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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
Current Opinion in Pharmacology Pub Date : 2024-09-10 DOI: 10.1016/j.coph.2024.102485
{"title":"Role of specific CDKs in regulating DNA damage repair responses and replication stress","authors":"","doi":"10.1016/j.coph.2024.102485","DOIUrl":"10.1016/j.coph.2024.102485","url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142168456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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
Current Opinion in Pharmacology Pub Date : 2024-09-06 DOI: 10.1016/j.coph.2024.102484
{"title":"Therapeutic innovations for geographic atrophy: A promising horizon","authors":"","doi":"10.1016/j.coph.2024.102484","DOIUrl":"10.1016/j.coph.2024.102484","url":null,"abstract":"<div><p>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.</p><p>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.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1471489224000547/pdfft?md5=df5b4fff4283445369fb45638e495d89&pid=1-s2.0-S1471489224000547-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142146764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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
Current Opinion in Pharmacology Pub Date : 2024-08-27 DOI: 10.1016/j.coph.2024.102477
{"title":"Targeting the soluble epoxide hydrolase pathway as a novel therapeutic approach for the treatment of pain","authors":"","doi":"10.1016/j.coph.2024.102477","DOIUrl":"10.1016/j.coph.2024.102477","url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S147148922400047X/pdfft?md5=a9b581da49f5aa67863f4733f9fed885&pid=1-s2.0-S147148922400047X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142084204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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
Current Opinion in Pharmacology Pub Date : 2024-08-22 DOI: 10.1016/j.coph.2024.102476
{"title":"Native botulinum toxin type A vs. redesigned botulinum toxins in pain: What did we learn so far?","authors":"","doi":"10.1016/j.coph.2024.102476","DOIUrl":"10.1016/j.coph.2024.102476","url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142044637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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
Current Opinion in Pharmacology Pub Date : 2024-08-01 DOI: 10.1016/j.coph.2024.102475
{"title":"Preoperative optimization: Review on nutritional assessment and strategies in IBD","authors":"","doi":"10.1016/j.coph.2024.102475","DOIUrl":"10.1016/j.coph.2024.102475","url":null,"abstract":"<div><p>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.</p><p>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.</p><p>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.</p><p>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.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141914448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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
Current Opinion in Pharmacology Pub Date : 2024-08-01 DOI: 10.1016/j.coph.2024.102474
{"title":"Drug effects on neuropeptides and their receptors: Big hopes but moderate success in the treatment of chronic pain","authors":"","doi":"10.1016/j.coph.2024.102474","DOIUrl":"10.1016/j.coph.2024.102474","url":null,"abstract":"<div><p>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 NK<sub>1</sub> 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.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1471489224000444/pdfft?md5=2c673f991bfcf2fb2e89749522e229b8&pid=1-s2.0-S1471489224000444-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141914447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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
Current Opinion in Pharmacology Pub Date : 2024-06-20 DOI: 10.1016/j.coph.2024.102466
John Martin , Zoe Hollowood , Jamie Chorlton , Carlene Dyer , Federica Marelli-Berg
{"title":"Modulating regulatory T cell migration in the treatment of autoimmunity and autoinflammation","authors":"John Martin ,&nbsp;Zoe Hollowood ,&nbsp;Jamie Chorlton ,&nbsp;Carlene Dyer ,&nbsp;Federica Marelli-Berg","doi":"10.1016/j.coph.2024.102466","DOIUrl":"https://doi.org/10.1016/j.coph.2024.102466","url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141434642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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
Current Opinion in Pharmacology Pub Date : 2024-06-18 DOI: 10.1016/j.coph.2024.102467
Shahid Husain, Ryan Leveckis
{"title":"Pharmacological regulation of HIF-1α, RGC death, and glaucoma","authors":"Shahid Husain,&nbsp;Ryan Leveckis","doi":"10.1016/j.coph.2024.102467","DOIUrl":"https://doi.org/10.1016/j.coph.2024.102467","url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141424289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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
Current Opinion in Pharmacology Pub Date : 2024-06-01 DOI: 10.1016/j.coph.2024.102465
Alexandra Conibear , Chris P. Bailey , Eamonn Kelly
{"title":"Biased signalling in analgesic research and development","authors":"Alexandra Conibear ,&nbsp;Chris P. Bailey ,&nbsp;Eamonn Kelly","doi":"10.1016/j.coph.2024.102465","DOIUrl":"10.1016/j.coph.2024.102465","url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1471489224000353/pdfft?md5=32e81c305fc6f36f94d7422b87926a4d&pid=1-s2.0-S1471489224000353-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141238739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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
Current Opinion in Pharmacology Pub Date : 2024-05-25 DOI: 10.1016/j.coph.2024.102464
Jade A. Najjar, John W. Calvert
{"title":"Effects of protein glycation and protective mechanisms against glycative stress","authors":"Jade A. Najjar,&nbsp;John W. Calvert","doi":"10.1016/j.coph.2024.102464","DOIUrl":"https://doi.org/10.1016/j.coph.2024.102464","url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141095837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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