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1.
Nat Neurosci ; 24(11): 1522-1533, 2021 11.
Article in English | MEDLINE | ID: covidwho-1500484

ABSTRACT

Coronavirus disease 2019 (COVID-19) can damage cerebral small vessels and cause neurological symptoms. Here we describe structural changes in cerebral small vessels of patients with COVID-19 and elucidate potential mechanisms underlying the vascular pathology. In brains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals and animal models, we found an increased number of empty basement membrane tubes, so-called string vessels representing remnants of lost capillaries. We obtained evidence that brain endothelial cells are infected and that the main protease of SARS-CoV-2 (Mpro) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, Mpro induces the death of human brain endothelial cells and the occurrence of string vessels in mice. Deletion of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood-brain barrier due to NEMO ablation. Importantly, a pharmacological inhibitor of RIPK signaling prevented the Mpro-induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.


Subject(s)
Blood-Brain Barrier/metabolism , Brain/metabolism , Coronavirus 3C Proteases/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Microvessels/metabolism , SARS-CoV-2/metabolism , Animals , Blood-Brain Barrier/pathology , Brain/pathology , Chlorocebus aethiops , Coronavirus 3C Proteases/genetics , Cricetinae , Female , Humans , Intracellular Signaling Peptides and Proteins/genetics , Male , Mesocricetus , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Microvessels/pathology , SARS-CoV-2/genetics , Vero Cells
2.
Proc Natl Acad Sci U S A ; 118(41)2021 10 12.
Article in English | MEDLINE | ID: covidwho-1486398

ABSTRACT

The COVID-19 pandemic led to widespread mandates requiring the wearing of face masks, which led to debates on their benefits and possible adverse effects. To that end, the physiological effects at the systemic and at the brain level are of interest. We have investigated the effect of commonly available face masks (FFP2 and surgical) on cerebral hemodynamics and oxygenation, particularly microvascular cerebral blood flow (CBF) and blood/tissue oxygen saturation (StO2), measured by transcranial hybrid near-infrared spectroscopies and on systemic physiology in 13 healthy adults (ages: 23 to 33 y). The results indicate small but significant changes in cerebral hemodynamics while wearing a mask. However, these changes are comparable to those of daily life activities. This platform and the protocol provides the basis for large or targeted studies of the effects of mask wearing in different populations and while performing critical tasks.


Subject(s)
Brain/physiology , Masks , Activities of Daily Living , Adult , Brain/blood supply , Brain/metabolism , COVID-19/prevention & control , Female , Healthy Volunteers , Hemodynamics , Humans , Male , Microcirculation , Monitoring, Physiologic , Oxygen/metabolism , SARS-CoV-2 , Spectroscopy, Near-Infrared , Young Adult
3.
Med Hypotheses ; 157: 110706, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1466787

ABSTRACT

SARS-COV-2 infection causes severe respiratory tract illness leading to asphyxia and death. The onset of infection is associated with loss of smell, blurred vision, headache with bronchopulmonary symptoms. The clinical observations of neurological abnormalities lead us to address the question, does the virus enter into brain and what is the underlying mechanism of brain infection? The working hypothesis is, SARS-COV-2 Spike epitopes modify blood brain barrier and infect glial cells to induce brain inflammation in genetically diverse human population. The hypothesis is tested by determining binding or interacting ability of virus Spike epitope peptides M1Lys60 and Ala240Glu300 with human toll-like receptor 8 (TLR 8), brain targeted Vascular Cell adhesion Molecules (VCAM1) proteins, Zonula Occludens (ZO), glial cell specific protein NDRG2 and Apo- S100B. The molecular dynamic experiments are performed, and root mean square deviation (RMSD) values are determined for interactions between the Spike peptides and selected proteins. The observations demonstrate formation of heterodimeric complex between the epitope peptides and selected protein structures. The viral epitopes have ability to bind with HLA-DRB1 15:01, 07:01 or 03.01 alleles thus found immunogenic in nature. The observations altogether suggest entry of these Spike protein epitopes into human brain causes inflammation.


Subject(s)
COVID-19 , SARS-CoV-2 , Brain/metabolism , Epitopes , Humans , Molecular Docking Simulation , Neuroglia , Peptides , Spike Glycoprotein, Coronavirus/metabolism , Toll-Like Receptor 8 , Tumor Suppressor Proteins
4.
Biomed Pharmacother ; 144: 112291, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1466070

ABSTRACT

BACKGROUND: Oxytocin (OXT), a neuropeptide involved in mammal reproductive and prosocial behaviors, has been reported to interact with various stressor-provoked neurobiological changes, including neuroendocrine, neurotransmitter, and inflammatory processes. In view of disturbances in psychosocial relationships due to social isolation and physical distancing measures amid the COVID-19 pandemic, being one of the triggering factors for the recent rise in depression and anxiety, OXT is a potential candidate for a new antidepressant. METHODS: In this present study, we have aimed to investigate the effects of oral administration of Rosmarinus officinalis extract (RE), extracted from distillation residue of rosemary essential oil, on central OXT level in the context of other stress biomarkers and neurotransmitter levels in mice models. Tail suspension test (TST) and elevated plus maze test (EPMT) following LPS injection were employed to assess depressive- and anxiety-like behavior in mice, respectively. FINDINGS: Pretreatment with RE for seven days significantly improved behavior in TST and EPMT. Whole-genome microarray analysis reveals that RE significantly reversed TST stress-induced alterations in gene expressions related to oxytocinergic and neurotransmitter pathways and inflammatory processes. In both models, RE significantly increased central Oxt and Oxtr expressions, as well as OXT protein levels. RE also significantly attenuated stress-induced changes in serum corticosterone, brain and serum BDNF levels, and brain neurotransmitters levels in both models. INTERPRETATION: Altogether, our study is the first to report antidepressant- and anxiolytic-like activities of RE through modulating oxytocinergic system in mice brain and thus highlights the prospects of RE in the treatment of depressive disorders of psychosocial nature.


Subject(s)
Anti-Anxiety Agents/therapeutic use , Antidepressive Agents/therapeutic use , Oxytocin/metabolism , Plant Extracts/therapeutic use , Receptors, Oxytocin/metabolism , Rosmarinus , Animals , Anti-Anxiety Agents/isolation & purification , Anti-Anxiety Agents/pharmacology , Antidepressive Agents/isolation & purification , Antidepressive Agents/pharmacology , Anxiety/drug therapy , Anxiety/metabolism , Brain/drug effects , Brain/metabolism , Depression/drug therapy , Depression/metabolism , Dose-Response Relationship, Drug , Inflammation Mediators/antagonists & inhibitors , Inflammation Mediators/metabolism , Male , Mice , Mice, Inbred ICR , Oxytocin/agonists , Plant Extracts/isolation & purification , Plant Extracts/pharmacology , Receptors, Oxytocin/agonists
5.
Folia Neuropathol ; 59(3): 232-238, 2021.
Article in English | MEDLINE | ID: covidwho-1463957

ABSTRACT

The major route of entry for the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) into human host cells is by means of the angiotensin-converting enzyme-2 (ACE2) transmembrane receptor. This zinc-containing carboxypeptidase and membrane-integral surface receptor is ubiquitous and widely expressed in multiple cell types. Hence SARS-CoV-2, an unusually large RNA virus that causes coronavirus disease 2019 (COVID-19) has the remarkable capacity to invade many different types of human host cells simultaneously. Although COVID-19 is generally considered to be primarily an acute respiratory disease SARS-CoV-2 also targets specific anatomical regions of the central nervous system (CNS). In the normal CNS the highest ACE2 levels of expression are found within the medullary respiratory centers of the brainstem and this, in part, may explain the susceptibility of numerous COVID-19 patients to severe respiratory distress. About ~35% of all COVID-19 patients experience neurological and neuropsychiatric symptoms, and a pre-existing diagnosis of Alzheimer's disease (AD) predicts the highest risk of COVID-19 yet identified, with the highest mortality among elderly AD patients. In the current study of multiple anatomical regions of AD brains compared to age-, post-mortem interval- and gender-matched controls (n = 10 regions, n = 32 brains), ACE2 expression was found to be significantly up-regulated in AD in the occipital lobe, temporal lobe neocortex and hippocampal CA1. The temporal lobe and hippocampus of the brain are also targeted by the inflammatory neuropathology that accompanies AD, suggesting a significant mechanistic overlap between COVID-19 and AD, strongly centered on invasion by the neurotropic SARS-CoV-2 virus via the increased presence of ACE2 receptors in limbic regions of the AD-affected brain.


Subject(s)
Alzheimer Disease/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Brain/metabolism , COVID-19 , Aged , Aged, 80 and over , Female , Humans , Male , SARS-CoV-2 , Up-Regulation
6.
Viruses ; 13(10)2021 10 08.
Article in English | MEDLINE | ID: covidwho-1463838

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the coronavirus disease (COVID-19), is currently infecting millions of people worldwide and is causing drastic changes in people's lives. Recent studies have shown that neurological symptoms are a major issue for people infected with SARS-CoV-2. However, the mechanism through which the pathological effects emerge is still unclear. Brain endothelial cells (ECs), one of the components of the blood-brain barrier, are a major hurdle for the entry of pathogenic or infectious agents into the brain. They strongly express angiotensin converting enzyme 2 (ACE2) for its normal physiological function, which is also well-known to be an opportunistic receptor for SARS-CoV-2 spike protein, facilitating their entry into host cells. First, we identified rapid internalization of the receptor-binding domain (RBD) S1 domain (S1) and active trimer (Trimer) of SARS-CoV-2 spike protein through ACE2 in brain ECs. Moreover, internalized S1 increased Rab5, an early endosomal marker while Trimer decreased Rab5 in the brain ECs. Similarly, the permeability of transferrin and dextran was increased in S1 treatment but decreased in Trimer, respectively. Furthermore, S1 and Trimer both induced mitochondrial damage including functional deficits in mitochondrial respiration. Overall, this study shows that SARS-CoV-2 itself has toxic effects on the brain ECs including defective molecular delivery and metabolic function, suggesting a potential pathological mechanism to induce neurological signs in the brain.


Subject(s)
Blood-Brain Barrier/metabolism , Brain/pathology , COVID-19/pathology , Endothelial Cells/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Animals , Brain/metabolism , Brain/virology , Endothelial Cells/virology , Humans , Mice , Mitochondria/metabolism , Protein Domains , SARS-CoV-2/metabolism , rab5 GTP-Binding Proteins/metabolism
7.
Biomed Res Int ; 2021: 7880448, 2021.
Article in English | MEDLINE | ID: covidwho-1455779

ABSTRACT

COVID-19-associated neuropsychiatric complications are soaring. There is an urgent need to understand the link between COVID-19 and neuropsychiatric disorders. To that end, this article addresses the premise that SARS-CoV-2 infection results in gut dysbiosis and an altered microbiota-gut-brain (MGB) axis that in turn contributes to the neuropsychiatric ramifications of COVID-19. Altered MGB axis activity has been implicated independently as a risk of neuropsychiatric disorders. A review of the changes in gut microbiota composition in individual psychiatric and neurological disorders and gut microbiota in COVID-19 patients revealed a shared "microbial signature" characterized by a lower microbial diversity and richness and a decrease in health-promoting anti-inflammatory commensal bacteria accompanied by an increase in opportunistic proinflammatory pathogens. Notably, there was a decrease in short-chain fatty acid (SCFA) producing bacteria. SCFAs are key bioactive microbial metabolites with anti-inflammatory functions and have been recognized as a critical signaling pathway in the MGB axis. SCFA deficiency is associated with brain inflammation, considered a cardinal feature of neuropsychiatric disorders. The link between SARS-CoV-2 infection, gut dysbiosis, and altered MGB axis is further supported by COVID-19-associated gastrointestinal symptoms, a high number of SARS-CoV-2 receptors, angiotensin-cleaving enzyme-2 (ACE-2) in the gut, and viral presence in the fecal matter. The binding of SARS-CoV-2 to the receptor results in ACE-2 deficiency that leads to decreased transport of vital dietary components, gut dysbiosis, proinflammatory gut status, increased permeability of the gut-blood barrier (GBB), and systemic inflammation. More clinical research is needed to substantiate further the linkages described above and evaluate the potential significance of gut microbiota as a diagnostic tool. Meanwhile, it is prudent to propose changes in dietary recommendations in favor of a high fiber diet or supplementation with SCFAs or probiotics to prevent or alleviate the neuropsychiatric ramifications of COVID-19.


Subject(s)
COVID-19/psychology , Fatty Acids, Volatile/metabolism , Gastrointestinal Microbiome/physiology , Bacteria/metabolism , Brain/metabolism , Brain/pathology , COVID-19/metabolism , COVID-19/microbiology , COVID-19/virology , Diet , Dysbiosis , Feces/microbiology , Gastrointestinal Diseases/microbiology , Gastrointestinal Microbiome/immunology , Humans , Inflammation , Probiotics/pharmacology , SARS-CoV-2/isolation & purification
8.
J Artif Organs ; 23(3): 292-295, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-1453765

ABSTRACT

A 71-year-old man undergoing hemodialysis (HD) was admitted to our hospital with congestive heart failure (CHF) and pneumonia. After admission, ultrafiltration with HD was urgently performed because of a lack of respiratory improvement despite the use of noninvasive positive pressure ventilation. During HD, cerebral regional saturation of oxygen (rSO2) was monitored by INVOS 5100c oxygen saturation monitor (Covidien Japan, Japan) to evaluate changes in tissue oxygenation. At HD initiation, cerebral rSO2 was very low at 34% under the fraction of inspiratory oxygen (FiO2) of 0.4. Ultrafiltration was performed at the rate of 0.5 L/h thereafter, cerebral rSO2 gradually improved even as inhaling oxygen concentration decreased. At the end of HD, cerebral rSO2 improved at 40% under a FiO2 of 0.28 as excess body fluid was removed. After pneumonia and CHF improved, he was discharged. Reports of the association between cerebral oxygenation and acute CHF status in patients undergoing HD are limited; therefore, in our experience with this case, cerebral oxygenation deteriorated with the CHF status but was improved by adequate body-fluid management during HD.


Subject(s)
Brain/metabolism , Heart Failure/complications , Oxygen Consumption/physiology , Renal Dialysis , Renal Insufficiency/therapy , Aged , Heart Failure/metabolism , Heart Failure/physiopathology , Humans , Male , Monitoring, Physiologic , Renal Insufficiency/complications , Renal Insufficiency/metabolism
9.
Int J Mol Sci ; 22(19)2021 Sep 28.
Article in English | MEDLINE | ID: covidwho-1444228

ABSTRACT

For a yet unknown reason, a substantial share of patients suffering from COVID-19 develop long-lasting neuropsychiatric symptoms ranging from cognitive deficits to mood disorders and/or an extreme fatigue. We previously reported that in non-neural cells, angiotensin-1 converting enzyme 2 (ACE2), the gene coding for the SARS-CoV2 host receptor, harbors tight co-expression links with dopa-decarboxylase (DDC), an enzyme involved in the metabolism of dopamine. Here, we mined and integrated data from distinct human expression atlases and found that, among a wide range of tissues and cells, enterocytes of the small intestine express the highest expression levels of ACE2, DDC and several key genes supporting the metabolism of neurotransmitters. Based on these results, we performed co-expression analyses on a recently published set of RNA-seq data obtained from SARS-CoV2-infected human intestinal organoids. We observed that in SARS-CoV2-infected enterocytes, ACE2 co-regulates not only with DDC but also with a specific group of genes involved in (i) the dopamine/trace amines metabolic pathway, (ii) the absorption of microbiota-derived L-DOPA and (iii) the absorption of neutral amino acids serving as precursors to neurotransmitters. We conclude that in patients with long COVID, a chronic infection and inflammation of small intestine enterocytes might be indirectly responsible for prolonged brain alterations.


Subject(s)
Brain/pathology , COVID-19/complications , Gene Expression Regulation , Intestine, Small/pathology , Angiotensin-Converting Enzyme 2/genetics , Aromatic-L-Amino-Acid Decarboxylases/genetics , Brain/metabolism , COVID-19/genetics , COVID-19/pathology , Cells, Cultured , Enterocytes/metabolism , Enterocytes/pathology , Humans , Intestine, Small/metabolism , SARS-CoV-2/isolation & purification
10.
Front Immunol ; 12: 729776, 2021.
Article in English | MEDLINE | ID: covidwho-1403478

ABSTRACT

Coronavirus disease 2019 (COVID-19) pandemic is caused by the novel coronavirus that has spread rapidly around the world, leading to high mortality because of multiple organ dysfunction; however, its underlying molecular mechanism is unknown. To determine the molecular mechanism of multiple organ dysfunction, a bioinformatics analysis method based on a time-order gene co-expression network (TO-GCN) was performed. First, gene expression profiles were downloaded from the gene expression omnibus database (GSE161200), and a TO-GCN was constructed using the breadth-first search (BFS) algorithm to infer the pattern of changes in the different organs over time. Second, Gene Ontology enrichment analysis was used to analyze the main biological processes related to COVID-19. The initial gene modules for the immune response of different organs were defined as the research object. The STRING database was used to construct a protein-protein interaction network of immune genes in different organs. The PageRank algorithm was used to identify five hub genes in each organ. Finally, the Comparative Toxicogenomics Database played an important role in exploring the potential compounds that target the hub genes. The results showed that there were two types of biological processes: the body's stress response and cell-mediated immune response involving the lung, trachea, and olfactory bulb (olf) after being infected by COVID-19. However, a unique biological process related to the stress response is the regulation of neuronal signals in the brain. The stress response was heterogeneous among different organs. In the lung, the regulation of DNA morphology, angiogenesis, and mitochondrial-related energy metabolism are specific biological processes related to the stress response. In particular, an effect on tracheal stress response was made by the regulation of protein metabolism and rRNA metabolism-related biological processes, as biological processes. In the olf, the distinctive stress responses consist of neural signal transmission and brain behavior. In addition, myeloid leukocyte activation and myeloid leukocyte-mediated immunity in response to COVID-19 can lead to a cytokine storm. Immune genes such as SRC, RHOA, CD40LG, CSF1, TNFRSF1A, FCER1G, ICAM1, LAT, LCN2, PLAU, CXCL10, ICAM1, CD40, IRF7, and B2M were predicted to be the hub genes in the cytokine storm. Furthermore, we inferred that resveratrol, acetaminophen, dexamethasone, estradiol, statins, curcumin, and other compounds are potential target drugs in the treatment of COVID-19.


Subject(s)
COVID-19/complications , Multiple Organ Failure/genetics , Antiviral Agents/therapeutic use , Brain/metabolism , Brain/virology , COVID-19/drug therapy , COVID-19/genetics , COVID-19/virology , Gene Expression Profiling , Gene Ontology , Humans , Lung/metabolism , Lung/virology , Multiple Organ Failure/drug therapy , Multiple Organ Failure/etiology , Multiple Organ Failure/metabolism , Olfactory Bulb/metabolism , Olfactory Bulb/virology , Protein Interaction Maps , SARS-CoV-2/physiology , Trachea/metabolism , Trachea/virology , Transcriptome
11.
CNS Neurosci Ther ; 27(1): 36-47, 2021 01.
Article in English | MEDLINE | ID: covidwho-1388231

ABSTRACT

The blood-brain barrier (BBB) is an important physiological barrier that separates the central nervous system (CNS) from the peripheral circulation, which contains inflammatory mediators and immune cells. The BBB regulates cellular and molecular exchange between the blood vessels and brain parenchyma. Normal functioning of the BBB is crucial for the homeostasis and proper function of the brain. It has been demonstrated that peripheral inflammation can disrupt the BBB by various pathways, resulting in different CNS diseases. Recently, clinical research also showed CNS complications following SARS-CoV-2 infection and chimeric antigen receptor (CAR)-T cell therapy, which both lead to a cytokine storm in the circulation. Therefore, elucidation of the mechanisms underlying the BBB disruption induced by peripheral inflammation will provide an important basis for protecting the CNS in the context of exacerbated peripheral inflammatory diseases. In the present review, we first summarize the physiological properties of the BBB that makes the CNS an immune-privileged organ. We then discuss the relevance of peripheral inflammation-induced BBB disruption to various CNS diseases. Finally, we elaborate various factors and mechanisms of peripheral inflammation that disrupt the BBB.


Subject(s)
Blood-Brain Barrier/metabolism , Brain/metabolism , COVID-19/metabolism , Inflammation Mediators/metabolism , Animals , Blood-Brain Barrier/immunology , Blood-Brain Barrier/pathology , Brain/immunology , Brain/pathology , COVID-19/immunology , COVID-19/pathology , Endothelial Cells/immunology , Endothelial Cells/metabolism , Humans , Inflammation/immunology , Inflammation/metabolism , Inflammation/pathology , Inflammation Mediators/immunology
12.
Viruses ; 13(8)2021 08 04.
Article in English | MEDLINE | ID: covidwho-1359300

ABSTRACT

Transcriptomics, proteomics and pathogen-host interactomics data are being explored for the in silico-informed selection of drugs, prior to their functional evaluation. The effectiveness of this kind of strategy has been put to the test in the current COVID-19 pandemic, and it has been paying off, leading to a few drugs being rapidly repurposed as treatment against SARS-CoV-2 infection. Several neglected tropical diseases, for which treatment remains unavailable, would benefit from informed in silico investigations of drugs, as performed in this work for Dengue fever disease. We analyzed transcriptomic data in the key tissues of liver, spleen and blood profiles and verified that despite transcriptomic differences due to tissue specialization, the common mechanisms of action, "Adrenergic receptor antagonist", "ATPase inhibitor", "NF-kB pathway inhibitor" and "Serotonin receptor antagonist", were identified as druggable (e.g., oxprenolol, digoxin, auranofin and palonosetron, respectively) to oppose the effects of severe Dengue infection in these tissues. These are good candidates for future functional evaluation and clinical trials.


Subject(s)
Antiviral Agents/therapeutic use , Dengue/drug therapy , Transcriptome , Adenosine Triphosphatases/antagonists & inhibitors , Adrenergic Antagonists/pharmacology , Adrenergic Antagonists/therapeutic use , Antiviral Agents/pharmacology , Brain/metabolism , Computer Simulation , Dengue/blood , Dengue/genetics , Dengue/metabolism , Drug Discovery , Drug Evaluation, Preclinical , Drug Repositioning , Humans , Liver/metabolism , Metabolic Networks and Pathways/drug effects , NF-kappa B/metabolism , Serotonin Antagonists/pharmacology , Serotonin Antagonists/therapeutic use , Severe Dengue/blood , Severe Dengue/drug therapy , Severe Dengue/genetics , Severe Dengue/metabolism , Spleen/metabolism
13.
Exp Neurol ; 345: 113837, 2021 11.
Article in English | MEDLINE | ID: covidwho-1356232

ABSTRACT

We examined cell type-specific expression and distribution of rat brain angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2, in the rodent brain. ACE2 is ubiquitously present in brain vasculature, with the highest density of ACE2 expressing capillaries found in the olfactory bulb, the hypothalamic paraventricular, supraoptic, and mammillary nuclei, the midbrain substantia nigra and ventral tegmental area, and the hindbrain pontine nucleus, the pre-Bötzinger complex, and nucleus of tractus solitarius. ACE2 was expressed in astrocytes and astrocytic foot processes, pericytes and endothelial cells, key components of the blood-brain barrier. We found discrete neuronal groups immunopositive for ACE2 in brainstem respiratory rhythm generating centers, including the pontine nucleus, the parafascicular/retrotrapezoid nucleus, the parabrachial nucleus, the Bötzinger, and pre-Bötzinger complexes and the nucleus of tractus solitarius; in the arousal-related pontine reticular nucleus and gigantocellular reticular nuclei; in brainstem aminergic nuclei, including substantia nigra, ventral tegmental area, dorsal raphe, and locus coeruleus; in the epithalamic habenula, hypothalamic paraventricular and supramammillary nuclei; and in the hippocampus. Identification of ACE2-expressing neurons in rat brain within well-established functional circuits facilitates prediction of possible neurological manifestations of brain ACE2 dysregulation during and after COVID-19 infection.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Brain/metabolism , COVID-19 , Central Nervous System Diseases/metabolism , Animals , Male , Rats , Rats, Wistar , SARS-CoV-2
14.
Front Immunol ; 12: 679425, 2021.
Article in English | MEDLINE | ID: covidwho-1344264

ABSTRACT

Gliomas are the most common primary brain tumors in adults. Despite the fact that they are relatively rare, they cause significant morbidity and mortality. High-grade gliomas or glioblastomas are rapidly progressing tumors with a very poor prognosis. The presence of an intrinsic immune system in the central nervous system is now more accepted. During the last decade, there has been no major progress in glioma therapy. The lack of effective treatment for gliomas can be explained by the strategies that cancer cells use to escape the immune system. This being said, immunotherapy, which involves blockade of immune checkpoint inhibitors, has improved patients' survival in different cancer types. This novel cancer therapy appears to be one of the most promising approaches. In the present study, we will start with a review of the general concept of immune response within the brain and glioma microenvironment. Then, we will try to decipher the role of various immune checkpoint inhibitors within the glioma microenvironment. Finally, we will discuss some promising therapeutic pathways, including immune checkpoint blockade and the body's effective anti-glioma immune response.


Subject(s)
Brain Neoplasms/drug therapy , Brain Neoplasms/pathology , Glioma/drug therapy , Glioma/pathology , Immune Checkpoint Inhibitors/therapeutic use , Tumor Microenvironment/drug effects , Biomarkers, Tumor , Brain/drug effects , Brain/immunology , Brain/metabolism , Brain/pathology , Brain Neoplasms/etiology , Brain Neoplasms/mortality , Disease Susceptibility , Glioma/etiology , Glioma/mortality , Humans , Immune Checkpoint Inhibitors/administration & dosage , Immune Checkpoint Inhibitors/adverse effects , Immune Checkpoint Proteins/genetics , Immune Checkpoint Proteins/metabolism , Molecular Targeted Therapy , Prognosis , Treatment Outcome , Tumor Microenvironment/genetics , Tumor Microenvironment/immunology
15.
Br J Anaesth ; 127(4): 648-659, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1329691

ABSTRACT

Mechanical ventilation induces a number of systemic responses for which the brain plays an essential role. During the last decade, substantial evidence has emerged showing that the brain modifies pulmonary responses to physical and biological stimuli by various mechanisms, including the modulation of neuroinflammatory reflexes and the onset of abnormal breathing patterns. Afferent signals and circulating factors from injured peripheral tissues, including the lung, can induce neuronal reprogramming, potentially contributing to neurocognitive dysfunction and psychological alterations seen in critically ill patients. These impairments are ubiquitous in the presence of positive pressure ventilation. This narrative review summarises current evidence of lung-brain crosstalk in patients receiving mechanical ventilation and describes the clinical implications of this crosstalk. Further, it proposes directions for future research ranging from identifying mechanisms of multiorgan failure to mitigating long-term sequelae after critical illness.


Subject(s)
Brain/metabolism , Lung Injury/physiopathology , Respiration, Artificial/methods , Animals , Central Nervous System/metabolism , Critical Illness , Humans , Multiple Organ Failure/physiopathology , Positive-Pressure Respiration/methods
16.
Mol Neurobiol ; 58(10): 5356-5368, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1326854

ABSTRACT

The pandemic of novel coronavirus 2 (SARS-CoV-2) has made global chaos for normal human living. Despite common COVID-19 symptoms, variability in clinical phenotypes was reported worldwide. Reports on SARS-CoV-2 suggest causing neurological manifestation. In addition, the susceptibility of SARS-CoV-2 in patients with neurodegenerative diseases and its complexity are largely unclear. Here, we aimed to demonstrate the possible transport of exosome from SARS-CoV-2-infected lungs to the brain regions associated with neurodegenerative diseases using multiple transcriptome datasets of SARS-CoV-2-infected lungs, RNA profiles from lung exosome, and gene expression profiles of the human brain. Upon transport, the transcription factors localized in the exosome regulate genes at lateral substantia nigra, medial substantia nigra, and superior frontal gyrus regions of Parkinson's disease (PD) and frontal cortex, hippocampus, and temporal cortex of Alzheimer's disease (AD). On SARS-CoV-2 infection, BCL3, JUND, MXD1, IRF2, IRF9, and STAT1 transcription factors in the exosomes influence the neuronal gene regulatory network and accelerate neurodegeneration. STAT1 transcription factor regulates 64 PD genes at lateral substantia nigra, 65 at superior frontal gyrus, and 19 at medial substantia nigra. Similarly, in AD, STAT1 regulates 74 AD genes at the temporal cortex, 40 genes at the hippocampus, and 16 genes at the frontal cortex. We further demonstrate that dysregulated neuronal genes showed involvement in immune response, signal transduction, apoptosis, and stress response process. In conclusion, SARS-CoV-2 may dysregulate neuronal gene regulatory network through exosomes that attenuate disease severity of neurodegeneration.


Subject(s)
Brain/metabolism , COVID-19/metabolism , Exosomes/metabolism , Lung/metabolism , Neurons/metabolism , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Databases, Factual , Exosomes/genetics , Humans , Parkinson Disease/genetics , Parkinson Disease/metabolism , Transcriptome
17.
Biochimie ; 179: 281-284, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-1326920

ABSTRACT

Poxytrins (Pufa Oxygenated Trienes) are dihydroxy derivatives from polyunsaturated fatty acids (PUFA) with adjacent hydroxyl groups to a conjugated triene having the specific E,Z,E geometry. They are made by the double action of one lipoxygenase or the combined actions of two lipoxygenases, followed by reduction of the resulting hydroperoxides with glutathione peroxidase. Because of their E,Z,E conjugated triene, poxytrins may inhibit inflammation associated with cyclooxygenase (COX) activities, and reactive oxygen species (ROS) formation. In addition of inhibiting COX activities, at least one poxytrin, namely protectin DX (PDX) from docosahexaenoic acid (DHA), has also been reported as able to inhibit influenza virus replication by targeting its RNA metabolism.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Antiviral Agents/pharmacology , Docosahexaenoic Acids/pharmacology , Fatty Acids, Unsaturated/pharmacology , Animals , Anti-Inflammatory Agents/chemistry , Antiviral Agents/chemistry , Brain/drug effects , Brain/metabolism , Docosahexaenoic Acids/chemistry , Fatty Acids, Unsaturated/chemistry , Humans , Prostaglandin-Endoperoxide Synthases/drug effects , Reactive Oxygen Species/metabolism , Virus Replication/drug effects
18.
Genome Med ; 13(1): 118, 2021 07 19.
Article in English | MEDLINE | ID: covidwho-1318291

ABSTRACT

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has been associated with neurological and neuropsychiatric illness in many individuals. We sought to further our understanding of the relationship between brain tropism, neuro-inflammation, and host immune response in acute COVID-19 cases. METHODS: Three brain regions (dorsolateral prefrontal cortex, medulla oblongata, and choroid plexus) from 5 patients with severe COVID-19 and 4 controls were examined. The presence of the virus was assessed by western blot against viral spike protein, as well as viral transcriptome analysis covering > 99% of SARS-CoV-2 genome and all potential serotypes. Droplet-based single-nucleus RNA sequencing (snRNA-seq) was performed in the same samples to examine the impact of COVID-19 on transcription in individual cells of the brain. RESULTS: Quantification of viral spike S1 protein and viral transcripts did not detect SARS-CoV-2 in the postmortem brain tissue. However, analysis of 68,557 single-nucleus transcriptomes from three distinct regions of the brain identified an increased proportion of stromal cells, monocytes, and macrophages in the choroid plexus of COVID-19 patients. Furthermore, differential gene expression, pseudo-temporal trajectory, and gene regulatory network analyses revealed transcriptional changes in the cortical microglia associated with a range of biological processes, including cellular activation, mobility, and phagocytosis. CONCLUSIONS: Despite the absence of detectable SARS-CoV-2 in the brain at the time of death, the findings suggest significant and persistent neuroinflammation in patients with acute COVID-19.


Subject(s)
Brain/metabolism , COVID-19/immunology , Gene Expression Profiling/methods , Immunity/genetics , Immunity/immunology , Transcriptome , Choroid Plexus/metabolism , Gene Expression , Gene Regulatory Networks , Humans , Inflammation , Microglia , Prefrontal Cortex/metabolism , SARS-CoV-2/genetics
19.
Inflammopharmacology ; 29(4): 1049-1059, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1303332

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can enter the central nervous system and cause several neurological manifestations. Data from cerebrospinal fluid analyses and postmortem samples have been shown that SARS-CoV-2 has neuroinvasive properties. Therefore, ongoing studies have focused on mechanisms involved in neurotropism and neural injuries of SARS-CoV-2. The inflammasome is a part of the innate immune system that is responsible for the secretion and activation of several pro-inflammatory cytokines, such as interleukin-1ß, interleukin-6, and interleukin-18. Since cytokine storm has been known as a major mechanism followed by SARS-CoV-2, inflammasome may trigger an inflammatory form of lytic programmed cell death (pyroptosis) following SARS-CoV-2 infection and contribute to associated neurological complications. We reviewed and discussed the possible role of inflammasome and its consequence pyroptosis following coronavirus infections as potential mechanisms of neurotropism by SARS-CoV-2. Further studies, particularly postmortem analysis of brain samples obtained from COVID-19 patients, can shed light on the possible role of the inflammasome in neurotropism of SARS-CoV-2.


Subject(s)
COVID-19/metabolism , Central Nervous System/metabolism , Inflammasomes/metabolism , Pyroptosis/physiology , SARS-CoV-2/metabolism , Brain/immunology , Brain/metabolism , COVID-19/immunology , Central Nervous System/immunology , Humans , Inflammasomes/immunology , SARS-CoV-2/immunology
20.
Elife ; 102021 07 06.
Article in English | MEDLINE | ID: covidwho-1298242

ABSTRACT

Background: To understand a causal role of modifiable lifestyle factors in angiotensin-converting enzyme 2 (ACE2) expression (a putative severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] receptor) across 44 human tissues/organs, and in coronavirus disease 2019 (COVID-19) susceptibility and severity, we conducted a phenome-wide two-sample Mendelian randomization (MR) study. Methods: More than 500 genetic variants were used as instrumental variables to predict smoking and alcohol consumption. Inverse-variance weighted approach was adopted as the primary method to estimate a causal association, while MR-Egger regression, weighted median, and MR pleiotropy residual sum and outlier (MR-PRESSO) were performed to identify potential horizontal pleiotropy. Results: We found that genetically predicted smoking intensity significantly increased ACE2 expression in thyroid (ß=1.468, p=1.8×10-8), and increased ACE2 expression in adipose, brain, colon, and liver with nominal significance. Additionally, genetically predicted smoking initiation significantly increased the risk of COVID-19 onset (odds ratio=1.14, p=8.7×10-5). No statistically significant result was observed for alcohol consumption. Conclusions: Our work demonstrates an important role of smoking, measured by both status and intensity, in the susceptibility to COVID-19. Funding: XJ is supported by research grants from the Swedish Research Council (VR-2018-02247) and Swedish Research Council for Health, Working Life and Welfare (FORTE-2020-00884).


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/pathology , Mendelian Randomization Analysis , SARS-CoV-2/physiology , Tobacco Smoking/adverse effects , Adipose Tissue/metabolism , Alcohol Drinking/genetics , Angiotensin-Converting Enzyme 2/genetics , Brain/metabolism , COVID-19/virology , Causality , Colon/metabolism , Gene Expression Regulation , Humans , Liver/metabolism , Polymorphism, Single Nucleotide , Thyroid Gland/metabolism
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