Pathophysiology of Lipid Droplets in Neuroglia

In recent years, increasing evidence regarding the functional importance of lipid droplets (LDs), cytoplasmic storage organelles in the central nervous system (CNS), has emerged. Although not abundantly present in the CNS under normal conditions in adulthood, LDs accumulate in the CNS during development and aging, as well as in some neurologic disorders. LDs are actively involved in cellular lipid turnover and stress response. By regulating the storage of excess fatty acids, cholesterol, and ceramides in addition to their subsequent release in response to cell needs and/or environmental stressors, LDs are involved in energy production, in the synthesis of membranes and signaling molecules, and in the protection of cells against lipotoxicity and free radicals. Accumulation of LDs in the CNS appears predominantly in neuroglia (astrocytes, microglia, oligodendrocytes, ependymal cells), which provide trophic, metabolic, and immune support to neuronal networks. Here we review the most recent findings on the characteristics and functions of LDs in neuroglia, focusing on astrocytes, the key homeostasis-providing cells in the CNS. We discuss the molecular mechanisms affecting LD turnover in neuroglia under stress and how this may protect neural cell function. We also highlight the role (and potential contribution) of neuroglial LDs in aging and in neurologic disorders.

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The Role of Exosomal Non-Coding RNAs in Coronary Artery Disease

Frontiers in Pharmacology ◽

10.3389/fphar.2020.603104 ◽

2020 ◽

Vol 11 ◽

Author(s):

Jia Liu ◽

Junduo Wu ◽

Longbo Li ◽

Tianyi Li ◽

Junnan Wang

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Molecular Mechanisms ◽

Cell Function ◽

Biologically Active ◽

Potential Contribution ◽

Key Factors ◽

Non Coding Rnas ◽

Artery Disease

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide. Atherosclerosis (AS) is a major cause of CVD. Oxidative stress, endothelial dysfunction, and inflammation are key factors involved in the development and progression of AS. Exosomes are nano-sized vesicles secreted into the extracellular space by most types of cells, and are ideal substances for the transmission and integration of signals between cells. Cells can selectively encapsulate biologically active substances, such as lipids, proteins and RNA in exosomes and act through paracrine mechanisms. Non-coding RNAs (ncRNAs) are important for communication between cells. They can reach the recipient cells through exosomes, causing phenotypic changes and playing a molecular regulatory role in cell function. Elucidating their molecular mechanisms can help identify therapeutic targets or strategies for CVD. Coronary artery disease (CAD) is the most important disease in CVD. Here, we review the role and the regulatory mechanism of exosomal ncRNAs in the pathophysiology of CAD, as well as the potential contribution of exosomal ncRNA to diagnosis and treatment of CAD.

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Resolution-Associated Molecular Patterns (RAMPs) as Endogenous Regulators of Glia Functions in Neuroinflammatory Disease

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527319666200702143719 ◽

2020 ◽

Vol 19 (7) ◽

pp. 483-494

Author(s):

Tyler J. Wenzel ◽

Evan Kwong ◽

Ekta Bajwa ◽

Andis Klegeris

Keyword(s):

Molecular Mechanisms ◽

Inflammatory Responses ◽

Bioactive Lipids ◽

Prothymosin Α ◽

Neuroinflammatory Disease ◽

Cellular Debris ◽

Αb Crystallin ◽

Endogenous Regulators ◽

The Central Nervous System ◽

Molecular Patterns

: Glial cells, including microglia and astrocytes, facilitate the survival and health of all cells within the Central Nervous System (CNS) by secreting a range of growth factors and contributing to tissue and synaptic remodeling. Microglia and astrocytes can also secrete cytotoxins in response to specific stimuli, such as exogenous Pathogen-Associated Molecular Patterns (PAMPs), or endogenous Damage-Associated Molecular Patterns (DAMPs). Excessive cytotoxic secretions can induce the death of neurons and contribute to the progression of neurodegenerative disorders, such as Alzheimer’s disease (AD). The transition between various activation states of glia, which include beneficial and detrimental modes, is regulated by endogenous molecules that include DAMPs, cytokines, neurotransmitters, and bioactive lipids, as well as a diverse group of mediators sometimes collectively referred to as Resolution-Associated Molecular Patterns (RAMPs). RAMPs are released by damaged or dying CNS cells into the extracellular space where they can induce signals in autocrine and paracrine fashions by interacting with glial cell receptors. While the complete range of their effects on glia has not been described yet, it is believed that their overall function is to inhibit adverse CNS inflammatory responses, facilitate tissue remodeling and cellular debris removal. This article summarizes the available evidence implicating the following RAMPs in CNS physiological processes and neurodegenerative diseases: cardiolipin (CL), prothymosin α (ProTα), binding immunoglobulin protein (BiP), heat shock protein (HSP) 10, HSP 27, and αB-crystallin. Studies on the molecular mechanisms engaged by RAMPs could identify novel glial targets for development of therapeutic agents that effectively slow down neuroinflammatory disorders including AD.

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SARS-CoV-2 and the Nervous System: From Clinical Features to Molecular Mechanisms

International Journal of Molecular Sciences ◽

10.3390/ijms21155475 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5475 ◽

Cited By ~ 11

Author(s):

Manuela Pennisi ◽

Giuseppe Lanza ◽

Luca Falzone ◽

Francesco Fisicaro ◽

Raffaele Ferri ◽

...

Keyword(s):

Nervous System ◽

Molecular Mechanisms ◽

Neuronal Damage ◽

Neurological Complications ◽

Neurological Manifestations ◽

Wide Range ◽

Inflammatory State ◽

Acute Polyneuropathy ◽

The Central Nervous System ◽

The Impact

Increasing evidence suggests that Severe Acute Respiratory Syndrome-coronavirus-2 (SARS-CoV-2) can also invade the central nervous system (CNS). However, findings available on its neurological manifestations and their pathogenic mechanisms have not yet been systematically addressed. A literature search on neurological complications reported in patients with COVID-19 until June 2020 produced a total of 23 studies. Overall, these papers report that patients may exhibit a wide range of neurological manifestations, including encephalopathy, encephalitis, seizures, cerebrovascular events, acute polyneuropathy, headache, hypogeusia, and hyposmia, as well as some non-specific symptoms. Whether these features can be an indirect and unspecific consequence of the pulmonary disease or a generalized inflammatory state on the CNS remains to be determined; also, they may rather reflect direct SARS-CoV-2-related neuronal damage. Hematogenous versus transsynaptic propagation, the role of the angiotensin II converting enzyme receptor-2, the spread across the blood-brain barrier, the impact of the hyperimmune response (the so-called “cytokine storm”), and the possibility of virus persistence within some CNS resident cells are still debated. The different levels and severity of neurotropism and neurovirulence in patients with COVID-19 might be explained by a combination of viral and host factors and by their interaction.

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Cannabidiol induces autophagy via ERK1/2 activation in neural cells

Scientific Reports ◽

10.1038/s41598-021-84879-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Talita A. M. Vrechi ◽

Anderson H. F. F. Leão ◽

Ingrid B. M. Morais ◽

Vanessa C. Abílio ◽

Antonio W. Zuardi ◽

...

Keyword(s):

Central Nervous System ◽

Neurodegenerative Disorders ◽

Molecular Mechanisms ◽

Cannabis Sativa ◽

Autophagic Flux ◽

Neural Cells ◽

Human Neuroblastoma ◽

Trpv1 Receptor ◽

The Central Nervous System ◽

Catabolic Process

AbstractAutophagy is a lysosomal catabolic process essential to cell homeostasis and is related to the neuroprotection of the central nervous system. Cannabidiol (CBD) is a non-psychotropic phytocannabinoid present in Cannabis sativa. Many therapeutic actions have been linked to this compound, including autophagy activation. However, the precise underlying molecular mechanisms remain unclear, and the downstream functional significance of these actions has yet to be determined. Here, we investigated CBD-evoked effects on autophagy in human neuroblastoma SH-SY5Y and murine astrocyte cell lines. We found that CBD-induced autophagy was substantially reduced in the presence of CB1, CB2 and TRPV1 receptor antagonists, AM 251, AM 630 and capsazepine, respectively. This result strongly indicates that the activation of these receptors mediates the autophagic flux. Additionally, we demonstrated that CBD activates autophagy through ERK1/2 activation and AKT suppression. Interestingly, CBD-mediated autophagy activation is dependent on the autophagy initiator ULK1, but mTORC1 independent. Thus, it is plausible that a non-canonical pathway is involved. Our findings collectively provide evidence that CBD stimulates autophagy signal transduction via crosstalk between the ERK1/2 and AKT kinases, which represent putative regulators of cell proliferation and survival. Furthermore, our study sheds light on potential therapeutic cannabinoid targets that could be developed for treating neurodegenerative disorders.

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Metabolic Profiling Analysis Reveals the Potential Contribution of Barley Sprouts against Oxidative Stress and Related Liver Cell Damage in Habitual Alcohol Drinkers

Antioxidants ◽

10.3390/antiox10030459 ◽

2021 ◽

Vol 10 (3) ◽

pp. 459

Author(s):

Hyerin Park ◽

Eunok Lee ◽

Yunsoo Kim ◽

Hye Yoon Jung ◽

Kwang-Min Kim ◽

...

Keyword(s):

Oxidative Stress ◽

Fatty Liver ◽

Molecular Mechanisms ◽

Learning Algorithm ◽

Controlled Trial ◽

Liver Fat ◽

Glutathione Metabolism ◽

Ros Generation ◽

Potential Contribution ◽

Glutamyl Transferase

Chronic excessive alcohol consumption is associated with multiple liver defects, such as steatosis and cirrhosis, mainly attributable to excessive reactive oxygen species (ROS) production. Barley sprouts (Hordeum vulgare L.) contain high levels of polyphenols that may serve as potential antioxidants. This study aimed to investigate whether barley sprouts extract powder (BSE) relieves alcohol-induced oxidative stress and related hepatic damages in habitual alcohol drinkers with fatty liver. In a 12-week randomized controlled trial with two arms (placebo or 480 mg/day BSE; n = 76), we measured clinical markers and metabolites at the baseline and endpoint to understand the complex molecular mechanisms. BSE supplementation reduced the magnitude of ROS generation and lipid peroxidation and improved the glutathione antioxidant system. Subsequent metabolomic analysis identified alterations in glutathione metabolism, amino acid metabolism, and fatty acid synthesis pathways, confirming the role of BSE in glutathione-related lipid metabolism. Finally, the unsupervised machine learning algorithm indicated that subjects with lower glutathione reductase at the baseline were responders for liver fat content, and those with higher fatigue and lipid oxidation were responders for γ-glutamyl transferase. These findings suggest that BSE administration may protect against hepatic injury by reducing oxidative stress and changing the metabolism in habitual alcohol drinkers with fatty liver.

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Ketamine Alters Functional Plasticity of Astroglia: An Implication for Antidepressant Effect

Life ◽

10.3390/life11060573 ◽

2021 ◽

Vol 11 (6) ◽

pp. 573

Author(s):

Matjaž Stenovec

Keyword(s):

Molecular Mechanisms ◽

Neuronal Firing ◽

Fusion Pore ◽

Antidepressant Effect ◽

Intracellular Camp ◽

Lateral Habenula ◽

Vesicle Recycling ◽

The Central Nervous System ◽

Inward Rectifying Potassium Channel ◽

Antidepressant Action

Ketamine, a non-competitive N–methyl–d–aspartate receptor (NMDAR) antagonist, exerts a rapid, potent and long-lasting antidepressant effect, although the cellular and molecular mechanisms of this action are yet to be clarified. In addition to targeting neuronal NMDARs fundamental for synaptic transmission, ketamine also affects the function of astrocytes, the key homeostatic cells of the central nervous system that contribute to pathophysiology of major depressive disorder. Here, I review studies revealing that (sub)anesthetic doses of ketamine elevate intracellular cAMP concentration ([cAMP]i) in astrocytes, attenuate stimulus-evoked astrocyte calcium signaling, which regulates exocytotic secretion of gliosignaling molecules, and stabilize the vesicle fusion pore in a narrow configuration, possibly hindering cargo discharge or vesicle recycling. Next, I discuss how ketamine affects astrocyte capacity to control extracellular K+ by reducing vesicular delivery of the inward rectifying potassium channel (Kir4.1) to the plasmalemma that reduces the surface density of Kir4.1. Modified astroglial K+ buffering impacts upon neuronal firing pattern as demonstrated in lateral habenula in a rat model of depression. Finally, I highlight the discovery that ketamine rapidly redistributes cholesterol in the astrocyte plasmalemma, which may alter the flux of cholesterol to neurons. This structural modification may further modulate a host of processes that synergistically contribute to ketamine’s rapid antidepressant action.

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Neuroinflammation and the Kynurenine Pathway in CNS Disease: Molecular Mechanisms and Therapeutic Implications

Cells ◽

10.3390/cells10061548 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1548

Author(s):

Mustafa N. Mithaiwala ◽

Danielle Santana-Coelho ◽

Grace A. Porter ◽

Jason C. O’Connor

Keyword(s):

Molecular Mechanisms ◽

Treatment Options ◽

Treatment Strategies ◽

Kynurenine Pathway ◽

Economic Problem ◽

Cns Disease ◽

Therapeutic Implications ◽

Efficacious Treatment ◽

The Central Nervous System ◽

Significant Health

Diseases of the central nervous system (CNS) remain a significant health, social and economic problem around the globe. The development of therapeutic strategies for CNS conditions has suffered due to a poor understanding of the underlying pathologies that manifest them. Understanding common etiological origins at the cellular and molecular level is essential to enhance the development of efficacious and targeted treatment options. Over the years, neuroinflammation has been posited as a common link between multiple neurological, neurodegenerative and neuropsychiatric disorders. Processes that precipitate neuroinflammatory conditions including genetics, infections, physical injury and psychosocial factors, like stress and trauma, closely link dysregulation in kynurenine pathway (KP) of tryptophan metabolism as a possible pathophysiological factor that ‘fuel the fire’ in CNS diseases. In this study, we aim to review emerging evidence that provide mechanistic insights between different CNS disorders, neuroinflammation and the KP. We provide a thorough overview of the different branches of the KP pertinent to CNS disease pathology that have therapeutic implications for the development of selected and efficacious treatment strategies.

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When the Blood Hits Your Brain: The Neurotoxicity of Extravasated Blood

International Journal of Molecular Sciences ◽

10.3390/ijms22105132 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5132

Author(s):

Jesse A. Stokum ◽

Gregory J. Cannarsa ◽

Aaron P. Wessell ◽

Phelan Shea ◽

Nicole Wenger ◽

...

Keyword(s):

Molecular Mechanisms ◽

Surgical Intervention ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Critical Factor ◽

Mass Effect ◽

Direct Role ◽

Scientific Curiosity ◽

Clot Removal ◽

Clinical Literature ◽

The Central Nervous System

Hemorrhage in the central nervous system (CNS), including intracerebral hemorrhage (ICH), intraventricular hemorrhage (IVH), and aneurysmal subarachnoid hemorrhage (aSAH), remains highly morbid. Trials of medical management for these conditions over recent decades have been largely unsuccessful in improving outcome and reducing mortality. Beyond its role in creating mass effect, the presence of extravasated blood in patients with CNS hemorrhage is generally overlooked. Since trials of surgical intervention to remove CNS hemorrhage have been generally unsuccessful, the potent neurotoxicity of blood is generally viewed as a basic scientific curiosity rather than a clinically meaningful factor. In this review, we evaluate the direct role of blood as a neurotoxin and its subsequent clinical relevance. We first describe the molecular mechanisms of blood neurotoxicity. We then evaluate the clinical literature that directly relates to the evacuation of CNS hemorrhage. We posit that the efficacy of clot removal is a critical factor in outcome following surgical intervention. Future interventions for CNS hemorrhage should be guided by the principle that blood is exquisitely toxic to the brain.

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Robot-Assisted Stereotactic Shunting as a Novel Treatment for Pontine Glioependymal Cysts

Journal of Neurological Surgery Part A Central European Neurosurgery ◽

10.1055/s-0041-1726109 ◽

2021 ◽

Author(s):

Simon Schieferdecker ◽

Stefan Hunsche ◽

Faycal El Majdoub ◽

Mohammad Maarouf

Keyword(s):

Abducens Nerve ◽

Ependymal Cells ◽

Robot Assisted ◽

Quick Recovery ◽

Glioependymal Cyst ◽

Novel Treatment ◽

First Case ◽

Mri Scans ◽

The Central Nervous System ◽

Magnetic Resonance Imaging Mri

AbstractIn this case report, the authors describe the first case of a glioependymal cyst of the brainstem managed by robot-assisted, stereotactic, cysto-ventricular shunting. Glioependymal cysts are rare congenital cystic lesions that are thought to form by displacement of ependymal cells during the embryonal period. Glioependymal cysts have been reported in a variety of different locations within the central nervous system. However, glioependymal cysts of the brainstem have only been described once before. Here, we report the case of a 53-year-old man who was referred to our department due to hemiparesis, hemihypesthesia, and hemidysesthesia, as well as facial and abducens nerve palsy. A large pontine glioependymal cyst was confirmed via magnetic resonance imaging (MRI) scans. The cyst was subsequently decompressed by connecting the cyst with the fourth ventricle via robot-assisted stereotactic shunt placement. In the postoperative course, the patient made a quick recovery and did not report any permanent neurologic deficits.

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Microglia extracellular vesicles: focus on molecular composition and biological function

Biochemical Society Transactions ◽

10.1042/bst20210202 ◽

2021 ◽

Vol 49 (4) ◽

pp. 1779-1790 ◽

Cited By ~ 1

Author(s):

Lorenzo Ceccarelli ◽

Chiara Giacomelli ◽

Laura Marchetti ◽

Claudia Martini

Keyword(s):

Extracellular Vesicles ◽

Molecular Mechanisms ◽

Biological Function ◽

Biological Effects ◽

Genetic Material ◽

Cell Communication ◽

Molecular Composition ◽

Cargo Proteins ◽

A Cell ◽

The Central Nervous System

Extracellular vesicles (EVs) are a heterogeneous family of cell-derived lipid bounded vesicles comprising exosomes and microvesicles. They are potentially produced by all types of cells and are used as a cell-to-cell communication method that allows protein, lipid, and genetic material exchange. Microglia cells produce a large number of EVs both in resting and activated conditions, in the latter case changing their production and related biological effects. Several actions of microglia in the central nervous system are ascribed to EVs, but the molecular mechanisms by which each effect occurs are still largely unknown. Conflicting functions have been ascribed to microglia-derived EVs starting from the neuronal support and ending with the propagation of inflammation and neurodegeneration, confirming the crucial role of these organelles in tuning brain homeostasis. Despite the increasing number of studies reported on microglia-EVs, there is also a lot of fragmentation in the knowledge on the mechanism at the basis of their production and modification of their cargo. In this review, a collection of literature data about the surface and cargo proteins and lipids as well as the miRNA content of EVs produced by microglial cells has been reported. A special highlight was given to the works in which the EV molecular composition is linked to a precise biological function.

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