Journal of cellular signaling最新文献

英文中文

Novel Therapeutic Strategies for Exosome-Related Diseases 外泌体相关疾病的新治疗策略

Journal of cellular signaling

Pub Date : 2022-06-02 DOI: 10.33696/signaling.3.072

H. Ageta, K. Tsuchida

The multivesicular body (MVB), also called late endosome, is a subset of specialized endosomal compartments rich in intraluminal vesicles (ILVs). Multiple ILVs accumulate within MVBs [1,2]. ILVs are formed by invagination of the limiting membrane of early endosomes and budding into the lumen of the organelle. ILVs sequester specific proteins, lipids and cytosolic components. Although exosome release is known to be mediated by MVB, its regulation is not fully understood. Once MVBs fuse with lysosomes, the cargo of the ILVs is degraded. On the other hand, when MVBs fuse with the plasma membrane, the contents of ILVs are secreted outside the cell via exosomes. Most synthesized proteins are modified by post-translational modifiers, which regulate the amount, localization, stability, and activity of proteins. Post-translational modifications (PTM) are involved in the regulation of cellular functions [3]. The formation of MVB is known to be regulated by the endosomal sorting complexes required for transport (ESCRT) systems [1], as well as tetraspanins and UBLs. ESCRT systems are also dependent on ubiquitination [4]. Recently, ubiquitin and UBLs were reported to be involved in the regulation of ILV and MVB. Proteins modified by ubiquitin, SUMO, or UBL3 were incorporated into MVB.

多泡体(MVB)，也称为晚期核内体，是富含腔内囊泡(ILVs)的特化核内体区室的一个子集。多个ilv在MVBs中积累[1,2]。ilv是由早期核内体的限制膜内陷并出芽进入细胞器的管腔形成的。ilv隔离特定的蛋白质、脂质和细胞质成分。虽然已知外泌体释放是由MVB介导的，但其调控机制尚不完全清楚。一旦MVBs与溶酶体融合，ilv的货物就会被降解。另一方面，当MVBs与质膜融合时，ilv的内容物通过外泌体分泌到细胞外。大多数合成的蛋白质都被翻译后修饰剂修饰，这些修饰剂调节着蛋白质的数量、定位、稳定性和活性。翻译后修饰(PTM)参与细胞功能的调控。众所周知，MVB的形成受运输所需的内体分选复合物(ESCRT)系统[1]以及四跨蛋白和ubl的调节。ESCRT系统也依赖于泛素化[4]。最近，有报道称泛素和UBLs参与ILV和MVB的调控。将泛素、SUMO或UBL3修饰的蛋白掺入MVB中。

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引用次数: 0

TRPM8 Channels and SOCE: Modulatory Crosstalk between Na+ and Ca2+ Signaling TRPM8通道和SOCE: Na+和Ca2+信号之间的调制串扰

Journal of cellular signaling

Pub Date : 2022-02-24 DOI: 10.33696/signaling.3.063

G. H. Bomfim

The electrochemical driving forces across the plasma membrane mediated by ion channels, pumps, and exchangers are essential for cellular homeostasis, regulating a wide range of biological processes [1,2]. Although both excitable (e.g., neurons) and non-excitable (e.g., lymphocytes) cells manage their cellular functions through plasmalemmal ion flux, excitable cells change the membrane potential mediated by depolarization and voltage-gated ion channels, while nonexcitable cells control this process by the different downstream processes and ligand-gated ion channels [2,3]. Sodium (Na+) is the principal extracellular cation, being carried to the intracellular space mainly through inward Na+ currents (INa) [2]. Pioneering studies documented that inhibition of INa, but not the calcium (Ca2+) absence, abolished the action potential, indicating that Na+ influx is essential for cell excitability, action Abstract

离子通道、泵和交换器介导的跨质膜的电化学驱动力对细胞内稳态至关重要，调节着广泛的生物过程[1,2]。虽然可兴奋细胞(如神经元)和不可兴奋细胞(如淋巴细胞)都通过质浆离子通量来调节细胞功能，但可兴奋细胞通过去极化和电压门控离子通道来改变膜电位，而不可兴奋细胞通过不同的下游过程和配体门控离子通道来控制这一过程[2,3]。钠离子(Na+)是主要的细胞外阳离子，主要通过向内的Na+电流(INa)进入细胞内空间[2]。开创性的研究表明，抑制INa，而不是钙(Ca2+)缺失，消除了动作电位，这表明Na+内流对细胞兴奋性和动作至关重要

引用次数: 1

AID and APOBEC3 Involvements in Non-Conventional IgD Class Switch Recombination in Mice AID和APOBEC3参与小鼠非常规IgD类开关重组

Journal of cellular signaling

Pub Date : 2022-02-24 DOI: 10.33696/signaling.3.066

Mélissa Ferrad, N. Ghazzaui, Hussein Issaoui, J. Cook-Moreau, Y. Denizot

Melissa Ferrad1,#, Nour Ghazzaui1,#, Hussein Issaoui2, Jeanne Cook-Moreau1, Yves Denizot1* 1Equipe Labellisée LIGUE 2018, UMR CNRS 7276, INSERM U1262, Université de Limoges, CBRS, rue Pr. Descottes, 87025 Limoges, France 2Present address : Nour Ghazzaui Vaccine Research Institute, INSERM U955, Hôpital Henri Mondor, 94010 Créteil, France; Hussein Issaoui Université Côte d'Azur, INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3 M), 06204, Nice, France #These authors contributed equally to this work *Correspondence should be addressed to Yves Denizot, yves.denizot@unilim.fr

Melissa Ferrad1，#， Nour Ghazzaui1，#， Hussein Issaoui2, Jeanne Cook-Moreau1, Yves Denizot1* 1team labeled LIGUE 2018, UMR CNRS 7276, INSERM U1262, universite de Limoges, CBRS, rue Pr. Descottes, 87025 Limoges，法国2Present地址:Nour Ghazzaui疫苗研究所，INSERM U955, hospital Henri Mondor, 94010 creteil，法国;Hussein Issaoui universite cote d’Azur, INSERM U1065, Centre mediterrenne de medecine molmolecular (C3 M)， 06204, Nice, France #这些作者对这项工作做出了同等的贡献*通信应发送到Yves Denizot, yves.denizot@unilim.fr

引用次数: 0

Differentiation and Subtype Specification of Enteric Neurons: Current Knowledge of Transcription Factors, Signaling Molecules and Signaling Pathways Involved 肠神经元的分化和亚型规范:转录因子、信号分子和信号通路的最新知识

Journal of cellular signaling

Pub Date : 2022-02-24 DOI: 10.33696/signaling.3.064

Nastasia Popowycz, L. Uyttebroek, G. Hubens, L. Nassauw

The enteric nervous system (ENS) forms the largest component of the autonomic nervous system (ANS). In humans, it contains between 200 and 600 million neurons which are part of intrinsic neuronal circuits managing to generate reflex gastrointestinal (GI) contractile activity without intervention of the central nervous system (CNS) [1,2]. The ENS is located along the length of the GI tract and oversees controlling the main functions such as secretion, motility, and blood flow. In addition, it is also responsible for the communication with the immune system and microbiome [3–5]. The ENS contains a network of neurons and glial cells which are dispersed over two major ganglionated and interconnected plexuses, the myenteric (Auerbach) plexus, and the submucosal (Meissner) plexus. In larger mammals, the submucosal plexus is further subdivided into smaller plexuses [4,6-10]. The neurons of the myenteric plexus are primarily involved in GI motility regulation, while the neurons of the submucosal plexus are involved in the regulation of secretion and vascular tone [3,6,11,12]. The ENS is a highly complex nervous system of which the functioning is dependent on many different neuronal subtypes. To keep an overview of the neuronal subtypes, they are categorized in different classes according to certain characteristics. Among these features are their morphology, electrical properties, chemical coding, and Abstract

肠神经系统(ENS)是自主神经系统(ANS)的最大组成部分。在人类中，它包含2亿到6亿个神经元，这些神经元是内在神经回路的一部分，负责产生反射性胃肠道(GI)收缩活动，而不需要中枢神经系统(CNS)的干预[1,2]。ENS位于胃肠道的长度，并监督控制主要功能，如分泌、运动和血液流动。此外，它还负责与免疫系统和微生物群的沟通[3-5]。ENS包含一个由神经元和胶质细胞组成的网络，它们分布在两个主要的神经节神经丛和相互连接的神经丛，肌丛(奥尔巴赫神经丛)和粘膜下神经丛(迈斯纳神经丛)。在大型哺乳动物中，粘膜下神经丛进一步细分为更小的神经丛[4,6-10]。肌肠丛神经元主要参与胃肠道运动调节，而粘膜下丛神经元主要参与分泌和血管张力调节[3,6,11,12]。ENS是一个高度复杂的神经系统，其功能依赖于许多不同的神经元亚型。为了保持对神经元亚型的概述，它们根据某些特征被分类为不同的类。这些特征包括它们的形态、电学性质、化学编码和摘要

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引用次数: 0

Expression and Localization of Phosphoinositide-Specific Phospholipases C in Cultured, Differentiating and Stimulated Human Osteoblasts 磷酸肌肽特异性磷脂酶C在培养、分化和刺激的人成骨细胞中的表达和定位

Journal of cellular signaling

Pub Date : 2022-02-24 DOI: 10.33696/signaling.3.067

Sara Daisy Casoni, Alessia Romanelli, M. Checchi, Serena Truocchio, M. Ferretti, C. Palumbo, V. L. Vasco

Sara Daisy Casoni1#, Alessia Romanelli1#, Marta Checchi1, Serena Truocchio1,2, Marzia Ferretti1, Carla Palumbo1, Vincenza Rita Lo Vasco1* 1Human Morphology Section, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Largo del Pozzo, 41121 Modena, Italy 2Biomedical and Neuromotor Sciences DIBINEM, University of Bologna, Italy #These authors contributed equally to this work *Correspondence should be addressed to Vincenza Rita Lo Vasco, MD, PhD, ritalovasco@hotmail.it

Sara Daisy Casoni1#， Alessia Romanelli1#， Marta Checchi1, Serena Truocchio1,2, Marzia Ferretti1, Carla Palumbo1, Vincenza Rita Lo Vasco1* 1意大利摩dena大学生物医学、代谢和神经科学系人类形态组，意大利摩dena大学和Reggio Emilia, Largo del Pozzo, 41121意大利摩dena 2意大利博洛尼亚大学生物医学和神经运动科学DIBINEM这些作者对这项工作做出了同样的贡献*信件应发送给Vincenza Rita Lo Vasco, MD, PhD，ritalovasco@hotmail.it

引用次数: 0

Interferon Gamma, MHC Class I Regulation and Immunotherapy 干扰素γ， MHC I类调节和免疫治疗

Journal of cellular signaling

Pub Date : 2022-02-24 DOI: 10.33696/signaling.3.065

Maria Gómez-Herranz, Magdalena Pilch, T. Hupp, S. Kote

The activation of endogenous IFNγ signaling pathway or the administration of recombinant IFNγ increases the expression of MHC-I. MHC-I molecules are core elements for antigen recognition in tumor cells. A better understanding of the regulation of their expression would contribute to counteracting tumor immune escape and enduring permanent tumor rejection. Efficient and functional expression of HLAs dramatically impacts the number of tumor-associated antigens presented to CTL for cell recognition. Many patients diagnosed with various types of cancer have inhibited the IFNγ signaling pathway. This review explores how anomalies associated with IFNγ signaling in tumor cells affect HLA-I expression, current immunotherapies association, and outcome. Globally, MHC-I lesions could be divided into reversible and permanent. Irreversible lesions cannot be recapitulated; hence, the patient will not respond to immunotherapies requiring MHC-I activity. However, gaining precise and systematic molecular knowledge improves tumor stratification, which could help predict which tumors will recover expression of MHC-I. Complementary IFNγ effectors can function as a compensatory mechanism that restores the expression of HLA-I proteins in tumors with deleterious IFNγ pathways. For those non-responsive patients with inactive IFNγ pathways, designing personalized approaches to recover HLA-I expression can make the tumor sensitive to immunotherapy, leading to a better outcome.

内源性IFNγ信号通路的激活或重组IFNγ的管理增加MHC-I的表达。mhc - 1分子是肿瘤细胞抗原识别的核心元件。更好地了解它们的表达调控将有助于对抗肿瘤免疫逃逸和持久的永久性肿瘤排斥反应。高效和功能性的hla表达显著影响肿瘤相关抗原呈交给CTL进行细胞识别的数量。许多被诊断为各种类型癌症的患者抑制了IFNγ信号通路。这篇综述探讨了肿瘤细胞中与IFNγ信号相关的异常如何影响hla - 1表达、当前免疫疗法的相关性和结果。在全球范围内，MHC-I病变可分为可逆性和永久性。不可逆的病变不能重述;因此，患者对需要mhc - 1活性的免疫疗法没有反应。然而，获得精确和系统的分子知识可以改善肿瘤分层，从而有助于预测哪些肿瘤将恢复MHC-I的表达。互补的IFNγ效应物可以作为一种补偿机制，在具有有害IFNγ通路的肿瘤中恢复hla - 1蛋白的表达。对于那些IFNγ通路不活跃的无应答患者，设计个性化的方法来恢复hla - 1表达可以使肿瘤对免疫治疗敏感，从而获得更好的结果。

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引用次数: 0

The Outcome of Tumor Ablation Therapies is Determined by Stress Signaling Networks 肿瘤消融治疗的结果是由应激信号网络决定的

Journal of cellular signaling

Pub Date : 2022-02-24 DOI: 10.33696/signaling.3.062

M. Korbelik

Increasingly prominent roles in interventional oncology are held by various tumor ablation therapies performed by direct applications of local acute trauma-inducing insult to the targeted lesion aiming for its rapid in situ destruction. These therapies include treatments based on various forms of thermal energy delivery (photothermal, cryoablation, microwave ablation, radiofrequency ablation), non-thermal illumination (photodynamic therapy), electric field exposure, or high hydrostatic pressure [1-3]. Common injury inflicted in cells of tumors treated by ablation therapies is the impairment of proteostasis due to accumulation of misfolded/damaged proteins. This is sensed by afflicted cells as a trauma typically associated with thermal or oxidative stress that threatens the integrity and homeostasis at the affected site [4]. These types of stress provoke evolutionary well conserved canonic protection mechanisms based on cellular stress signaling network that serves to re-balance biochemical activities within the cell. They work by conversing the incoming signal (appearance of stressor molecule) towards downstream effector molecules involved in transcriptome reprogramming aimed at activation or inhibition of targeted biochemical tasks [4,5]. The aim of this commentary is to emphasize that the activity of the engaged intracellular signaling pathways determines the fate of involved tumor cells and ultimately the outcome of the applied therapies.

在介入肿瘤学中，各种肿瘤消融疗法的作用越来越突出，这些疗法是通过直接应用局部急性创伤诱导损伤来实现病灶的原位快速破坏。这些疗法包括基于各种形式的热能输送(光热、冷冻消融、微波消融、射频消融)、非热照明(光动力疗法)、电场暴露或高静水压力的治疗[1-3]。在消融治疗的肿瘤细胞中，常见的损伤是由于错误折叠/受损蛋白质的积累而导致的蛋白质平衡受损。这被受影响的细胞感知为创伤，通常与热应激或氧化应激相关，威胁到受影响部位的完整性和体内平衡[4]。这些类型的应激引发了基于细胞应激信号网络的进化性保守的经典保护机制，用于重新平衡细胞内的生化活动。它们的工作原理是将输入信号(应激源分子的出现)转换为参与转录组重编程的下游效应分子，目的是激活或抑制靶向生化任务[4,5]。这篇评论的目的是强调参与的细胞内信号通路的活性决定了相关肿瘤细胞的命运，并最终决定了应用治疗的结果。

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引用次数: 1

c-JUN n-Terminal Kinase (JNK) Signaling in Autosomal Dominant Polycystic Kidney Disease 常染色体显性多囊肾病中c-JUN n-末端激酶(JNK)信号传导

Journal of cellular signaling

Pub Date : 2022-02-17 DOI: 10.33696/Signaling.3.068

Abigail O. Smith, J. Jonassen, Kenley M. Preval, R. Davis, G. Pazour

Polycystic kidney disease is an inherited degenerative disease in which the uriniferous tubules are replaced by expanding fluid-filled cysts that ultimately destroy organ function. Autosomal dominant polycystic kidney disease (ADPKD) is the most common form, afflicting approximately 1 in 1,000 people and is caused by mutations in the transmembrane proteins polycystin-1 (Pkd1) and polycystin-2 (Pkd2). The mechanisms by which polycystin mutations induce cyst formation are not well understood, however pro-proliferative signaling must be involved for tubule epithelial cell number to increase over time. We recently found that the stress-activated mitogen-activated protein kinase (MAPK) pathway c-Jun N-terminal kinase (JNK) pathway is activated in cystic disease and genetically removing JNK reduces cyst growth driven by a loss of Pkd2. This review covers the current state of knowledge of signaling in ADPKD with an emphasis on the JNK pathway.

多囊肾病是一种遗传性退行性疾病，其中尿小管被扩张的充满液体的囊肿所取代，最终破坏器官功能。常染色体显性多囊肾病(ADPKD)是最常见的形式，大约每1000人中就有1人患病，由跨膜蛋白多囊蛋白-1 (Pkd1)和多囊蛋白-2 (Pkd2)突变引起。多囊蛋白突变诱导囊肿形成的机制尚不清楚，但促增殖信号必须参与小管上皮细胞数量随时间增加的过程。我们最近发现应激激活的丝裂原激活蛋白激酶(MAPK)通路c-Jun n-末端激酶(JNK)通路在囊性疾病中被激活，遗传去除JNK可减少由Pkd2缺失驱动的囊肿生长。这篇综述涵盖了ADPKD信号传导的现状，重点是JNK通路。

引用次数: 1

Oxidative DNA Damage: A Role in Altering Neuronal Function. 氧化性DNA损伤:在改变神经元功能中的作用。

Journal of cellular signaling

Pub Date : 2022-01-01 DOI: 10.33696/signaling.3.079

Adib Behrouzi, Mark R Kelley, Jill C Fehrenbacher

A role for oxidative stress in the etiology of myriad neuropathologies is well accepted. However, the specific effects of oxidative DNA damage in the onset or promotion of neuronal dysfunction have been less studied. In our recent publication by Behrouzi et al. (Oxidative DNA Damage and Cisplatin Neurotoxicity Is Exacerbated by Inhibition of OGG1 Glycosylase Activity and APE1 Endonuclease Activity in Sensory Neurons), inhibition of enzymes that play a role in repairing oxidative DNA damage exacerbated neurotoxic effects of the chemotherapeutic agent, cisplatin. In this Commentary, we aim to expand on the contribution of oxidative DNA damage to other neuropathologies within the peripheral and central nervous systems, including irritable bowel disease, aging and Alzheimer's disease, amyotrophic lateral sclerosis, and other neurodegenerative diseases. Consistently, clinical neuropathology and disease progression correlates with increases in oxidative DNA damage within clinical biopsies. Progress in animal models of these diseases has elucidated a causative role for oxidative DNA damage in disease progression, as dampening the DNA repair response exacerbates disease, whereas promoting DNA repair mitigates disease. Overall, this Commentary highlights the importance of expanding our studies on oxidative DNA damage in the nervous system, as enhancing oxidative DNA repair might prove to be a potential therapeutic target for the mitigation of neurodegeneration.

氧化应激在各种神经病变的病因学中所起的作用已被广泛接受。然而，氧化性DNA损伤在神经元功能障碍发生或促进中的具体作用研究较少。在Behrouzi等人最近发表的文章(感觉神经元中OGG1糖基酶活性和APE1内切酶活性的抑制加剧了氧化DNA损伤和顺铂神经毒性)中，对修复氧化DNA损伤的酶的抑制加剧了化疗药物顺铂的神经毒性作用。在这篇评论中，我们的目标是扩展氧化DNA损伤对周围和中枢神经系统内其他神经病变的贡献，包括肠易激病、衰老和阿尔茨海默病、肌萎缩侧索硬化症和其他神经退行性疾病。一致地，临床神经病理学和疾病进展与临床活检中氧化DNA损伤的增加相关。这些疾病的动物模型的进展已经阐明了氧化性DNA损伤在疾病进展中的致病作用，因为抑制DNA修复反应会加剧疾病，而促进DNA修复则会减轻疾病。总的来说，这篇评论强调了扩大我们对神经系统氧化DNA损伤研究的重要性，因为增强氧化DNA修复可能被证明是缓解神经变性的潜在治疗靶点。

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引用次数: 3

Redox Homeostasis in Well-differentiated Primary Human Nasal Epithelial Cells. 分化良好的原代人鼻上皮细胞的氧化还原稳态。

Journal of cellular signaling

Pub Date : 2022-01-01 DOI: 10.33696/signaling.3.083

Ayaho Yamamoto, Peter D Sly, Anna Henningham, Nelufa Begum, Abrey J Yeo, Emmanuelle Fantino

Oxidative stress (OS) in the airway epithelium is associated with inflammation, cell damage, and mitochondrial dysfunction that may initiate or worsen respiratory disease. Redox regulation maintains the equilibrium of pro-oxidant/antioxidant reactions but can be disturbed by environmental exposures. The mechanism(s) underlying the induction and impact of OS on airway epithelium and how these influences on respiratory disease is poorly understood. The aim of this study was to develop a stress response model in primary human nasal epithelial cells (NECs) grown at the air-liquid interface (ALI) into a well-differentiated epithelium and to use this model to investigate the mechanisms underlying OS. Hydrogen peroxide (H₂O₂) was used to induce acute OS and the responses were measured with trans epithelial electrical resistance (TEER), membrane permeability, cell death (LDH release), mitochondrial reactive oxygen species (mtROS) generation, redox status (GSH/GSSG ratio), cellular ATP, and signaling pathways (SIRT1, FOXO3, p53, p21, PINK1, PARKIN, NRF2). Following 25 mM (sensitive) or 50mM (resistant) H₂O₂ exposure, cell integrity decreased (p<0.05), GSH/GSSG ratio reduced (p<0.05), and ATP production declined by 83% (p<0.05) in the sensitive and 55% (p<0.05) in the resistant group; mtROS production increased 3.4-fold (p<0.001). Significant inter-individual differences between healthy humans with regards to susceptibility to OS, and differential activation of various pathways (FOXO3, PARKIN) were observed. These intra-individual differences in susceptibility to OS may be attributed to resistant individuals having more mitochondria or greater mitochondrial function.

气道上皮氧化应激(OS)与炎症、细胞损伤和线粒体功能障碍相关，可引发或加重呼吸道疾病。氧化还原调节维持促氧化/抗氧化反应的平衡，但可能受到环境暴露的干扰。OS对气道上皮的诱导和影响的机制以及这些影响如何影响呼吸系统疾病尚不清楚。本研究的目的是建立在气液界面(ALI)培养的原代人鼻上皮细胞(NECs)向分化良好的上皮细胞的应激反应模型，并利用该模型研究OS的机制。使用过氧化氢(H2O2)诱导急性OS，并通过跨上皮电阻(TEER)、膜通透性、细胞死亡(LDH释放)、线粒体活性氧(mtROS)生成、氧化还原状态(GSH/GSSG比率)、细胞ATP和信号通路(SIRT1、FOXO3、p53、p21、PINK1、PARKIN、NRF2)来测量反应。在25 mM(敏感)或50mM(耐)H2O2暴露后，细胞完整性下降(ppppp)

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引用次数: 1

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