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Role of specific CDKs in regulating DNA damage repair responses and replication stress 特定 CDK 在调节 DNA 损伤修复反应和复制压力中的作用
IF 4 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-10 DOI: 10.1016/j.coph.2024.102485

Cyclins along with their catalytic units, Cyclin-dependent kinases (CDKs) regulate the cell cycle transition and transcription; and are essentially known as ‘master regulators’ in modulating DNA damage response (DDR) and replication stress. In addition to influencing DNA repair and damage signaling, CDKs also play a pivotal role in cell division fidelity and the maintenance of genomic integrity after DNA damage. In this review, we focus on the intricate ways by which specific CDKs mainly CDK7, CDK9, and CDK12/13, regulate the cell cycle progression and transcription and how their modulation can lead to lethal effects on the integrity of the genome. With a better knowledge of how these CDKs control the DDR and replication stress, it is now possible to combine CDK inhibitors with chemotherapeutic drugs that damage DNA in ways that can be applied in clinical settings as successful therapeutic strategies.

细胞周期蛋白及其催化单元--细胞周期蛋白依赖性激酶(CDKs)调控细胞周期的转换和转录,被称为调节 DNA 损伤反应(DDR)和复制应激的 "主调节器"。除了影响 DNA 修复和损伤信号转导外,CDK 还在 DNA 损伤后细胞分裂的保真度和基因组完整性的维护方面发挥着关键作用。在这篇综述中,我们将重点关注特定 CDK(主要是 CDK7、CDK9 和 CDK12/13)调控细胞周期进程和转录的复杂方式,以及它们的调控如何导致对基因组完整性的致命影响。随着人们对这些 CDK 如何控制 DDR 和复制应激有了更深入的了解,现在有可能将 CDK 抑制剂与损伤 DNA 的化疗药物结合起来,作为成功的治疗策略应用于临床。
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引用次数: 0
Therapeutic innovations for geographic atrophy: A promising horizon 地理萎缩的治疗创新:前景光明。
IF 4 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-06 DOI: 10.1016/j.coph.2024.102484

This mini review spotlights the most promising treatments for geographic atrophy, the advanced form of age-related macular degeneration, often resulting in severe and irreversible vision loss. The pathophysiology is complex, and various therapeutic strategies, including anticomplement therapies, gene therapies, cell-based interventions, and artificial intelligence–driven diagnostics are discussed.

Anticomplement therapies (antifactors C3 and C5) showed promise in reducing the inflammatory response and the progression of the atrophy. Gene therapies, targeting specific genetic mutations, are under development to correct underlying defects and potentially reverse disease progression. Cell-based therapies are gaining momentum, with early studies indicating encouraging results in the replacement of damaged retinal pigment epithelium cells.

地理萎缩是老年性黄斑变性的晚期形式,通常会导致严重和不可逆的视力丧失。病理生理学非常复杂,本文将讨论各种治疗策略,包括抗互补疗法、基因疗法、细胞干预和人工智能诊断。抗互补疗法(抗原 C3 和 C5)在减轻炎症反应和减少萎缩进展方面显示出前景。目前正在开发针对特定基因突变的基因疗法,以纠正潜在的缺陷,并有可能逆转疾病的进展。以细胞为基础的疗法势头正劲,早期研究表明,在替换受损视网膜色素上皮细胞方面取得了令人鼓舞的成果。
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引用次数: 0
Targeting the soluble epoxide hydrolase pathway as a novel therapeutic approach for the treatment of pain 将可溶性环氧化物水解酶途径作为治疗疼痛的一种新方法
IF 4 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-27 DOI: 10.1016/j.coph.2024.102477

Chronic pain is a major burden and the complexities of chronic pain pathophysiology, including both peripheral and central sensitisation mechanisms, involves multiple cell types (neuronal, immune, neuroimmune, and vascular) which substantially complicates the development of new effective analgesic treatments. The epoxy fatty acids (EpFAs), including the epoxyeicosatrienoic acids (EETs), are derived from the metabolism of polyunsaturated fatty acids (PUFAs) via the cytochrome P450 enzymatic pathway and act to shut-down inflammatory signalling and provide analgesia. The EpFAs are rapidly metabolised by the enzyme soluble epoxide hydrolase (sEH) into their corresponding diol metabolites, which recent studies suggest are pro-inflammatory and pro-nociceptive. This review discusses clinical and mechanistic evidence for targeting the sEH pathway for the treatment of pain.

慢性疼痛是一种主要负担,慢性疼痛病理生理学复杂,包括外周和中枢敏化机制,涉及多种细胞类型(神经元、免疫、神经免疫和血管),这大大增加了开发新的有效镇痛疗法的难度。环氧脂肪酸(EpFAs),包括环氧二十碳三烯酸(EETs),是多不饱和脂肪酸(PUFAs)通过细胞色素 P450 酶途径代谢产生的,其作用是关闭炎症信号并提供镇痛。EpFAs 通过可溶性环氧化物水解酶(sEH)迅速代谢为相应的二元醇代谢物,最近的研究表明这些代谢物具有促炎和促痛觉的作用。本综述讨论了针对 sEH 途径治疗疼痛的临床和机理证据。
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引用次数: 0
Native botulinum toxin type A vs. redesigned botulinum toxins in pain: What did we learn so far? A型肉毒杆菌毒素与重新设计的肉毒杆菌毒素在疼痛治疗中的对比:迄今为止我们学到了什么?
IF 4 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-22 DOI: 10.1016/j.coph.2024.102476

Driven by the clinical success of botulinum toxin serotype A (BoNT/A) and the need for improved chronic pain management, researchers attempted to develop re-designed botulinum toxin (BoNT)-based molecules as novel analgesics. Various recombinant protein expression strategies including retargeted binding domains, and chimeric toxins combining different serotypes were tested to improve BoNT/A therapeutic safety margin and expand its efficacy. The aim of this review is to re-evaluate the current design strategies for recombinant BoNT-based molecules for pain treatment, compares their analgesic profile against the native BoNT/A, as well as to discuss the main strengths and potential weaknesses of reported approaches.

由于 A 血清型肉毒毒素(BoNT/A)在临床上取得了成功,而且慢性疼痛治疗需要得到改善,研究人员试图开发重新设计的基于肉毒毒素(BoNT)的分子作为新型镇痛剂。研究人员测试了各种重组蛋白表达策略,包括重定向结合域和结合不同血清型的嵌合毒素,以提高 BoNT/A 的治疗安全系数并扩大其疗效。本综述旨在重新评估目前基于重组 BoNT 分子的疼痛治疗设计策略,比较其与原生 BoNT/A 的镇痛效果,并讨论已报道方法的主要优势和潜在不足。
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引用次数: 0
Preoperative optimization: Review on nutritional assessment and strategies in IBD 术前优化:回顾 IBD 的营养评估和策略。
IF 4 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-01 DOI: 10.1016/j.coph.2024.102475

Inflammatory bowel diseases (IBD), encompassing conditions like Crohn's disease and ulcerative colitis, present multifaceted challenges requiring a comprehensive management approach. Patients often necessitate a combination of medical therapy, surgical interventions, and nutritional support. Despite advancements in medical and dietary therapies, the prevalence of surgery remains high among the IBD population, alongside the persistent risk of malnutrition. Preoperative nutritional optimization has thus become a critical element in the perioperative pathway, given its association with improved surgical outcomes. However, standardized protocols for preoperative optimization of IBD patients are lacking, and available data are mainly retrospective.

This review provides an overview of the current knowledge on preoperative nutritional screening and optimization in IBD patients and identifies avenues for future research and clinical practice.

Interdisciplinary collaboration among healthcare professionals, including gastroenterologists, surgeons, dietitians, physiotherapists, and psychologists, is crucial for comprehensive preoperative nutritional management in IBD patients. By addressing the interplay between inflammation, malnutrition, and surgical risk, clinicians can strive to enhance surgical care and postoperative outcomes.

In conclusion, while recognizing the importance of preoperative nutritional optimization in improving surgical outcomes for IBD patients, challenges persist in standardizing management protocols. Prospective studies are needed to establish such protocols and evaluate the effectiveness of different nutritional strategies.

炎症性肠病(IBD)包括克罗恩病(Crohn's disease)和溃疡性结肠炎(ulcerative colitis)等疾病,它带来了多方面的挑战,需要全面的治疗方法。患者通常需要结合药物治疗、手术干预和营养支持。尽管医疗和饮食疗法取得了进步,但在 IBD 患者中,手术的发生率仍然很高,同时营养不良的风险也持续存在。因此,术前营养优化已成为围手术期的关键因素,因为它与手术效果的改善息息相关。然而,目前还缺乏针对 IBD 患者术前优化的标准化方案,现有数据也主要是回顾性的。本综述概述了目前有关 IBD 患者术前营养筛查和优化的知识,并指出了未来研究和临床实践的方向。包括消化内科医生、外科医生、营养师、理疗师和心理学家在内的医护人员之间的跨学科合作对于 IBD 患者术前的全面营养管理至关重要。通过解决炎症、营养不良和手术风险之间的相互作用,临床医生可以努力提高手术护理和术后效果。总之,虽然认识到术前营养优化对改善 IBD 患者手术预后的重要性,但标准化管理方案仍面临挑战。需要进行前瞻性研究来制定此类方案并评估不同营养策略的效果。
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引用次数: 0
Drug effects on neuropeptides and their receptors: Big hopes but moderate success in the treatment of chronic pain 药物对神经肽及其受体的影响:在治疗慢性疼痛方面希望很大,但成效一般。
IF 4 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-01 DOI: 10.1016/j.coph.2024.102474

Neuropeptides, including tachykinins, CGRP, and somatostatin, are localized in a peptidergic subgroup of nociceptive primary afferent neurons. Tachykinins and CGRP are pronociceptive, somatostatin is an antinociceptive mediator. Intensive drug research has been performed to develop tachykinin and CGRP antagonists, and somatostatin agonists as analgesics. CGRP receptor antagonists are efficacious and well-tolerated drugs in migraine. Monoclonal antibodies against CGRP or its receptor are used for the prophylactic treatment of migraine. Tachykinin NK1 receptor antagonists failed as analgesics but are used for chemotherapy-induced nausea and vomiting. New, orally active somatostatin 4 receptor agonists are promising drug candidates for treating various pain conditions.

神经肽,包括速激肽、血管内皮生长因子和体生长抑素,定位于痛觉初级传入神经元的肽能亚群。速激肽和 CGRP 具有代痛觉作用,而体生长抑素则是一种抗痛觉介质。为开发速激肽和 CGRP 拮抗剂以及体生长抑素激动剂作为镇痛剂,人们进行了大量的药物研究。CGRP 受体拮抗剂是治疗偏头痛的有效且耐受性良好的药物。针对 CGRP 或其受体的单克隆抗体可用于偏头痛的预防性治疗。速激肽 NK1 受体拮抗剂镇痛效果不佳,但可用于化疗引起的恶心和呕吐。新型口服活性体生长抑素 4 受体激动剂是治疗各种疼痛病症的有希望的候选药物。
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引用次数: 0
Modulating regulatory T cell migration in the treatment of autoimmunity and autoinflammation 调节调节性 T 细胞迁移以治疗自身免疫和自身炎症
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-06-20 DOI: 10.1016/j.coph.2024.102466
John Martin , Zoe Hollowood , Jamie Chorlton , Carlene Dyer , Federica Marelli-Berg

Treatment of autoimmunity and autoinflammation with regulatory T cells has received much attention in the last twenty years. Despite the well-documented clinical benefit of Treg therapy, a large-scale application has proven elusive, mainly due to the extensive culture facilities required and associated costs. A possible way to overcome these hurdles in part is to target Treg migration to inflammatory sites using a small molecule. Here we review recent advances in this strategy and introduce the new concept of pharmacologically enhanced delivery of endogenous Tregs to control inflammation, which has been recently validated in humans.

过去二十年来,用调节性 T 细胞治疗自身免疫和自身炎症受到了广泛关注。尽管调节性 T 细胞疗法的临床疗效有据可查,但大规模应用却一直难以实现,主要原因是需要大量培养设施和相关成本。部分克服这些障碍的可能方法是使用小分子靶向 Treg 迁移到炎症部位。在此,我们回顾了这一策略的最新进展,并介绍了药理增强输送内源性 Tregs 以控制炎症的新概念,这一概念最近已在人体中得到验证。
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引用次数: 0
Pharmacological regulation of HIF-1α, RGC death, and glaucoma 对 HIF-1α、RGC 死亡和青光眼的药理调节
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-06-18 DOI: 10.1016/j.coph.2024.102467
Shahid Husain, Ryan Leveckis

Hypoxia can regulate oxygen-sensitive pathways that could be neuroprotective to compensate for the detrimental effects of low oxygen. However, prolonged hypoxia can activate neurodegenerative pathways. HIF-1α is upregulated/stabilized in hypoxic conditions, promoting alteration of gene expression, and ultimately leading to cell-death. Therefore, regulation of HIF-1α expression pharmacologically is a vital approach to mitigate cell death. In this review, we provide information showing the role of HIF-1α and its associated pathways in ocular retinopathies. We also discuss the beneficial roles of HIF-1α inhibitor, KC7F2, in ocular pathologies. Finally, we provided our own data demonstrating RGC neuroprotection by KC7F2 in glaucomatous animals.

缺氧可以调节对氧敏感的途径,从而起到保护神经的作用,弥补低氧的有害影响。然而,长期缺氧会激活神经退行性病变途径。HIF-1α 在缺氧条件下上调/稳定,促进基因表达的改变,最终导致细胞死亡。因此,通过药物调节 HIF-1α 的表达是缓解细胞死亡的重要方法。在这篇综述中,我们提供的信息显示了 HIF-1α 及其相关通路在眼部视网膜病变中的作用。我们还讨论了 HIF-1α 抑制剂 KC7F2 在眼部病变中的有益作用。最后,我们提供了自己的数据,证明了 KC7F2 对青光眼动物 RGC 神经的保护作用。
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引用次数: 0
Biased signalling in analgesic research and development 镇痛药研发中的偏差信号。
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-06-01 DOI: 10.1016/j.coph.2024.102465
Alexandra Conibear , Chris P. Bailey , Eamonn Kelly

Ligand bias offers a novel means to improve the therapeutic profile of drugs. With regard to G protein-coupled receptors involved in analgesia, it could be advantageous to develop such drugs if the analgesic effect is mediated by a different cellular signalling pathway than the adverse effects associated with the drug. Whilst this has been explored over a number of years for the μ receptor, it remains unclear whether this approach offers significant benefit for the treatment of pain. Nevertheless, the development of biased ligands at other G protein-coupled receptors in the CNS does offer some promise for the development of novel analgesic drugs in the future. Here we summarise and discuss the recent evidence to support this.

配体偏倚为改善药物的治疗效果提供了一种新方法。就参与镇痛的 G 蛋白偶联受体而言,如果镇痛效果是由不同的细胞信号途径介导的,而不是由与药物相关的不良反应介导的,那么开发此类药物就会很有优势。多年来,人们一直在探索如何治疗μ受体,但目前仍不清楚这种方法是否能为疼痛治疗带来显著益处。不过,中枢神经系统中其他 G 蛋白偶联受体的偏性配体的开发确实为未来新型镇痛药物的开发提供了一些希望。在此,我们总结并讨论了支持这一观点的最新证据。
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引用次数: 0
Effects of protein glycation and protective mechanisms against glycative stress 蛋白质糖化的影响和糖化应激的保护机制
IF 4 3区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-05-25 DOI: 10.1016/j.coph.2024.102464
Jade A. Najjar, John W. Calvert

Glycation is a posttranslational modification of proteins that contributes to the vast array of biological information that can be conveyed via a singular proteome. Understanding the role of advanced glycation end-products (AGEs) in human health and pathophysiology can be difficult, as the physiological effects of AGEs have been associated with multiple biological processes and disease state development, including acute myocardial ischemia-reperfusion injury, heart failure, and atherosclerosis, as well as tumor cell migration. The critical role of the glyoxalase system in the detoxification of methylglyoxal and other AGEs has been well established. Recently, evidence has emerged that DJ-1 displays antiglycative activity and may contribute to another mechanism of protection against protein glycation outside of the glyoxalase system. Identification of potential substrates of DJ-1 and determination of the pathways in which DJ-1 operates, is needed to fully understand the role of this protein in modulating biological homeostasis and the development of disease.

糖化是蛋白质的一种翻译后修饰,可通过单个蛋白质组传递大量生物信息。了解高级糖化终产物(AGEs)在人类健康和病理生理学中的作用可能很困难,因为 AGEs 的生理效应与多种生物过程和疾病状态的发展有关,包括急性心肌缺血再灌注损伤、心力衰竭、动脉粥样硬化以及肿瘤细胞迁移。乙二醛酶系统在甲基乙二醛和其他 AGEs 的解毒过程中的关键作用已得到公认。最近有证据表明,DJ-1 具有抗糖化活性,可能是乙二醛酶系统之外另一种防止蛋白质糖化的机制。要全面了解 DJ-1 蛋白在调节生物稳态和疾病发展中的作用,就需要鉴定 DJ-1 的潜在底物并确定 DJ-1 的作用途径。
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引用次数: 0
期刊
Current Opinion in Pharmacology
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