和体内蛋氨酸和胆碱缺乏饮食（MCD）诱导的MASH小鼠中评估了间充质干细胞-SEV对LSEC血管生成的影响。在此，我们发现间充质干细胞-SEV通过靶向血管生成标志物血管生成素2（Angiogenin 2，Ang-2）有效抑制了TNF-α处理的LSEC和MASH小鼠的血管生成。基因操作实验显示，MSC-sEV抑制LSEC血管生成的主要机制是通过调节核因子卡巴B抑制剂α（IκBα）/核因子卡巴B（NF-κB）/Ang-2通路。此外，质谱分析和共免疫沉淀（Co-IP）数据表明，MSC-sEV能将泛素特异性肽酶9 X-连锁（USP9X）蛋白传递到LSEC，从而增强IκBα去泛素化和NF-κB活化，最终导致抑制Ang-2介导的LSEC血管生成。敲除 USP9X 可减轻 MSC-sEV 对 Ang-2 表达、LSEC 血管生成和 MASH 进展的调控作用。总之，我们的研究结果表明，通过MSC-sEV传递的USP9X可抑制LSEC血管生成，并通过IκBα/NF-κB/Ang-2信号通路缓解MASH诱导的肝纤维化。

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