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Lymphocyte Depleting and Modulating Therapies for Chronic Lung Allograft Dysfunction. 淋巴细胞耗竭和调节治疗慢性肺移植物功能障碍。
IF 19.3 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-11-01 Epub Date: 2023-06-09 DOI: 10.1124/pharmrev.123.000834
Saskia Bos, Pauline Pradère, Hanne Beeckmans, Andrea Zajacova, Bart M Vanaudenaerde, Andrew J Fisher, Robin Vos

Chronic lung rejection, also called chronic lung allograft dysfunction (CLAD), remains the major hurdle limiting long-term survival after lung transplantation, and limited therapeutic options are available to slow the progressive decline in lung function. Most interventions are only temporarily effective in stabilizing the loss of or modestly improving lung function, with disease progression resuming over time in the majority of patients. Therefore, identification of effective treatments that prevent the onset or halt progression of CLAD is urgently needed. As a key effector cell in its pathophysiology, lymphocytes have been considered a therapeutic target in CLAD. The aim of this review is to evaluate the use and efficacy of lymphocyte depleting and immunomodulating therapies in progressive CLAD beyond usual maintenance immunosuppressive strategies. Modalities used include anti-thymocyte globulin, alemtuzumab, methotrexate, cyclophosphamide, total lymphoid irradiation, and extracorporeal photopheresis, and to explore possible future strategies. When considering both efficacy and risk of side effects, extracorporeal photopheresis, anti-thymocyte globulin and total lymphoid irradiation appear to offer the best treatment options currently available for progressive CLAD patients. SIGNIFICANCE STATEMENT: Effective treatments to prevent the onset and progression of chronic lung rejection after lung transplantation are still a major shortcoming. Based on existing data to date, considering both efficacy and risk of side effects, extracorporeal photopheresis, anti-thymocyte globulin, and total lymphoid irradiation are currently the most viable second-line treatment options. However, it is important to note that interpretation of most results is hampered by the lack of randomized controlled trials.

慢性肺排斥反应,也称为慢性肺移植物功能障碍(CLAD),仍然是限制肺移植后长期生存的主要障碍,并且可用于减缓肺功能逐渐下降的治疗选择有限。大多数干预措施只是暂时有效地稳定或适度改善肺功能,大多数患者的疾病进展会随着时间的推移而恢复。因此,迫切需要确定有效的治疗方法来预防CLAD的发作或阻止其进展。淋巴细胞作为其病理生理学中的关键效应细胞,已被认为是CLAD的治疗靶点。这篇综述的目的是评估淋巴细胞消耗和免疫调节疗法在进行性CLAD中的应用和疗效,而不是常规的维持性免疫抑制策略。所用的方法包括抗胸腺细胞球蛋白、阿仑单抗、甲氨蝶呤、环磷酰胺、全淋巴照射和体外光疗法,并探索未来可能的策略。在考虑疗效和副作用风险时,体外光疗法、抗胸腺细胞球蛋白和全淋巴照射似乎是目前进展性CLAD患者的最佳治疗选择。意义声明:有效的治疗方法预防肺移植后慢性肺排斥反应的发生和发展仍然是一个主要的缺点。根据迄今为止的现有数据,考虑到疗效和副作用风险,体外光疗法、抗胸腺细胞球蛋白和全淋巴照射是目前最可行的二线治疗选择。然而,需要注意的是,由于缺乏随机对照试验,对大多数结果的解释受到阻碍。
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引用次数: 0
International Union of Basic and Clinical Pharmacology CXIII: Nuclear Receptor Superfamily-Update 2023. 国际基础与临床药理学联合会CXIII:核受体超家族-2023年更新。
IF 19.3 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-11-01 Epub Date: 2023-08-16 DOI: 10.1124/pharmrev.121.000436
Thomas P Burris, Ian Mitchelle S de Vera, Isabelle Cote, Colin A Flaveny, Udayanga S Wanninayake, Arindam Chatterjee, John K Walker, Nickolas Steinauer, Jinsong Zhang, Laurel A Coons, Kenneth S Korach, Derek W Cain, Anthony N Hollenberg, Paul Webb, Douglas Forrest, Anton M Jetten, Dean P Edwards, Sandra L Grimm, Sean Hartig, Carol A Lange, Jennifer K Richer, Carol A Sartorius, Marc Tetel, Cyrielle Billon, Bahaa Elgendy, Lamees Hegazy, Kristine Griffett, Nahuel Peinetti, Kerry L Burnstein, Travis S Hughes, Sadichha Sitaula, Keitch R Stayrook, Alexander Culver, Meghan H Murray, Brian N Finck, John A Cidlowski

The NR superfamily comprises 48 transcription factors in humans that control a plethora of gene network programs involved in a wide range of physiologic processes. This review will summarize and discuss recent progress in NR biology and drug development derived from integrating various approaches, including biophysical techniques, structural studies, and translational investigation. We also highlight how defective NR signaling results in various diseases and disorders and how NRs can be targeted for therapeutic intervention via modulation via binding to synthetic lipophilic ligands. Furthermore, we also review recent studies that improved our understanding of NR structure and signaling. SIGNIFICANCE STATEMENT: Nuclear receptors (NRs) are ligand-regulated transcription factors that are critical regulators of myriad physiological processes. NRs serve as receptors for an array of drugs, and in this review, we provide an update on recent research into the roles of these drug targets.

核受体(NR)超家族在人类中包括48个转录因子,这些转录因子控制着大量涉及广泛生理过程的基因网络程序。在这篇综述中,我们将总结和讨论NR生物学和药物开发的最新进展,这些进展源于各种方法的整合,包括生物物理技术、结构研究和转化研究。我们还强调了缺陷NR信号传导如何导致各种疾病和病症,以及NR如何通过与合成亲脂性配体结合进行调节而被靶向用于治疗干预。此外,我们还回顾了最近的研究,这些研究提高了我们对NR结构和信号传导的理解。意义声明核受体是配体调节的转录因子,作为广泛生理功能的关键调节因子。NRs也是无数药物的受体,在这篇综述中,我们提供了对这一药物靶点家族功能的最新研究。
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引用次数: 0
Effects of Medications on Heat Loss Capacity in Chronic Disease Patients: Health Implications Amidst Global Warming. 药物对慢性病患者热损失能力的影响:全球变暖对健康的影响。
IF 21.1 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-11-01 Epub Date: 2023-06-16 DOI: 10.1124/pharmrev.122.000782
Jericho Wee, Xiang Ren Tan, Samuel H Gunther, Mohammed Ihsan, Melvin Khee Shing Leow, Doreen Su-Yin Tan, Johan G Eriksson, Jason Kai Wei Lee

Pharmacological agents used to treat or manage diseases can modify the level of heat strain experienced by chronically ill and elderly patients via different mechanistic pathways. Human thermoregulation is a crucial homeostatic process that maintains body temperature within a narrow range during heat stress through dry (i.e., increasing skin blood flow) and evaporative (i.e., sweating) heat loss, as well as active inhibition of thermogenesis, which is crucial to avoid overheating. Medications can independently and synergistically interact with aging and chronic disease to alter homeostatic responses to rising body temperature during heat stress. This review focuses on the physiologic changes, with specific emphasis on thermolytic processes, associated with medication use during heat stress. The review begins by providing readers with a background of the global chronic disease burden. Human thermoregulation and aging effects are then summarized to give an understanding of the unique physiologic changes faced by older adults. The effects of common chronic diseases on temperature regulation are outlined in the main sections. Physiologic impacts of common medications used to treat these diseases are reviewed in detail, with emphasis on the mechanisms by which these medications alter thermolysis during heat stress. The review concludes by providing perspectives on the need to understand the effects of medication use in hot environments, as well as a summary table of all clinical considerations and research needs of the medications included in this review. SIGNIFICANCE STATEMENT: Long-term medications modulate thermoregulatory function, resulting in excess physiological strain and predisposing patients to adverse health outcomes during prolonged exposures to extreme heat during rest and physical work (e.g., exercise). Understanding the medication-specific mechanisms of altered thermoregulation has importance in both clinical and research settings, paving the way for work toward refining current medication prescription recommendations and formulating mitigation strategies for adverse drug effects in the heat in chronically ill patients.

用于治疗或管理疾病的药物可以通过不同的机制途径改变慢性病患者和老年患者所经历的热应激水平。人体体温调节是一个至关重要的稳态过程,在热应激期间,通过干燥(即增加皮肤血流量)和蒸发(即出汗)的热量损失,以及积极抑制产热,将体温保持在狭窄范围内,这对避免过热至关重要。药物可以与衰老和慢性病独立协同作用,改变热应激期间对体温升高的稳态反应。这篇综述的重点是热应激期间与药物使用相关的生理变化,特别是热解过程。这篇综述首先为读者提供了全球慢性病负担的背景。然后总结了人类的体温调节和衰老效应,以了解老年人面临的独特生理变化。常见慢性疾病对体温调节的影响在主要章节中概述。详细回顾了用于治疗这些疾病的常见药物的生理影响,重点介绍了这些药物在热应激期间改变热解的机制。该综述最后提供了了解在高温环境中使用药物影响的必要性的观点,以及本综述中包括的药物的所有临床考虑因素和研究需求的汇总表。意义声明:长期药物调节体温调节功能,导致过度的生理压力,并使患者在休息和体力劳动(如锻炼)期间长时间暴露在极端高温下,容易产生不良健康后果。了解体温调节改变的药物特异性机制在临床和研究环境中都很重要,为完善当前的药物处方建议和制定慢性病患者高温下药物不良反应的缓解策略铺平了道路。
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引用次数: 0
Optical Approaches for Investigating Neuromodulation and G Protein-Coupled Receptor Signaling. 研究神经调控和G蛋白偶联受体信号的光学方法。
IF 21.1 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-11-01 Epub Date: 2023-07-10 DOI: 10.1124/pharmrev.122.000584
David J Marcus, Michael R Bruchas

Despite the fact that roughly 40% of all US Food and Drug Administration (FDA)-approved pharmacological therapeutics target G protein-coupled receptors (GPCRs), there remains a gap in our understanding of the physiologic and functional role of these receptors at the systems level. Although heterologous expression systems and in vitro assays have revealed a tremendous amount about GPCR signaling cascades, how these cascades interact across cell types, tissues, and organ systems remains obscure. Classic behavioral pharmacology experiments lack both the temporal and spatial resolution to resolve these long-standing issues. Over the past half century, there has been a concerted effort toward the development of optical tools for understanding GPCR signaling. From initial ligand uncaging approaches to more recent development of optogenetic techniques, these strategies have allowed researchers to probe longstanding questions in GPCR pharmacology both in vivo and in vitro. These tools have been employed across biologic systems and have allowed for interrogation of everything from specific intramolecular events to pharmacology at the systems level in a spatiotemporally specific manner. In this review, we present a historical perspective on the motivation behind and development of a variety of optical toolkits that have been generated to probe GPCR signaling. Here we highlight how these tools have been used in vivo to uncover the functional role of distinct populations of GPCRs and their signaling cascades at a systems level. SIGNIFICANCE STATEMENT: G protein-coupled receptors (GPCRs) remain one of the most targeted classes of proteins for pharmaceutical intervention, yet we still have a limited understanding of how their unique signaling cascades effect physiology and behavior at the systems level. In this review, we discuss a vast array of optical techniques that have been devised to probe GPCR signaling both in vitro and in vivo.

尽管美国食品药品监督管理局(FDA)批准的所有药物治疗药物中,约有40%针对G蛋白偶联受体(GPCR),但我们对这些受体在系统水平上的生理和功能作用的理解仍存在差距。尽管异源表达系统和体外测定已经揭示了大量关于GPCR信号级联的信息,但这些级联如何在细胞类型、组织和器官系统中相互作用仍然不清楚。经典的行为药理学实验缺乏时间和空间分辨率来解决这些长期存在的问题。在过去的半个世纪里,人们共同致力于开发用于理解GPCR信号的光学工具。从最初的配体解锁方法到光遗传学技术的最新发展,这些策略使研究人员能够在体内和体外探索GPCR药理学中长期存在的问题。这些工具已被应用于整个生物系统,并允许以时空特定的方式在系统水平上询问从特定分子内事件到药理学的一切。在这篇综述中,我们从历史的角度介绍了各种用于探测GPCR信号的光学工具包背后的动机和开发。在这里,我们强调了这些工具是如何在体内使用的,以揭示不同群体的GPCR及其信号级联在系统水平上的功能作用。意义声明:G蛋白偶联受体(GPCR)仍然是药物干预最具针对性的蛋白质类之一,但我们对其独特的信号级联如何在系统水平上影响生理和行为仍有有限的了解。在这篇综述中,我们讨论了一系列用于在体外和体内探测GPCR信号的光学技术。
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引用次数: 0
Targeting Epidermal Growth Factor Receptor for Cancer Treatment: Abolishing Both Kinase-Dependent and Kinase-Independent Functions of the Receptor. 靶向表皮生长因子受体治疗癌症:消除受体的激酶依赖性和激酶非依赖性功能。
IF 21.1 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-11-01 Epub Date: 2023-06-20 DOI: 10.1124/pharmrev.123.000906
Yuesheng Zhang

Epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, is activated by ligand binding, overexpression, or mutation. It is well known for its tyrosine kinase-dependent oncogenic activities in a variety of human cancers. A large number of EGFR inhibitors have been developed for cancer treatment, including monoclonal antibodies, tyrosine kinase inhibitors, and a vaccine. The EGFR inhibitors are aimed at inhibiting the activation or the activity of EGFR tyrosine kinase. However, these agents have shown efficacy in only a few types of cancers. Drug resistance, both intrinsic and acquired, is common even in cancers where the inhibitors have shown efficacy. The drug resistance mechanism is complex and not fully known. The key vulnerability of cancer cells that are resistant to EGFR inhibitors has not been identified. Nevertheless, it has been increasingly recognized in recent years that EGFR also possesses kinase-independent oncogenic functions and that these noncanonical functions may play a crucial role in cancer resistance to EGFR inhibitors. In this review, both kinase-dependent and -independent activities of EGFR are discussed. Also discussed are the mechanisms of actions and therapeutic activities of clinically used EGFR inhibitors and sustained EGFR overexpression and EGFR interaction with other receptor tyrosine kinases to counter the EGFR inhibitors. Moreover, this review discusses emerging experimental therapeutics that have shown potential for overcoming the limitation of the current EGFR inhibitors in preclinical studies. The findings underscore the importance and feasibility of targeting both kinase-dependent and -independent functions of EGFR to enhance therapeutic efficacy and minimize drug resistance. SIGNIFICANCE STATEMENT: EGFR is a major oncogenic driver and therapeutic target, but cancer resistance to current EGFR inhibitors remains a significant unmet clinical problem. This article reviews the cancer biology of EGFR as well as the mechanisms of actions and the therapeutic efficacies of current and emerging EGFR inhibitors. The findings could potentially lead to development of more effective treatments for EGFR-positive cancers.

表皮生长因子受体(EGFR)是一种受体酪氨酸激酶,通过配体结合、过表达或突变激活。众所周知,它在多种人类癌症中具有酪氨酸激酶依赖性致癌活性。已经开发了大量用于癌症治疗的EGFR抑制剂,包括单克隆抗体、酪氨酸激酶抑制剂和疫苗。EGFR抑制剂旨在抑制EGFR酪氨酸激酶的活化或活性。然而,这些药物仅在少数类型的癌症中显示出疗效。耐药性,包括内在耐药性和获得性耐药性,即使在抑制剂显示出疗效的癌症中也很常见。耐药性机制复杂,尚不完全清楚。癌症细胞对EGFR抑制剂具有耐药性的关键脆弱性尚未确定。然而,近年来人们越来越认识到,EGFR也具有激酶依赖性致癌功能,这些非致癌功能可能在癌症对EGFR抑制剂的耐药性中发挥关键作用。在这篇综述中,EGFR的激酶依赖性和非依赖性活性都进行了讨论。还讨论了临床使用的EGFR抑制剂的作用机制和治疗活性,以及持续的EGFR过表达和EGFR与其他受体酪氨酸激酶的相互作用以对抗EGFR抑制剂。此外,这篇综述讨论了新兴的实验疗法,这些疗法在临床前研究中显示出克服当前EGFR抑制剂局限性的潜力。这些发现强调了靶向EGFR激酶依赖性和非依赖性功能的重要性和可行性,以提高疗效并最大限度地减少耐药性。意义声明:EGFR是一个主要的致癌驱动因素和治疗靶点,但癌症对目前EGFR抑制剂的耐药性仍然是一个尚未解决的重大临床问题。本文综述了EGFR的癌症生物学,以及目前和新出现的EGFR抑制剂的作用机制和疗效。这些发现可能会为EGFR阳性癌症开发更有效的治疗方法。
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引用次数: 0
The Myc Family and the Metastasis Suppressor NDRG1: Targeting Key Molecular Interactions with Innovative Therapeutics. Myc家族和转移抑制因子NDRG1:创新疗法靶向关键分子相互作用。
IF 21.1 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-09-01 DOI: 10.1124/pharmrev.122.000795
Zhao Deng, Des R Richardson

Cancer is a leading cause of death worldwide, resulting in ∼10 million deaths in 2020. Major oncogenic effectors are the Myc proto-oncogene family, which consists of three members including c-Myc, N-Myc, and L-Myc. As a pertinent example of the role of the Myc family in tumorigenesis, amplification of MYCN in childhood neuroblastoma strongly correlates with poor patient prognosis. Complexes between Myc oncoproteins and their partners such as hypoxia-inducible factor-1α and Myc-associated protein X (MAX) result in proliferation arrest and pro-proliferative effects, respectively. Interactions with other proteins are also important for N-Myc activity. For instance, the enhancer of zest homolog 2 (EZH2) binds directly to N-Myc to stabilize it by acting as a competitor against the ubiquitin ligase, SCFFBXW7, which prevents proteasomal degradation. Heat shock protein 90 may also be involved in N-Myc stabilization since it binds to EZH2 and prevents its degradation. N-Myc downstream-regulated gene 1 (NDRG1) is downregulated by N-Myc and participates in the regulation of cellular proliferation via associating with other proteins, such as glycogen synthase kinase-3β and low-density lipoprotein receptor-related protein 6. These molecular interactions provide a better understanding of the biologic roles of N-Myc and NDRG1, which can be potentially used as therapeutic targets. In addition to directly targeting these proteins, disrupting their key interactions may also be a promising strategy for anti-cancer drug development. This review examines the interactions between the Myc proteins and other molecules, with a special focus on the relationship between N-Myc and NDRG1 and possible therapeutic interventions. SIGNIFICANCE STATEMENT: Neuroblastoma is one of the most common childhood solid tumors, with a dismal five-year survival rate. This problem makes it imperative to discover new and more effective therapeutics. The molecular interactions between major oncogenic drivers of the Myc family and other key proteins; for example, the metastasis suppressor, NDRG1, may potentially be used as targets for anti-neuroblastoma drug development. In addition to directly targeting these proteins, disrupting their key molecular interactions may also be promising for drug discovery.

癌症是世界范围内死亡的主要原因,在2020年导致约1000万人死亡。主要的致癌效应因子是Myc原癌基因家族,由c-Myc、N-Myc和L-Myc三个成员组成。作为Myc家族在肿瘤发生中作用的一个相关例子,MYCN在儿童神经母细胞瘤中的扩增与患者预后不良密切相关。Myc癌蛋白与其伴侣如缺氧诱导因子-1α和Myc相关蛋白X (MAX)之间的复合物分别导致增殖抑制和促增殖作用。与其他蛋白质的相互作用对N-Myc活性也很重要。例如,zest同源物2的增强子(EZH2)直接结合到N-Myc上,通过与泛素连接酶SCFFBXW7竞争来稳定它,从而防止蛋白酶体降解。热休克蛋白90也可能参与N-Myc的稳定,因为它与EZH2结合并阻止其降解。N-Myc下游调控基因1 (NDRG1)被N-Myc下调,并通过与糖原合成酶激酶3β和低密度脂蛋白受体相关蛋白6等蛋白结合参与细胞增殖调控。这些分子相互作用提供了对N-Myc和NDRG1生物学作用的更好理解,它们可能被用作治疗靶点。除了直接靶向这些蛋白质外,破坏它们的关键相互作用也可能是抗癌药物开发的一种很有前途的策略。本文综述了Myc蛋白与其他分子之间的相互作用,特别关注N-Myc和NDRG1之间的关系以及可能的治疗干预措施。意义声明:神经母细胞瘤是最常见的儿童实体瘤之一,5年生存率低。这个问题使得发现新的和更有效的治疗方法势在必行。Myc家族主要致癌驱动因子与其他关键蛋白之间的分子相互作用;例如,转移抑制因子NDRG1可能被用作抗神经母细胞瘤药物开发的潜在靶点。除了直接靶向这些蛋白质外,破坏它们的关键分子相互作用也可能是药物发现的希望。
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引用次数: 2
Paradoxes of Cellular SUMOylation Regulation: A Role of Biomolecular Condensates? 细胞SUMOY化调控的悖论:生物分子缩合物的作用?
IF 19.3 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-09-01 Epub Date: 2023-05-03 DOI: 10.1124/pharmrev.122.000784
Xiaodong Cheng, Wenli Yang, Wei Lin, Fang Mei

Protein SUMOylation is a major post-translational modification essential for maintaining cellular homeostasis. SUMOylation has long been associated with stress responses as a diverse array of cellular stress signals are known to trigger rapid alternations in global protein SUMOylation. In addition, while there are large families of ubiquitination enzymes, all small ubiquitin-like modifiers (SUMOs) are conjugated by a set of enzymatic machinery comprising one heterodimeric SUMO-activating enzyme, a single SUMO-conjugating enzyme, and a small number of SUMO protein ligases and SUMO-specific proteases. How a few SUMOylation enzymes specifically modify thousands of functional targets in response to diverse cellular stresses remains an enigma. Here we review recent progress toward understanding the mechanisms of SUMO regulation, particularly the potential roles of liquid-liquid phase separation/biomolecular condensates in regulating cellular SUMOylation during cellular stresses. In addition, we discuss the role of protein SUMOylation in pathogenesis and the development of novel therapeutics targeting SUMOylation. SIGNIFICANCE STATEMENT: Protein SUMOylation is one of the most prevalent post-translational modifications and plays a vital role in maintaining cellular homeostasis in response to stresses. Protein SUMOylation has been implicated in human pathogenesis, such as cancer, cardiovascular diseases, neurodegeneration, and infection. After more than a quarter century of extensive research, intriguing enigmas remain regarding the mechanism of cellular SUMOylation regulation and the therapeutic potential of targeting SUMOylation.

蛋白质SUMO化是维持细胞稳态所必需的主要翻译后修饰。SUMOylation长期以来一直与应激反应有关,因为已知一系列不同的细胞应激信号会触发全局蛋白质SUMOylation。此外,虽然存在泛素化酶的大家族,但所有小的泛素样修饰物(SUMO)都是通过一组酶机制偶联的,该酶机制包括一种异二聚体SUMO活化酶、一种单一的SUMO偶联酶以及少量的SUMO蛋白连接酶和SUMO特异性蛋白酶。一些SUMO化酶如何特异性修饰数千个功能靶标以应对不同的细胞应激仍然是个谜。在这里,我们回顾了最近在理解SUMO调节机制方面的进展,特别是液-液相分离/生物分子缩合物在细胞应激过程中调节细胞SUMO化的潜在作用。此外,我们还讨论了蛋白质SUMO化在发病机制中的作用以及针对SUMO化的新疗法的开发。意义声明:蛋白质SUMOY化是最普遍的翻译后修饰之一,在维持细胞稳态以应对压力方面发挥着至关重要的作用。蛋白质SUMO化与人类发病机制有关,如癌症、心血管疾病、神经退行性变和感染。经过超过四分之一个世纪的广泛研究,关于细胞SUMO化调节的机制和靶向SUMO化的治疗潜力仍然存在有趣的谜团。
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引用次数: 0
Goods and Bads of the Endocannabinoid System as a Therapeutic Target: Lessons Learned after 30 Years. 内源性大麻素系统作为治疗靶点的利弊:30 年后的经验教训。
IF 19.3 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2023-09-01 Epub Date: 2023-05-10 DOI: 10.1124/pharmrev.122.000600
Mauro Maccarrone, Vincenzo Di Marzo, Jürg Gertsch, Uwe Grether, Allyn C Howlett, Tian Hua, Alexandros Makriyannis, Daniele Piomelli, Natsuo Ueda, Mario van der Stelt

The cannabis derivative marijuana is the most widely used recreational drug in the Western world and is consumed by an estimated 83 million individuals (∼3% of the world population). In recent years, there has been a marked transformation in society regarding the risk perception of cannabis, driven by its legalization and medical use in many states in the United States and worldwide. Compelling research evidence and the Food and Drug Administration cannabis-derived cannabidiol approval for severe childhood epilepsy have confirmed the large therapeutic potential of cannabidiol itself, Δ9-tetrahydrocannabinol and other plant-derived cannabinoids (phytocannabinoids). Of note, our body has a complex endocannabinoid system (ECS)-made of receptors, metabolic enzymes, and transporters-that is also regulated by phytocannabinoids. The first endocannabinoid to be discovered 30 years ago was anandamide (N-arachidonoyl-ethanolamine); since then, distinct elements of the ECS have been the target of drug design programs aimed at curing (or at least slowing down) a number of human diseases, both in the central nervous system and at the periphery. Here a critical review of our knowledge of the goods and bads of the ECS as a therapeutic target is presented to define the benefits of ECS-active phytocannabinoids and ECS-oriented synthetic drugs for human health. SIGNIFICANCE STATEMENT: The endocannabinoid system plays important roles virtually everywhere in our body and is either involved in mediating key processes of central and peripheral diseases or represents a therapeutic target for treatment. Therefore, understanding the structure, function, and pharmacology of the components of this complex system, and in particular of key receptors (like cannabinoid receptors 1 and 2) and metabolic enzymes (like fatty acid amide hydrolase and monoacylglycerol lipase), will advance our understanding of endocannabinoid signaling and activity at molecular, cellular, and system levels, providing new opportunities to treat patients.

大麻衍生物大麻是西方世界使用最广泛的娱乐性药物,估计有 8,300 万人(占世界人口的 3%)吸食大麻。近年来,随着大麻在美国和世界许多州的合法化和医疗使用,社会对大麻风险的认识发生了显著转变。令人信服的研究证据以及美国食品和药物管理局批准将大麻二酚用于治疗严重的儿童癫痫,证实了大麻二酚、Δ9-四氢大麻酚和其他植物提取的大麻素(植物大麻素)具有巨大的治疗潜力。值得注意的是,我们的身体有一个由受体、代谢酶和转运体组成的复杂的内源性大麻素系统(ECS),它也受植物大麻素的调节。30 年前发现的第一种内源性大麻素是安乃近(N-arachidonoyl-ethanolamine);从那时起,ECS 的不同元素就成为药物设计计划的目标,目的是治疗(或至少减缓)中枢神经系统和外周的多种人类疾病。在此,我们将对 ECS 作为治疗靶点的利弊进行批判性回顾,以明确具有 ECS 活性的植物大麻素和以 ECS 为导向的合成药物对人类健康的益处。意义声明:内源性大麻素系统在人体内几乎无处不在地发挥着重要作用,要么参与中枢和外周疾病的关键过程,要么是治疗的靶点。因此,了解这一复杂系统各组成部分的结构、功能和药理学,特别是关键受体(如大麻素受体 1 和 2)和代谢酶(如脂肪酸酰胺水解酶和单酰基甘油脂肪酶)的结构、功能和药理学,将推动我们在分子、细胞和系统水平上对内源性大麻素信号和活性的了解,从而为治疗患者提供新的机会。
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引用次数: 0
Extracellular Vesicle Heterogeneity and Its Impact for Regenerative Medicine Applications. 细胞外囊泡的异质性及其对再生医学应用的影响。
IF 21.1 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-09-01 Epub Date: 2023-06-06 DOI: 10.1124/pharmrev.123.000841
Simonides Immanuel van de Wakker, Fleur Michelle Meijers, Joost Petrus Gerardus Sluijter, Pieter Vader

Extracellular vesicles (EVs) are cell-derived membrane-enclosed particles that are involved in physiologic and pathologic processes. EVs are increasingly being studied for therapeutic applications in the field of regenerative medicine. Therapeutic application of stem cell-derived EVs has shown great potential to stimulate tissue repair. However, the exact mechanisms through which they induce this effect have not been fully clarified. This may to a large extent be attributed to a lack of knowledge on EV heterogeneity. Recent studies suggest that EVs represent a heterogeneous population of vesicles with distinct functions. The heterogeneity of EVs can be attributed to differences in their biogenesis, and as such, they can be classified into distinct populations that can then be further subcategorized into various subpopulations. A better understanding of EV heterogeneity is crucial for elucidating their mechanisms of action in tissue regeneration. This review provides an overview of the latest insights on EV heterogeneity related to tissue repair, including the different characteristics that contribute to such heterogeneity and the functional differences among EV subtypes. It also sheds light on the challenges that hinder clinical translation of EVs. Additionally, innovative EV isolation techniques for studying EV heterogeneity are discussed. Improved knowledge of active EV subtypes would promote the development of tailored EV therapies and aid researchers in the translation of EV-based therapeutics to the clinic. SIGNIFICANCE STATEMENT: Within this review we discuss the differences in regenerative properties of extracellular vesicle (EV) subpopulations and implications of EV heterogeneity for development of EV-based therapeutics. We aim to provide new insights into which aspects are leading to heterogeneity in EV preparations and stress the importance of EV heterogeneity studies for clinical applications.

细胞外小泡(EVs)是一种细胞衍生的膜包裹颗粒,参与生理和病理过程。电动汽车越来越多地被研究用于再生医学领域的治疗应用。干细胞衍生EVs的治疗应用已显示出刺激组织修复的巨大潜力。然而,它们诱导这种效应的确切机制尚未完全阐明。这可能在很大程度上归因于缺乏对电动汽车异质性的了解。最近的研究表明,EVs代表了一个具有不同功能的异质性囊泡群体。EVs的异质性可以归因于其生物发生的差异,因此,它们可以被分类为不同的种群,然后可以进一步细分为不同的亚种群。更好地了解EV的异质性对于阐明其在组织再生中的作用机制至关重要。这篇综述概述了与组织修复相关的EV异质性的最新见解,包括导致这种异质性的不同特征以及EV亚型之间的功能差异。它还揭示了阻碍EVs临床翻译的挑战。此外,还讨论了用于研究电动汽车异质性的创新电动汽车隔离技术。对活性EV亚型的了解的提高将促进量身定制的EV疗法的发展,并帮助研究人员将基于EV的疗法转化为临床。意义声明:在这篇综述中,我们讨论了细胞外囊泡(EV)亚群再生特性的差异,以及EV异质性对开发基于EV的治疗方法的影响。我们旨在为EV制剂中哪些方面导致异质性提供新的见解,并强调EV异质性研究对临床应用的重要性。
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引用次数: 6
Pharmacological Regulation of Endoplasmic Reticulum Structure and Calcium Dynamics: Importance for Neurodegenerative Diseases. 内质网结构和钙动力学的药理调节:对神经退行性疾病的重要性。
IF 21.1 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-09-01 DOI: 10.1124/pharmrev.122.000701
Ilmari Parkkinen, Anna Their, Muhammad Yasir Asghar, Sreesha Sree, Eija Jokitalo, Mikko Airavaara

The endoplasmic reticulum (ER) is the largest organelle of the cell, composed of a continuous network of sheets and tubules, and is involved in protein, calcium (Ca2+), and lipid homeostasis. In neurons, the ER extends throughout the cell, both somal and axodendritic compartments, and is highly important for neuronal functions. A third of the proteome of a cell, secreted and membrane-bound proteins, are processed within the ER lumen and most of these proteins are vital for neuronal activity. The brain itself is high in lipid content, and many structural lipids are produced, in part, by the ER. Cholesterol and steroid synthesis are strictly regulated in the ER of the blood-brain barrier protected brain cells. The high Ca2+ level in the ER lumen and low cytosolic concentration is needed for Ca2+-based intracellular signaling, for synaptic signaling and Ca2+ waves, and for preparing proteins for correct folding in the presence of high Ca2+ concentrations to cope with the high concentrations of extracellular milieu. Particularly, ER Ca2+ is controlled in axodendritic areas for proper neurito- and synaptogenesis and synaptic plasticity and remodeling. In this review, we cover the physiologic functions of the neuronal ER and discuss it in context of common neurodegenerative diseases, focusing on pharmacological regulation of ER Ca2+ Furthermore, we postulate that heterogeneity of the ER, its protein folding capacity, and ensuring Ca2+ regulation are crucial factors for the aging and selective vulnerability of neurons in various neurodegenerative diseases. SIGNIFICANCE STATEMENT: Endoplasmic reticulum (ER) Ca2+ regulators are promising therapeutic targets for degenerative diseases for which efficacious drug therapies do not exist. The use of pharmacological probes targeting maintenance and restoration of ER Ca2+ can provide restoration of protein homeostasis (e.g., folding of complex plasma membrane signaling receptors) and slow down the degeneration process of neurons.

内质网(ER)是细胞中最大的细胞器,由片状和小管组成的连续网络,参与蛋白质、钙(Ca2+)和脂质稳态。在神经元中,内质网延伸到整个细胞,包括染色体和轴突隔室,对神经元功能非常重要。细胞蛋白质组的三分之一,分泌和膜结合蛋白,在内质网管内处理,其中大多数蛋白质对神经元活动至关重要。大脑本身脂质含量很高,许多结构性脂质部分是由内质网产生的。胆固醇和类固醇的合成在受血脑屏障保护的脑细胞内质网中受到严格的调节。内质网腔内的高Ca2+水平和低细胞质浓度是基于Ca2+的细胞内信号,突触信号和Ca2+波,以及在高Ca2+浓度存在下为正确折叠准备蛋白质以应对高浓度的细胞外环境所需要的。特别是,内质网Ca2+在轴突区域受到控制,以实现适当的神经和突触发生以及突触的可塑性和重塑。在这篇综述中,我们涵盖了神经元内质网的生理功能,并在常见的神经退行性疾病的背景下讨论了它,重点是内质网Ca2+的药理调节。此外,我们假设内质网的异质性、其蛋白质折叠能力和确保Ca2+调节是各种神经退行性疾病中神经元衰老和选择性易感性的关键因素。意义声明:内质网(ER) Ca2+调节剂是目前尚无有效药物治疗的退行性疾病的有希望的治疗靶点。使用靶向ER Ca2+维持和恢复的药理学探针可以恢复蛋白质稳态(例如,复杂质膜信号受体的折叠)并减缓神经元的变性过程。
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引用次数: 2
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Pharmacological Reviews
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