Endogenous Modulators of Neurotrophin Signaling: Landscape of the Transient ATP- NGF Interactions

Identifying biomarkers is essential for early diagnosis of neurodegenerative diseases (NDs). Large (LEVs) and small extracellular vesicles (SEVs) are extracellular vesicles (EVs) of different sizes and biological functions transported in blood and they may be valid biomarkers for NDs. The aim of our study was to investigate common and different miRNA signatures in plasma derived LEVs and SEVs of Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic Lateral Sclerosis (ALS) and Fronto-Temporal Dementia (FTD) patients. LEVs and SEVs were isolated from plasma of patients and healthy volunteers (CTR) by filtration and differential centrifugation and RNA was extracted. Small RNAs libraries were carried out by Next Generation Sequencing (NGS). MiRNAs discriminate all NDs diseases from CTRs and they can provide a signature for each NDs. Common enriched pathways for SEVs were instead linked to ubiquitin mediated proteolysis and Toll-like receptor signaling pathways and for LEVs to neurotrophin signaling and Glycosphingolipid biosynthesis pathway. LEVs and SEVs are involved in different pathways and this might give a specificity to their role in the spreading of the disease. The study of common and different miRNAs transported by LEVs and SEVs can be of great interest for biomarker discovery and for pathogenesis studies in neurodegeneration.

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Identification of upregulated NF-κB inhibitor alpha and IRAK3 targeting lncRNA following intracranial aneurysm rupture-induced subarachnoid hemorrhage

BMC Neurology ◽

10.1186/s12883-021-02156-1 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Wei Leng ◽

Dan Fan ◽

Zhong Ren ◽

Qiaoying Li

Keyword(s):

Subarachnoid Hemorrhage ◽

Intracranial Aneurysm ◽

Signaling Pathway ◽

Aneurysm Rupture ◽

Cytokine Receptor ◽

Gene Set Enrichment Analysis ◽

Receptor Interaction ◽

Regulatory Pathways ◽

Ruptured Intracranial Aneurysm ◽

Neurotrophin Signaling

Abstract Background This study was performed to identify genes and lncRNAs involved in the pathogenesis of subarachnoid hemorrhage (SAH) from ruptured intracranial aneurysm (RIA). Methods Microarray GSE36791 was downloaded from Gene Expression Omnibus (GEO) database followed by the identification of significantly different expressed RNAs (DERs, including lncRNA and mRNA) between patients with SAH and healthy individuals. Then, the functional analyses of DEmRNAs were conducted and weighted gene co-expression network analysis (WGCNA) was also performed to extract the modules associated with SAH. Following, the lncRNA-mRNA co-expression network was constructed and the gene set enrichment analysis (GSEA) was performed to screen key RNA biomarkers involved in the pathogenesis of SAH from RIA. We also verified the results in a bigger dataset GSE7337. Results Totally, 561 DERs, including 25 DElncRNAs and 536 DEmRNAs, were identified. Functional analysis revealed that the DEmRNAs were mainly associated with immune response-associated GO-BP terms and KEGG pathways. Moreover, there were 6 modules significantly positive-correlated with SAH. The lncRNA-mRNA co-expression network contained 2 lncRNAs (LINC00265 and LINC00937) and 169 mRNAs. The GSEA analysis showed that these two lncRNAs were associated with three pathways (cytokine-cytokine receptor interaction, neurotrophin signaling pathway, and apoptosis). Additionally, IRAK3 and NFKBIA involved in the neurotrophin signaling pathway and apoptosis while IL1R2, IL18RAP and IL18R1 was associated with cytokine-cytokine receptor interaction pathway. The expression levels of these genes have the same trend in GSE36791 and GSE7337. Conclusion LINC00265 and LINC00937 may be implicated with the pathogenesis of SAH from RIA. They were involved in three important regulatory pathways. 5 mRNAs played important roles in the three pathways.

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Leukemia inhibitory factor and NGF regulate signal transducers and activators of transcription activation in sympathetic ganglia: convergence of cytokine- and neurotrophin-signaling pathways

Brain Research ◽

10.1016/s0006-8993(98)00611-8 ◽

1998 ◽

Vol 802 (1-2) ◽

pp. 198-204 ◽

Cited By ~ 16

Author(s):

Prithi Rajan ◽

Thomas Gearan ◽

J.Stephen Fink

Keyword(s):

Signaling Pathways ◽

Leukemia Inhibitory Factor ◽

Transcription Activation ◽

Sympathetic Ganglia ◽

Inhibitory Factor ◽

Signal Transducers ◽

Neurotrophin Signaling ◽

Signal Transducers And Activators

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Endogenous Modulators of TRP Channels

Current Topics in Medicinal Chemistry ◽

10.2174/1568026611313030014 ◽

2013 ◽

Vol 13 (3) ◽

pp. 398-407 ◽

Cited By ~ 18

Author(s):

Enza Palazzo ◽

Francesco Rossi ◽

Vito de Novellis ◽

Sabatino Maione

Keyword(s):

Trp Channels ◽

Endogenous Modulators

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Activated leukocyte cell adhesion molecule modulates neurotrophin signaling

Journal of Neurochemistry ◽

10.1111/j.1471-4159.2012.07658.x ◽

2012 ◽

Vol 121 (4) ◽

pp. 575-586 ◽

Cited By ~ 13

Author(s):

Anna Wade ◽

Claire Thomas ◽

Bernadett Kalmar ◽

Marco Terenzio ◽

Jerome Garin ◽

...

Keyword(s):

Cell Adhesion ◽

Adhesion Molecule ◽

Cell Adhesion Molecule ◽

Neurotrophin Signaling

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AMPA receptor inhibition by synaptically released zinc

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1512296112 ◽

2015 ◽

Vol 112 (51) ◽

pp. 15749-15754 ◽

Cited By ~ 54

Author(s):

Bopanna I. Kalappa ◽

Charles T. Anderson ◽

Jacob M. Goldberg ◽

Stephen J. Lippard ◽

Thanos Tzounopoulos

Keyword(s):

Dorsal Cochlear Nucleus ◽

Fine Tuning ◽

Receptor Inhibition ◽

Endogenous Modulator ◽

Excitatory Neurotransmission ◽

Zinc Levels ◽

Zinc Inhibition ◽

Endogenous Modulators ◽

Activity Dependent

The vast amount of fast excitatory neurotransmission in the mammalian central nervous system is mediated by AMPA-subtype glutamate receptors (AMPARs). As a result, AMPAR-mediated synaptic transmission is implicated in nearly all aspects of brain development, function, and plasticity. Despite the central role of AMPARs in neurobiology, the fine-tuning of synaptic AMPA responses by endogenous modulators remains poorly understood. Here we provide evidence that endogenous zinc, released by single presynaptic action potentials, inhibits synaptic AMPA currents in the dorsal cochlear nucleus (DCN) and hippocampus. Exposure to loud sound reduces presynaptic zinc levels in the DCN and abolishes zinc inhibition, implicating zinc in experience-dependent AMPAR synaptic plasticity. Our results establish zinc as an activity-dependent, endogenous modulator of AMPARs that tunes fast excitatory neurotransmission and plasticity in glutamatergic synapses.

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Autoantibodies as Endogenous Modulators of GPCR Signaling

Trends in Pharmacological Sciences ◽

10.1016/j.tips.2020.11.013 ◽

2020 ◽

Author(s):

Meredith A. Skiba ◽

Andrew C. Kruse

Keyword(s):

Gpcr Signaling ◽

Endogenous Modulators

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Identification of Potential Genes Associated with Vemurafenib Efficacy and Melanoma Prognosis

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207324666210603152044 ◽

2021 ◽

Vol 24 ◽

Author(s):

Yue Qi ◽

GuiE Ma

Keyword(s):

Signaling Pathway ◽

Estrogen Signaling ◽

Akt Signaling Pathway ◽

Ppi Network ◽

Hub Genes ◽

Ampk Signaling ◽

Melanoma Patients ◽

Key Genes ◽

Neurotrophin Signaling ◽

Upregulated Genes

Objective: This work aimed to investigate the molecular mechanisms underlying the efficacy of vemurafenib as a treatment for melanoma. Methods: The GSE52882 dataset, which includes A375 and A2058 melanoma cell lines treated with vemurafenib and dimethyl sulfoxide (DMSO), and clinical information associated with melanoma patients, were acquired from the Gene Expression Omnibus (GEO) database and University of California Santa Cruz (UCSC), respectively. Functional enrichment analysis, protein-protein interaction (PPI) network construction, sub-module analysis, and transcriptional regulation analysis were performed on overlapping differentially expressed genes (DEGs) identified in both cell lines. Finally, we performed a survival analysis based on the genes identified. Results: A total of 447 consistently overlapping DEGs (176 up- and 271 down-regulated DEGs) were screened. Upregulated genes were enriched in pathways of neurotrophin signaling, estrogen signaling, and transcriptional misregulation in cancer. Downregulated DEGs played essential roles in melanogenesis, pathways of cancer, PI3K-Akt signaling pathway, and AMPK signaling pathway. Upregulated (MMP2, JUN, KAT28, and PIK3R3) and downregulated genes (CXCL8, CCND1, IGF1R, and ITGB3) were considered as hub genes in the PPI network. Additionally, PIK3R3 and LEF1 served as key genes in the regulatory network. The overexpression of MMP2 and CXCL8 was associated with a poor prognosis in melanoma patients. Results: A total of 447 consistently overlapping DEGs (176 up- and 271 down-regulated DEGs) were screened. Upregulated genes were enriched in pathways of neurotrophin signaling, estrogen signaling, and transcriptional misregulation in cancer. Downregulated DEGs played essential roles in melanogenesis, pathways of cancer, PI3K-Akt signaling pathway, and AMPK signaling pathway. Upregulated (MMP2, JUN, KAT28, and PIK3R3) and downregulated genes (CXCL8, CCND1, IGF1R, and ITGB3) were considered as hub genes in the PPI network. Additionally, PIK3R3 and LEF1 served as key genes in the regulatory network. The overexpression of MMP2 and CXCL8 was associated with a poor prognosis in melanoma patients. Conclusion: MMP2, CXCL8, PIK3R3, ITGB3, and LEF1 may play roles in the efficacy of vemurafenib treatment in melanoma; for example, MMP2 and PIK3R3 are likely associated with vemurafenib resistance. These findings will contribute to the development of novel therapies for melanoma.

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