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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 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-06-01 DOI: 10.1016/j.coph.2023.102380
Lisa M. Carson, Rachel L. Flynn

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 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.

端粒选择性延长(ALT)途径是一种端粒延长机制,在一小部分但往往具有侵袭性的癌症中发现。ALT阳性细胞的端粒延长依赖于断裂诱导的复制,依赖于DNA复制应激的基线水平来启动延长事件。这导致DNA损伤水平升高,并可能在ALT靶向癌症疗法的开发中被利用。目前,还没有针对ALT机制或ALT阳性肿瘤的特异性治疗方案。在这里,我们回顾了ALT靶向疗法的最新发展和有希望的发展方向,其中许多涉及将平衡转向ALT活性的抑制或恶化,以选择性地靶向这些细胞。
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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 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-06-01 DOI: 10.1016/j.coph.2023.102378
Hunter Newman , Shyni Varghese

Purinergic signaling is a key molecular pathway in the maintenance of bone health and regeneration. P1 receptor 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.

嘌呤能信号传导是维持骨骼健康和再生的关键分子途径。P1受体信号传导被细胞外腺苷激活,已成为调节骨组织形成、功能和稳态的关键代谢途径。细胞外腺苷主要由外核苷酸酶产生,这些酶功能的改变或腺苷生成受损可导致骨骼疾病,如骨质疏松和骨折愈合受损。这篇小型综述讨论了腺苷在骨骼健康中发挥的关键作用,以及其改变如何导致骨骼疾病,以及外源性腺苷在对抗骨质疏松和损伤等骨骼疾病中的潜在治疗应用。
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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 Q1 Pharmacology, Toxicology and Pharmaceutics 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

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 BRCA 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.

DNA修复靶向治疗是癌症的一种很有前途的精准治疗策略。PARP抑制剂的开发和临床应用改变了许多BRCA种系缺陷型乳腺癌和卵巢癌症以及铂敏感上皮性卵巢癌患者的生活。然而,从PARP抑制剂的临床使用中吸取的经验教训也证实,并非所有患者都因固有或获得性耐药性而有反应。因此,寻找额外的合成杀伤方法是转化和临床研究的一个活跃领域。在此,我们回顾了PARP抑制剂和其他进化的DNA修复靶点的当前临床状态,包括ATM、ATR、WEE1抑制剂和癌症中的其他。
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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 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-06-01 DOI: 10.1016/j.coph.2023.102363
Matthias Ceulemans , Lucas Wauters , Tim Vanuytsel

Duodenal micro-inflammation and microbial dysregulation are increasingly recognized to play an important role in functional dyspepsia (FD) pathophysiology, previously regarded as a purely functional disorder. With current therapeutic options contested through insufficient efficacy or unfavorable adverse effects 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 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 symptomatology.

十二指肠微炎症和微生物失调越来越被认为在功能性消化不良(FD)的病理生理学中发挥着重要作用,以前被认为是一种纯粹的功能性疾病。由于目前的治疗方案因疗效不足或不良反应而存在争议,针对十二指肠病变的新治疗方法可能会在至少一部分患者中获得更好的症状控制。事实上,FD研究的最新进展为抗炎疗法通过减少十二指肠嗜酸性粒细胞或肥大细胞来缓解胃十二指肠症状提供了证据。此外,通过益生菌恢复微生物稳态在FD中被证明是成功的。由于这些新的药理学方法产生临床益处的确切机制往往还有待阐明,未来的研究应该集中在免疫激活和失调如何转化为典型的FD症状。
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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 Q1 Pharmacology, Toxicology and Pharmaceutics 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

Hepatic arterial infusion chemotherapy with oxaliplatin, 5-fluorouracil, and leucovorin (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 alcoholic liver disease, and is often diagnosed at an early stage, when the tumor is small or the 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 (> 5 cm) (or T3 by TNM stage), and rich blood supply.

奥沙利铂、5-氟尿嘧啶和亚叶酸(FOLFOX-HAIC)肝动脉灌注化疗在中国肝细胞癌中显示出强大的抗肿瘤作用。与我国肝细胞癌不同,西方国家的肝细胞癌是由丙型肝炎和酒精性肝病引起的,通常在肿瘤较小或血栓不严重的早期诊断。尽管在西方国家没有FOLFOX-HAIC治疗肝细胞癌的疗效报告,但FOLFOX-HAIC可用于大肿瘤(>;5cm)(或TNM分期为T3)和丰富血液供应的患者。
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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 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-04-01 DOI: 10.1016/j.coph.2023.102356
Takashi Murayama , Nagomi Kurebayashi , Ryosuke Ishida , Hiroyuki Kagechika

Type 1 ryanodine receptor (RyR1) is an intracellular Ca2+ release channel on the sarcoplasmic reticulum of skeletal muscle, and it plays a central role in excitation–contraction (E-C) coupling. Mutations in RyR1 are implicated in various muscle diseases including malignant hyperthermia, 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 Ca2+-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.

1型赖氨酸受体(RyR1)是骨骼肌肌浆网上的细胞内Ca2+释放通道,在兴奋-收缩(E-C)偶联中发挥核心作用。RyR1的突变与各种肌肉疾病有关,包括恶性热疗、中枢核心疾病和肌病。目前,这些疾病大多没有特效治疗方法。最近,已经开发了高通量筛选(HTS)测定法来鉴定治疗RyR相关肌肉疾病的潜在候选者。目前,有两种不同的方法,即基于FRET的测定和基于内质网Ca2+的测定。这些测定确定了几种化合物为新型RyR1抑制剂。此外,重组平台的开发允许对E-C偶联调节剂进行HTS测定。在这篇综述中,我们将重点关注HTS分析的最新进展,并讨论这些有前景的方法的未来前景。
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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 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-04-01 DOI: 10.1016/j.coph.2023.102359
Michael Koval , Wyatt J. Schug , Brant E. Isakson

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.

Pannexin通道在调节炎症中发挥着基本作用,并与许多疾病有关,包括高血压、中风和神经性疼痛。因此,在药理学上阻断这些通道的能力是几种治疗方法的重要组成部分。对模型系统的药理学询问也为发现血管内皮素在细胞生理学中的新作用提供了一种手段。在这里,我们回顾了可用于阻断pannexin通道的药物的现状,重点是作用于pannexin1的化学药物和肽模拟物。讨论了在实验系统中解释pannexin药理学结果的指导,以及不同药物的优势和注意事项,包括临床应用的特异性和可行性。
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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 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-04-01 DOI: 10.1016/j.coph.2023.102358
Natalia R. Rodriguez, Trinisia Fortune, Thien Vuong, Talia H. Swartz

Human Immunodeficiency Virus Type 1 (HIV-1) causes a chronic, incurable infection associated with chronic inflammation 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 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 P2X receptors in HIV-1 pathogenesis, describing the known intersection with the HIV-1 life cycle in mediating immunopathogenesis 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.

人类免疫缺陷病毒1型(HIV-1)会导致与慢性炎症相关的慢性、不可治愈的感染,尽管抗病毒治疗(ART)受到病毒抑制。这种慢性炎症是严重合并症的基础,包括心血管疾病、神经认知能力下降和恶性肿瘤。慢性炎症的机制在一定程度上归因于细胞外ATP和P2X型嘌呤能受体的作用,这些受体感知受损或垂死的细胞,并经历激活炎症和免疫调节的信号反应。这篇综述描述了目前关于细胞外ATP和P2X受体在HIV-1发病机制中的作用的文献,描述了已知的与HIV-1生命周期在介导免疫发病和神经元疾病中的交叉点。文献支持这种信号机制在细胞间通讯和激活影响炎症状态导致疾病进展的转录变化中的关键作用。未来的研究必须表征ATP和P2X受体在HIV-1发病机制中的多种功能,为未来的治疗靶向提供信息。
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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 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-04-01 DOI: 10.1016/j.coph.2023.102355
Joao Carlos Ribeiro-Silva , Caio A.M. Tavares , Adriana C.C. Girardi

The incretin hormone 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 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.

肠促生长素-胰高血糖素样肽1(GLP-1)是促进葡萄糖稳态的信号机制的关键组成部分。临床和实验研究表明,GLP-1受体激动剂,包括GLP-1本身,对血压有良好影响,并降低重大心血管事件的风险,与它们对血糖控制的影响无关。GLP-1受体存在于下丘脑和脑干、颈动脉体、血管系统和肾脏中。这些器官参与血压调节,在高血压中其功能发生改变,并且通过GLP-1受体激动剂的治疗而积极受益。在这里,我们讨论了GLP-1R信号的激活发挥血糖控制之外的降压作用的潜在机制。
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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 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-04-01 DOI: 10.1016/j.coph.2023.102360
Carlotta Giorgi, Shafi Kuchay
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引用次数: 0
期刊
Current Opinion in Pharmacology
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