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Voltage-gated sodium channels, sodium transport and progression of solid tumours. 电压门控钠通道,钠转运和实体肿瘤的进展。
4区 生物学 Q4 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-01-01 Epub Date: 2023-10-04 DOI: 10.1016/bs.ctm.2023.09.005
Jodie R Malcolm, Nattanan Sajjaboontawee, Serife Yerlikaya, Charlotte Plunkett-Jones, Peter J Boxall, William J Brackenbury

Sodium (Na+) concentration in solid tumours of different origin is highly dysregulated, and this corresponds to the aberrant expression of Na+ transporters. In particular, the α subunits of voltage gated Na+ channels (VGSCs) raise intracellular Na+ concentration ([Na+]i) in malignant cells, which influences the progression of solid tumours, predominantly driving cancer cells towards a more aggressive and metastatic phenotype. Conversely, re-expression of VGSC β subunits in cancer cells can either enhance tumour progression or promote anti-tumourigenic properties. Metastasis is the leading cause of cancer-related mortality, highlighting an important area of research which urgently requires improved therapeutic interventions. Here, we review the extent to which VGSC subunits are dysregulated in solid tumours, and consider the implications of such dysregulation on solid tumour progression. We discuss current understanding of VGSC-dependent mechanisms underlying increased invasive and metastatic potential of solid tumours, and how the complex relationship between the tumour microenvironment (TME) and VGSC expression may further drive tumour progression, in part due to the interplay of infiltrating immune cells, cancer-associated fibroblasts (CAFs) and insufficient supply of oxygen (hypoxia). Finally, we explore past and present clinical trials that investigate utilising existing VGSC modulators as potential pharmacological options to support adjuvant chemotherapies to prevent cancer recurrence. Such research demonstrates an exciting opportunity to repurpose therapeutics in order to improve the disease-free survival of patients with aggressive solid tumours.

钠(Na+)浓度在不同来源的实体瘤中高度失调,这与Na+转运体的异常表达相对应。特别是,电压门控Na+通道(VGSCs)的α亚基提高恶性细胞内Na+浓度([Na+]i),影响实体肿瘤的进展,主要驱动癌细胞向更具侵袭性和转移性的表型发展。相反,癌细胞中VGSC β亚基的重新表达可以促进肿瘤进展或促进抗肿瘤特性。转移是癌症相关死亡的主要原因,突出了一个迫切需要改进治疗干预的重要研究领域。在这里,我们回顾了VGSC亚基在实体肿瘤中失调的程度,并考虑了这种失调对实体肿瘤进展的影响。我们讨论了目前对实体肿瘤侵袭性和转移性增加的VGSC依赖机制的理解,以及肿瘤微环境(TME)和VGSC表达之间的复杂关系如何进一步推动肿瘤进展,部分原因是浸润性免疫细胞、癌症相关成纤维细胞(CAFs)和氧气供应不足(缺氧)的相互作用。最后,我们探讨了过去和现在的临床试验,研究利用现有的VGSC调节剂作为潜在的药理学选择来支持辅助化疗以预防癌症复发。这样的研究显示了一个令人兴奋的机会,以改变治疗目的,以提高侵袭性实体瘤患者的无病生存。
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引用次数: 0
Preface. 序言
4区 生物学 Q4 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-01-01 DOI: 10.1016/S1063-5823(23)00015-7
Ibra S Fancher, Andreia Z Chignalia
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引用次数: 0
The role of ion channels in the relationship between the immune system and cancer. 离子通道在免疫系统和癌症关系中的作用。
4区 生物学 Q4 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-01-01 Epub Date: 2023-09-22 DOI: 10.1016/bs.ctm.2023.09.001
Mumin Alper Erdogan, D'Amora Ugo, Fasolino Ines

The immune system is capable of identifying and eliminating cancer, a complicated illness marked by unchecked cellular proliferation. The significance of ion channels in the complex interaction between the immune system and cancer has been clarified by recent studies. Ion channels, which are proteins that control ion flow across cell membranes, have variety of physiological purposes, such as regulating immune cell activity and tumor development. Immune cell surfaces contain ion channels, which have been identified to control immune cell activation, motility, and effector activities. The regulation of immune responses against cancer cells has been linked to a number of ion channels, including potassium, calcium, and chloride channels. As an example, potassium channels are essential for regulating T cell activation and proliferation, which are vital for anti-tumor immunity. Calcium channels play a crucial role when immune cells produce cytotoxic chemicals in order to eliminate cancer cells. Chloride channels also affect immune cell infiltration and invasion into malignancies. Additionally, tumor cells' own expressed ion channels have an impact on their behavior and in the interaction with the immune system. The proliferation, resistance to apoptosis, and immune evasion of cancer cells may all be impacted by changes in ion channel expression and function. Ion channels may also affect the tumor microenvironment by controlling angiogenesis, inflammatory responses, and immune cell infiltration. Ion channel function in the interaction between the immune system and cancer has important implications for cancer treatment. A possible method to improve anti-tumor immune responses and stop tumor development is to target certain ion channels. Small compounds and antibodies are among the ion channel modulators under investigation as possible immunotherapeutics. The complex interaction between ion channels, the immune system, and cancer highlights the significance of these channels for tumor immunity. The development of novel therapeutic strategies for the treatment of cancer will be made possible by unraveling the processes by which ion channels control immune responses and tumor activity. Hence, the main driving idea of the present chapter is trying to understand the possible function of ion channels in the complex crosstalk between cancer and immunoresponse. To this aim, after giving a brief journey of ion channels throughout the history, a classification of the main ion channels involved in cancer disease will be discussed. Finally, the last paragraph will focus on more recently advancements in the use of biomaterials as therapeutic strategy for cancer treatment. The hope is that future research will take advantage of the promising combination of ion channels, immunomodulation and biomaterials filed to provide better solutions in the treatment of cancer disease.

免疫系统能够识别和消除癌症,这是一种复杂的疾病,其特征是不受控制的细胞增殖。离子通道在免疫系统与肿瘤复杂相互作用中的重要作用已被近年来的研究所阐明。离子通道是一种控制离子在细胞膜上流动的蛋白质,具有多种生理目的,如调节免疫细胞活性和肿瘤的发展。免疫细胞表面含有离子通道,已被确定控制免疫细胞的激活、运动和效应活性。针对癌细胞的免疫反应的调节与许多离子通道有关,包括钾、钙和氯离子通道。例如,钾通道在调节T细胞的活化和增殖中是必不可少的,而T细胞的活化和增殖对抗肿瘤免疫至关重要。当免疫细胞产生细胞毒性化学物质以消灭癌细胞时,钙通道起着至关重要的作用。氯离子通道也影响免疫细胞的浸润和对恶性肿瘤的侵袭。此外,肿瘤细胞自身表达的离子通道对其行为和与免疫系统的相互作用也有影响。肿瘤细胞的增殖、抗凋亡和免疫逃逸都可能受到离子通道表达和功能变化的影响。离子通道也可能通过控制血管生成、炎症反应和免疫细胞浸润来影响肿瘤微环境。离子通道在免疫系统与肿瘤相互作用中的作用对癌症治疗具有重要意义。一种可能提高抗肿瘤免疫反应和阻止肿瘤发展的方法是靶向某些离子通道。小化合物和抗体是正在研究的离子通道调节剂中可能的免疫治疗药物。离子通道、免疫系统和癌症之间复杂的相互作用凸显了这些通道对肿瘤免疫的重要性。通过揭示离子通道控制免疫反应和肿瘤活性的过程,癌症治疗新治疗策略的发展将成为可能。因此,本章的主要驱动思想是试图理解离子通道在癌症和免疫反应之间复杂的串扰中的可能功能。为此,在简要介绍了离子通道的历史之后,我们将讨论与癌症疾病有关的主要离子通道的分类。最后,最后一段将重点介绍生物材料作为癌症治疗策略的最新进展。希望未来的研究将利用离子通道,免疫调节和生物材料领域的有前途的组合,为癌症疾病的治疗提供更好的解决方案。
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引用次数: 0
Ion channels and their role in chemo-resistance. 离子通道及其在化学抗性中的作用。
4区 生物学 Q4 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-01-01 Epub Date: 2023-11-10 DOI: 10.1016/bs.ctm.2023.09.008
Davide Antonio Delisi, Maedeh Vakili Saatloo

Ion channels play a crucial role in cellular signaling, homeostasis, and generation of electrical and chemical signals. Aberrant expression and dysregulation of ion channels have been associated with cancer development and resistance to conventional cancer treatment such as chemotherapy. Several molecular mechanisms have been proposed to explain this phenomenon. Including evasion of apoptosis, decreased drug accumulation in cancer cells, detoxifying and activation of alternative escape pathways such as autophagy. Each of these mechanisms leads to a reduction of the therapeutic efficacy of administered drugs, causing more difficulty in cancer treatment. This review highlights the linkages between ion channels and resistance to chemotherapy. Furthermore, it elaborates their molecular mechanisms and the potential of being therapeutic targets in clinical management.

离子通道在细胞信号传导、体内平衡以及电信号和化学信号的产生中起着至关重要的作用。离子通道的异常表达和失调与癌症的发展和对化疗等常规癌症治疗的耐药性有关。人们提出了几种分子机制来解释这一现象。包括逃避细胞凋亡,减少癌细胞中的药物积累,解毒和激活其他逃逸途径,如自噬。这些机制中的每一种都会导致药物治疗效果的降低,给癌症治疗带来更多的困难。本文综述了离子通道与化疗耐药之间的联系。进一步阐述了它们的分子机制和在临床管理中作为治疗靶点的潜力。
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引用次数: 0
The role of hyaluronan in endothelial glycocalyx and potential preventative lifestyle strategy with advancing age. 透明质酸在内皮细胞糖萼中的作用以及随着年龄增长的潜在预防性生活方式策略。
4区 生物学 Q4 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-01-01 Epub Date: 2023-03-10 DOI: 10.1016/bs.ctm.2023.02.006
Jisok Lim, Daniel Robert Machin, Anthony John Donato

The endothelial glycocalyx (EG) is a gel-like structure that forms a layer in between the surface of the endothelium and lumen. EG was once thought to be merely a structural support for the endothelium. However, in recent years, the importance of EG as a first line of defense and a key regulator to endothelial integrity has been illuminated. With advanced age, EG deterioration becomes more noticeable and at least partially associated with endothelial dysfunction. Hyaluronan (HA), one of the critical components of the EG, has distinct properties and roles to the maintenance of EG and endothelial function. Therefore, given the intimate relationship between the EG and endothelium during the aging process, HA may serve as a promising therapeutic target to prevent endothelial dysfunction.

内皮糖萼(EG)是一种凝胶状结构,在内皮表面和管腔之间形成一层。人们曾一度认为 EG 只是内皮的结构支撑。然而,近年来,EG 作为第一道防线和内皮完整性的关键调节因子的重要性已被揭示。随着年龄的增长,EG 的退化越来越明显,至少部分与内皮功能障碍有关。透明质酸(HA)是 EG 的关键成分之一,在维持 EG 和内皮功能方面具有独特的性质和作用。因此,鉴于衰老过程中 EG 与内皮之间的密切关系,HA 可作为预防内皮功能障碍的治疗靶点。
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引用次数: 0
Potassium channels activity unveils cancer vulnerability. 钾离子通道活动揭示癌症易感性。
4区 生物学 Q4 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-01-01 Epub Date: 2023-09-22 DOI: 10.1016/bs.ctm.2023.09.002
Najmeh Eskandari, Saverio Gentile

"No cell could exist without ion channels" (Clay Armstrong; 1999). Since the discovery in the early 1950s, that ions move across biological membranes, the idea that changes of ionic gradients can generate biological signals has fascinated scientists in any fields. Soon later (1960s) it was found that ionic flows were controlled by a class of specific and selective proteins called ion channels. Thus, it became clear that the concerted activities of these proteins can initiate, arrest, and finely tune a variety of biochemical cascades which offered the opportunity to better understand both biology and pathology. Cancer is a disease that is notoriously difficult to treat due its heterogeneous nature which makes it the deadliest disease in the developed world. Recently, emerging evidence has established that potassium channels are critical modulators of several hallmarks of cancer including tumor growth, metastasis, and metabolism. Nevertheless, the role of potassium ion channels in cancer biology and the therapeutic potential offered by targeting these proteins has not been explored thoroughly. This chapter is addressed to both cancer biologists and ion channels scientists and it aims to shine a light on the established and potential roles of potassium ion channels in cancer biology and on the therapeutic benefit of targeting potassium channels with activator molecules.

“没有离子通道细胞就不能存在”(克莱·阿姆斯特朗;1999)。自从20世纪50年代早期发现离子在生物膜上移动以来,离子梯度变化可以产生生物信号的想法吸引了各个领域的科学家。不久之后(20世纪60年代),人们发现离子流动是由一类被称为离子通道的特异性和选择性蛋白质控制的。因此,很明显,这些蛋白质的协同活动可以启动、阻止和微调各种生化级联反应,这为更好地理解生物学和病理学提供了机会。癌症是一种众所周知的难以治疗的疾病,因为它的异质性使它成为发达国家最致命的疾病。最近,新出现的证据表明,钾通道是肿瘤生长、转移和代谢等几个癌症特征的关键调节剂。然而,钾离子通道在癌症生物学中的作用以及针对这些蛋白质提供的治疗潜力尚未得到充分探讨。本章针对癌症生物学家和离子通道科学家,旨在阐明钾离子通道在癌症生物学中的既定和潜在作用,以及用激活剂分子靶向钾通道的治疗益处。
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引用次数: 0
CLIC1 regulation of cancer stem cells in glioblastoma. CLIC1在胶质母细胞瘤中对肿瘤干细胞的调控。
4区 生物学 Q4 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-01-01 Epub Date: 2023-09-29 DOI: 10.1016/bs.ctm.2023.09.004
Kamaldeep Randhawa, Arezu Jahani-Asl

Chloride intracellular channel 1 (CLIC1) has emerged as a therapeutic target in various cancers. CLIC1 promotes cell cycle progression and cancer stem cell (CSC) self-renewal. Furthermore, CLIC1 is shown to play diverse roles in proliferation, cell volume regulation, tumour invasion, migration, and angiogenesis. In glioblastoma (GB), CLIC1 facilitates the G1/S phase transition and tightly regulates glioma stem-like cells (GSCs), a rare population of self-renewing CSCs with central roles in tumour resistance to therapy and tumour recurrence. CLIC1 is found as either a monomeric soluble protein or as a non-covalent dimeric protein that can form an ion channel. The ratio of dimeric to monomeric protein is altered in GSCs and depends on the cell redox state. Elucidating the mechanisms underlying the alterations in CLIC1 expression and structural transitions will further our understanding of its role in GSC biology. This review will highlight the role of CLIC1 in GSCs and its significance in facilitating different hallmarks of cancer.

细胞内氯离子通道1 (CLIC1)已成为多种癌症的治疗靶点。CLIC1促进细胞周期进程和癌症干细胞(CSC)自我更新。此外,CLIC1被证明在增殖、细胞体积调节、肿瘤侵袭、迁移和血管生成中发挥多种作用。在胶质母细胞瘤(GB)中,CLIC1促进G1/S期转变并严格调控胶质瘤干细胞样细胞(GSCs), GSCs是一种罕见的自我更新的CSCs群体,在肿瘤耐药和肿瘤复发中起核心作用。CLIC1是一种单体可溶性蛋白,或者是一种可以形成离子通道的非共价二聚体蛋白。二聚体与单体蛋白的比例在GSCs中发生改变,并取决于细胞氧化还原状态。阐明CLIC1表达改变和结构转变的机制将进一步了解其在GSC生物学中的作用。本文将重点介绍CLIC1在GSCs中的作用及其在促进不同癌症标志中的意义。
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引用次数: 0
Mechanotransduction and the endothelial glycocalyx: Interactions with membrane and cytoskeletal proteins to transduce force. 机械转导和内皮糖萼:与膜和细胞骨架蛋白相互作用以转导力。
4区 生物学 Q4 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-01-01 DOI: 10.1016/bs.ctm.2023.02.003
Hassan Askari, Masoumeh Sadeghinejad, Ibra S Fancher

The endothelial glycocalyx is an extracellular matrix that coats the endothelium and extends into the lumen of blood vessels, acting as a barrier between the vascular wall and blood flowing through the vessel. This positioning of the glycocalyx permits a variety of its constituents, including the major endothelial proteoglycans glypican-1 and syndecan-1, as well as the major glycosaminoglycans heparan sulfate and hyaluronic acid, to contribute to the processes of mechanosensation and subsequent mechanotransduction following such stimuli as elevated shear stress. To coordinate the vast array of processes that occur in response to physical force, the glycocalyx interacts with a plethora of membrane and cytoskeletal proteins to carry out specific signaling pathways resulting in a variety of responses of endothelial cells and, ultimately, blood vessels to mechanical force. This review focuses on proposed glycocalyx-protein relationships whereby the endothelial glycocalyx interacts with a variety of membrane and cytoskeletal proteins to transduce force into a myriad of chemical signaling pathways. The established and proposed interactions at the molecular level are discussed in context of how the glycocalyx regulates membrane/cytoskeletal protein function in the many processes of endothelial mechanotransduction.

内皮糖萼是一种细胞外基质,覆盖在内皮细胞上并延伸到血管腔内,作为血管壁和血管内血液流动之间的屏障。糖萼的这种定位允许其多种成分,包括主要的内皮蛋白聚糖glyypican -1和syndecan-1,以及主要的糖胺聚糖肝素硫酸盐和透明质酸,在剪切应力升高等刺激下参与机械感觉和随后的机械转导过程。为了协调发生在物理力响应中的大量过程,糖萼与过多的膜和细胞骨架蛋白相互作用,以执行特定的信号通路,导致内皮细胞和最终血管对机械力的各种反应。这篇综述的重点是提出的糖萼与蛋白的关系,即内皮糖萼与各种膜和细胞骨架蛋白相互作用,将力转化为无数的化学信号通路。在内皮机械转导的许多过程中,糖萼如何调节膜/细胞骨架蛋白的功能,讨论了在分子水平上已建立和提出的相互作用。
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引用次数: 2
The glycocalyx and calcium dynamics in endothelial cells. 内皮细胞的糖萼和钙动力学。
4区 生物学 Q4 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-01-01 DOI: 10.1016/bs.ctm.2023.02.002
Cameron M Mortazavi, Jillian M Hoyt, Aamir Patel, Andreia Z Chignalia

The endothelial glycocalyx is a dynamic surface layer composed of proteoglycans, glycoproteins, and glycosaminoglycans with a key role in maintaining endothelial cell homeostasis. Its functions include the regulation of endothelial barrier permeability and stability, the transduction of mechanical forces from the vascular lumen to the vessel walls, serving as a binding site to multiple growth factors and vasoactive agents, and mediating the binding of platelets and the migration of leukocytes during an inflammatory response. Many of these processes are associated with changes in intracellular calcium levels that may occur through mechanisms that alter calcium entry in the endothelium or the release of calcium from the endoplasmic reticulum. Whether the endothelial glycocalyx can regulate calcium dynamics in endothelial cells is unresolved. Interestingly, during cardiovascular disease progression, changes in calcium dynamics are observed in association with the degradation of the glycocalyx and with changes in barrier permeability and vascular reactivity. Herein, we aim to provide a summarized overview of what is known regarding the role of the glycocalyx as a regulator of endothelial barrier and vascular reactivity during homeostatic and pathological conditions and to provide a perspective on how such processes may relate to calcium dynamics in endothelial cells, exploring a possible connection between components of the glycocalyx and calcium-sensitive pathways in the endothelium.

内皮糖萼是由蛋白聚糖、糖蛋白和糖胺聚糖组成的动态表面层,在维持内皮细胞稳态中起关键作用。它的功能包括调节内皮屏障的通透性和稳定性,将机械力从血管腔传递到血管壁,作为多种生长因子和血管活性物质的结合位点,在炎症反应中介导血小板的结合和白细胞的迁移。许多这些过程都与细胞内钙水平的变化有关,这种变化可能通过改变钙进入内皮或钙从内质网释放的机制发生。内皮糖萼是否能调节内皮细胞内钙动力学尚不清楚。有趣的是,在心血管疾病进展过程中,观察到钙动力学的变化与糖萼降解以及屏障通透性和血管反应性的变化有关。在本文中,我们的目的是概述糖萼在稳态和病理状态下作为内皮屏障和血管反应性调节剂的已知作用,并提供这些过程如何与内皮细胞中的钙动力学相关的观点,探索糖萼成分与内皮中钙敏感途径之间的可能联系。
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引用次数: 1
Non-conducting functions of potassium channels in cancer and neurological disease. 钾通道在癌症和神经系统疾病中的非传导功能。
4区 生物学 Q4 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-01-01 Epub Date: 2023-09-22 DOI: 10.1016/bs.ctm.2023.09.007
Federico Sesti, Alessandro Bortolami, Elena Forzisi Kathera-Ibarra

Cancer and neurodegenerative disease, albeit fundamental differences, share some common pathogenic mechanisms. Accordingly, both conditions are associated with aberrant cell proliferation and migration. Here, we review the causative role played by potassium (K+) channels, a fundamental class of proteins, in cancer and neurodegenerative disease. The concept that emerges from the review of the literature is that K+ channels can promote the development and progression of cancerous and neurodegenerative pathologies by dysregulating cell proliferation and migration. K+ channels appear to control these cellular functions in ways that not necessarily depend on their conducting properties and that involve the ability to directly or indirectly engage growth and survival signaling pathways. As cancer and neurodegenerative disease represent global health concerns, identifying commonalities may help understand the molecular basis for those devastating conditions and may facilitate the design of new drugs or the repurposing of existing drugs.

癌症和神经退行性疾病,尽管有根本的区别,但有一些共同的致病机制。因此,这两种情况都与异常细胞增殖和迁移有关。在这里,我们回顾了钾离子通道在癌症和神经退行性疾病中的致病作用,钾离子通道是一类基本的蛋白质。从文献综述中出现的概念是,K+通道可以通过失调细胞增殖和迁移来促进癌症和神经退行性病变的发生和进展。K+通道似乎以不一定依赖于其传导特性的方式控制这些细胞功能,并涉及直接或间接参与生长和生存信号通路的能力。由于癌症和神经退行性疾病代表着全球健康问题,确定共性可能有助于了解这些毁灭性疾病的分子基础,并可能促进新药的设计或现有药物的重新利用。
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引用次数: 0
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