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Highlighting vulnerabilities in the alternative lengthening of telomeres pathway 强调端粒替代延长途径的脆弱性
IF 4 3区 医学
Current Opinion in Pharmacology Pub Date : 2023-06-01 DOI: 10.1016/j.coph.2023.102380
Lisa M. Carson, Rachel L. Flynn
{"title":"Highlighting vulnerabilities in the alternative lengthening of telomeres pathway","authors":"Lisa M. Carson,&nbsp;Rachel L. Flynn","doi":"10.1016/j.coph.2023.102380","DOIUrl":"10.1016/j.coph.2023.102380","url":null,"abstract":"<div><p><span>The alternative lengthening of telomeres (ALT) pathway is a telomere elongation mechanism found in a small but often aggressive subset of cancers. Dependent on break-induced replication, telomere extension in ALT-positive cells relies on a baseline level of </span>DNA replication stress to initiate elongation events. This results in an elevated level of DNA damage and presents a possible vulnerability to be exploited in the development of ALT-targeted cancer therapies. Currently, there are no treatment options that target the ALT mechanism or that are specific for ALT-positive tumors. Here, we review recent developments and promising directions in the development of ALT-targeted therapeutics, many of which involve tipping the balance towards inhibition or exacerbation of ALT activity to selectively target these cells.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"70 ","pages":"Article 102380"},"PeriodicalIF":4.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10247456/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9978578","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: 1
Extracellular adenosine signaling in bone health and disease 细胞外腺苷信号在骨骼健康和疾病中的作用
IF 4 3区 医学
Current Opinion in Pharmacology Pub Date : 2023-06-01 DOI: 10.1016/j.coph.2023.102378
Hunter Newman , Shyni Varghese
{"title":"Extracellular adenosine signaling in bone health and disease","authors":"Hunter Newman ,&nbsp;Shyni Varghese","doi":"10.1016/j.coph.2023.102378","DOIUrl":"10.1016/j.coph.2023.102378","url":null,"abstract":"<div><p>Purinergic signaling is a key molecular pathway in the maintenance of bone health and regeneration. P1 receptor<span> signaling, which is activated by extracellular adenosine, has emerged as a key metabolic pathway that regulates bone tissue formation, function, and homeostasis. Extracellular adenosine is mainly produced by ectonucleotidases, and alterations in the function of these enzymes or compromised adenosine generation can result in bone disorders, such as osteoporosis and impaired fracture healing. This mini review discusses the key role played by adenosine in bone health and how its alterations contribute to bone diseases, as well as potential therapeutic applications of exogenous adenosine to combat bone diseases like osteoporosis and injury.</span></p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"70 ","pages":"Article 102378"},"PeriodicalIF":4.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10247430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9596720","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 DNA damage repair precision medicine strategies in cancer 癌症靶向DNA损伤修复精准医疗策略
IF 4 3区 医学
Current Opinion in Pharmacology Pub Date : 2023-06-01 DOI: 10.1016/j.coph.2023.102381
Juliette Brownlie , Sanat Kulkarni , Mashael Algethami , Jennie N. Jeyapalan , Nigel P. Mongan , Emad A. Rakha , Srinivasan Madhusudan
{"title":"Targeting DNA damage repair precision medicine strategies in cancer","authors":"Juliette Brownlie ,&nbsp;Sanat Kulkarni ,&nbsp;Mashael Algethami ,&nbsp;Jennie N. Jeyapalan ,&nbsp;Nigel P. Mongan ,&nbsp;Emad A. Rakha ,&nbsp;Srinivasan Madhusudan","doi":"10.1016/j.coph.2023.102381","DOIUrl":"10.1016/j.coph.2023.102381","url":null,"abstract":"<div><p>DNA repair targeted therapeutics is a promising precision medicine strategy in cancer. The development and clinical use of PARP inhibitors has transformed lives for many patients with <em>BRCA</em> germline deficient breast and ovarian cancer as well as platinum sensitive epithelial ovarian cancers. However, lessons learnt from the clinical use of PARP inhibitors also confirm that not all patients respond either due to intrinsic or acquired resistance. Therefore, the search for additional synthetic lethality approaches is an active area of translational and clinical research. Here, we review the current clinical state of PARP inhibitors and other evolving DNA repair targets including ATM, ATR, WEE1 inhibitors and others in cancer.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"70 ","pages":"Article 102381"},"PeriodicalIF":4.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9660135","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: 2
Targeting the altered duodenal microenvironment in functional dyspepsia 靶向改变的十二指肠微环境治疗功能性消化不良
IF 4 3区 医学
Current Opinion in Pharmacology Pub Date : 2023-06-01 DOI: 10.1016/j.coph.2023.102363
Matthias Ceulemans , Lucas Wauters , Tim Vanuytsel
{"title":"Targeting the altered duodenal microenvironment in functional dyspepsia","authors":"Matthias Ceulemans ,&nbsp;Lucas Wauters ,&nbsp;Tim Vanuytsel","doi":"10.1016/j.coph.2023.102363","DOIUrl":"10.1016/j.coph.2023.102363","url":null,"abstract":"<div><p><span><span>Duodenal micro-inflammation and microbial dysregulation are increasingly recognized to play an important role in functional dyspepsia (FD) </span>pathophysiology<span>, previously regarded as a purely functional disorder. With current therapeutic options contested through insufficient efficacy or unfavorable adverse effects<span> profiles, novel treatments directed to duodenal alterations could result in superior symptom control in at least a subset of patients. Indeed, recent advances in FD research provided evidence for anti-inflammatory therapies to relieve gastroduodenal symptoms by reducing duodenal eosinophils or mast cells. In addition, restoring microbial homeostasis by probiotics<span> proved to be successful in FD. As the exact mechanisms by which these novel pharmacological approaches result in clinical benefit often remain to be elucidated, future research should focus on how immune activation and dysbiosis translate into typical FD </span></span></span></span>symptomatology.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"70 ","pages":"Article 102363"},"PeriodicalIF":4.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9959781","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
Hepatic arterial infusion chemotherapy for patients with hepatocellular carcinoma: Applicability in Western countries 肝细胞癌患者肝动脉灌注化疗在西方国家的适用性
IF 4 3区 医学
Current Opinion in Pharmacology Pub Date : 2023-06-01 DOI: 10.1016/j.coph.2023.102362
MinKe He , ShuYue Liu , ZhiCheng Lai , ZeFeng Du , QiJiong Li , Li Xu , Anna Kan , JianXian Shen , Ming Shi
{"title":"Hepatic arterial infusion chemotherapy for patients with hepatocellular carcinoma: Applicability in Western countries","authors":"MinKe He ,&nbsp;ShuYue Liu ,&nbsp;ZhiCheng Lai ,&nbsp;ZeFeng Du ,&nbsp;QiJiong Li ,&nbsp;Li Xu ,&nbsp;Anna Kan ,&nbsp;JianXian Shen ,&nbsp;Ming Shi","doi":"10.1016/j.coph.2023.102362","DOIUrl":"10.1016/j.coph.2023.102362","url":null,"abstract":"<div><p>Hepatic arterial infusion chemotherapy with oxaliplatin<span>, 5-fluorouracil, and leucovorin<span><span><span> (FOLFOX-HAIC) has shown a strong anti-tumor effect in hepatocellular carcinoma in China. Different from hepatocellular carcinoma in China, hepatocellular carcinoma in Western countries is caused by hepatitis C and </span>alcoholic liver disease, and is often diagnosed at an early stage, when the tumor is small or the </span>thrombus is not serious. Although there are no reports of FOLFOX-HAIC efficacy for hepatocellular carcinoma in Western countries, FOLFOX-HAIC can be used in patients with large tumors (&gt; 5 cm) (or T3 by TNM stage), and rich blood supply.</span></span></p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"70 ","pages":"Article 102362"},"PeriodicalIF":4.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9605237","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 development for the treatment of RyR1-related skeletal muscle diseases 治疗RyR1相关骨骼肌疾病的药物开发
IF 4 3区 医学
Current Opinion in Pharmacology Pub Date : 2023-04-01 DOI: 10.1016/j.coph.2023.102356
Takashi Murayama , Nagomi Kurebayashi , Ryosuke Ishida , Hiroyuki Kagechika
{"title":"Drug development for the treatment of RyR1-related skeletal muscle diseases","authors":"Takashi Murayama ,&nbsp;Nagomi Kurebayashi ,&nbsp;Ryosuke Ishida ,&nbsp;Hiroyuki Kagechika","doi":"10.1016/j.coph.2023.102356","DOIUrl":"10.1016/j.coph.2023.102356","url":null,"abstract":"<div><p>Type 1 ryanodine receptor (RyR1) is an intracellular Ca<sup>2+</sup><span> release channel on the sarcoplasmic reticulum<span> of skeletal muscle, and it plays a central role in excitation–contraction (E-C) coupling. Mutations in RyR1 are implicated in various muscle diseases<span> including malignant hyperthermia<span>, central core disease, and myopathies. Currently, no specific treatment exists for most of these diseases. Recently, high-throughput screening (HTS) assays have been developed for identifying potential candidates for treating RyR-related muscle diseases. Currently, two different methods, namely a FRET-based assay and an endoplasmic reticulum Ca</span></span></span></span><sup>2+</sup>-based assay, are available. These assays identified several compounds as novel RyR1 inhibitors. In addition, the development of a reconstituted platform permitted HTS assays for E-C coupling modulators. In this review, we will focus on recent progress in HTS assays and discuss future perspectives of these promising approaches.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"69 ","pages":"Article 102356"},"PeriodicalIF":4.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9497217","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: 2
Pharmacology of pannexin channels 血管紧张素通道的药理学
IF 4 3区 医学
Current Opinion in Pharmacology Pub Date : 2023-04-01 DOI: 10.1016/j.coph.2023.102359
Michael Koval , Wyatt J. Schug , Brant E. Isakson
{"title":"Pharmacology of pannexin channels","authors":"Michael Koval ,&nbsp;Wyatt J. Schug ,&nbsp;Brant E. Isakson","doi":"10.1016/j.coph.2023.102359","DOIUrl":"10.1016/j.coph.2023.102359","url":null,"abstract":"<div><p>Pannexin channels play fundamental roles in regulating inflammation and have been implicated in many diseases including hypertension, stroke, and neuropathic pain. Thus, the ability to pharmacologically block these channels is a vital component of several therapeutic approaches. Pharmacologic interrogation of model systems also provides a means to discover new roles for pannexins in cell physiology. Here, we review the state of the art for agents that can be used to block pannexin channels, with a focus on chemical pharmaceuticals and peptide mimetics that act on pannexin 1. Guidance on interpreting results obtained with pannexin pharmacologics in experimental systems is discussed, as well as strengths and caveats of different agents, including specificity and feasibility of clinical application.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"69 ","pages":"Article 102359"},"PeriodicalIF":4.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10023479/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9512943","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: 10
The role of extracellular ATP and P2X receptors in the pathogenesis of HIV-1 细胞外ATP和P2X受体在HIV-1发病机制中的作用
IF 4 3区 医学
Current Opinion in Pharmacology Pub Date : 2023-04-01 DOI: 10.1016/j.coph.2023.102358
Natalia R. Rodriguez, Trinisia Fortune, Thien Vuong, Talia H. Swartz
{"title":"The role of extracellular ATP and P2X receptors in the pathogenesis of HIV-1","authors":"Natalia R. Rodriguez,&nbsp;Trinisia Fortune,&nbsp;Thien Vuong,&nbsp;Talia H. Swartz","doi":"10.1016/j.coph.2023.102358","DOIUrl":"10.1016/j.coph.2023.102358","url":null,"abstract":"<div><p><span><span>Human Immunodeficiency Virus Type 1 (HIV-1) causes a chronic, incurable infection associated with </span>chronic inflammation<span> despite virologic suppression on antiretroviral therapy (ART). This chronic inflammation underlies significant comorbidities, including cardiovascular disease, neurocognition decline, and malignancies. The mechanisms of chronic inflammation have been attributed, in part, to the role of extracellular ATP and P2X-type purinergic receptors<span><span> that sense damaged or dying cells and undergo signaling responses to activate inflammation and immunomodulation. This review describes the current literature on the role of extracellular ATP and </span>P2X receptors in HIV-1 pathogenesis, describing the known intersection with the HIV-1 life cycle in mediating </span></span></span>immunopathogenesis<span> and neuronal disease. The literature supports key roles for this signaling mechanism in cell-to-cell communication and in activating transcriptional changes that impact the inflammatory state leading to disease progression. Future studies must characterize the numerous functions of ATP and P2X receptors in HIV-1 pathogenesis to inform future therapeutic targeting.</span></p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"69 ","pages":"Article 102358"},"PeriodicalIF":4.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10023410/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9142018","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
The blood pressure lowering effects of glucagon-like peptide-1 receptor agonists: A mini-review of the potential mechanisms 胰高血糖素样肽-1受体激动剂的降压作用：潜在机制的初步综述
IF 4 3区 医学
Current Opinion in Pharmacology Pub Date : 2023-04-01 DOI: 10.1016/j.coph.2023.102355
Joao Carlos Ribeiro-Silva , Caio A.M. Tavares , Adriana C.C. Girardi
{"title":"The blood pressure lowering effects of glucagon-like peptide-1 receptor agonists: A mini-review of the potential mechanisms","authors":"Joao Carlos Ribeiro-Silva ,&nbsp;Caio A.M. Tavares ,&nbsp;Adriana C.C. Girardi","doi":"10.1016/j.coph.2023.102355","DOIUrl":"10.1016/j.coph.2023.102355","url":null,"abstract":"<div><p>The incretin hormone<span><span> glucagon-like peptide 1 (GLP-1) is a key component of the signaling mechanisms promoting glucose homeostasis. Clinical and experimental studies demonstrated that GLP-1 receptor agonists, including GLP-1 itself, have favorable effects on blood pressure and reduce the risk of major cardiovascular events, independently of their effect on glycemic control. GLP-1 receptors are present in the hypothalamus and brainstem, the </span>carotid body, the vasculature, and the kidneys. These organs are involved in blood pressure regulation, have their function altered in hypertension, and are positively benefited by the treatment with GLP-1 receptor agonists. Here, we discuss the potential mechanisms whereby activation of GLP-1R signaling exerts blood pressure-lowering effects beyond glycemic control.</span></p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"69 ","pages":"Article 102355"},"PeriodicalIF":4.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9143693","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: 1
Editorial overview: Immune regulation and cancers 编辑综述：免疫调节与癌症
IF 4 3区 医学
Current Opinion in Pharmacology Pub Date : 2023-04-01 DOI: 10.1016/j.coph.2023.102360
Carlotta Giorgi, Shafi Kuchay
{"title":"Editorial overview: Immune regulation and cancers","authors":"Carlotta Giorgi,&nbsp;Shafi Kuchay","doi":"10.1016/j.coph.2023.102360","DOIUrl":"10.1016/j.coph.2023.102360","url":null,"abstract":"","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"69 ","pages":"Article 102360"},"PeriodicalIF":4.0,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10002678","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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