RESUMO
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.
Assuntos
Nanopartículas , Vírus , Humanos , Imunidade InataRESUMO
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.
Assuntos
Tratamento Farmacológico da COVID-19 , Enzima de Conversão de Angiotensina 2 , Antivirais/farmacologia , Dexametasona , Glucocorticoides/farmacologia , Humanos , Hidrocortisona , Peptidil Dipeptidase A/metabolismo , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/metabolismoRESUMO
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.
Assuntos
COVID-19/metabolismo , Pulmão/fisiopatologia , Metaloproteinases da Matriz/metabolismo , Proteínas Quinases/metabolismo , Síndrome do Desconforto Respiratório/metabolismo , Quinases Proteína-Quinases Ativadas por AMP , COVID-19/enzimologia , COVID-19/fisiopatologia , COVID-19/virologia , Comorbidade , Citocinas/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/enzimologia , Inflamação/metabolismo , Inflamação/patologia , Pulmão/enzimologia , Pulmão/metabolismo , Pulmão/virologia , Inibidores de Metaloproteinases de Matriz/farmacologia , Síndrome do Desconforto Respiratório/enzimologia , Síndrome do Desconforto Respiratório/fisiopatologia , Síndrome do Desconforto Respiratório/virologia , SARS-CoV-2/patogenicidade , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genéticaRESUMO
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.
RESUMO
The breakthrough discovery of cardiac natriuretic peptides provided the first direct demonstration of the connection between the heart and the kidneys for the maintenance of sodium and volume homeostasis in health and disease. Yet, little is still known about how the heart and other organs cross-talk. Here, we review three physiological mechanisms of communication linking the heart to other organs through: i) cardiac natriuretic peptides, ii) the microRNA-208a/mediator complex subunit-13 axis and iii) the matrix metalloproteinase-2 (MMP-2)/C-C motif chemokine ligand-7/cardiac secreted phospholipase A2 (sPLA2) axis - a pathway which likely applies to the many cytokines, which are cleaved and regulated by MMP-2. We also suggest experimental strategies to answer still open questions on the latter pathway. In short, we review evidence showing how the cardiac secretome influences the metabolic and inflammatory status of non-cardiac organs as well as the heart.
RESUMO
Matrix metalloproteinase (MMP)-2 cleaves a broad spectrum of substrates, including extracellular matrix components (responsible for normal tissue remodeling) and cytokines (modulators of the inflammatory response to physiological insults such as tissue damage). MMP-2 expression is elevated in many cardiovascular pathologies (e.g., myocardial infarction, hypertensive heart disease) where tissue remodeling and inflammatory responses are perturbed. Thus, it has generally been assumed that blockade of MMP-2 activity will yield therapeutic effects. Here, we provide a counterargument to this dogma based on 1) preclinical studies on Mmp2-null ( Mmp2-/-) mice and 2) clinical studies on patients with inactivating MMP2 gene mutations. Furthermore, we put forward the hypothesis that, when MMP-2 activity falls below baseline, the bioavailability of proinflammatory cytokines normally cleaved and inactivated by MMP-2 increases, leading to the production of cytokines and cardiac secretion of phospholipase A2 activity into the circulation, which stimulate systemic inflammation that perturbs lipid metabolism in target organs. Finally, we suggest that insufficient understanding of the consequences of MMP-2 deficiency remains a major factor in the failure of MMP-2 inhibitor-based therapeutic approaches. This paucity of knowledge precludes our ability to effectively intervene in cardiovascular and noncardiovascular pathologies at the level of MMP-2.