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1.
Inflamm Res ; 70(8): 847-858, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1318745

ABSTRACT

BACKGROUND: Recognizing only sharp elevation in a short period of time, the COVID-19 SARS-CoV-2 propagation is more and more marked in the whole world. Induced inflammation afterwards infection engenders a high infiltration of immune cells and cytokines that triggers matrix metalloproteinases (MMPs) activation. These endopeptidases are mediators of the lung extracellular matrix (ECM), a basic element for alveoli structure and gas exchange. METHODS: When immune cells, MMPs, secreted cytokines and several other mediators are gathered a pathological matrix remodeling occurs. This phenomenon tends to tissue destruction in the first place and a pulmonary hypertrophy and fibrosis in the second place. FINDINGS: After pathological matrix remodeling establishment, pathological diseases take place even after infection state. Since post COVID-19 pulmonary fibrosis is an emerging complication of the disease, there is an urge to better understand and characterize the implication of ECM remodeling during SARS-CoV-2 infection. CONCLUSION: Targeting MMPs and their inhibitors could be a probable solution for occurred events since there are many cured patients that remain with severe sequels even after the end of infection.


Subject(s)
COVID-19/immunology , COVID-19/virology , Extracellular Matrix/metabolism , Matrix Metalloproteinases/metabolism , SARS-CoV-2 , Cell Communication , Cell Lineage , Cytokines/metabolism , Cytoplasm/metabolism , Fibrosis/immunology , Homeostasis , Humans , Hypertrophy , Immune System , Interferon-gamma/metabolism , Lung/physiopathology , Pulmonary Alveoli/metabolism , Pulmonary Fibrosis , Pulmonary Gas Exchange
2.
Eur Rev Med Pharmacol Sci ; 25(10): 3772-3790, 2021 05.
Article in English | MEDLINE | ID: covidwho-1264762

ABSTRACT

Multiple epidemiological studies have suggested that industrialization and progressive urbanization should be considered one of the main factors responsible for the rising of atherosclerosis in the developing world. In this scenario, the role of trace metals in the insurgence and progression of atherosclerosis has not been clarified yet. In this paper, the specific role of selected trace elements (magnesium, zinc, selenium, iron, copper, phosphorus, and calcium) is described by focusing on the atherosclerotic prevention and pathogenesis plaque. For each element, the following data are reported: daily intake, serum levels, intra/extracellular distribution, major roles in physiology, main effects of high and low levels, specific roles in atherosclerosis, possible interactions with other trace elements, and possible influences on plaque development. For each trace element, the correlations between its levels and clinical severity and outcome of COVID-19 are discussed. Moreover, the role of matrix metalloproteinases, a family of zinc-dependent endopeptidases, as a new medical therapeutical approach to atherosclerosis is discussed. Data suggest that trace element status may influence both atherosclerosis insurgence and plaque evolution toward a stable or an unstable status. However, significant variability in the action of these traces is evident: some - including magnesium, zinc, and selenium - may have a protective role, whereas others, including iron and copper, probably have a multi-faceted and more complex role in the pathogenesis of the atherosclerotic plaque. Finally, calcium and phosphorus are implicated in the calcification of atherosclerotic plaques and in the progression of the plaque toward rupture and severe clinical complications. In particular, the role of calcium is debated. Focusing on the COVID-19 pandemia, optimized magnesium and zinc levels are indicated as important protective tools against a severe clinical course of the disease, often related to the ability of SARS-CoV-2 to cause a systemic inflammatory response, able to transform a stable plaque into an unstable one, with severe clinical complications.


Subject(s)
Atherosclerosis/pathology , Trace Elements/metabolism , Atherosclerosis/metabolism , COVID-19/pathology , COVID-19/virology , Calcium/blood , Calcium/metabolism , Copper/blood , Copper/metabolism , Humans , Iron/blood , Iron/metabolism , Magnesium/blood , Magnesium/metabolism , Matrix Metalloproteinases/metabolism , Phosphorus/blood , Phosphorus/metabolism , Risk , SARS-CoV-2/isolation & purification , Selenium/blood , Selenium/metabolism , Severity of Illness Index , Trace Elements/blood , Zinc/blood , Zinc/metabolism
3.
Viruses ; 13(6)2021 05 21.
Article in English | MEDLINE | ID: covidwho-1244141

ABSTRACT

Patients with coronavirus disease 2019 (COVID-19) predominantly have a respiratory tract infection with various symptoms and high mortality is associated with respiratory failure second to severe disease. The risk factors leading to severe disease remain unclear. Here, we reanalyzed a published single-cell RNA-Seq (scRNA-Seq) dataset and found that bronchoalveolar lavage fluid (BALF) of patients with severe disease compared to those with mild disease contained decreased TH17-type cells, decreased IFNA1-expressing cells with lower expression of toll-like receptor 7 (TLR7) and TLR8, increased IgA-expressing B cells, and increased hyperactive epithelial cells (and/or macrophages) expressing matrix metalloproteinases (MMPs), hyaluronan synthase 2 (HAS2), and plasminogen activator inhibitor-1 (PAI-1), which may together contribute to the pulmonary pathology in severe COVID-19. We propose IFN-I (and TLR7/TLR8) and PAI-1 as potential biomarkers to predict the susceptibility to severe COVID-19.


Subject(s)
COVID-19/pathology , Lung/pathology , B-Lymphocytes/metabolism , B-Lymphocytes/pathology , Biomarkers/metabolism , Bronchoalveolar Lavage Fluid/immunology , COVID-19/immunology , COVID-19/metabolism , Databases, Genetic , Humans , Hyaluronan Synthases/metabolism , Immunoglobulin A/metabolism , Interferon-alpha/metabolism , Lung/immunology , Lung/metabolism , Matrix Metalloproteinases/metabolism , Mucin-1/metabolism , Plasminogen Activator Inhibitor 1/metabolism , RNA-Seq , SARS-CoV-2 , Th17 Cells/metabolism , Th17 Cells/pathology
4.
Pharmacol Ther ; 225: 107839, 2021 09.
Article in English | MEDLINE | ID: covidwho-1152612

ABSTRACT

Structural changes involving tissue remodelling and fibrosis are major features of many pulmonary diseases, including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Abnormal deposition of extracellular matrix (ECM) proteins is a key factor in the development of tissue remodelling that results in symptoms and impaired lung function in these diseases. Tissue remodelling in the lungs is complex and differs between compartments. Some pathways are common but tissue remodelling around the airways and in the parenchyma have different morphologies. Hence it is critical to evaluate both common fibrotic pathways and those that are specific to different compartments; thereby expanding the understanding of the pathogenesis of fibrosis and remodelling in the airways and parenchyma in asthma, COPD and IPF with a view to developing therapeutic strategies for each. Here we review the current understanding of remodelling features and underlying mechanisms in these major respiratory diseases. The differences and similarities of remodelling are used to highlight potential common therapeutic targets and strategies. One central pathway in remodelling processes involves transforming growth factor (TGF)-ß induced fibroblast activation and myofibroblast differentiation that increases ECM production. The current treatments and clinical trials targeting remodelling are described, as well as potential future directions. These endeavours are indicative of the renewed effort and optimism for drug discovery targeting tissue remodelling and fibrosis.


Subject(s)
Lung Diseases/drug therapy , Lung Diseases/physiopathology , Airway Remodeling/physiology , Asthma/drug therapy , Asthma/physiopathology , Calcium-Binding Proteins/metabolism , Extracellular Matrix/metabolism , Fibroblasts , Fibrosis/physiopathology , Glycoproteins/metabolism , Humans , Idiopathic Pulmonary Fibrosis/drug therapy , Idiopathic Pulmonary Fibrosis/physiopathology , Matrix Metalloproteinases/metabolism , Pulmonary Disease, Chronic Obstructive/drug therapy , Pulmonary Disease, Chronic Obstructive/physiopathology , Transforming Growth Factor beta
5.
Biomolecules ; 11(3)2021 03 06.
Article in English | MEDLINE | ID: covidwho-1134010

ABSTRACT

Many individuals infected with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) develop no or only mild symptoms, but some can go on onto develop a spectrum of pathologies including pneumonia, acute respiratory distress syndrome, respiratory failure, systemic inflammation, and multiorgan failure. Many pathogens, viral and non-viral, can elicit these pathologies, which justifies reconsidering whether the target of therapeutic approaches to fight pathogen infections should be (a) the pathogen itself, (b) the pathologies elicited by the pathogen interaction with the human host, or (c) a combination of both. While little is known about the immunopathology of SARS-CoV-2, it is well-established that the above-mentioned pathologies are associated with hyper-inflammation, tissue damage, and the perturbation of target organ metabolism. Mounting evidence has shown that these processes are regulated by endoproteinases (particularly, matrix metalloproteinases (MMPs)). Here, we review what is known about the roles played by MMPs in the development of COVID-19 and postulate a mechanism by which MMPs could influence energy metabolism in target organs, such as the lung. Finally, we discuss the suitability of MMPs as therapeutic targets to increase the metabolic tolerance of the host to damage inflicted by the pathogen infection, with a focus on SARS-CoV-2.


Subject(s)
COVID-19/metabolism , Lung/physiopathology , Matrix Metalloproteinases/metabolism , Protein Kinases/metabolism , Respiratory Distress Syndrome/metabolism , COVID-19/enzymology , COVID-19/physiopathology , COVID-19/virology , Comorbidity , Cytokines/metabolism , Humans , Inflammation/drug therapy , Inflammation/enzymology , Inflammation/metabolism , Inflammation/pathology , Lung/enzymology , Lung/metabolism , Lung/virology , Matrix Metalloproteinase Inhibitors/pharmacology , Respiratory Distress Syndrome/enzymology , Respiratory Distress Syndrome/physiopathology , Respiratory Distress Syndrome/virology , SARS-CoV-2/pathogenicity , Signal Transduction/drug effects , Signal Transduction/genetics
6.
Hum Exp Toxicol ; 40(2): 325-341, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1067095

ABSTRACT

To assess the chondroprotective effect and influence of N,N'-bis(1,5-dimethyl-2-phenyl-1,2-dihydro-3-oxopyrazol-4-yl) sebacamide (dpdo) that was synthesized through the reaction of phenazone with sebacoyl chloride and screened for its biological activity especially as anti-arthritic and anti-inflammatory agent in a monoiodoacetate (MA)-induced experimental osteoarthritis (OA) model. Thirty male albino rats weighing "190-200 g" were divided randomly into three groups (10 each): control, MA-induced OA, and MA-induced OA + dpdo. In MA-induced OA rat, the tumor necrosis factor alpha, interleukin 6, C-reactive protein, rheumatoid factors, reactive oxygen species, as well as all the mitochondrial markers such as mitochondria membrane potential, swelling mitochondria, cytochrome c oxidase (complex IV), and serum oxidative/antioxidant status (malondialdehyde level and activities of myeloperoxidase and xanthine oxidase) are elevated. Also, the activity of succinate dehydrogenase (complex II), levels of ATP, the level of glutathione (GSH), and thiol were markedly diminished in the MA-induced OA group compared to the normal control rats. These findings showed that mitochondrial function is associated with OA pathophysiological alterations and high gene expressions of (IL-6, TNF-a, and IL-1b) and suggests a promising use of dpdo as potential ameliorative agents in the animal model of OA and could act as anti-inflammatory agent in case of severe infection with COVID-19. It is clearly appeared in improving the bone cortex and bone marrow in the treated group with the novel compound in histological and transmission electron microscopic sections which is a very important issue today in fighting severe infections that have significant effects on the blood indices and declining of blood corpuscles like COVID-19, in addition to declining the genotoxicity and inflammation induced by MA in male rats. The novel synthesized compound was highly effective in improving all the above mentioned parameters.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/drug therapy , Osteoarthritis/drug therapy , SARS-CoV-2 , Adenosine Triphosphate/metabolism , Animals , Anti-Inflammatory Agents/pharmacology , Bone and Bones/drug effects , Bone and Bones/pathology , Bone and Bones/ultrastructure , C-Reactive Protein/analysis , Cytochromes c/metabolism , Cytokines/metabolism , Disease Models, Animal , Glutathione/metabolism , Iodoacetic Acid , Lipid Peroxidation/drug effects , Male , Matrix Metalloproteinases/metabolism , Membrane Potential, Mitochondrial/drug effects , Mitochondria/drug effects , Mitochondria/physiology , Osteoarthritis/chemically induced , Osteoarthritis/metabolism , Osteoarthritis/pathology , Rats , Reactive Oxygen Species/metabolism , Succinate Dehydrogenase/metabolism
7.
Neurobiol Dis ; 146: 105131, 2020 12.
Article in English | MEDLINE | ID: covidwho-872391

ABSTRACT

As researchers across the globe have focused their attention on understanding SARS-CoV-2, the picture that is emerging is that of a virus that has serious effects on the vasculature in multiple organ systems including the cerebral vasculature. Observed effects on the central nervous system include neurological symptoms (headache, nausea, dizziness), fatal microclot formation and in rare cases encephalitis. However, our understanding of how the virus causes these mild to severe neurological symptoms and how the cerebral vasculature is impacted remains unclear. Thus, the results presented in this report explored whether deleterious outcomes from the SARS-CoV-2 viral spike protein on primary human brain microvascular endothelial cells (hBMVECs) could be observed. The spike protein, which plays a key role in receptor recognition, is formed by the S1 subunit containing a receptor binding domain (RBD) and the S2 subunit. First, using postmortem brain tissue, we show that the angiotensin converting enzyme 2 or ACE2 (a known binding target for the SARS-CoV-2 spike protein), is ubiquitously expressed throughout various vessel calibers in the frontal cortex. Moreover, ACE2 expression was upregulated in cases of hypertension and dementia. ACE2 was also detectable in primary hBMVECs maintained under cell culture conditions. Analysis of cell viability revealed that neither the S1, S2 or a truncated form of the S1 containing only the RBD had minimal effects on hBMVEC viability within a 48 h exposure window. Introduction of spike proteins to invitro models of the blood-brain barrier (BBB) showed significant changes to barrier properties. Key to our findings is the demonstration that S1 promotes loss of barrier integrity in an advanced 3D microfluidic model of the human BBB, a platform that more closely resembles the physiological conditions at this CNS interface. Evidence provided suggests that the SARS-CoV-2 spike proteins trigger a pro-inflammatory response on brain endothelial cells that may contribute to an altered state of BBB function. Together, these results are the first to show the direct impact that the SARS-CoV-2 spike protein could have on brain endothelial cells; thereby offering a plausible explanation for the neurological consequences seen in COVID-19 patients.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Blood-Brain Barrier/metabolism , Capillary Permeability/physiology , Endothelial Cells/metabolism , Inflammation/metabolism , Matrix Metalloproteinases/metabolism , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/physiology , Blood-Brain Barrier/drug effects , COVID-19 , Capillary Permeability/drug effects , Cell Adhesion Molecules/drug effects , Cell Adhesion Molecules/metabolism , Cell Survival/drug effects , Dementia/metabolism , Electric Impedance , Endothelial Cells/drug effects , Frontal Lobe/metabolism , Humans , Hypertension/metabolism , In Vitro Techniques , Intercellular Junctions/metabolism , Interleukin-6/genetics , Interleukin-6/metabolism , Lab-On-A-Chip Devices , Matrix Metalloproteinases/drug effects , Primary Cell Culture , Protein Domains , Protein Subunits/metabolism , Protein Subunits/pharmacology , RNA, Messenger/drug effects , RNA, Messenger/metabolism , Spike Glycoprotein, Coronavirus/pharmacology
8.
ESC Heart Fail ; 7(5): 2838-2852, 2020 10.
Article in English | MEDLINE | ID: covidwho-643370

ABSTRACT

AIMS: Left ventricular (LV) dysfunction in viral myocarditis is attributed to myocardial inflammation and fibrosis, inducing acute and long-time cardiac damage. Interventions are not established. On the basis of the link between inflammation, fibrosis, aldosterone, and extracellular matrix regulation, we aimed to investigate the effect of an early intervention with the mineralocorticoid receptor antagonist (MRA) eplerenone on cardiac remodelling in a murine model of persistent coxsackievirus B3 (CVB3)-induced myocarditis. METHODS AND RESULTS: SWR/J mice were infected with 5 × 104 plaque-forming units of CVB3 (Nancy strain) and daily treated either with eplerenone (200 mg/kg body weight) or with placebo starting from Day 1. At Day 8 or 28 post infection, mice were haemodynamically characterized and subsequently sacrificed for immunohistological and molecular biology analyses. Eplerenone did not influence CVB3 load. Already at Day 8, 1.8-fold (P < 0.05), 1.4-fold (P < 0.05), 3.2-fold (P < 0.01), and 2.1-fold (P < 0.001) reduction in LV intercellular adhesion molecule 1 expression, presence of monocytes/macrophages, oxidative stress, and apoptosis, respectively, was observed in eplerenone-treated vs. untreated CVB3-infected mice. In vitro, eplerenone led to 1.4-fold (P < 0.01) and 1.2-fold (P < 0.01) less CVB3-induced cardiomyocyte oxidative stress and apoptosis. Furthermore, collagen production was 1.1-fold (P < 0.05) decreased in cardiac fibroblasts cultured with medium of eplerenone-treated vs. untreated CVB3-infected HL-1 cardiomyocytes. These ameliorations were in vivo translated into prevention of cardiac fibrosis, as shown by 1.4-fold (P < 0.01) and 2.1-fold (P < 0.001) lower collagen content in the LV of eplerenone-treated vs. untreated CVB3-infected mice at Days 8 and 28, respectively. This resulted in an early and long-lasting improvement of LV dimension and function, as indicated by reduced LV end-systolic volume and end-diastolic volume, and an increase in LV contractility (dP/dtmax ) and LV relaxation (dP/dtmin ), respectively (P < 0.05). CONCLUSIONS: Early intervention with the MRA eplerenone modulates the acute host and defence reaction and prevents cardiac disease progression in experimental CVB3-induced myocarditis without aggravation of viral load. The findings advocate for an initiation of therapy of viral myocarditis as early as possible, even before the onset of inflammation-induced myocardial dysfunction. This may also have implications for coronavirus disease-19 therapy.


Subject(s)
Endomyocardial Fibrosis/prevention & control , Enterovirus B, Human/pathogenicity , Eplerenone/pharmacology , Myocarditis/drug therapy , Myocarditis/virology , Ventricular Dysfunction, Left/virology , Analysis of Variance , Animals , Biopsy, Needle , Disease Models, Animal , Disease Progression , Endomyocardial Fibrosis/pathology , Immunohistochemistry , Male , Matrix Metalloproteinases/drug effects , Matrix Metalloproteinases/metabolism , Mice , Mice, Transgenic , Myocarditis/prevention & control , Random Allocation , Reference Values , Treatment Outcome , Ventricular Dysfunction, Left/pathology , Ventricular Dysfunction, Left/physiopathology
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