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1.
Epigenomics ; 14(3): 153-162, 2022 02.
Article in English | MEDLINE | ID: covidwho-1622527

ABSTRACT

Smoking could predispose individuals to a more severe COVID-19 by upregulating a particular gene known as mdig, which is mediated through a number of well-known histone modifications. Smoking might regulate the transcription-activating H3K4me3 mark, along with the transcription-repressing H3K9me3 and H3K27me3 marks, in a way to favor SARS-CoV-2 entry by enhancing the expression of ACE2, NRP1 and NRP2, AT1R, CTSD and CTSL, PGE2 receptors 2-4, SLC6A20 and IL-6, all of which interact either directly or indirectly with important receptors, facilitating viral entry in COVID-19.


Lay abstract The role of smoking in development of several respiratory diseases has been clearly established. A significant proportion of these deleterious effects is mediated through epigenetic mechanisms, particularly histone modifications. Recent evidence indicates that smoking induces the expression of a mediator known as mdig, which in turn alters the transcription of several key proteins that have been implicated in development of COVID-19.


Subject(s)
COVID-19/genetics , Dioxygenases/genetics , Epigenesis, Genetic , Histone Demethylases/genetics , Histones/genetics , Nuclear Proteins/genetics , Protein Processing, Post-Translational , Smoking/genetics , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/diagnosis , COVID-19/metabolism , COVID-19/virology , Cathepsin D/genetics , Cathepsin D/metabolism , Cathepsin L/genetics , Cathepsin L/metabolism , Dioxygenases/metabolism , Histone Demethylases/metabolism , Histones/metabolism , Humans , Interleukin-6/genetics , Interleukin-6/metabolism , Membrane Transport Proteins/genetics , Membrane Transport Proteins/metabolism , Methylation , Neuropilin-1/genetics , Neuropilin-1/metabolism , Neuropilin-2/genetics , Neuropilin-2/metabolism , Nuclear Proteins/metabolism , Protein Isoforms/genetics , Protein Isoforms/metabolism , Receptor, Angiotensin, Type 1/genetics , Receptor, Angiotensin, Type 1/metabolism , Receptors, Prostaglandin E/genetics , Receptors, Prostaglandin E/metabolism , Risk Factors , SARS-CoV-2/genetics , SARS-CoV-2/growth & development , SARS-CoV-2/metabolism , Smoking/metabolism , Smoking/pathology , Virus Internalization
2.
Life Sci ; 293: 120324, 2022 Mar 15.
Article in English | MEDLINE | ID: covidwho-1616648

ABSTRACT

AIMS: Angiotensin-converting enzyme (ACE) 2 is the receptor for severe acute respiratory syndrome coronavirus 2 which causes coronavirus disease 2019 (COVID-19). Viral cellular entry requires ACE2 and transmembrane protease serine 2 (TMPRSS2). ACE inhibitors (ACEIs) or angiotensin (Ang) receptor blockers (ARBs) influence ACE2 in animals, though evidence in human lungs is lacking. We investigated ACE2 and TMPRSS2 in type II pneumocytes, the key cells that maintain lung homeostasis, in lung parenchymal of ACEI/ARB-treated subjects compared to untreated control subjects. MAIN METHODS: Ang II and Ang-(1-7) levels and ACE2 and TMPRSS2 protein expression were measured by radioimmunoassay and immunohistochemistry, respectively. KEY FINDINGS: We found that the ratio Ang-(1-7)/Ang II, a surrogate marker of ACE2 activity, as well as the amount of ACE2-expressing type II pneumocytes were not different between ACEI/ARB-treated and untreated subjects. ACE2 protein content correlated positively with smoking habit and age. The percentage of TMPRSS2-expressing type II pneumocytes was higher in males than females and in subjects under 60 years of age but it was not different between ACEI/ARB-treated and untreated subjects. However, there was a positive association of TMPRSS2 protein content with age and smoking in ACEI/ARB-treated subjects, with high TMPRSS2 protein levels most evident in ACEI/ARB-treated older adults and smokers. SIGNIFICANCE: ACEI/ARB treatment influences human lung TMPRSS2 but not ACE2 protein content and this effect is dependent on age and smoking habit. This finding may help explain the increased susceptibility to COVID-19 seen in smokers and older patients with treated cardiovascular-related pathologies.


Subject(s)
Alveolar Epithelial Cells/metabolism , Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Renin-Angiotensin System/physiology , Serine Endopeptidases/metabolism , Adult , Age Factors , Aged , Alveolar Epithelial Cells/chemistry , Alveolar Epithelial Cells/drug effects , Angiotensin I/metabolism , Angiotensin II/metabolism , Angiotensin-Converting Enzyme 2/analysis , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Female , Humans , Lung/chemistry , Lung/drug effects , Lung/metabolism , Male , Middle Aged , Peptide Fragments/metabolism , Renin-Angiotensin System/drug effects , Retrospective Studies , Serine Endopeptidases/analysis , Smoking/metabolism , Smoking/pathology
3.
Int J Mol Sci ; 22(14)2021 Jul 16.
Article in English | MEDLINE | ID: covidwho-1323266

ABSTRACT

Smoking is a major risk factor for chronic obstructive pulmonary disease (COPD) and causes remodeling of the small airways. However, the exact smoke-induced effects on the different types of small airway epithelial cells (SAECs) are poorly understood. Here, using air-liquid interface (ALI) cultures, single-cell RNA-sequencing reveals previously unrecognized transcriptional heterogeneity within the small airway epithelium and cell type-specific effects upon acute and chronic cigarette smoke exposure. Smoke triggers detoxification and inflammatory responses and aberrantly activates and alters basal cell differentiation. This results in an increase of inflammatory basal-to-secretory cell intermediates and, particularly after chronic smoke exposure, a massive expansion of a rare inflammatory and squamous metaplasia associated KRT6A+ basal cell state and an altered secretory cell landscape. ALI cultures originating from healthy non-smokers and COPD smokers show similar responses to cigarette smoke exposure, although an increased pro-inflammatory profile is conserved in the latter. Taken together, the in vitro models provide high-resolution insights into the smoke-induced remodeling of the small airways resembling the pathological processes in COPD airways. The data may also help to better understand other lung diseases including COVID-19, as the data reflect the smoke-dependent variable induction of SARS-CoV-2 entry factors across SAEC populations.


Subject(s)
Airway Remodeling/drug effects , Alveolar Epithelial Cells/drug effects , Cigarette Smoking/adverse effects , Epithelial Cells/metabolism , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/pathology , Cell Differentiation/drug effects , Cells, Cultured , Cigarette Smoking/metabolism , Epithelial Cells/drug effects , Humans , Neoplasms, Basal Cell/metabolism , Primary Cell Culture , Pulmonary Disease, Chronic Obstructive/etiology , Pulmonary Disease, Chronic Obstructive/metabolism , Pulmonary Disease, Chronic Obstructive/pathology , Respiratory Mucosa/metabolism , Respiratory Mucosa/pathology , Smoke , Smoking/adverse effects , Smoking/metabolism
4.
Int J Mol Sci ; 22(14)2021 Jul 18.
Article in English | MEDLINE | ID: covidwho-1314669

ABSTRACT

A large body of evidence shows the harmful effects of cigarette smoke to oral and systemic health. More recently, a link between smoking and susceptibility to coronavirus disease 2019 (COVID-19) was proposed. COVID-19 is due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which uses the receptor ACE2 and the protease TMPRSS2 for entry into host cells, thereby infecting cells of the respiratory tract and the oral cavity. Here, we examined the effects of cigarette smoke on the expression of SARS-CoV-2 receptors and infection in human gingival epithelial cells (GECs). We found that cigarette smoke condensates (CSC) upregulated ACE2 and TMPRSS2 expression in GECs, and that CSC activated aryl hydrocarbon receptor (AhR) signaling in the oral cells. ACE2 was known to mediate SARS-CoV-2 internalization, and we demonstrate that CSC treatment potentiated the internalization of SARS-CoV-2 pseudovirus in GECs in an AhR-dependent manner. AhR depletion using small interference RNA decreased SARS-CoV-2 pseudovirus internalization in CSC-treated GECs compared with control GECs. Our study reveals that cigarette smoke upregulates SARS-CoV-2 receptor expression and infection in oral cells. Understanding the mechanisms involved in SARS-CoV-2 infection in cells of the oral cavity may suggest therapeutic interventions for preventing viral infection and transmission.


Subject(s)
COVID-19/metabolism , COVID-19/virology , Cigarette Smoking/adverse effects , SARS-CoV-2/drug effects , Smoking/adverse effects , Virus Internalization/drug effects , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Cigarette Smoking/physiopathology , Disease Susceptibility , Epithelial Cells/metabolism , Epithelial Cells/virology , Gingiva/metabolism , Gingiva/virology , Humans , Receptors, Aryl Hydrocarbon/genetics , Receptors, Aryl Hydrocarbon/metabolism , Receptors, Virus/metabolism , Respiratory Mucosa/metabolism , SARS-CoV-2/physiology , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Smoking/metabolism
5.
Eur Rev Med Pharmacol Sci ; 24(23): 12500-12509, 2020 12.
Article in English | MEDLINE | ID: covidwho-995007

ABSTRACT

OBJECTIVE: Since the emergence of coronavirus disease (COVID-19), the death toll has been increasing daily. Many risk factors are associated with a high mortality rate in COVID-19. Establishment of a common pathway among these risk factors could improve our understanding of COVID-19 severity and mortality. This review aims at establishing this common pathway and its possible effect on COVID-19 mortality. MATERIALS AND METHODS: The current review was executed in five consecutive stages starting from determining the risk factors of COVID-19 mortality and trying to find a common pathway among them depending on the available literature. This was followed by proposing a mechanism explaining how this common pathway could increase the mortality. Finally, its potential role in managing COVID-19 was proposed. RESULTS: This review identified this common pathway to be a low baseline of reduced glutathione (i.e., GSH) level. In particular, this review provided an in-depth discussion regarding the pathophysiology by which COVID-19 leads to GSH depletion, tissue damage, and acute respiratory distress syndrome. In addition, the current review demonstrated how GSH depletion could result in failure of the immune system and rendering the end organs vulnerable to damage from the oxidative stress. CONCLUSIONS: This preclinical study shows that GSH depletion may have a central role in COVID-19 mortality and pathophysiology. Therefore, elevating the GSH level in tissues may decrease the severity and mortality rates of COVID-19.


Subject(s)
COVID-19/mortality , Cytokine Release Syndrome/immunology , Glutathione/metabolism , Acute Lung Injury/metabolism , Age Factors , Antioxidants/metabolism , Apoptosis , COVID-19/immunology , COVID-19/metabolism , Cytokine Release Syndrome/metabolism , Diabetes Mellitus/epidemiology , Diabetes Mellitus/metabolism , Glutathione/immunology , Humans , Hypertension/epidemiology , Hypertension/metabolism , Macrophages/immunology , Myocardial Ischemia/epidemiology , Myocardial Ischemia/metabolism , Obesity/epidemiology , Obesity/metabolism , Reactive Oxygen Species/metabolism , Respiratory Distress Syndrome/metabolism , Risk Factors , SARS-CoV-2 , Smoking/epidemiology , Smoking/metabolism
6.
FEBS J ; 287(17): 3656-3663, 2020 09.
Article in English | MEDLINE | ID: covidwho-960857

ABSTRACT

There is an urgent need to address the devastating pandemic, COVID-19, caused by SARS-CoV-2. The efforts to understand the details of this disease in hope of providing effective treatments are commendable. It is clear now that the virus can cause far more damage in patients with comorbid conditions-particularly in those with respiratory, cardiovascular, or immune-compromised system-than in patients without such comorbidities. Drug use can further exacerbate the condition. In this regard, the ill effects of smoking are amply documented, and no doubt can be a confounding factor in COVID-19 progression. Although conflicting hypotheses on the potential role of nicotine in COVID-19 pathology have recently been offered, we believe that nicotine itself, through its interaction with the nicotinic cholinergic system, as well as ACE2, may not only be of use in a variety of neuropsychiatric and neurodegenerative diseases, but may also be of potential use in COVID-19. Thus, on one hand, while we strongly support smoking cessation as a means of harm reduction associated with COVID-19, on the other hand, we support a potential therapeutic role for nicotine, nicotinic agonists, or positive allosteric modulators of nicotinic cholinergic receptors in COVID-19, owing to their varied effects including mood regulation, anti-inflammatory, and purported interference with SARS-CoV-2 entry and/or replication.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/metabolism , Cytokine Release Syndrome/metabolism , Nicotine/pharmacology , Receptors, Nicotinic/genetics , Smoking/metabolism , Spike Glycoprotein, Coronavirus/genetics , Angiotensin-Converting Enzyme 2/immunology , COVID-19/genetics , COVID-19/immunology , COVID-19/virology , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/virology , Gene Expression Regulation , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Humans , Lung/drug effects , Lung/metabolism , Lung/pathology , Lung/virology , Receptors, Nicotinic/immunology , Receptors, Virus/genetics , Receptors, Virus/immunology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Severity of Illness Index , Signal Transduction , Smoking/genetics , Smoking/immunology , Spike Glycoprotein, Coronavirus/immunology
7.
Eur J Clin Invest ; 51(4): e13439, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-901034

ABSTRACT

BACKGROUND: Diabetes mellitus has been associated with a chronic low-grade inflammation and a higher risk of cardiovascular and infectious disease, that could be prevented by the effects of vitamin D. We aimed at evaluating the impact of vitamin D levels on the biomarkers of acute-phase response, inflammation and glucose metabolism in a large cohort of diabetic patients with cardiovascular disease. MATERIALS AND METHODS: Consecutive patients undergoing coronary angiography were included. Diabetes mellitus was defined as previous diagnosis, specific treatment administration (oral drug or insulin), fasting glycaemia >6.99 mmol/L or HbA1c >48 mmol/L. Glucose parameters, white blood cells, Neutrophil-to-Lymphocyte Ratio (NLR), Monocyte-to-Lymphocyte Ratio (MLR), C-reactive protein (CRP) and vitamin D were measured at admission. Vitamin D levels were measured by chemiluminescence immunoassay kit LIAISON® Vitamin D assay (Diasorin Inc). RESULTS: We included 1472 diabetic patients and 2499 non-diabetic patients that were divided according to vitamin D tertiles. Among diabetic patients, lower levels of vitamin D were associated with female gender (P = .02), obesity (P = .004), active smoking and acute presentation (P < .001) and with a more atherogenic metabolic profile. The levels of white blood cells, leucocytes subfamilies, and inflammatory parameters significantly correlated with vitamin D levels in both patients with and without diabetes (diabetic: P = .012 for WBC, P = .004 for NLR and P < .001 for MLR and C-reactive protein, non-diabetic: P < .001 for WBC; NLR, MLR and C-reactive protein, respectively). Among diabetic patients, results were confirmed at multivariate analysis with no significant interaction according to glycaemic control. CONCLUSION: The present study demonstrates that, among patients with cardiovascular disease, vitamin D deficiency is associated with metabolic dysregulation and with an elevation of cellular and humoural inflammatory parameters, especially among diabetics, although not being dependent from glycaemic control.


Subject(s)
Coronary Angiography , Diabetes Mellitus/metabolism , Vitamin D/blood , Acute Coronary Syndrome/blood , Acute Coronary Syndrome/diagnosis , Acute Coronary Syndrome/metabolism , Aged , Aged, 80 and over , Angina, Stable/blood , Angina, Stable/diagnosis , Angina, Stable/metabolism , Arrhythmias, Cardiac/blood , Arrhythmias, Cardiac/diagnosis , Arrhythmias, Cardiac/metabolism , Blood Glucose/metabolism , C-Reactive Protein/metabolism , Diabetes Mellitus/blood , Diabetes Mellitus/drug therapy , Female , Glycated Hemoglobin A/metabolism , Heart Valve Diseases/blood , Heart Valve Diseases/diagnosis , Heart Valve Diseases/metabolism , Humans , Hypoglycemic Agents/therapeutic use , Inflammation/metabolism , Leukocyte Count , Lymphocyte Count , Male , Middle Aged , Monocytes , Neutrophils , Sex Factors , Smoking/metabolism , Ventricular Dysfunction, Left/blood , Ventricular Dysfunction, Left/diagnosis , Ventricular Dysfunction, Left/metabolism
10.
Int J Mol Sci ; 21(10)2020 May 21.
Article in English | MEDLINE | ID: covidwho-327277

ABSTRACT

The COVID-19 pandemic is marked by a wide range of clinical disease courses, ranging from asymptomatic to deadly. There have been many studies seeking to explore the correlations between COVID-19 clinical outcomes and various clinical variables, including age, sex, race, underlying medical problems, and social habits. In particular, the relationship between smoking and COVID-19 outcome is controversial, with multiple conflicting reports in the current literature. In this study, we aim to analyze how smoking may affect the SARS-CoV-2 infection rate. We analyzed sequencing data from lung and oral epithelial samples obtained from The Cancer Genome Atlas (TCGA). We found that the receptor and transmembrane protease necessary for SARS-CoV-2 entry into host cells, ACE2 and TMPRSS2, respectively, were upregulated in smoking samples from both lung and oral epithelial tissue. We then explored the mechanistic hypothesis that smoking may upregulate ACE2 expression through the upregulation of the androgen pathway. ACE2 and TMPRSS2 upregulation were both correlated to androgen pathway enrichment and the specific upregulation of central pathway regulatory genes. These data provide a potential model for the increased susceptibility of smoking patients to COVID-19 and encourage further exploration into the androgen and tobacco upregulation of ACE2 to understand the potential clinical ramifications.


Subject(s)
Androgens/metabolism , Coronavirus Infections/metabolism , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/metabolism , Serine Endopeptidases/genetics , Smoking/metabolism , Up-Regulation , Alveolar Epithelial Cells/metabolism , Angiotensin-Converting Enzyme 2 , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/genetics , Humans , Mouth Mucosa/metabolism , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/epidemiology , Pneumonia, Viral/genetics , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , Serine Endopeptidases/metabolism , Smoking/epidemiology , Smoking/genetics
11.
Am J Respir Crit Care Med ; 202(2): 219-229, 2020 07 15.
Article in English | MEDLINE | ID: covidwho-324576

ABSTRACT

Rationale: Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease (COVID-19), a predominantly respiratory illness. The first step in SARS-CoV-2 infection is binding of the virus to ACE2 (angiotensin-converting enzyme 2) on the airway epithelium.Objectives: The objective was to gain insight into the expression of ACE2 in the human airway epithelium.Methods: Airway epithelia sampled by fiberoptic bronchoscopy of trachea, large airway epithelia (LAE), and small airway epithelia (SAE) of nonsmokers and smokers were analyzed for expression of ACE2 and other coronavirus infection-related genes using microarray, RNA sequencing, and 10x single-cell transcriptome analysis, with associated examination of ACE2-related microRNA.Measurements and Main Results: 1) ACE2 is expressed similarly in the trachea and LAE, with lower expression in the SAE; 2) in the SAE, ACE2 is expressed in basal, intermediate, club, mucus, and ciliated cells; 3) ACE2 is upregulated in the SAE by smoking, significantly in men; 4) levels of miR-1246 expression could play a role in ACE2 upregulation in the SAE of smokers; and 5) ACE2 is expressed in airway epithelium differentiated in vitro on air-liquid interface cultures from primary airway basal stem/progenitor cells; this can be replicated using LAE and SAE immortalized basal cell lines derived from healthy nonsmokers.Conclusions: ACE2, the gene encoding the receptor for SARS-CoV-2, is expressed in the human airway epithelium, with variations in expression relevant to the biology of initial steps in SARS-CoV-2 infection.


Subject(s)
Betacoronavirus , Coronavirus Infections/metabolism , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/metabolism , Respiratory Mucosa/metabolism , Angiotensin-Converting Enzyme 2 , COVID-19 , Case-Control Studies , Female , Humans , Lung/metabolism , Male , Pandemics , RNA, Messenger/genetics , RNA, Messenger/metabolism , SARS-CoV-2 , Sex Factors , Smoking/metabolism , Trachea/metabolism
13.
ACS Chem Neurosci ; 11(9): 1206-1209, 2020 05 06.
Article in English | MEDLINE | ID: covidwho-101631

ABSTRACT

The novel coronavirus SARS-CoV-2, which was identified after a recent outbreak in Wuhan, China, in December 2019, has kept the whole world in tenterhooks due to its severe life-threatening nature of the infection. The virus is unlike its previous counterparts, SARS-CoV and MERS-CoV, or anything the world has encountered before both in terms of virulence and severity of the infection. If scientific reports relevant to the SARS-CoV-2 virus are noted, it can be seen that the virus owes much of its killer properties to its unique structure that has a stronger binding affinity with the human angiotensin-converting enzyme 2 (hACE2) protein, which the viruses utilize as an entry point to gain accesses to its hosts. Recent reports suggest that it is not just the lung that the virus may be targeting; the human brain may soon emerge as the new abode of the virus. Already instances of patients with COVID-19 have been reported with mild (anosmia and ageusia) to severe (encephalopathy) neurological manifestations, and if that is so, then it gives us more reasons to be frightened of this killer virus. Keeping in mind that the situation does not worsen from here, immediate awareness and more thorough research regarding the neuroinvasive nature of the virus is the immediate need of the hour. Scientists globally also need to up their game to design more specific therapeutic strategies with the available information to counteract the pandemic. In this Viewpoint, we provide a brief outline of the currently known neurological manifestations of COVID-19 and discuss some probable ways to design therapeutic strategies to overcome the present global crisis.


Subject(s)
Betacoronavirus/pathogenicity , Brain/virology , Coronavirus Infections/physiopathology , Pneumonia, Viral/physiopathology , Aged , Ageusia/virology , Angiotensin-Converting Enzyme 2 , Autopsy , BCG Vaccine/administration & dosage , BCG Vaccine/immunology , Betacoronavirus/chemistry , Betacoronavirus/metabolism , Brain/pathology , Brain/physiopathology , Brain Diseases/immunology , Brain Diseases/pathology , Brain Diseases/virology , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/transmission , Coronavirus Infections/virology , Cytokines/immunology , Humans , Inflammation/immunology , Inflammation/pathology , Inflammation/virology , MicroRNAs/genetics , Olfaction Disorders/virology , Olfactory Mucosa/pathology , Olfactory Mucosa/physiopathology , Olfactory Mucosa/virology , Pandemics , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/diagnosis , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Pneumonia, Viral/transmission , Pneumonia, Viral/virology , RNA Interference , Receptors, Nicotinic/metabolism , SARS-CoV-2 , Serine Endopeptidases/metabolism , Smoking/metabolism , Smoking/pathology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
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