scholarly journals The Functional Role of microRNAs in the Pathogenesis of Tauopathy

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2262
Author(s):  
Domenico Praticò
Keyword(s):  
Small Molecules ◽  
Tau Protein ◽  
Biological Fluids ◽  
Corticobasal Degeneration ◽  
Brain Regions ◽  
Post Translational Modifications ◽  
Master Regulators ◽  
Non Invasive ◽  
The Central Nervous System

Tauopathies are neurodegenerative disorders which include Alzheimer’s disease, Pick’s disease, corticobasal degeneration, and progressive supranuclear palsy among others. Pathologically, they are characterized by the accumulation of highly phosphorylated and aggregated tau protein in different brain regions. Currently, the mechanisms responsible for their pathogenesis are not known, and for this reason, there is no cure. MicroRNAs (miRNAs) are abundantly present in the central nervous system where they act as master regulators of pathways considered important for tau post-translational modifications, metabolism, and clearance. Although in recent years, several miRNAs have been reported to be altered in tauopathy, we still do not know whether these changes contribute to the onset and progression of the disorder, or are secondary events following the development of tau neuropathology. Additionally, since miRNAs are relatively stable in biological fluids and their measurement is easy and non-invasive, these small molecules hold the potential to function as biomarkers for tauopathy. Herein, we showcase recent findings on the biological link between miRNAs and the pathogenesis of tauopathy, and present emerging evidence supporting their role as biomarkers and targets for novel therapies against them.

scholarly journals Extraction of Exosomes from Glioblastoma Multiforme Patients’ Blood Plasma

2019 ◽  
Vol 9 (3) ◽  
pp. 234-238
Author(s):  
I. F. Gareev ◽  
O. A. Beylerli ◽  
Sh. Zhao ◽  
G. Yang ◽  
J. Sun ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Blood Plasma ◽  
Biological Fluids ◽  
Morphological Characteristics ◽  
Spherical Shape ◽  
Experimental Protocol ◽  
Malignant Brain Tumour ◽  
Non Invasive ◽  
Diagnosis And Prognosis

Introduction. Glioblastoma multiforme (GBM) is the most common and aggressive form of primary malignant brain tumour in adults associated with a poor prognosis. Exosomes have been shown to be useful non-invasive biomarkers for the diagnosis and prognosis of tumours, GBM included. Exosomes play a role of biological carriers which can perform various tasks through various signalling pathways of carcinogenesis, such as PI3K/AKT, SOX2, PTEN, ERK and STAT3.Materials and methods. Exosomes were isolated from blood plasma taken from patients diagnosed with GBM prior to surgical resection.Results and discussion. Plasma exosomes from patients with GBM had spherical shape and varied in size from 40 to 100 nm matching the exosomes’ morphological characteristics. The combination of ultrafiltration and double ultracentrifugation makes it possible to extract exosome examples from plasma without the presence of contaminating particles over 100 nm in size; the shape and size of these vesicles match the characteristics of exosomes isolated from other biological fluids.Conclusion. The experimental protocol for the extraction of exosomes from GBM patients’ plasma described here proves effective as a method used to ensure the purity of exosomes. Applying this method offers further opportunities for research into the role of exosomes in GBM pathogenesis. Equally this method can be used in research involving other human pathologies.

scholarly journals The role of anatomical connection strength for interareal communication in macaque cortex

2020 ◽  
Author(s):  
Julien Vezoli ◽  
Martin Vinck ◽  
Conrado A. Bosman ◽  
Andre M. Bastos ◽  
Christopher M Lewis ◽  
...  
Keyword(s):  
Large Scale ◽  
Functional Organization ◽  
Brain Regions ◽  
Connection Strength ◽  
Non Invasive ◽  
Large Scale Networks ◽  
Invasive Techniques ◽  
The Relationship ◽  
Anatomical Connection

What is the relationship between anatomical connection strength and rhythmic synchronization? Simultaneous recordings of 15 cortical areas in two macaque monkeys show that interareal networks are functionally organized in spatially distinct modules with specific synchronization frequencies, i.e. frequency-specific functional connectomes. We relate the functional interactions between 91 area pairs to their anatomical connection strength defined in a separate cohort of twenty six subjects. This reveals that anatomical connection strength predicts rhythmic synchronization and vice-versa, in a manner that is specific for frequency bands and for the feedforward versus feedback direction, even if interareal distances are taken into account. These results further our understanding of structure-function relationships in large-scale networks covering different modality-specific brain regions and provide strong constraints on mechanistic models of brain function. Because this approach can be adapted to non-invasive techniques, it promises to open new perspectives on the functional organization of the human brain.

scholarly journals Angiostatic cues from the matrix: Endothelial cell autophagy meets hyaluronan biology

2020 ◽  
Vol 295 (49) ◽  
pp. 16797-16812
Author(s):  
Carolyn G. Chen ◽  
Renato V. Iozzo
Keyword(s):  
Molecular Mechanisms ◽  
Biological Functions ◽  
Post Translational Modifications ◽  
Binding Partner ◽  
Master Regulators ◽  
The Matrix ◽  
Vascular Endothelia ◽  
Insight Into ◽  
Review Current

The extracellular matrix encompasses a reservoir of bioactive macromolecules that modulates a cornucopia of biological functions. A prominent body of work posits matrix constituents as master regulators of autophagy and angiogenesis and provides molecular insight into how these two processes are coordinated. Here, we review current understanding of the molecular mechanisms underlying hyaluronan and HAS2 regulation and the role of soluble proteoglycan in affecting autophagy and angiogenesis. Specifically, we assess the role of proteoglycan-evoked autophagy in regulating angiogenesis via the HAS2-hyaluronan axis and ATG9A, a novel HAS2 binding partner. We discuss extracellular hyaluronan biology and the post-transcriptional and post-translational modifications that regulate its main synthesizer, HAS2. We highlight the emerging group of proteoglycans that utilize outside-in signaling to modulate autophagy and angiogenesis in cancer microenvironments and thoroughly review the most up-to-date understanding of endorepellin signaling in vascular endothelia, providing insight into the temporal complexities involved.

scholarly journals Role of molecular polymorphism in defining tau filament structures in neurodegenerative diseases

2021 ◽  
Author(s):  
Xinyu Xiang ◽  
Tamta Arakhamia ◽  
Yari Carlomagno ◽  
Shikhar Dhingra ◽  
Manon Thierry ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Tau Protein ◽  
Molecular Level ◽  
Corticobasal Degeneration ◽  
Molecular Polymorphism ◽  
Cofactor Binding ◽  
Tau Isoforms ◽  
The Brain ◽  
Disease Specific

Misfolding and aggregation of tau protein is implicated in many neurodegenerative diseases that are typified by the presence of large, filamentous tau inclusions. The aggregation of tau in human brain is disease-specific with characteristic filaments defining the neuropathology. An understanding of how identical tau isoforms aggregate into disparate filament morphologies in phenotypically distinct tau-related diseases remains elusive. Here, we determine the structure of a brain-derived twisted tau filament in progressive supranuclear palsy and compare it to a dissimilar tau fold found in corticobasal degeneration. While the tau filament core in both diseases is comprised of residues 274 to 380, molecular-level polymorphism exists. Potential origins of the molecular polymorphism, such as noncovalent cofactor binding, are identified and predicted to modulate tau filament structures in the brain.

scholarly journals Noninvasive evaluation of intracranial hypertension? Is there a gold standard?

2012 ◽  
Vol 31 (04) ◽  
pp. 224-230 ◽  
Author(s):  
Leonardo Christian Welling ◽  
Eberval Gadelha Figueiredo ◽  
Fábio Santana Machado ◽  
Almir Ferreira Andrade ◽  
Vinicius Monteiro Guirado ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Intracranial Hypertension ◽  
Structural Damage ◽  
Ct Scanning ◽  
Noninvasive Evaluation ◽  
Non Invasive ◽  
Invasive Method ◽  
The Central Nervous System ◽  
The Brain

AbstractComputed tomography is essential in head injuried patients for the detection of structural damage to the brain. However, the ability of CT scanning to predict the presence or absence of intracranial hypertension has been debated in the literature. Since the optic nerve is part of the central nervous system and in case of raised pressure in the cerebrospinal fluid its sheath inflates. Based in this hypothesis the authors reviewed the role of the optic nerve sheat diameter in diagnosis intracranial hypertension after traumatic brain injury. This non-invasive method is useful to predict the risk of intracranial hypertension and select patients to ICP monitoring, especially in those with normal CT scans.

Circulating Biomarkers for Tumor Angiogenesis: Where Are We?

2020 ◽  
Vol 27 (14) ◽  
pp. 2361-2380 ◽  
Author(s):  
Virginia Di Paolo ◽  
Marta Colletti ◽  
Valentina Ferruzzi ◽  
Ida Russo ◽  
Angela Galardi ◽  
...  
Keyword(s):  
Biological Fluids ◽  
Membrane Vesicles ◽  
Clinical Settings ◽  
Circulating Biomarkers ◽  
Tumor Treatment ◽  
Invasive Strategy ◽  
Angiogenic Therapy ◽  
Non Invasive ◽  
Clinical Benefits

Background: In recent years, several anti-angiogenic drugs have been developed and their addition to standard treatment has been associated with clinical benefits. However, the response to anti-angiogenic therapy is characterized by considerable variability. In this context, the development of dynamic non-invasive biomarkers would be helpful to elucidate the emergence of anti-angiogenic resistance as well as to correctly address the treatment. Objectives: The purpose of this review is to describe current reports on circulating diagnostic and prognostic biomarkers related to angiogenesis. We further discuss how this non-invasive strategy could improve the monitoring of tumor treatment and help clinical strategy. Results: We discuss the latest evidence in the literature regarding circulating anti-angiogenic markers. Besides growth factor proteins, different circulating miRNAs could exert a pro- or anti-angiogenic activity so as to represent suitable candidates for a non-invasive strategy. Recent reports indicate that tumor-derived exosomes, which are small membrane vesicles abundant in biological fluids, also have an impact on vascular remodeling. Conclusion: Numerous circulating biomarkers related to angiogenesis have been recently identified. Their use will allow identifying patients who are more likely to benefit from a specific anti-angiogenic treatment, as well as detecting those who will develop resistance and/or adverse effects. Nonetheless, further studies are required to elucidate the role of these biomarkers in clinical settings.

Noninvasive Brain Stimulation: Contribution to Research in Neuroaesthetics

2020 ◽  
Author(s):  
Zaira Cattaneo
Keyword(s):  
Brain Stimulation ◽  
Brain Regions ◽  
Transcranial Electrical Stimulation ◽  
Noninvasive Brain Stimulation ◽  
Aesthetic Experiences ◽  
Non Invasive ◽  
Future Potential ◽  
Brain Behavior ◽  
Shed Light

Noninvasive brain stimulation (NIBS) techniques, such as transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (tES), are largely employed in cognitive neuroscience to investigate the brain–behavior relationship. During the last decade, non-invasive brain stimulation techniques have been increasingly employed in the field of neuroaesthetics research to shed light on the possible causal role of different brain regions contributing to aesthetic appreciation. This chapter provides a synthetic description of mechanisms of actions of TMS and different types of tES, and reviews recent NIBS studies that have shed light on the neural underpinning of aesthetic evaluation of (visual) artworks. The chapter also considers methodological limitations of the reviewed studies and the future potential for non-invasive brain stimulation to significantly contribute to the understanding of the neural bases of visual aesthetic experiences.

Unveiling the Role of Cytochrome P450 (2E1) in Human Brain Specifically in Parkinson’s Disease - Literature Review

2021 ◽  
Vol 22 ◽  
Author(s):  
Amna Shah ◽  
Chin Eng Ong ◽  
Yan Pan
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cytochrome P450 ◽  
Literature Review ◽  
Brain Regions ◽  
Cytochrome P450 Enzymes ◽  
Negative Effects ◽  
Drug Biotransformation ◽  
The Central Nervous System

Background: In recent years, the significance of cytochrome P450 enzymes (CYPs) has expanded beyond their role in liver. Factors such as genetics, environmental toxins, drug biotransformation and underlying diseases mediate the expression of these enzymes. Among the CYP enzymes, CYP2E1, a well-recognized monooxygenase enzyme involved in the metabolism of various endogenous and exogenous substances, plays a crucial role in the brain concerning the development of Parkinson’s disease. The expression of CYP2E1 varies in different brain regions making certain regions more vulnerable than others. CYP2E1 expression is inducible which generates tissue-damaging radicals leading to oxidative stress, mitochondrial dysfunction and ultimately neurodegeneration. Objective: Less is understood about the role of CYP2E1 in the central nervous system, therefore the purpose of the study was to investigate the relationship between the expression and activity of CYP2E1 enzyme relevant to Parkinson’s disease and to identify whether an increase in the expression of CYP2E1 is associated with neurodegeneration. Methods: The objectives of the study were achieved by implicating an unsystematic integrative literature review approach in which the literature was qualitatively analysed, critically evaluated and a new theory with an overall view of the mechanism was presented. Results : The contribution of CYP2E1 in the development of Parkinson’s disease was found to be significant as the negative effects of CYP2E1 overshadowed its protective detoxifying role. Conclusion: Overexpression of CYP2E1 seems detrimental to dopaminergic neurons, therefore, to overcome this, a synthetic biochemical is required which paves the way for further research and development of valuable biomolecules.

Abstract P324: Brd4 Degradation Enhances Cardiac Reprogramming And Regeneration By Inhibiting JAK/STAT Pathway

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Liu Liu ◽  
Yijing Guo ◽  
Ienglam Lei ◽  
Shuo Tian ◽  
Wenbin Gao ◽  
...  
Keyword(s):  
Small Molecules ◽  
Molecular Mechanisms ◽  
Cardiac Regeneration ◽  
Epigenetic Factors ◽  
Gene Expressions ◽  
Post Translational Modifications ◽  
Promising Strategy ◽  
Stat Pathway

Reprogramming of fibroblasts into induced cardiomyocytes (iCMs) is a potentially promising strategy for regenerating a damaged heart. However, low conversion rate of fibroblasts to cardiomyocytes and poor in vivo application efficacy are major challenges in this reprogramming process. To address this issue, we attempted to identify small molecules related to histone acyl post-translational modifications that could enhance the reprogramming ability towards cardiac fate. Using α-muscle heavy chain-GFP-tagged mouse embryo fibroblasts as a starting cell type, we screened 46 inhibitors target histone acyl post-translational modifications and related epigenetic factors and identified an important role of Brd4 in modulating iCM reprogramming. In particular, we observed that a novel Brd4 degrader repressed many genes involved in immune responses especially JAK/STAT pathway. Mechanically, Brd4 degrader repressed JAK/STAT related gene expressions by affecting Brd4 binding to promoters of those genes. More importantly, Brd4 degrader treatment enhanced MGT induced cardiac regeneration in vivo and markedly improved myocardial performance after myocardial infarction. These findings shed new light on the molecular mechanisms underlying the cardiac conversion of fibroblasts and provide novel targets and small molecules to improve iCM reprogramming for clinical applications.

scholarly journals Yin and Yang in Post-Translational Modifications of Human D-Amino Acid Oxidase

2021 ◽  
Vol 8 ◽  
Author(s):  
Silvia Sacchi ◽  
Valentina Rabattoni ◽  
Matteo Miceli ◽  
Loredano Pollegioni
Keyword(s):  
Amino Acid ◽  
Enzymatic Activity ◽  
Serine Racemase ◽  
Acid Oxidase ◽  
Amino Acid Oxidase ◽  
Post Translational Modifications ◽  
Functional Relationships ◽  
Yin And Yang ◽  
The Central Nervous System

In the central nervous system, the flavoprotein D-amino acid oxidase is responsible for catabolizing D-serine, the main endogenous coagonist of N-methyl-D-aspartate receptor. Dysregulation of D-serine brain levels in humans has been associated with neurodegenerative and psychiatric disorders. This D-amino acid is synthesized by the enzyme serine racemase, starting from the corresponding L-enantiomer, and degraded by both serine racemase (via an elimination reaction) and the flavoenzyme D-amino acid oxidase. To shed light on the role of human D-amino acid oxidase (hDAAO) in D-serine metabolism, the structural/functional relationships of this enzyme have been investigated in depth and several strategies aimed at controlling the enzymatic activity have been identified. Here, we focused on the effect of post-translational modifications: by using a combination of structural analyses, biochemical methods, and cellular studies, we investigated whether hDAAO is subjected to nitrosylation, sulfhydration, and phosphorylation. hDAAO is S-nitrosylated and this negatively affects its activity. In contrast, the hydrogen sulfide donor NaHS seems to alter the enzyme conformation, stabilizing a species with higher affinity for the flavin adenine dinucleotide cofactor and thus positively affecting enzymatic activity. Moreover, hDAAO is phosphorylated in cerebellum; however, the protein kinase involved is still unknown. Taken together, these findings indicate that D-serine levels can be also modulated by post-translational modifications of hDAAO as also known for the D-serine synthetic enzyme serine racemase.

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