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The Role of Neurons in Human Health and Disease 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: 30 June 2024 | Viewed by 15697

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Special Issue Editor

Dr. Yasemin M. Akay

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Guest Editor

Department of Biomedical Engineering, University of Houston, Houston, TX 77204-5060, USA
Interests: coronary artery disease; stent; noninvasive monitoring; nonlinear dynamics analysis; approximate entropy; 3D co-culture; glioblastoma; astrocytes; tumor microenvironment; PEGDA; addiction; cancer research; data science in medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The brain is the central regulator of the organism, responsible for maintaining homeostasis. Neurons are the most critical components of the central and peripheral nervous systems. The immune system protects us from all possible threats that could endanger the well-being of a human body. A strong immune system or a weakened one could make all the differences between the healthy and diseased conditions of a human body. The nervous and immune systems are both crucial for the survival of the human beings. The nervous system affects the activity of the immune system due to its unique anatomical structure and function. The brain can directly regulate the function of the most physiological systems. Neuronal regulation can improve the conditions under which the immune system works by synchronizing its activity with other physiological functions. The brain has the ability to perceive and evaluate the threats before they physically affect the organism. This predictive capacity also helps the immune system prepare for a possible danger in advance and could induce a more effective and faster response. One of the most prominent differences between the nervous and the immune systems is their speed of reaction. The nervous system can react within milliseconds, whereas immunological responses often require from several minutes up to weeks to develop. Although a slower immune reaction is mostly sufficient, a faster response can be beneficial in some cases. In this Special Issue, we focus mainly on how the brain and the nervous system affect immunity, specifically peripheral immunity, and how they play an essential role in human health and disease.

Dr. Yasemin M. Akay
Guest Editor

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Keywords

brain
nervous system
neurons
immune system
human health and disease

Published Papers (6 papers)

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Research

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14 pages, 5215 KiB

Open AccessArticle

Disruption of Intranasal GnRH Neuronal Migration Route into the Brain Induced by Proinflammatory Cytokine IL-6: Ex Vivo and In Vivo Rodent Models

by Viktoria Sharova, Vasilina Ignatiuk, Marina Izvolskaia and Liudmila Zakharova

Int. J. Mol. Sci. 2023, 24(21), 15983; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms242115983 - 05 Nov 2023

Viewed by 895

Abstract

Maternal immune activation results in altered levels of cytokines in the maternal–fetal system, which has a negative impact on fetal development, including the gonadotropin-releasing hormone (GnRH) system, which is crucial for the reproduction. Suppression of GnRH–neuron migration may be associated with cytokine imbalances, and primarily with proinflammatory cytokine interleukin (IL)-6. This study aimed to determine the effects of IL-6 and monoclonal antibody to IL-6 or IL-6R or polyclonal IgG on the formation of migration route of GnRH–neurons in ex vivo and in vivo rodent models on day 11.5 of embryonic development. The increased level of IL-6 in mouse nasal explants suppressed peripherin-positive fiber outgrowth, while this led to an increase in the number of GnRH–neurons in the nose and olfactory bulbs and a decrease in their number in the fetal brain. This effect is likely to be realized via IL-6 receptors along the olfactory nerves. The suppressive effect of IL-6 was diminished by monoclonal antibodies to IL-6 or its receptors and by IgG. Full article

(This article belongs to the Special Issue The Role of Neurons in Human Health and Disease 2.0)

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14 pages, 2467 KiB

Open AccessArticle

Neurotrophin Analog ENT-A044 Activates the p75 Neurotrophin Receptor, Regulating Neuronal Survival in a Cell Context-Dependent Manner

by Maria Anna Papadopoulou, Thanasis Rogdakis, Despoina Charou, Maria Peteinareli, Katerina Ntarntani, Achille Gravanis, Konstantina Chanoumidou and Ioannis Charalampopoulos

Int. J. Mol. Sci. 2023, 24(14), 11683; https://doi.org/10.3390/ijms241411683 - 20 Jul 2023

Cited by 1 | Viewed by 1034

Abstract

Neuronal cell fate is predominantly controlled based on the effects of growth factors, such as neurotrophins, and the activation of a variety of signaling pathways acting through neurotrophin receptors, namely Trk and p75 (p75NTR). Despite their beneficial effects on brain function, their therapeutic use is compromised due to their polypeptidic nature and blood–brain-barrier impermeability. To overcome these limitations, our previous studies have proven that DHEA-derived synthetic analogs can act like neurotrophins, as they lack endocrine side effects. The present study focuses on the biological characterization of a newly synthesized analog, ENT-A044, and its role in inducing cell-specific functions of p75NTR. We show that ENT-A044 can induce cell death and phosphorylation of JNK protein by activating p75NTR. Additionally, ENT-A044 can induce the phosphorylation of TrkB receptor, indicating that our molecule can activate both neurotrophin receptors, enabling the protection of neuronal populations that express both receptors. Furthermore, the present study demonstrates, for the first time, the expression of p75NTR in human-induced Pluripotent Stem Cells-derived Neural Progenitor Cells (hiPSC-derived NPCs) and receptor-dependent cell death induced via ENT-A044 treatment. In conclusion, ENT-A044 is proposed as a lead molecule for the development of novel pharmacological agents, providing new therapeutic approaches and research tools, by controlling p75NTR actions. Full article

(This article belongs to the Special Issue The Role of Neurons in Human Health and Disease 2.0)

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16 pages, 3762 KiB

Open AccessArticle

Sugar Beverage Habitation Relieves Chronic Stress-Induced Anxiety-like Behavior but Elicits Compulsive Eating Phenotype via vLS^GAD2 Neurons

by Dan Liu, Haohao Hu, Yuchuan Hong, Qian Xiao and Jie Tu

Int. J. Mol. Sci. 2023, 24(1), 661; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24010661 - 30 Dec 2022

Cited by 4 | Viewed by 2265

Abstract

Chronically stressed individuals are reported to overconsume tasty, palatable foods like sucrose to blunt the psychological and physiological impacts of stress. Negative consequences of high-sugar intake on feeding behavior include increased metabolic disease burdens like obesity. However, the neural basis underlying long-term high-sugar intake-induced overeating during stress is not fully understood. To investigate this question, we used the two-bottle sucrose choice paradigm in mice exposed to chronic unpredictable mild stressors (CUMS) that mimic those of daily life stressors. After 21 days of CUMS paralleled by consecutive sucrose drinking, we explored anxiety-like behavior using the elevated plus maze and open field tests. The normal water-drinking stressed mice displayed more anxiety than the sucrose-drinking stressed mice. Although sucrose-drinking displayed anxiolytic effects, the sucrose-drinking mice exhibited binge eating (chow) and a compulsive eating phenotype. The sucrose-drinking mice also showed a significant body-weight gain compared to the water-drinking control mice during stress. We further found that c-Fos expression was significantly increased in the ventral part of the lateral septum (vLS) of the sucrose-treated stressed mice after compulsive eating. Pharmacogenetic activation of the vLS glutamate decarboxylase 2(GAD2) neurons maintained plain chow intake but induced a compulsive eating phenotype in the naïve GAD2-Cre mice when mice feeding was challenged by flash stimulus, mimicking the negative consequences of excessive sucrose drinking during chronic stress. Further, pharmacogenetic activation of the vLS^GAD2 neurons aggravated anxiety of the stressed GAD2-Cre mice but did not alter the basal anxiety level of the naïve ones. These findings indicate the GABAergic neurons within the vLS may be a potential intervention target for anxiety comorbid eating disorders during stress. Full article

(This article belongs to the Special Issue The Role of Neurons in Human Health and Disease 2.0)

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25 pages, 13380 KiB

Open AccessArticle

Novel Small Molecule Positive Allosteric Modulator SPAM1 Triggers the Nuclear Translocation of PAC1-R to Exert Neuroprotective Effects through Neuron-Restrictive Silencer Factor

by Guangchun Fan, Shang Chen, Lili Liang, Huahua Zhang and Rongjie Yu

Int. J. Mol. Sci. 2022, 23(24), 15996; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232415996 - 15 Dec 2022

Cited by 1 | Viewed by 1473

Abstract

The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) exerts effective neuroprotective activity through its specific receptor, PAC1-R. We accidentally discovered that as a positive allosteric modulator (PAM) of PAC1-R, the small-molecule PAM (SPAM1) has a hydrazide-like structure, but different binding characteristics, from hydrazide for the N-terminal extracellular domain of PAC1-R (PAC1-R-EC1). SPAM1 had a significant neuroprotective effect against oxidative stress, both in a cell model treated with hydrogen peroxide (H₂O₂) and an aging mouse model induced by D-galactose (D-gal). SPAM1 was found to block the decrease in PACAP levels in brain tissues induced by D-gal and significantly induced the nuclear translocation of PAC1-R in PAC1R-CHO cells and mouse retinal ganglion cells. Nuclear PAC1-R was subjected to fragmentation and the nuclear 35 kDa, but not the 15 kDa fragments, of PAC1-R interacted with SP1 to upregulate the expression of Huntingtin (Htt), which then exerted a neuroprotective effect by attenuating the binding availability of the neuron-restrictive silencer factor (NRSF) to the neuron-restrictive silencer element (NRSE). This resulted in an upregulation of the expression of NRSF-related neuropeptides, including PACAP, the brain-derived neurotrophic factor (BDNF), tyrosine hydroxylase (TH), and synapsin-1 (SYN1). The novel mechanism reported in this study indicates that SPAM1 has potential use as a drug, as it exerts a neuroprotective effect by regulating NRSF. Full article

(This article belongs to the Special Issue The Role of Neurons in Human Health and Disease 2.0)

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Review

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22 pages, 2269 KiB

Open AccessReview

Targeting Progranulin as an Immuno-Neurology Therapeutic Approach

by Maria A. Boylan, Andrew Pincetic, Gary Romano, Nadine Tatton, Sara Kenkare-Mitra and Arnon Rosenthal

Int. J. Mol. Sci. 2023, 24(21), 15946; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms242115946 - 03 Nov 2023

Viewed by 2464

Abstract

Immuno-neurology is an emerging therapeutic strategy for dementia and neurodegeneration designed to address immune surveillance failure in the brain. Microglia, as central nervous system (CNS)-resident myeloid cells, routinely perform surveillance of the brain and support neuronal function. Loss-of-function (LOF) mutations causing decreased levels of progranulin (PGRN), an immune regulatory protein, lead to dysfunctional microglia and are associated with multiple neurodegenerative diseases, including frontotemporal dementia caused by the progranulin gene (GRN) mutation (FTD-GRN), Alzheimer’s disease (AD), Parkinson’s disease (PD), limbic-predominant age-related transactivation response deoxyribonucleic acid binding protein 43 (TDP-43) encephalopathy (LATE), and amyotrophic lateral sclerosis (ALS). Immuno-neurology targets immune checkpoint-like proteins, offering the potential to convert aging and dysfunctional microglia into disease-fighting cells that counteract multiple disease pathologies, clear misfolded proteins and debris, promote myelin and synapse repair, optimize neuronal function, support astrocytes and oligodendrocytes, and maintain brain vasculature. Several clinical trials are underway to elevate PGRN levels as one strategy to modulate the function of microglia and counteract neurodegenerative changes associated with various disease states. If successful, these and other immuno-neurology drugs have the potential to revolutionize the treatment of neurodegenerative disorders by harnessing the brain’s immune system and shifting it from an inflammatory/pathological state to an enhanced physiological/homeostatic state. Full article

(This article belongs to the Special Issue The Role of Neurons in Human Health and Disease 2.0)

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20 pages, 1809 KiB

Open AccessReview

Neurons, Nose, and Neurodegenerative Diseases: Olfactory Function and Cognitive Impairment

by Irene Fatuzzo, Giovanni Francesco Niccolini, Federica Zoccali, Luca Cavalcanti, Mario Giuseppe Bellizzi, Gabriele Riccardi, Marco de Vincentiis, Marco Fiore, Carla Petrella, Antonio Minni and Christian Barbato

Int. J. Mol. Sci. 2023, 24(3), 2117; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032117 - 20 Jan 2023

Cited by 12 | Viewed by 6224

Abstract

Olfactory capacity declines with aging, but increasing evidence shows that smell dysfunction is one of the early signs of prodromal neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. The study of olfactory ability and its role in neurodegenerative diseases arouses much interest in the scientific community. In neurology, olfactory impairment is a potential early marker for the onset of neurodegenerative diseases, but the underlying mechanism is poorly understood. The loss of smell is considered a clinical sign of early-stage disease and a marker of the disease’s progression and cognitive impairment. Highlighting the importance of biological bases of smell and molecular pathways could be fundamental to improve neuroprotective and therapeutic strategies. We focused on the review articles and meta-analyses on olfactory and cognitive impairment. We depicted the neurobiology of olfaction and the most common olfactory tests in neurodegenerative diseases. In addition, we underlined the close relationship between the olfactory and cognitive deficit due to nasal neuroepithelium, which is a direct extension of the CNS in communication with the external environment. Neurons, Nose, and Neurodegenerative diseases highlights the role of olfactory dysfunction as a clinical marker for early stages of neurodegenerative diseases when it is associated with molecular, clinical, and neuropathological correlations. Full article

(This article belongs to the Special Issue The Role of Neurons in Human Health and Disease 2.0)

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