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Article ; Online: Could Endogenous Glucocorticoids Influence SARS-CoV-2 Infectivity?

Hardy, Eugenio / Fernandez-Patron, Carlos

2022 Volume 11, Issue 19

Abstract: Endogenous glucocorticoids and their synthetic analogues, such as dexamethasone, stimulate receptor-mediated signal transduction mechanisms on target cells. Some of these mechanisms result in beneficial outcomes whereas others are deleterious in the ... ...

Abstract	Endogenous glucocorticoids and their synthetic analogues, such as dexamethasone, stimulate receptor-mediated signal transduction mechanisms on target cells. Some of these mechanisms result in beneficial outcomes whereas others are deleterious in the settings of pathogen infections and immunological disorders. Here, we review recent studies by several groups, including our group, showing that glucocorticoids can directly interact with protein components on SARS-CoV-2, the causative agent of COVID-19. We postulate an antiviral defence mechanism by which endogenous glucocorticoids (e.g., cortisol produced in response to SARS-CoV-2 infection) can bind to multiple sites on SARS-CoV-2 surface protein, Spike, inducing conformational alterations in Spike subunit 1 (S1) that inhibit SARS-CoV-2 interaction with the host SARS-CoV-2 receptor, ACE2. We suggest that glucocorticoids-mediated inhibition of S1 interaction with ACE2 may, consequently, affect SARS-CoV-2 infectivity. Further, glucocorticoids interactions with Spike could protect against a broad spectrum of coronaviruses and their variants that utilize Spike for infection of the host. These notions may be useful for the design of new antivirals for coronavirus diseases.
MeSH term(s)	Angiotensin-Converting Enzyme 2 ; Antiviral Agents/pharmacology ; COVID-19/drug therapy ; Dexamethasone ; Glucocorticoids/pharmacology ; Humans ; Hydrocortisone ; Peptidyl-Dipeptidase A/metabolism ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus/metabolism
Chemical Substances	Antiviral Agents ; Glucocorticoids ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; Dexamethasone (7S5I7G3JQL) ; Peptidyl-Dipeptidase A (EC 3.4.15.1) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Hydrocortisone (WI4X0X7BPJ)
Language	English
Publishing date	2022-09-21
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11192955
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Matrix Metalloproteinases in Health and Disease in the Times of COVID-19.

Fernandez-Patron, Carlos / Hardy, Eugenio

Biomolecules

2022 Volume 12, Issue 5

Abstract: Much has been written about matrix metalloproteinases (MMPs) in health and disease conditions, but their roles in the setting of COVID-19 and associated illnesses remain understudied [ ... ]. ...

Abstract	Much has been written about matrix metalloproteinases (MMPs) in health and disease conditions, but their roles in the setting of COVID-19 and associated illnesses remain understudied [...].
MeSH term(s)	COVID-19 ; Humans ; Matrix Metalloproteinases
Chemical Substances	Matrix Metalloproteinases (EC 3.4.24.-)
Language	English
Publishing date	2022-05-11
Publishing country	Switzerland
Document type	Editorial ; Research Support, Non-U.S. Gov't
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom12050692
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Article ; Online: Could a Non-Cellular Molecular Interactome in the Blood Circulation Influence Pathogens' Infectivity?

Hardy, Eugenio / Sarker, Hassan / Fernandez-Patron, Carlos

Cells

2023 Volume 12, Issue 13

Abstract: We advance the notion that much like artificial nanoparticles, relatively more complex biological entities with nanometric dimensions such as pathogens (viruses, bacteria, and other microorganisms) may also acquire a biomolecular corona upon entering the ...

Abstract	We advance the notion that much like artificial nanoparticles, relatively more complex biological entities with nanometric dimensions such as pathogens (viruses, bacteria, and other microorganisms) may also acquire a biomolecular corona upon entering the blood circulation of an organism. We view this biomolecular corona as a component of a much broader non-cellular blood interactome that can be highly specific to the organism, akin to components of the innate immune response to an invading pathogen. We review published supporting data and generalize these notions from artificial nanoparticles to viruses and bacteria. Characterization of the non-cellular blood interactome of an organism may help explain apparent differences in the susceptibility to pathogens among individuals. The non-cellular blood interactome is a candidate therapeutic target to treat infectious and non-infectious conditions.
MeSH term(s)	Humans ; Immunity, Innate ; Nanoparticles ; Viruses
Language	English
Publishing date	2023-06-23
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells12131699
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Article ; Online: Targeting MMP-Regulation of Inflammation to Increase Metabolic Tolerance to COVID-19 Pathologies: A Hypothesis.

Hardy, Eugenio / Fernandez-Patron, Carlos

Biomolecules

2021 Volume 11, Issue 3

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, ... ...

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.
MeSH term(s)	COVID-19/enzymology ; COVID-19/metabolism ; COVID-19/physiopathology ; COVID-19/virology ; Comorbidity ; Cytokines/metabolism ; Humans ; Inflammation/drug therapy ; Inflammation/enzymology ; Inflammation/metabolism ; Inflammation/pathology ; Lung/enzymology ; Lung/metabolism ; Lung/physiopathology ; Lung/virology ; Matrix Metalloproteinase Inhibitors/pharmacology ; Matrix Metalloproteinases/metabolism ; Protein Kinases/metabolism ; Respiratory Distress Syndrome/enzymology ; Respiratory Distress Syndrome/metabolism ; Respiratory Distress Syndrome/physiopathology ; Respiratory Distress Syndrome/virology ; SARS-CoV-2/pathogenicity ; Signal Transduction/drug effects ; Signal Transduction/genetics
Chemical Substances	Cytokines ; Matrix Metalloproteinase Inhibitors ; Protein Kinases (EC 2.7.-) ; AMP-activated protein kinase kinase (EC 2.7.1.-) ; Matrix Metalloproteinases (EC 3.4.24.-)
Language	English
Publishing date	2021-03-06
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom11030390
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Article ; Online: Potential of dissimilarity measure-based computation of protein thermal stability data for determining protein interactions.

Teitz, Joshua / Sander, Joerg / Sarker, Hassan / Fernandez-Patron, Carlos

Briefings in bioinformatics

2023 Volume 24, Issue 3

Abstract: Determining the interacting proteins in multiprotein complexes can be technically challenging. An emerging biochemical approach to this end is based on the 'thermal proximity co-aggregation' (TPCA) phenomenon. Accordingly, when two or more proteins ... ...

Abstract	Determining the interacting proteins in multiprotein complexes can be technically challenging. An emerging biochemical approach to this end is based on the 'thermal proximity co-aggregation' (TPCA) phenomenon. Accordingly, when two or more proteins interact to form a complex, they tend to co-aggregate when subjected to heat-induced denaturation and thus exhibit similar melting curves. Here, we explore the potential of leveraging TPCA for determining protein interactions. We demonstrate that dissimilarity measure-based information retrieval applied to melting curves tends to rank a protein-of-interest's interactors higher than its non-interactors, as shown in the context of pull-down assay results. Consequently, such rankings can reduce the number of confirmatory biochemical experiments needed to find bona fide protein-protein interactions. In general, rankings based on dissimilarity measures generated through metric learning further reduce the required number of experiments compared to those based on standard dissimilarity measures such as Euclidean distance. When a protein mixture's melting curves are obtained in two conditions, we propose a scoring function that uses melting curve data to inform how likely a protein pair is to interact in one condition but not another. We show that ranking protein pairs by their scores is an effective approach for determining condition-specific protein-protein interactions. By contrast, clustering melting curve data generally does not inform about the interacting proteins in multiprotein complexes. In conclusion, we report improved methods for dissimilarity measure-based computation of melting curves data that can greatly enhance the determination of interacting proteins in multiprotein complexes.
MeSH term(s)	Proteins ; Multiprotein Complexes
Chemical Substances	Proteins ; Multiprotein Complexes
Language	English
Publishing date	2023-04-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2068142-2
ISSN	1477-4054 ; 1467-5463
ISSN (online)	1477-4054
ISSN	1467-5463
DOI	10.1093/bib/bbad143
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Article: Destroy to Rebuild: The Connection Between Bone Tissue Remodeling and Matrix Metalloproteinases.

Hardy, Eugenio / Fernandez-Patron, Carlos

Frontiers in physiology

2020 Volume 11, Page(s) 47

Abstract: Bone is a dynamic organ that undergoes constant remodeling, an energetically costly process by which old bone is replaced and localized bone defects are repaired to renew the skeleton over time, thereby maintaining skeletal health. This review provides a ...

Abstract	Bone is a dynamic organ that undergoes constant remodeling, an energetically costly process by which old bone is replaced and localized bone defects are repaired to renew the skeleton over time, thereby maintaining skeletal health. This review provides a general overview of bone's main players (bone lining cells, osteocytes, osteoclasts, reversal cells, and osteoblasts) that participate in bone remodeling. Placing emphasis on the family of extracellular matrix metalloproteinases (MMPs), we describe how: (i) Convergence of multiple protease families (including MMPs and cysteine proteinases) ensures complexity and robustness of the bone remodeling process, (ii) Enzymatic activity of MMPs affects bone physiology at the molecular and cellular levels and (iii) Either overexpression or deficiency/insufficiency of individual MMPs impairs healthy bone remodeling and systemic metabolism. Today, it is generally accepted that proteolytic activity is required for the degradation of bone tissue in osteoarthritis and osteoporosis. However, it is increasingly evident that inactivating mutations in MMP genes can also lead to bone pathology including osteolysis and metabolic abnormalities such as delayed growth. We argue that there remains a need to rethink the role played by proteases in bone physiology and pathology.
Language	English
Publishing date	2020-02-05
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2020.00047
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Article ; Online: Biomarkers of ageing and frailty may predict COVID-19 severity.

Wanhella, Kailyn J / Fernandez-Patron, Carlos

Ageing research reviews

2021 Volume 73, Page(s) 101513

Abstract: Coronavirus Disease 2019 (COVID-19) is caused by the novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) - the culprit of an ongoing pandemic responsible for the loss of over 3 million lives worldwide within a year and a half. ...

Abstract	Coronavirus Disease 2019 (COVID-19) is caused by the novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) - the culprit of an ongoing pandemic responsible for the loss of over 3 million lives worldwide within a year and a half. While the majority of SARS-CoV-2 infected people develop no or mild symptoms, some become severely ill and may die from COVID-19-related complications. In this review, we compile and comment on a number of biomarkers that have been identified and are expected to enhance the detection, protection and treatment of individuals at high risk of developing severe illnesses, as well as enable the monitoring of COVID-19 prognosis and responsiveness to therapeutic interventions. Consistent with the emerging notion that the majority of COVID-19 deaths occur in older and frail individuals, we researched the scientific literature and report the identification of a subset of COVID-19 biomarkers indicative of increased vulnerability to developing severe COVID-19 in older and frail patients. Mechanistically, increased frailty results from reduced disease tolerance, a phenomenon aggravated by ageing and comorbidities. While biomarkers of ageing and frailty may predict COVID-19 severity, biomarkers of disease tolerance may predict resistance to COVID-19 with socio-economic factors such as access to adequate health care remaining as major non-biomolecular influencers of COVID-19 outcomes.
MeSH term(s)	Aged ; Aging ; Biomarkers ; COVID-19 ; Frailty/diagnosis ; Frailty/epidemiology ; Humans ; SARS-CoV-2
Chemical Substances	Biomarkers
Language	English
Publishing date	2021-11-24
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2075672-0
ISSN	1872-9649 ; 1568-1637
ISSN (online)	1872-9649
ISSN	1568-1637
DOI	10.1016/j.arr.2021.101513
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Article ; Online: The Emerging Role of Epigenetic Mechanisms in the Causation of Aberrant MMP Activity during Human Pathologies and the Use of Medicinal Drugs.

Sarker, Hassan / Haimour, Ayman / Toor, Ravneet / Fernandez-Patron, Carlos

Biomolecules

2021 Volume 11, Issue 4

Abstract: Matrix metalloproteinases (MMPs) cleave extracellular matrix proteins, growth factors, cytokines, and receptors to influence organ development, architecture, function, and the systemic and cell-specific responses to diseases and pharmacological drugs. ... ...

Abstract	Matrix metalloproteinases (MMPs) cleave extracellular matrix proteins, growth factors, cytokines, and receptors to influence organ development, architecture, function, and the systemic and cell-specific responses to diseases and pharmacological drugs. Conversely, many diseases (such as atherosclerosis, arthritis, bacterial infections (tuberculosis), viral infections (COVID-19), and cancer), cholesterol-lowering drugs (such as statins), and tetracycline-class antibiotics (such as doxycycline) alter MMP activity through transcriptional, translational, and post-translational mechanisms. In this review, we summarize evidence that the aforementioned diseases and drugs exert significant epigenetic pressure on genes encoding MMPs, tissue inhibitors of MMPs, and factors that transcriptionally regulate the expression of MMPs. Our understanding of human pathologies associated with alterations in the proteolytic activity of MMPs must consider that these pathologies and their medicinal treatments may impose epigenetic pressure on the expression of MMP genes. Whether the epigenetic mechanisms affecting the activity of MMPs can be therapeutically targeted warrants further research.
MeSH term(s)	Animals ; Anti-Bacterial Agents/pharmacology ; Anti-Bacterial Agents/therapeutic use ; Bacterial Infections/drug therapy ; Bacterial Infections/genetics ; Bone Diseases/drug therapy ; Bone Diseases/genetics ; COVID-19/drug therapy ; COVID-19/genetics ; Cardiovascular Diseases/drug therapy ; Cardiovascular Diseases/genetics ; Drug Discovery ; Epigenesis, Genetic/drug effects ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use ; Matrix Metalloproteinases/genetics ; Molecular Targeted Therapy ; Neoplasms/drug therapy ; Neoplasms/genetics ; Tetracyclines/pharmacology ; Tetracyclines/therapeutic use ; Virus Diseases/drug therapy ; Virus Diseases/genetics
Chemical Substances	Anti-Bacterial Agents ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Tetracyclines ; Matrix Metalloproteinases (EC 3.4.24.-)
Language	English
Publishing date	2021-04-15
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom11040578
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Article ; Online: Glucocorticoids Bind to SARS-CoV-2 S1 at Multiple Sites Causing Cooperative Inhibition of SARS-CoV-2 S1 Interaction With ACE2.

Sarker, Hassan / Panigrahi, Rashmi / Hardy, Eugenio / Glover, J N Mark / Elahi, Shokrollah / Fernandez-Patron, Carlos

Frontiers in immunology

2022 Volume 13, Page(s) 906687

Abstract: Dexamethasone may reduce mortality in COVID-19 patients. Whether dexamethasone or endogenous glucocorticoids, such as cortisol, biochemically interact with SARS-CoV-2 spike 1 protein (S1), or its cellular receptor ACE2, is unknown. Using molecular ... ...

Abstract	Dexamethasone may reduce mortality in COVID-19 patients. Whether dexamethasone or endogenous glucocorticoids, such as cortisol, biochemically interact with SARS-CoV-2 spike 1 protein (S1), or its cellular receptor ACE2, is unknown. Using molecular dynamics (MD) simulations and binding energy calculations, we identified 162 druggable pockets in various conformational states of S1 and all possible binding pockets for cortisol and dexamethasone. Through biochemical binding studies, we confirmed that cortisol and dexamethasone bind to S1. Limited proteolysis and mass spectrometry analyses validated several MD identified binding pockets for cortisol and dexamethasone on S1. Interaction assays indicated that cortisol and dexamethasone separately and cooperatively disrupt S1 interaction with ACE2, through direct binding to S1, without affecting ACE2 catalytic activity. Cortisol disrupted the binding of the mutant S1 Beta variant (E484K, K417N, N501Y) to ACE2. Delta and Omicron variants are mutated in or near identified cortisol-binding pockets in S1, which may affect cortisol binding to them. In the presence of cortisol, we find increased inhibition of S1 binding to ACE2 by an anti-SARS-CoV-2 S1 human chimeric monoclonal antibody against the receptor binding domain. Whether glucocorticoid/S1 direct interaction is an innate defence mechanism that may have contributed to mild or asymptomatic SARS-CoV-2 infection deserves further investigation.
MeSH term(s)	Angiotensin-Converting Enzyme 2 ; Antibodies, Viral ; COVID-19/drug therapy ; Dexamethasone/pharmacology ; Glucocorticoids/pharmacology ; Humans ; Hydrocortisone ; Peptidyl-Dipeptidase A/metabolism ; SARS-CoV-2
Chemical Substances	Antibodies, Viral ; Glucocorticoids ; Dexamethasone (7S5I7G3JQL) ; Peptidyl-Dipeptidase A (EC 3.4.15.1) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Hydrocortisone (WI4X0X7BPJ)
Language	English
Publishing date	2022-06-15
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.906687
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Article ; Online: Residual serum fibrinogen as a universal biomarker for all serotypes of Myasthenia gravis.

Hussain, Faraz S / Piragasam, Ramanaguru S / Sarker, Hassan / Blackmore, Derrick / Yacyshyn, Elaine / Fernandez-Patron, Carlos / Fahlman, Richard P / Siddiqi, Zaeem A

Scientific reports

2023 Volume 13, Issue 1, Page(s) 21229

Abstract: Myasthenia Gravis (MG) is an autoimmune disease associated with severe neuromuscular weakness. Diagnostic confirmation of MG is typically delayed and secured in about 85% and 50% of patients with generalized and ocular MG, respectively with serum ... ...

Abstract	Myasthenia Gravis (MG) is an autoimmune disease associated with severe neuromuscular weakness. Diagnostic confirmation of MG is typically delayed and secured in about 85% and 50% of patients with generalized and ocular MG, respectively with serum antibodies. We have identified a sensitive and specific diagnostic biomarker for various MG serotypes with quantitative proteomics. Serum proteomes of 18 individuals (MG patients, healthy controls (HC), Rheumatoid Arthritis (RA) were quantified in a pilot study and occurrence of high residual fibrinogen was validated by immunoblotting and further investigated by targeted mass spectrometry on the sera of 79 individuals (31 MG of various serotypes, 30 HC, 18 RA). Initial proteomic analysis identified high residual fibrinogen in MG patient sera which was then validated by antibody-based testing. Subsequently, a blinded study of independent samples showed 100% differentiation of MG patients from controls. A final serological quantification of 14 surrogate peptides derived from α-, β-, and γ-subunits of fibrinogen in 79 individuals revealed fibrinogen to be highly specific and 100% sensitive for MG (p < 0.00001), with a remarkable average higher abundance of > 1000-fold over control groups. Our unanticipated discovery of high levels of residual serum fibrinogen in all MG patients can secure rapid bedside diagnosis of MG.
MeSH term(s)	Humans ; Fibrinogen ; Proteomics ; Pilot Projects ; Serogroup ; Myasthenia Gravis ; Arthritis, Rheumatoid ; Hemostatics ; Biomarkers ; Autoantibodies
Chemical Substances	Fibrinogen (9001-32-5) ; Hemostatics ; Biomarkers ; Autoantibodies
Language	English
Publishing date	2023-12-01
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-47559-x
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