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1.
ACS Appl Bio Mater ; 5(2): 483-491, 2022 02 21.
Article in English | MEDLINE | ID: covidwho-1701160

ABSTRACT

Interleukin-mediated deep cytokine storm, an aggressive inflammatory response to SARS-CoV-2 virus infection in COVID-19 patients, is correlated directly with lung injury, multi-organ failure, and poor prognosis of severe COVID-19 patients. Curcumin (CUR), a phenolic antioxidant compound obtained from turmeric (Curcuma longa L.), is well-known for its strong anti-inflammatory activity. However, its in vivo efficacy is constrained due to poor bioavailability. Herein, we report that CUR-encapsulated polysaccharide nanoparticles (CUR-PS-NPs) potently inhibit the release of cytokines, chemokines, and growth factors associated with damage of SARS-CoV-2 spike protein (CoV2-SP)-stimulated liver Huh7.5 and lung A549 epithelial cells. Treatment with CUR-PS-NPs effectively attenuated the interaction of ACE2 and CoV2-SP. The effects of CUR-PS-NPs were linked to reduced NF-κB/MAPK signaling which in turn decreased CoV2-SP-mediated phosphorylation of p38 MAPK, p42/44 MAPK, and p65/NF-κB as well as nuclear p65/NF-κB expression. The findings of the study strongly indicate that organic NPs of CUR can be used to control hyper-inflammatory responses and prevent lung and liver injuries associated with CoV2-SP-mediated cytokine storm.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Curcumin/pharmacology , Cytokine Release Syndrome/prevention & control , MAP Kinase Signaling System/drug effects , NF-kappa B/metabolism , Nanoparticles/chemistry , Signal Transduction/drug effects , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/metabolism , Anti-Inflammatory Agents/pharmacokinetics , Cell Survival/drug effects , Chemokines/biosynthesis , Curcumin/chemistry , Curcumin/pharmacokinetics , Cytokines/biosynthesis , Humans , Intercellular Signaling Peptides and Proteins/biosynthesis , Phosphorylation , Spike Glycoprotein, Coronavirus/physiology
2.
Sci Rep ; 12(1): 1626, 2022 01 31.
Article in English | MEDLINE | ID: covidwho-1661980

ABSTRACT

The ongoing COVID-19 pandemic is one of the biggest health challenges of recent decades. Among the causes of mortality triggered by SARS-CoV-2 infection, the development of an inflammatory "cytokine storm" (CS) plays a determinant role. Here, we used transcriptomic data from the bronchoalveolar lavage fluid (BALF) of COVID-19 patients undergoing a CS to obtain gene-signatures associated to this pathology. Using these signatures, we interrogated the Connectivity Map (CMap) dataset that contains the effects of over 5000 small molecules on the transcriptome of human cell lines, and looked for molecules which effects on transcription mimic or oppose those of the CS. As expected, molecules that potentiate immune responses such as PKC activators are predicted to worsen the CS. In addition, we identified the negative regulation of female hormones among pathways potentially aggravating the CS, which helps to understand the gender-related differences in COVID-19 mortality. Regarding drugs potentially counteracting the CS, we identified glucocorticoids as a top hit, which validates our approach as this is the primary treatment for this pathology. Interestingly, our analysis also reveals a potential effect of MEK inhibitors in reverting the COVID-19 CS, which is supported by in vitro data that confirms the anti-inflammatory properties of these compounds.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/complications , COVID-19/drug therapy , Computer Simulation , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/prevention & control , Glucocorticoids/therapeutic use , Pandemics , Protein Kinase Inhibitors/therapeutic use , SARS-CoV-2 , Anti-Inflammatory Agents/pharmacology , Bronchoalveolar Lavage Fluid/virology , COVID-19/blood , COVID-19/epidemiology , Cytokine Release Syndrome/mortality , Cytokines/blood , Female , Gene Expression Profiling/methods , Glucocorticoids/pharmacology , Humans , MAP Kinase Kinase Kinases/antagonists & inhibitors , MAP Kinase Signaling System/drug effects , Male , Protein Kinase Inhibitors/pharmacology , Sex Factors , Transcriptome/genetics
3.
Cell Mol Life Sci ; 79(1): 65, 2022 Jan 10.
Article in English | MEDLINE | ID: covidwho-1616112

ABSTRACT

Coronavirus disease 2019 (COVID-19), the illness caused by a novel coronavirus now called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to more than 260 million confirmed infections and 5 million deaths to date. While vaccination is a powerful tool to control pandemic spread, medication to relieve COVID-19-associated symptoms and alleviate disease progression especially in high-risk patients is still lacking. In this study, we explore the suitability of the rapid accelerated fibrosarcoma/mitogen-activated protein kinase/extracellular signal-regulated kinase (Raf/MEK/ERK) pathway as a druggable target in the treatment of SARS-CoV-2 infections. We find that SARS-CoV-2 transiently activates Raf/MEK/ERK signaling in the very early infection phase and that ERK1/2 knockdown limits virus replication in cell culture models. We demonstrate that ATR-002, a specific inhibitor of the upstream MEK1/2 kinases which is currently evaluated in clinical trials as an anti-influenza drug, displays strong anti-SARS-CoV-2 activity in cell lines as well as in primary air-liquid-interphase epithelial cell (ALI) cultures, with a safe and selective treatment window. We also observe that ATR-002 treatment impairs the SARS-CoV-2-induced expression of pro-inflammatory cytokines, and thus might prevent COVID-19-associated hyperinflammation, a key player in COVID-19 progression. Thus, our data suggest that the Raf/MEK/ERK signaling cascade may represent a target for therapeutic intervention strategies against SARS-CoV-2 infections and that ATR-002 is a promising candidate for further drug evaluation.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Fenamates/pharmacology , MAP Kinase Signaling System/drug effects , Protein Kinase Inhibitors/pharmacology , SARS-CoV-2/drug effects , A549 Cells , Adult , Animals , COVID-19/metabolism , Cell Line , Cells, Cultured , Chlorocebus aethiops , Cytokines/metabolism , Humans , Inflammation/drug therapy , Inflammation/metabolism , MAP Kinase Kinase 1/antagonists & inhibitors , MAP Kinase Kinase 1/metabolism , MAP Kinase Kinase 2/antagonists & inhibitors , MAP Kinase Kinase 2/metabolism , SARS-CoV-2/physiology , Vero Cells , Virus Replication/drug effects
4.
Nutrients ; 13(12)2021 Dec 16.
Article in English | MEDLINE | ID: covidwho-1580557

ABSTRACT

The excessive synthesis of interleukin-6 (IL-6) is related to cytokine storm in COVID-19 patients. Moreover, blocking IL-6 has been suggested as a treatment strategy for inflammatory diseases such as sepsis. Sepsis is a severe systemic inflammatory response syndrome with high mortality. In the present study, we investigated the anti-inflammatory and anti-septic effects and the underlying mechanisms of Dracocephalum moldavica ethanol extract (DMEE) on lipopolysaccharide (LPS)-induced inflammatory stimulation in RAW 264.7 macrophages along with septic mouse models. We found that DMEE suppressed the release of inflammatory mediators NO and PGE2 and inhibited both the mRNA and protein expression levels of iNOS and COX-2, respectively. In addition, DMEE reduced the release of proinflammatory cytokines, mainly IL-6 and IL-1ß, in RAW 264.7 cells by inhibiting the phosphorylation of JNK, ERK and p65. Furthermore, treatment with DMEE increased the survival rate and decreased the level of IL-6 in plasma in LPS-induced septic shock mice. Our findings suggest that DMEE elicits an anti-inflammatory effect in LPS-stimulated RAW 264.7 macrophages and an anti-septic effect on septic mouse model through the inhibition of the ERK/JNK/NF-κB signaling cascades and production of IL-6.


Subject(s)
Interleukin-6/metabolism , Lamiaceae/chemistry , Lipopolysaccharides/toxicity , MAP Kinase Signaling System/drug effects , Plant Extracts/pharmacology , Transcription Factor RelA/metabolism , Animals , Ethanol/chemistry , Extracellular Signal-Regulated MAP Kinases/metabolism , Inflammation/chemically induced , Inflammation/drug therapy , Inflammation/metabolism , MAP Kinase Kinase 4/metabolism , Male , Mice , Plant Extracts/chemistry , RAW 264.7 Cells
5.
Signal Transduct Target Ther ; 6(1): 347, 2021 09 25.
Article in English | MEDLINE | ID: covidwho-1437669

ABSTRACT

SARS-CoV-2 mutations contribute to increased viral transmissibility and immune escape, compromising the effectiveness of existing vaccines and neutralizing antibodies. An in-depth investigation on COVID-19 pathogenesis is urgently needed to develop a strategy against SARS-CoV-2 variants. Here, we identified CD147 as a universal receptor for SARS-CoV-2 and its variants. Meanwhile, Meplazeumab, a humanized anti-CD147 antibody, could block cellular entry of SARS-CoV-2 and its variants-alpha, beta, gamma, and delta, with inhibition rates of 68.7, 75.7, 52.1, 52.1, and 62.3% at 60 µg/ml, respectively. Furthermore, humanized CD147 transgenic mice were susceptible to SARS-CoV-2 and its two variants, alpha and beta. When infected, these mice developed exudative alveolar pneumonia, featured by immune responses involving alveoli-infiltrated macrophages, neutrophils, and lymphocytes and activation of IL-17 signaling pathway. Mechanistically, we proposed that severe COVID-19-related cytokine storm is induced by a "spike protein-CD147-CyPA signaling axis": Infection of SARS-CoV-2 through CD147 initiated the JAK-STAT pathway, which further induced expression of cyclophilin A (CyPA); CyPA reciprocally bound to CD147 and triggered MAPK pathway. Consequently, the MAPK pathway regulated the expression of cytokines and chemokines, which promoted the development of cytokine storm. Importantly, Meplazumab could effectively inhibit viral entry and inflammation caused by SARS-CoV-2 and its variants. Therefore, our findings provided a new perspective for severe COVID-19-related pathogenesis. Furthermore, the validated universal receptor for SARS-CoV-2 and its variants can be targeted for COVID-19 treatment.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Monoclonal, Humanized/pharmacology , Basigin/antagonists & inhibitors , Basigin/metabolism , COVID-19/drug therapy , COVID-19/metabolism , Cytokine Release Syndrome/drug therapy , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/genetics , Animals , Basigin/genetics , COVID-19/genetics , Chlorocebus aethiops , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/metabolism , Humans , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/genetics , Mice , Mice, Transgenic , SARS-CoV-2/genetics , Vero Cells
6.
IUBMB Life ; 74(1): 93-100, 2022 01.
Article in English | MEDLINE | ID: covidwho-1353459

ABSTRACT

Unfolded protein response (UPR) and endoplasmic reticulum (ER) stress are aspects of SARS-CoV-2-host cell interaction with proposed role in the cytopathic and inflammatory pathogenesis of this viral infection. The role of the NF-kB pathway in these cellular processes remains poorly characterized. When investigated in VERO-E6 cells, SARS-CoV-2 infection was found to markedly stimulate NF-kB protein expression and activity. NF-kB activation occurs early in the infection process (6 hpi) and it is associated with increased MAPK signaling and expression of the UPR inducer IRE-1α. These signal transduction processes characterize the cellular stress response to the virus promoting a pro-inflammatory environment and caspase activation in the host cell. Inhibition of viral replication by the viral protease inhibitor Nelfinavir reverts all these molecular changes also stimulating c-Jun expression, a key component of the JNK/AP-1 pathway with important role in the IRE-1α-mediated transcriptional regulation of stress response genes with anti-inflammatory and cytoprotection function. The present study demonstrates that UPR signaling and its interaction with cellular MAPKs and the NF-kB activity are important aspects of SARS-CoV-2-host cell interaction that deserve further investigation to identify more efficient therapies for this viral infection.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/metabolism , Endoplasmic Reticulum Stress/drug effects , NF-kappa B/metabolism , SARS-CoV-2 , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Animals , COVID-19/virology , Caspase 9/metabolism , Chlorocebus aethiops , Cytopathogenic Effect, Viral/drug effects , Humans , MAP Kinase Signaling System/drug effects , Models, Biological , Nelfinavir/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , Unfolded Protein Response/drug effects , Vero Cells
7.
Eur J Pharmacol ; 908: 174374, 2021 Oct 05.
Article in English | MEDLINE | ID: covidwho-1322083

ABSTRACT

The efficacy of corticosteroids and its use for the treatment of SARS-CoV-2 infections is controversial. In this study, using data sets of SARS-CoV-2 infected lung tissues and nasopharyngeal swabs, as well as in vitro experiments, we show that SARS-CoV-2 infection significantly downregulates DUSP1 expression. This downregulation of DUSP1 could be the mechanism regulating the enhanced activation of MAPK pathway as well as the reported steroid resistance in SARS-CoV-2 infection. Moreover, chloroquine, an off labeled COVID-19 drug is able to induce DUSP1 and attenuate MAPK pathway; and is expected to improve sensitivity to steroid treatment. However, further mechanistic studies are required to confirm this effect.


Subject(s)
COVID-19/drug therapy , Chloroquine/pharmacology , Dual Specificity Phosphatase 1/genetics , Glucocorticoids/pharmacology , p38 Mitogen-Activated Protein Kinases/metabolism , Adult , Aged , COVID-19/pathology , COVID-19/virology , Case-Control Studies , Cells, Cultured , Chloroquine/therapeutic use , Datasets as Topic , Down-Regulation/drug effects , Drug Resistance/drug effects , Drug Resistance/genetics , Drug Synergism , Dual Specificity Phosphatase 1/metabolism , Fibroblasts , Glucocorticoids/therapeutic use , Healthy Volunteers , Humans , Lung/cytology , Lung/pathology , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/genetics , Middle Aged , Nasopharynx/virology , Off-Label Use , Primary Cell Culture , SARS-CoV-2/isolation & purification , SARS-CoV-2/pathogenicity
8.
Biomed Pharmacother ; 141: 111835, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1271574

ABSTRACT

Thymic stromal lymphopoietin (TSLP) produced by mast cells is involved in allergic inflammation pathogenesis. Chloroquine (CQ) is known to be an anti-malarial drug; however, additional protective functions of CQ have been discovered. This study aims to clarify an anti-inflammatory effect of CQ through modulating TSLP levels using an in vitro model of phorbol myristate acetate (PMA) + A23187-activated human mast cell line (HMC-1) and an in vivo model of PMA-irritated ear edema. CQ treatment reduced the production and mRNA expression levels of TSLP in activated HMC-1 cells. CQ down-regulated caspase-1 (CASP1), MAPKs, and NF-κB levels enhanced by stimulation with PMA + A23187. Moreover, ear thickness in ear edema was suppressed following CQ treatment. CQ decreased CASP1 and NF-κB levels in the ear tissue. TSLP levels in the ear tissue and serum were reduced following CQ treatment. Collectively, the above findings elucidate that CQ inhibits the pro-inflammatory mechanisms of TSLP via the down-regulation of distinct intracellular signaling cascade in mast cells. Therefore, CQ may have protective roles against TSLP-mediated inflammatory disorders.


Subject(s)
Caspase 1/drug effects , Caspase Inhibitors/pharmacology , Chloroquine/pharmacology , Cytokines/biosynthesis , Mast Cells/drug effects , Signal Transduction/drug effects , Stromal Cells/metabolism , Thymus Gland/metabolism , Animals , Calcimycin/pharmacology , Cell Line , Ear Diseases/drug therapy , Edema/drug therapy , Humans , MAP Kinase Signaling System/drug effects , Male , Mice , Mice, Inbred ICR , NF-kappa B/drug effects , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Stromal Cells/drug effects , Tetradecanoylphorbol Acetate/pharmacology , Thymus Gland/drug effects
9.
Int J Mol Sci ; 22(11)2021 May 24.
Article in English | MEDLINE | ID: covidwho-1273453

ABSTRACT

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common and devastating clinical disorders with high mortality and no specific therapy. Lipopolysaccharide (LPS) is usually used intratracheally to induce ALI in mice. The aim of this study was to examine the effects of an ultramicronized preparation of palmitoylethanolamide (um-PEA) in mice subjected to LPS-induced ALI. Histopathological analysis reveals that um-PEA reduced alteration in lung after LPS intratracheal administration. Besides, um-PEA decreased wet/dry weight ratio and myeloperoxidase, a marker of neutrophils infiltration, macrophages and total immune cells number and mast cells degranulation in lung. Moreover, um-PEA could also decrease cytokines release of interleukin (IL)-6, interleukin (IL)-1ß, tumor necrosis factor (TNF)-α and interleukin (IL)-18. Furthermore, um-PEA significantly inhibited the phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation in ALI, and at the same time decreased extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38/MAPK) expression, that was increased after LPS administration. Our study suggested that um-PEA contrasted LPS-induced ALI, exerting its potential role as an adjuvant anti-inflammatory therapeutic for treating lung injury, maybe also by p38/NF-κB pathway.


Subject(s)
Acute Lung Injury/drug therapy , Amides/pharmacology , Cytokines/metabolism , Ethanolamines/pharmacology , MAP Kinase Signaling System/drug effects , Palmitic Acids/pharmacology , Acute Lung Injury/metabolism , Acute Lung Injury/pathology , Amides/therapeutic use , Animals , Ethanolamines/therapeutic use , Immunohistochemistry , Inflammation/metabolism , Interleukin-18/metabolism , Interleukin-1beta/metabolism , Interleukin-6/metabolism , JNK Mitogen-Activated Protein Kinases/metabolism , Lipopolysaccharides/administration & dosage , Lipopolysaccharides/toxicity , Macrophages/drug effects , Macrophages/immunology , Male , Mast Cells/drug effects , Mast Cells/pathology , Mice , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , NF-KappaB Inhibitor alpha/metabolism , NF-kappa B/metabolism , Neutrophils/drug effects , Neutrophils/immunology , Palmitic Acids/therapeutic use , Peroxidase/metabolism , Tumor Necrosis Factor-alpha/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism
10.
Sci Rep ; 11(1): 11234, 2021 05 27.
Article in English | MEDLINE | ID: covidwho-1246399

ABSTRACT

Understanding the molecular basis of fibrosis, the lethal complication of COVID-19, is urgent. By the analysis of RNA-sequencing data of SARS-CoV-2-infected cells combined with data mining we identified genes involved in COVID-19 progression. To characterize their implication in the fibrosis development we established a correlation matrix based on the transcriptomic data of patients with idiopathic pulmonary fibrosis. With this method, we have identified a cluster of genes responsible for SARS-CoV-2-fibrosis including its entry receptor ACE2 and epidermal growth factor EGF. Then, we developed Vi-Fi scoring-a novel drug repurposing approach and simultaneously quantified antiviral and antifibrotic activities of the drugs based on their transcriptomic signatures. We revealed the strong dual antifibrotic and antiviral activity of EGFR/ErbB inhibitors. Before the in vitro validation, we have clustered 277 cell lines and revealed distinct COVID-19 transcriptomic signatures of the cells with similar phenotypes that defines their suitability for COVID-19 research. By ERK activity monitoring in living lung cells, we show that the drugs with predicted antifibrotic activity downregulate ERK in the host lung cells. Overall, our study provides novel insights on SARS-CoV-2 dependence on EGFR/ERK signaling and demonstrates the utility of EGFR/ErbB inhibitors for COVID-19 treatment.


Subject(s)
COVID-19/metabolism , Cytokines/metabolism , Fibrosis/metabolism , MAP Kinase Signaling System/drug effects , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacology , COVID-19/complications , COVID-19/drug therapy , COVID-19/genetics , COVID-19/physiopathology , Cell Line, Tumor , Cytokines/genetics , Disease Progression , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , Fibrosis/complications , Fibrosis/genetics , Fibrosis/virology , Gene Expression Profiling , Humans , Inflammation/genetics , Inflammation/metabolism , Multigene Family , RNA-Seq
11.
J Clin Invest ; 131(6)2021 03 15.
Article in English | MEDLINE | ID: covidwho-1172783

ABSTRACT

Monocyte homing to the liver and adhesion to the liver sinusoidal endothelial cells (LSECs) are key elements in nonalcoholic steatohepatitis (NASH) pathogenesis. We reported previously that VCAM-1 mediates monocyte adhesion to LSECs. However, the pathogenic role of VCAM-1 in NASH is unclear. Herein, we report that VCAM-1 was a top upregulated adhesion molecule in the NASH mouse liver transcriptome. Open chromatin landscape profiling combined with genome-wide transcriptome analysis showed robust transcriptional upregulation of LSEC VCAM-1 in murine NASH. Moreover, LSEC VCAM-1 expression was significantly increased in human NASH. LSEC VCAM-1 expression was upregulated by palmitate treatment in vitro and reduced with inhibition of the mitogen-activated protein 3 kinase (MAP3K) mixed lineage kinase 3 (MLK3). Likewise, LSEC VCAM-1 expression was reduced in the Mlk3-/- mice with diet-induced NASH. Furthermore, VCAM-1 neutralizing Ab or pharmacological inhibition attenuated diet-induced NASH in mice, mainly via reducing the proinflammatory monocyte hepatic population as examined by mass cytometry by time of flight (CyTOF). Moreover, endothelium-specific Vcam1 knockout mice were also protected against NASH. In summary, lipotoxic stress enhances the expression of LSEC VCAM-1, in part, through MLK3 signaling. Inhibition of VCAM-1 was salutary in murine NASH and might serve as a potential therapeutic strategy for human NASH.


Subject(s)
Non-alcoholic Fatty Liver Disease/etiology , Vascular Cell Adhesion Molecule-1/metabolism , Animals , Antibodies, Neutralizing/administration & dosage , Disease Models, Animal , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Gene Expression Profiling , Humans , Liver/drug effects , Liver/metabolism , Liver/pathology , MAP Kinase Signaling System/drug effects , Mice , Mice, Inbred C57BL , Mice, Knockout , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/metabolism , Palmitates/toxicity , RNA, Messenger/genetics , Up-Regulation/drug effects , Vascular Cell Adhesion Molecule-1/antagonists & inhibitors , Vascular Cell Adhesion Molecule-1/genetics
12.
Cell Rep ; 35(1): 108940, 2021 04 06.
Article in English | MEDLINE | ID: covidwho-1157178

ABSTRACT

SARS-CoV-2 has currently precipitated the COVID-19 global health crisis. We developed a medium-throughput drug-screening system and identified a small-molecule library of 34 of 430 protein kinase inhibitors that were capable of inhibiting the SARS-CoV-2 cytopathic effect in human epithelial cells. These drug inhibitors are in various stages of clinical trials. We detected key proteins involved in cellular signaling pathways mTOR-PI3K-AKT, ABL-BCR/MAPK, and DNA-damage response that are critical for SARS-CoV-2 infection. A drug-protein interaction-based secondary screen confirmed compounds, such as the ATR kinase inhibitor berzosertib and torin2 with anti-SARS-CoV-2 activity. Berzosertib exhibited potent antiviral activity against SARS-CoV-2 in multiple cell types and blocked replication at the post-entry step. Berzosertib inhibited replication of SARS-CoV-1 and the Middle East respiratory syndrome coronavirus (MERS-CoV) as well. Our study highlights key promising kinase inhibitors to constrain coronavirus replication as a host-directed therapy in the treatment of COVID-19 and beyond as well as provides an important mechanism of host-pathogen interactions.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , DNA Damage , Isoxazoles/pharmacology , Pyrazines/pharmacology , SARS-CoV-2/physiology , Virus Replication/drug effects , A549 Cells , Animals , COVID-19/metabolism , COVID-19/pathology , Chlorocebus aethiops , Drug Evaluation, Preclinical , HEK293 Cells , HeLa Cells , Humans , MAP Kinase Signaling System/drug effects , Middle East Respiratory Syndrome Coronavirus/metabolism , Vero Cells
14.
Biomed Res Int ; 2020: 8827752, 2020.
Article in English | MEDLINE | ID: covidwho-1021158

ABSTRACT

The mitogen-activated protein kinase (MAPK) pathway links the cell-surface receptors to the transcription machinery, transducing the extracellular signals into several outputs, which may also adapt the host defense mechanism to viral attacks. The Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) that causes the COrona VIrus Disease 2019 (COVID-19) has infected upwards of nearly 70 million people and worldwide has claimed more than 1,600,000 deaths. So far, there continues to be no specific treatment for this novel coronavirus-induced disease. In the search to control the global COVID-19 pandemic, some eastern and developing countries have approved a variety of treatments with controversial efficacy, among which is the use of the antimalarial hydroxychloroquine (HCQ). Interestingly, prior data had indicated that the HCQ/CQ could influence the MAPK cascade. The main aim of this review is to address molecular mechanisms, beyond drugs, that can be helpful against viral infection for this and future pandemics. We will highlight (1) the contribution of the MAPK cascade in viral infection and (2) the possible use of MAPK inhibitors in curbing viral infections, alone or in combination with HCQ and quinoline analogues. We are convinced that understanding the molecular patterns of viral infections will be critical for new therapeutical approaches to control this and other severe diseases.


Subject(s)
COVID-19/drug therapy , Enzyme Inhibitors/therapeutic use , Hydroxychloroquine/therapeutic use , MAP Kinase Signaling System/genetics , Pandemics , SARS-CoV-2/drug effects , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19/virology , Humans , Hydroxychloroquine/analogs & derivatives , MAP Kinase Signaling System/drug effects
15.
Cytokine Growth Factor Rev ; 59: 101-110, 2021 06.
Article in English | MEDLINE | ID: covidwho-1014439

ABSTRACT

GM-CSF acts as a pro-inflammatory cytokine and a key growth factor produced by several immune cells such as macrophages and activated T cells. In this review, we discuss recent studies that point to the crucial role of GM-CSF in the immune response against infections. Upon induction, GM-CSF activates four main signalling networks including the JAK/STAT, PI3K, MAPK, and NFκB pathways. Many of these transduction pathways such as JAK/STAT signal via proteins commonly activated with other antiviral signalling cascades, such as those induced by IFNs. GM-CSF also helps defend against respiratory infections by regulating alveolar macrophage differentiation and enhancing innate immunity in the lungs. Here, we also summarize the numerous clinical trials that have taken advantage of GM-CSF's mechanistic attributes in immunotherapy. Moreover, we discuss how GM-CSF is used as an adjuvant in vaccines and how its activity is interfered with to reduce inflammation such as in the case of COVID-19. This review brings forth the current knowledge on the antiviral actions of GM-CSF, the associated signalling cascades, and its application in immunotherapy.


Subject(s)
Adjuvants, Immunologic/therapeutic use , Antiviral Agents , COVID-19 Vaccines/immunology , COVID-19/immunology , Granulocyte-Macrophage Colony-Stimulating Factor , MAP Kinase Signaling System , SARS-CoV-2/immunology , Animals , Antiviral Agents/immunology , Antiviral Agents/therapeutic use , COVID-19/prevention & control , COVID-19 Vaccines/therapeutic use , Granulocyte-Macrophage Colony-Stimulating Factor/immunology , Granulocyte-Macrophage Colony-Stimulating Factor/therapeutic use , Humans , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/immunology , Macrophages, Alveolar/immunology , Recombinant Proteins/immunology , Recombinant Proteins/therapeutic use
16.
Theranostics ; 10(26): 12223-12240, 2020.
Article in English | MEDLINE | ID: covidwho-934619

ABSTRACT

Rationale: Many viral infections are known to activate the p38 mitogen-activated protein kinase (MAPK) signaling pathway. However, the role of p38 activation in viral infection and the underlying mechanism remain unclear. The role of virus-hijacked p38 MAPK activation in viral infection was investigated in this study. Methods: The correlation of hepatitis C virus (HCV) infection and p38 activation was studied in patient tissues and primary human hepatocytes (PHHs) by immunohistochemistry and western blotting. Coimmunoprecipitation, GST pulldown and confocal microscopy were used to investigate the interaction of p38α and the HCV core protein. In vitro kinase assays and mass spectrometry were used to analyze the phosphorylation of the HCV core protein. Plaque assays, quantitative real time PCR (qRT-PCR), western blotting, siRNA and CRISPR/Cas9 were used to determine the effect of p38 activation on viral replication. Results: HCV infection was associated with p38 activation in clinical samples. HCV infection increased p38 phosphorylation by triggering the interaction of p38α and TGF-ß activated kinase 1 (MAP3K7) binding protein 1 (TAB1). TAB1-mediated p38α activation facilitated HCV replication, and pharmaceutical inhibition of p38α activation by SB203580 suppressed HCV infection at the viral assembly step. Activated p38α interacted with the N-terminal region of the HCV core protein and subsequently phosphorylated the HCV core protein, which promoted HCV core protein oligomerization, an essential step for viral assembly. As expected, SB203580 or the HCV core protein N-terminal peptide (CN-peptide) disrupted the p38α-HCV core protein interaction, efficiently impaired HCV assembly and impeded normal HCV replication in both cultured cells and primary human hepatocytes. Similarly, severe fever with thrombocytopenia syndrome virus (SFTSV), herpes simplex virus type 1 (HSV-1) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection also activated p38 MAPK. Most importantly, pharmacological blockage of p38 activation by SB203580 effectively inhibited SFTSV, HSV-1 and SARS-CoV-2. Conclusion: Our study shows that virus-hijacked p38 activation is a key event for viral replication and that pharmacological blockage of p38 activation is an antiviral strategy.


Subject(s)
COVID-19/metabolism , Hepacivirus/metabolism , Hepatitis C/metabolism , Mitogen-Activated Protein Kinase 14/metabolism , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , A549 Cells , Adaptor Proteins, Signal Transducing/metabolism , Animals , COVID-19/virology , Chlorocebus aethiops , Enzyme Activation , HEK293 Cells , Hepatitis C/pathology , Hepatitis C/virology , Hepatocytes/metabolism , Humans , Imidazoles/pharmacology , MAP Kinase Kinase Kinases/metabolism , MAP Kinase Signaling System/drug effects , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Phosphorylation , Pyridines/pharmacology , Vero Cells , Viral Core Proteins/metabolism , Virus Replication/drug effects
17.
Pharmacol Ther ; 221: 107745, 2021 05.
Article in English | MEDLINE | ID: covidwho-922109

ABSTRACT

While COVID-19, the disease driven by SARS-CoV-2 has ignited interest in the host immune response to this infection, it has also highlighted the lack of treatment options for the damaging inflammatory responses driven by pathogens that precipitate the acute respiratory distress syndrome (ARDS). With the global prevalence of SARS-CoV-2 and the likelihood of a second winter spike alongside seasonal flu, the need for effective and targeted anti-inflammatory agents is even more pressing. Here we discuss the aetiology of COVID-19 and the common signalling pathways driven by SARS-CoV-2, namely p38 MAP kinase. We highlight that p38 MAP kinase becomes elevated with increasing age, thereby driving many of the inflammatory pathways that precipitate death in old people with the added drawback of impairing vaccine efficacy in this susceptible age group. Finally, we review drugs available to inhibit p38 MAP kinase, their risks-versus-benefits as well as suggested dosing regimen to combat over-exuberant innate immune responses and potentially reverse vaccine inefficacy in older patients.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/drug therapy , MAP Kinase Signaling System/drug effects , Pneumonia/drug therapy , Protein Kinase Inhibitors/therapeutic use , Respiratory Distress Syndrome/drug therapy , Anti-Inflammatory Agents/pharmacology , COVID-19/epidemiology , COVID-19/immunology , Clinical Trials as Topic/methods , Humans , Immunity, Innate/drug effects , Immunity, Innate/immunology , MAP Kinase Signaling System/physiology , Pneumonia/epidemiology , Pneumonia/immunology , Protein Kinase Inhibitors/pharmacology , Respiratory Distress Syndrome/epidemiology , Respiratory Distress Syndrome/immunology
18.
Comb Chem High Throughput Screen ; 24(9): 1377-1394, 2021.
Article in English | MEDLINE | ID: covidwho-902235

ABSTRACT

OBJECTIVE: Shufeng Jiedu capsule (SFJDC) is a well-known Chinese patent drug that is recommended as a basic prescription and applied widely in the clinical treatment of COVID-19. However, the exact molecular mechanism of SFJDC remains unclear. The present study aims to determine the potential pharmacological mechanisms of SFJDC in the treatment of COVID-19 based on network pharmacology. METHODS: The network pharmacology-based strategy includes collection and analysis of active compounds and target genes, network construction, identification of key compounds and hub target genes, KEGG and GO enrichment, recognition and analysis of main modules, as well as molecule docking. RESULTS: A total of 214 active chemical compounds and 339 target genes of SFJDC were collected. Of note, 5 key compounds (ß -sitosterol, luteolin, kaempferol, quercetin, and stigmasterol) and 10 hub target genes (TP53, AKT1, NCOA1, EGFR, PRKCA, ANXA1, CTNNB1, NCOA2, RELA and FOS) were identified based on network analysis. The hub target genes mainly enriched in pathways including MAPK signaling pathway, PI3K-Akt signaling pathway and cAMP signaling pathway, which could be the underlying pharmacological mechanisms of SFJDC for treating COVID-19. Moreover, the key compounds had high binding activity with three typical target proteins including ACE2, 2OFZ, and 1SSK. CONCLUSION: By network pharmacology analysis, SFJDC was found to effectively improve immune function and reduce inflammatory responses based on its key compounds, hub target genes, and the relevant pathways. These findings may provide valuable evidence for explaining how SFJDC exerting the therapeutic effects on COVID-19, providing a holistic view for further clinical application.


Subject(s)
COVID-19/drug therapy , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use , Adjuvants, Immunologic/pharmacology , Adjuvants, Immunologic/therapeutic use , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Computer Simulation , Gene Regulatory Networks/drug effects , Gene Targeting , Humans , MAP Kinase Signaling System/drug effects , Medicine, Chinese Traditional , Molecular Docking Simulation , Protein Binding , SARS-CoV-2/chemistry , SARS-CoV-2/drug effects , Signal Transduction/drug effects
19.
Antiviral Res ; 173: 104651, 2020 01.
Article in English | MEDLINE | ID: covidwho-824493

ABSTRACT

Emerging coronaviruses (CoVs) primarily cause severe gastroenteric or respiratory diseases in humans and animals, and no approved therapeutics are currently available. Here, A9, a receptor tyrosine kinase inhibitor (RTKI) of the tyrphostin class, is identified as a robust inhibitor of transmissible gastroenteritis virus (TGEV) infection in cell-based assays. Moreover, A9 exhibited potent antiviral activity against the replication of various CoVs, including murine hepatitis virus (MHV), porcine epidemic diarrhea virus (PEDV) and feline infectious peritonitis virus (FIPV). We further performed a comparative phosphoproteomic analysis to investigate the mechanism of action of A9 against TGEV infection in vitro. We specifically identified p38 and JNK1, which are the downstream molecules of receptor tyrosine kinases (RTKs) required for efficient TGEV replication, as A9 targets through plaque assays, qRT-PCR and Western blotting assays. p38 and JNK1 inhibitors and RNA interference further showed that the inhibitory activity of A9 against TGEV infection was mainly mediated by the p38 mitogen-activated protein kinase (MAPK) signaling pathway. All these findings indicated that the RTKI A9 directly inhibits TGEV replication and that its inhibitory activity against TGEV replication mainly occurs by targeting p38, which provides vital clues to the design of novel drugs against CoVs.


Subject(s)
Antiviral Agents/pharmacology , Host-Pathogen Interactions , MAP Kinase Signaling System/drug effects , Protein Kinase Inhibitors/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Transmissible gastroenteritis virus/drug effects , Virus Replication/drug effects , Animals , Antiviral Agents/chemistry , Cats , Cell Line , Cells, Cultured , Chlorocebus aethiops , Chromatography, Liquid , Gastroenteritis, Transmissible, of Swine/drug therapy , Gastroenteritis, Transmissible, of Swine/metabolism , Gastroenteritis, Transmissible, of Swine/virology , High-Throughput Screening Assays , Life Cycle Stages , Phosphoproteins/metabolism , Protein Kinase Inhibitors/chemistry , Proteomics/methods , Small Molecule Libraries , Swine , Tandem Mass Spectrometry , Vero Cells
20.
Med Hypotheses ; 144: 109957, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-548595

ABSTRACT

SARS-CoV-2 or COVID-19 is representing the major global burden that implicated more than 4.7 million infected cases and 310 thousand deaths worldwide in less than 6 months. The prevalence of this pandemic disease is expected to rise every day. The challenge is to control its rapid spread meanwhile looking for a specific treatment to improve patient outcomes. Hesperidin is a classical herbal medicine used worldwide for a long time with an excellent safety profile. Hesperidin is a well-known herbal medication used as an antioxidant and anti-inflammatory agent. Available shreds of evidence support the promising use of hesperidin in prophylaxis and treatment of COVID 19. Herein, we discuss the possible prophylactic and treatment mechanisms of hesperidin based on previous and recent findings. Hesperidin can block coronavirus from entering host cells through ACE2 receptors which can prevent the infection. Anti-viral activity of hesperidin might constitute a treatment option for COVID-19 through improving host cellular immunity against infection and its good anti-inflammatory activity may help in controlling cytokine storm. Hesperidin mixture with diosmin co-administrated with heparin protect against venous thromboembolism which may prevent disease progression. Based on that, hesperidin might be used as a meaningful prophylactic agent and a promising adjuvant treatment option against SARS-CoV-2 infection.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/prevention & control , Hesperidin/therapeutic use , Pandemics/prevention & control , Phytotherapy , SARS-CoV-2/drug effects , Virus Internalization/drug effects , Angiotensin-Converting Enzyme 2/drug effects , Anticoagulants/administration & dosage , Anticoagulants/therapeutic use , COVID-19/complications , COVID-19/epidemiology , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/prevention & control , Diosmin/administration & dosage , Diosmin/therapeutic use , Drug Therapy, Combination , Heparin/administration & dosage , Heparin/therapeutic use , Hesperidin/administration & dosage , Hesperidin/pharmacology , Humans , MAP Kinase Signaling System/drug effects , Receptors, Virus/drug effects , Venous Thromboembolism/etiology , Venous Thromboembolism/prevention & control
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