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1.
Sci Adv ; 8(5): eabl8920, 2022 02 04.
Article in English | MEDLINE | ID: covidwho-1673337

ABSTRACT

Dexamethasone is widely used as an immunosuppressive therapy and recently as COVID-19 treatment. Here, we demonstrate that dexamethasone sensitizes to ferroptosis, a form of iron-catalyzed necrosis, previously suggested to contribute to diseases such as acute kidney injury, myocardial infarction, and stroke, all of which are triggered by glutathione (GSH) depletion. GSH levels were significantly decreased by dexamethasone. Mechanistically, we identified that dexamethasone up-regulated the GSH metabolism regulating protein dipeptidase-1 (DPEP1) in a glucocorticoid receptor (GR)-dependent manner. DPEP1 knockdown reversed the phenotype of dexamethasone-induced ferroptosis sensitization. Ferroptosis inhibitors, the DPEP1 inhibitor cilastatin, or genetic DPEP1 inactivation reversed the dexamethasone-induced increase in tubular necrosis in freshly isolated renal tubules. Our data indicate that dexamethasone sensitizes to ferroptosis by a GR-mediated increase in DPEP1 expression and GSH depletion. Together, we identified a previously unknown mechanism of glucocorticoid-mediated sensitization to ferroptosis bearing clinical and therapeutic implications.


Subject(s)
Dexamethasone/pharmacology , Dipeptidases/genetics , Ferroptosis/drug effects , Ferroptosis/genetics , Gene Expression Regulation/drug effects , Glutathione/metabolism , Receptors, Glucocorticoid/metabolism , Carbolines/adverse effects , Carbolines/pharmacology , Cell Line , Dipeptidases/metabolism , Fluorescent Antibody Technique , GPI-Linked Proteins/genetics , GPI-Linked Proteins/metabolism , Gene Knockdown Techniques , Humans , Immunophenotyping , Oxidation-Reduction/drug effects , Piperazines/adverse effects , Piperazines/pharmacology
2.
Front Immunol ; 12: 699389, 2021.
Article in English | MEDLINE | ID: covidwho-1450805

ABSTRACT

The impact of zinc (Zn) sufficiency/supplementation on COVID-19-associated mortality and incidence (SARS-CoV-2 infections) remains unknown. During an infection, the levels of free Zn are reduced as part of "nutritional immunity" to limit the growth and replication of pathogen and the ensuing inflammatory damage. Considering its key role in immune competency and frequently recorded deficiency in large sections of different populations, Zn has been prescribed for both prophylactic and therapeutic purposes in COVID-19 without any corroborating evidence for its protective role. Multiple trials are underway evaluating the effect of Zn supplementation on COVID-19 outcome in patients getting standard of care treatment. However, the trial designs presumably lack the power to identify negative effects of Zn supplementation, especially in the vulnerable groups of elderly and patients with comorbidities (contributing 9 out of 10 deaths; up to >8,000-fold higher mortality). In this study, we have analyzed COVID-19 mortality and incidence (case) data from 23 socially similar European populations with comparable confounders (population: 522.47 million; experiencing up to >150-fold difference in death rates) and at the matching stage of the pandemic (March 12 to June 26, 2020; first wave of COVID-19 incidence and mortality). Our results suggest a positive correlation between populations' Zn-sufficiency status and COVID-19 mortality [r (23): 0.7893-0.6849, p-value < 0.0003] as well as incidence [r (23):0.8084-0.5658; p-value < 0.005]. The observed association is contrary to what would be expected if Zn sufficiency was protective in COVID-19. Thus, controlled trials or retrospective analyses of the adverse event patients' data should be undertaken to correctly guide the practice of Zn supplementation in COVID-19.


Subject(s)
COVID-19/diet therapy , COVID-19/mortality , SARS-CoV-2/drug effects , Zinc/blood , Zinc/therapeutic use , COVID-19/epidemiology , Comorbidity , Dietary Supplements , Europe/epidemiology , Humans , Oxidation-Reduction/drug effects , Oxidative Stress , SARS-CoV-2/immunology
3.
Molecules ; 26(17)2021 Sep 02.
Article in English | MEDLINE | ID: covidwho-1390702

ABSTRACT

Human neutrophil elastase (HNE) is a uniquely destructive serine protease with the ability to unleash a wave of proteolytic activity by destroying the inhibitors of other proteases. Although this phenomenon forms an important part of the innate immune response to invading pathogens, it is responsible for the collateral host tissue damage observed in chronic conditions such as chronic obstructive pulmonary disease (COPD), and in more acute disorders such as the lung injuries associated with COVID-19 infection. Previously, a combinatorially selected activity-based probe revealed an unexpected substrate preference for oxidised methionine, which suggests a link to oxidative pathogen clearance by neutrophils. Here we use oxidised model substrates and inhibitors to confirm this observation and to show that neutrophil elastase is specifically selective for the di-oxygenated methionine sulfone rather than the mono-oxygenated methionine sulfoxide. We also posit a critical role for ordered solvent in the mechanism of HNE discrimination between the two oxidised forms methionine residue. Preference for the sulfone form of oxidised methionine is especially significant. While both host and pathogens have the ability to reduce methionine sulfoxide back to methionine, a biological pathway to reduce methionine sulfone is not known. Taken together, these data suggest that the oxidative activity of neutrophils may create rapidly cleaved elastase "super substrates" that directly damage tissue, while initiating a cycle of neutrophil oxidation that increases elastase tissue damage and further neutrophil recruitment.


Subject(s)
Immunity, Innate , Leukocyte Elastase/metabolism , Methionine/analogs & derivatives , Neutrophils/immunology , Biocatalysis , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Catalytic Domain/genetics , Enzyme Assays , Host-Pathogen Interactions/immunology , Humans , Leukocyte Elastase/antagonists & inhibitors , Leukocyte Elastase/genetics , Lung/immunology , Lung/pathology , Lung/virology , Methionine/metabolism , Molecular Dynamics Simulation , Neutrophil Infiltration , Neutrophils/enzymology , Oxidation-Reduction/drug effects , Proteolysis/drug effects , Pulmonary Disease, Chronic Obstructive/immunology , Pulmonary Disease, Chronic Obstructive/pathology , SARS-CoV-2/immunology , Substrate Specificity/immunology
4.
Adv Sci (Weinh) ; 8(18): e2101498, 2021 09.
Article in English | MEDLINE | ID: covidwho-1316192

ABSTRACT

Acute kidney injury (AKI), as a common oxidative stress-related renal disease, causes high mortality in clinics annually, and many other clinical diseases, including the pandemic COVID-19, have a high potential to cause AKI, yet only rehydration, renal dialysis, and other supportive therapies are available for AKI in the clinics. Nanotechnology-mediated antioxidant therapy represents a promising therapeutic strategy for AKI treatment. However, current enzyme-mimicking nanoantioxidants show poor biocompatibility and biodegradability, as well as non-specific ROS level regulation, further potentially causing deleterious adverse effects. Herein, the authors report a novel non-enzymatic antioxidant strategy based on ultrathin Ti3 C2 -PVP nanosheets (TPNS) with excellent biocompatibility and great chemical reactivity toward multiple ROS for AKI treatment. These TPNS nanosheets exhibit enzyme/ROS-triggered biodegradability and broad-spectrum ROS scavenging ability through the readily occurring redox reaction between Ti3 C2 and various ROS, as verified by theoretical calculations. Furthermore, both in vivo and in vitro experiments demonstrate that TPNS can serve as efficient antioxidant platforms to scavenge the overexpressed ROS and subsequently suppress oxidative stress-induced inflammatory response through inhibition of NF-κB signal pathway for AKI treatment. This study highlights a new type of therapeutic agent, that is, the redox-mediated non-enzymatic antioxidant MXene nanoplatforms in treatment of AKI and other ROS-associated diseases.


Subject(s)
Acute Kidney Injury/drug therapy , Antioxidants/pharmacology , Oxidation-Reduction/drug effects , Polyvinyls/pharmacology , Pyrrolidines/pharmacology , Titanium/pharmacology , Acute Kidney Injury/metabolism , Apoptosis/drug effects , Humans , Kidney/drug effects , Kidney/metabolism , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects
5.
Int J Mol Sci ; 22(7)2021 Mar 30.
Article in English | MEDLINE | ID: covidwho-1299437

ABSTRACT

Host-directed therapy using drugs that target cellular pathways required for virus lifecycle or its clearance might represent an effective approach for treating infectious diseases. Changes in redox homeostasis, including intracellular glutathione (GSH) depletion, are one of the key events that favor virus replication and contribute to the pathogenesis of virus-induced disease. Redox homeostasis has an important role in maintaining an appropriate Th1/Th2 balance, which is necessary to mount an effective immune response against viral infection and to avoid excessive inflammatory responses. It is known that excessive production of reactive oxygen species (ROS) induced by viral infection activates nuclear factor (NF)-kB, which orchestrates the expression of viral and host genes involved in the viral replication and inflammatory response. Moreover, redox-regulated protein disulfide isomerase (PDI) chaperones have an essential role in catalyzing formation of disulfide bonds in viral proteins. This review aims at describing the role of GSH in modulating redox sensitive pathways, in particular that mediated by NF-kB, and PDI activity. The second part of the review discusses the effectiveness of GSH-boosting molecules as broad-spectrum antivirals acting in a multifaceted way that includes the modulation of immune and inflammatory responses.


Subject(s)
Glutathione/metabolism , Virus Diseases/drug therapy , Virus Replication/drug effects , Animals , Antiviral Agents/pharmacology , Humans , NF-kappa B/metabolism , Oxidation-Reduction/drug effects , Protein Disulfide-Isomerases/metabolism , Reactive Oxygen Species/metabolism , Virus Diseases/metabolism
6.
Free Radic Res ; 55(7): 745-756, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1258678

ABSTRACT

It has been shown that the development of coronavirus infection (COVID-19), especially in severe cases, is accompanied by hypoxia as a result of several pathological processes: alveolar blood supply disorders, hemolysis, COVID-associated coagulopathy. Under these conditions, the level of reactive oxygen species is increased and it is more likely that free-radical damage to biomolecules is caused by the process of free-radical fragmentation than oxidation. In contrast to the oxidation process, free-radical fragmentation reactions are more effectively inhibited by oxidizing agents than reducing agents. Therefore, the use of substances possessing both reducing and oxidizing properties, such as natural and synthetic quinones, bioflavonoids, curcuminoids, should reduce the probability of biomolecule destruction by oxidation as well as free-radical fragmentation processes.HighlightsCOVID-19 is accompanied by the iron release from the heme and «silent¼ hypoxiaROS initiate fragmentation reactions of biomolecules under conditions of hypoxiaBlocking of fragmentation process by oxidizers may lead to mitigation of COVID-19.


Subject(s)
COVID-19/metabolism , Free Radicals/metabolism , SARS-CoV-2/metabolism , COVID-19/pathology , COVID-19/virology , Free Radicals/adverse effects , Heme/metabolism , Humans , Iron/metabolism , Oxidation-Reduction/drug effects , Reactive Oxygen Species/adverse effects , Reactive Oxygen Species/metabolism , SARS-CoV-2/pathogenicity
7.
Mar Drugs ; 19(5)2021 May 11.
Article in English | MEDLINE | ID: covidwho-1256603

ABSTRACT

Background: Echinochrome A (EchA) is a pigment from sea urchins. EchA is a polyhydroxylated 1,4-naphthoquinone that contains several hydroxyl groups appropriate for free-radical scavenging and preventing redox imbalance. EchA is the most studied molecule of this family and is an active principle approved to be used in humans, usually for cardiopathies and glaucoma. EchA is used as a pharmaceutical drug. Methods: A comprehensive literature and patent search review was undertaken using PubMed, as well as Google Scholar and Espacenet search engines to review these areas. Conclusions: In the bloodstream, EchA can mediate cellular responses, act as a radical scavenger, and activate the glutathione pathway. It decreases ROS imbalance, prevents and limits lipid peroxidation, and enhances mitochondrial functions. Most importantly, EchA contributes to the modulation of the immune system. EchA can regulate the generation of regulatory T cells, inhibit pro-inflammatory IL-1ß and IL-6 cytokine production, while slightly reducing IL-8, TNF-α, INF-α, and NKT, thus correcting immune imbalance. These characteristics suggest that EchA is a candidate drug to alleviate the cytokine storm syndrome (CSS).


Subject(s)
Cytokine Release Syndrome/drug therapy , Naphthoquinones/pharmacology , Naphthoquinones/therapeutic use , Pigments, Biological/pharmacology , Pigments, Biological/therapeutic use , Sea Urchins/chemistry , Animals , Cytokine Release Syndrome/metabolism , Humans , Immunity/drug effects , Oxidation-Reduction/drug effects , Reactive Oxygen Species/metabolism
8.
Br J Nutr ; 125(6): 618-627, 2021 03 28.
Article in English | MEDLINE | ID: covidwho-1139692

ABSTRACT

Se is a micronutrient essential for human health. Sub-optimal Se status is common, occurring in a significant proportion of the population across the world including parts of Europe and China. Human and animal studies have shown that Se status is a key determinant of the host response to viral infections. In this review, we address the question whether Se intake is a factor in determining the severity of response to coronavirus disease 2019 (COVID-19). Emphasis is placed on epidemiological and animal studies which suggest that Se affects host response to RNA viruses and on the molecular mechanisms by which Se and selenoproteins modulate the inter-linked redox homeostasis, stress response and inflammatory response. Together these studies indicate that Se status is an important factor in determining the host response to viral infections. Therefore, we conclude that Se status is likely to influence human response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and that Se status is one (of several) risk factors which may impact on the outcome of SARS-CoV-2 infection, particularly in populations where Se intake is sub-optimal or low. We suggest the use of appropriate markers to assess the Se status of COVID-19 patients and possible supplementation may be beneficial in limiting the severity of symptoms, especially in countries where Se status is regarded as sub-optimal.


Subject(s)
COVID-19/physiopathology , RNA, Viral/drug effects , SARS-CoV-2/drug effects , Selenium/pharmacology , Virus Diseases/physiopathology , Animals , COVID-19/virology , Humans , Inflammation/virology , Micronutrients/pharmacology , Nutritional Status , Oxidation-Reduction/drug effects , Stress, Physiological/drug effects , Virus Diseases/virology
9.
J Enzyme Inhib Med Chem ; 36(1): 659-668, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1109085

ABSTRACT

Human intestinal epithelial cell line-6 (HIEC-6) cells and primary human hepatocytes (PHHs) were treated with 3-amidinophenylalanine-derived inhibitors of trypsin-like serine proteases for 24 hours. It was proven that treatment with MI-1900 and MI-1907 was tolerated up to 50 µM in HIEC-6. These inhibitors did not cause elevations in extracellular H2O2 levels and in the concentrations of interleukin (IL)-6 and IL-8 and did not alter occludin distribution in HIEC-6. It was also found that MI-1900 and MI-1907 up to 50 µM did not affect cell viability, IL-6 and IL-8 and occludin levels of PHH. Based on our findings, these inhibitors could be safely applicable at 50 µM in HIEC-6 and in PHH; however, redox status was disturbed in case of PHH. Moreover, it has recently been demonstrated that MI-1900 prevents the replication and spread of the new SARS-CoV-2 in infected Calu-3 cells, most-likely via an inhibition of the membrane-bound host protease TMPRSS2.


Subject(s)
Antiviral Agents/pharmacology , Epithelial Cells/drug effects , Hepatocytes/drug effects , Phenylalanine/pharmacology , Protease Inhibitors/pharmacology , Serine Endopeptidases/metabolism , Cell Line , Cell Survival/drug effects , Epithelial Cells/cytology , Epithelial Cells/enzymology , Gene Expression Regulation/drug effects , Hepatocytes/cytology , Hepatocytes/enzymology , Humans , Hydrogen Peroxide/metabolism , Interleukin-6/genetics , Interleukin-6/metabolism , Interleukin-8/genetics , Interleukin-8/metabolism , Intestinal Mucosa/cytology , Intestinal Mucosa/drug effects , Intestinal Mucosa/enzymology , Occludin/genetics , Occludin/metabolism , Oxidation-Reduction/drug effects , Phenylalanine/analogs & derivatives , Primary Cell Culture , Serine Endopeptidases/genetics
10.
Oxid Med Cell Longev ; 2021: 6646923, 2021.
Article in English | MEDLINE | ID: covidwho-1093883

ABSTRACT

Inflammatory lung disease results in a high global burden of death and disability. There are no effective treatments for the most severe forms of many inflammatory lung diseases, such as chronic obstructive pulmonary disease, emphysema, corticosteroid-resistant asthma, and coronavirus disease 2019; hence, new treatment options are required. Here, we review the role of oxidative imbalance in the development of difficult-to-treat inflammatory lung diseases. The inflammation-induced overproduction of reactive oxygen species (ROS) means that endogenous antioxidants may not be sufficient to prevent oxidative damage, resulting in an oxidative imbalance in the lung. In turn, intracellular signaling events trigger the production of proinflammatory mediators that perpetuate and aggravate the inflammatory response and may lead to tissue damage. The production of high levels of ROS in inflammatory lung diseases can induce the phosphorylation of mitogen-activated protein kinases, the inactivation of phosphoinositide 3-kinase (PI3K) signaling and histone deacetylase 2, a decrease in glucocorticoid binding to its receptor, and thus resistance to glucocorticoid treatment. Hence, antioxidant treatment might be a therapeutic option for inflammatory lung diseases. Preclinical studies have shown that antioxidants (alone or combined with anti-inflammatory drugs) are effective in the treatment of inflammatory lung diseases, although the clinical evidence of efficacy is weaker. Despite the high level of evidence for the efficacy of antioxidants in the treatment of inflammatory lung diseases, the discovery and clinical investigation of safer, more efficacious compounds are now a priority.


Subject(s)
Antioxidants/therapeutic use , Inflammation/drug therapy , Inflammation/metabolism , Lung Diseases/drug therapy , Lung Diseases/metabolism , Animals , Humans , Inflammation/immunology , Lung/drug effects , Lung/metabolism , Lung Diseases/immunology , Oxidation-Reduction/drug effects , Phosphatidylinositol 3-Kinases/metabolism , Pulmonary Disease, Chronic Obstructive/drug therapy , Pulmonary Disease, Chronic Obstructive/immunology , Pulmonary Disease, Chronic Obstructive/metabolism , Reactive Oxygen Species/metabolism
11.
Redox Biol ; 38: 101810, 2021 01.
Article in English | MEDLINE | ID: covidwho-1065551

ABSTRACT

The recent global pandemic due to COVID-19 is caused by a type of coronavirus, SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2). Despite rigorous efforts worldwide to control the spread and human to human transmission of this virus, incidence and death due to COVID-19 continue to rise. Several drugs have been tested for treatment of COVID-19, including hydroxychloroquine. While a number of studies have shown that hydroxychloroquine can prolong QT interval, potentially increasing risk of ventricular arrhythmias and Torsade de Pointes, its effects on immune cell function have not been extensively examined. In the current review, an overview of coronaviruses, viral entry and pathogenicity, immunity upon coronavirus infection, and current therapy options for COVID-19 are briefly discussed. Further based on preclinical studies, we provide evidences that i) hydroxychloroquine impairs autophagy, which leads to accumulation of damaged/oxidized cytoplasmic constituents and interferes with cellular homeostasis, ii) this impaired autophagy in part reduces antigen processing and presentation to immune cells and iii) inhibition of endosome-lysosome system acidification by hydroxychloroquine not only impairs the phagocytosis process, but also potentially alters pulmonary surfactant in the lungs. Therefore, it is likely that hydroxychloroquine treatment may in fact impair host immunity in response to SARS-CoV-2, especially in elderly patients or those with co-morbidities. Further, this review provides a rationale for developing and selecting antiviral drugs and includes a brief review of traditional strategies combined with new drugs to combat COVID-19.


Subject(s)
Antigen Presentation/drug effects , Antiviral Agents , Autophagic Cell Death , COVID-19 , Hydroxychloroquine , Pandemics , SARS-CoV-2/immunology , Antiviral Agents/adverse effects , Antiviral Agents/therapeutic use , Autophagic Cell Death/drug effects , Autophagic Cell Death/immunology , COVID-19/drug therapy , COVID-19/epidemiology , COVID-19/immunology , COVID-19/pathology , Humans , Hydroxychloroquine/adverse effects , Hydroxychloroquine/therapeutic use , Oxidation-Reduction/drug effects
12.
Redox Biol ; 38: 101810, 2021 01.
Article in English | MEDLINE | ID: covidwho-997462

ABSTRACT

The recent global pandemic due to COVID-19 is caused by a type of coronavirus, SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2). Despite rigorous efforts worldwide to control the spread and human to human transmission of this virus, incidence and death due to COVID-19 continue to rise. Several drugs have been tested for treatment of COVID-19, including hydroxychloroquine. While a number of studies have shown that hydroxychloroquine can prolong QT interval, potentially increasing risk of ventricular arrhythmias and Torsade de Pointes, its effects on immune cell function have not been extensively examined. In the current review, an overview of coronaviruses, viral entry and pathogenicity, immunity upon coronavirus infection, and current therapy options for COVID-19 are briefly discussed. Further based on preclinical studies, we provide evidences that i) hydroxychloroquine impairs autophagy, which leads to accumulation of damaged/oxidized cytoplasmic constituents and interferes with cellular homeostasis, ii) this impaired autophagy in part reduces antigen processing and presentation to immune cells and iii) inhibition of endosome-lysosome system acidification by hydroxychloroquine not only impairs the phagocytosis process, but also potentially alters pulmonary surfactant in the lungs. Therefore, it is likely that hydroxychloroquine treatment may in fact impair host immunity in response to SARS-CoV-2, especially in elderly patients or those with co-morbidities. Further, this review provides a rationale for developing and selecting antiviral drugs and includes a brief review of traditional strategies combined with new drugs to combat COVID-19.


Subject(s)
Antigen Presentation/drug effects , Antiviral Agents , Autophagic Cell Death , COVID-19 , Hydroxychloroquine , Pandemics , SARS-CoV-2/immunology , Antiviral Agents/adverse effects , Antiviral Agents/therapeutic use , Autophagic Cell Death/drug effects , Autophagic Cell Death/immunology , COVID-19/drug therapy , COVID-19/epidemiology , COVID-19/immunology , COVID-19/pathology , Humans , Hydroxychloroquine/adverse effects , Hydroxychloroquine/therapeutic use , Oxidation-Reduction/drug effects
14.
Int J Mol Sci ; 21(11)2020 Jun 08.
Article in English | MEDLINE | ID: covidwho-574726

ABSTRACT

Viruses use cell machinery to replicate their genome and produce viral proteins. For this reason, several intracellular factors, including the redox state, might directly or indirectly affect the progression and outcome of viral infection. In physiological conditions, the redox balance between oxidant and antioxidant species is maintained by enzymatic and non-enzymatic systems, and it finely regulates several cell functions. Different viruses break this equilibrium and induce an oxidative stress that in turn facilitates specific steps of the virus lifecycle and activates an inflammatory response. In this context, many studies highlighted the importance of redox-sensitive pathways as novel cell-based targets for therapies aimed at blocking both viral replication and virus-induced inflammation. In the review, we discuss the most recent findings in this field. In particular, we describe the effects of natural or synthetic redox-modulating molecules in inhibiting DNA or RNA virus replication as well as inflammatory pathways. The importance of the antioxidant transcription factor Nrf2 is also discussed. Most of the data reported here are on influenza virus infection. We believe that this approach could be usefully applied to fight other acute respiratory viral infections characterized by a strong inflammatory response, like COVID-19.


Subject(s)
Antiviral Agents/therapeutic use , Oxidation-Reduction/drug effects , Virus Diseases/drug therapy , Animals , COVID-19/drug therapy , Coronavirus Infections/drug therapy , Glutathione/metabolism , Humans , Inflammation/drug therapy , Influenza, Human/drug therapy , Virus Diseases/immunology , Virus Diseases/pathology , Virus Replication/drug effects
15.
Med Hypotheses ; 144: 109920, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-457482

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 19 (COVID-19), was declared pandemic by the World Health Organization in March 2020. SARS-CoV-2 binds its host cell receptor, angiotensin-converting enzyme 2 (ACE2), through the viral spike (S) protein. The mortality related to severe acute respiratory distress syndrome (ARDS) and multi-organ failure in COVID-19 patients has been suggested to be connected with cytokine storm syndrome (CSS), an excessive immune response that severely damages healthy lung tissue. In addition, cardiac symptoms, including fulminant myocarditis, are frequent in patients in a severe state of illness. Diacerein (DAR) is an anthraquinone derivative drug whose active metabolite is rhein. Different studies have shown that this compound inhibits the IL-1, IL-2, IL-6, IL-8, IL-12, IL-18, TNF-α, NF-κB and NALP3 inflammasome pathways. The antiviral activity of rhein has also been documented. This metabolite prevents hepatitis B virus (HBV) replication and influenza A virus (IAV) adsorption and replication through mechanisms involving regulation of oxidative stress and alterations of the TLR4, Akt, MAPK, and NF-κB signalling pathways. Importantly, rhein inhibits the interaction between the SARS-CoV S protein and ACE2 in a dose-dependent manner, suggesting rhein as a potential therapeutic agent for the treatment of SARS-CoV infection. Based on these findings, we hypothesize that DAR is a multi-target drug useful for COVID-19 treatment. This anthraquinone may control hyperinflammatory conditions by multi-faceted cytokine inhibition and by reducing viral infection.


Subject(s)
Anthraquinones/therapeutic use , COVID-19/drug therapy , Angiotensin-Converting Enzyme 2/drug effects , Angiotensin-Converting Enzyme 2/metabolism , Animals , Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/metabolism , COVID-19/virology , Cytokines/metabolism , Drug Evaluation, Preclinical , Host Microbial Interactions/drug effects , Humans , Male , Mice, Inbred C57BL , Models, Biological , Oxidation-Reduction/drug effects , Pandemics , Receptors, Coronavirus/drug effects , Receptors, Coronavirus/metabolism , SARS-CoV-2/drug effects , Signal Transduction/drug effects , Virus Replication/drug effects
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