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1.
Front Endocrinol (Lausanne) ; 12: 714909, 2021.
Article in English | MEDLINE | ID: covidwho-1497067

ABSTRACT

Background: Clinically, evidence shows that uterine corpus endometrial carcinoma (UCEC) patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may have a higher death-rate. However, current anti-UCEC/coronavirus disease 2019 (COVID-19) treatment is lacking. Plumbagin (PLB), a pharmacologically active alkaloid, is an emerging anti-cancer inhibitor. Accordingly, the current report was designed to identify and characterize the anti-UCEC function and mechanism of PLB in the treatment of patients infected with SARS-CoV-2 via integrated in silico analysis. Methods: The clinical analyses of UCEC and COVID-19 in patients were conducted using online-accessible tools. Meanwhile, in silico methods including network pharmacology and biological molecular docking aimed to screen and characterize the anti-UCEC/COVID-19 functions, bio targets, and mechanisms of the action of PLB. Results: The bioinformatics data uncovered the clinical characteristics of UCEC patients infected with SARS-CoV-2, including specific genes, health risk, survival rate, and prognostic index. Network pharmacology findings disclosed that PLB-exerted anti-UCEC/COVID-19 effects were achieved through anti-proliferation, inducing cytotoxicity and apoptosis, anti-inflammation, immunomodulation, and modulation of some of the key molecular pathways associated with anti-inflammatory and immunomodulating actions. Following molecular docking analysis, in silico investigation helped identify the anti-UCEC/COVID-19 pharmacological bio targets of PLB, including mitogen-activated protein kinase 3 (MAPK3), tumor necrosis factor (TNF), and urokinase-type plasminogen activator (PLAU). Conclusions: Based on the present bioinformatic and in silico findings, the clinical characterization of UCEC/COVID-19 patients was revealed. The candidate, core bio targets, and molecular pathways of PLB action in the potential treatment of UCEC/COVID-19 were identified accordingly.


Subject(s)
COVID-19 , Carcinoma, Endometrioid , Endometrial Neoplasms , Host-Pathogen Interactions , Naphthoquinones/pharmacology , Adult , Aged , Aged, 80 and over , COVID-19/complications , COVID-19/diagnosis , COVID-19/drug therapy , COVID-19/genetics , Calcium-Binding Proteins/drug effects , Calcium-Binding Proteins/metabolism , Carcinoma, Endometrioid/complications , Carcinoma, Endometrioid/diagnosis , Carcinoma, Endometrioid/drug therapy , Carcinoma, Endometrioid/genetics , Computational Biology , Drug Screening Assays, Antitumor/methods , Endometrial Neoplasms/complications , Endometrial Neoplasms/diagnosis , Endometrial Neoplasms/drug therapy , Endometrial Neoplasms/genetics , Female , Gene Expression Regulation, Neoplastic/drug effects , Gene Regulatory Networks/drug effects , Genetic Association Studies , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Humans , Membrane Proteins/drug effects , Membrane Proteins/metabolism , Middle Aged , Mitogen-Activated Protein Kinase 3/drug effects , Mitogen-Activated Protein Kinase 3/metabolism , Molecular Docking Simulation/methods , Naphthoquinones/therapeutic use , Prognosis , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Signal Transduction/drug effects , Signal Transduction/genetics , Tumor Necrosis Factor-alpha/drug effects , Tumor Necrosis Factor-alpha/metabolism , Uterus/drug effects , Uterus/metabolism , Uterus/pathology , Uterus/virology
2.
Biomed Pharmacother ; 137: 111419, 2021 May.
Article in English | MEDLINE | ID: covidwho-1392160

ABSTRACT

BACKGROUND: Atherosclerosis, inflammatory disease, is a major reason for cardiovascular diseases and stroke. Kaempferol (Kae) has been well-documented to have pharmacological activities in the previous studies. However, the detailed mechanisms by which Kae regulates inflammation, oxidative stress, and apoptosis in Human Umbilical Vein Endothelial Cells (HUVECs) remain unknown. METHODS AND RESULTS: The real-time quantitative polymerase chain reaction (RT-qPCR) was used to measure expression levels of circNOL12, nucleolar protein 12 (NOL12), miR-6873-3p, and Fibroblast growth factor receptor substrate 2 (FRS2) in HUVECs treated with either oxidized low-density lipoprotein (ox-LDL) alone or in combination with Kae. The cells viability was assessed by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-2H-tetrazol-3-ium bromide (MTT) assay. The inflammation and oxidative stress were assessed by checking inflammatory factors, Reactive Oxygen Species (ROS), Superoxide Dismutase (SOD), and Malondialdehyde (MDA) levels in ox-LDL-induced HUVECs. The apoptotic cells were quantified by flow cytometry assay. The western blot assay was used for measuring protein expression. The interaction relationship between miR-6873-3p and circNOL12 or FRS2 was analyzed by dual-luciferase reporter and RNA pull-down assays. Treatment with Kae could inhibit ox-LDL-induced the upregulation of circNOL12 in HUVECs. Importantly, Kae weakened ox-LDL-induced inflammation, oxidative stress, and apoptosis in HUVECs, which was abolished by overexpression of circNOL12. What's more, miR-6873-3p was a target of circNOL12 in HUVECs, and the upregulation of miR-6873-3p overturned circNOL12 overexpression-induced effects on HUVECs treated with ox-LDL and Kae. FRS2 was negatively regulated by miR-6873-3p in HUVECs. CONCLUSION: Kae alleviated ox-LDL-induced inflammation, oxidative stress, and apoptosis in HUVECs by regulating circNOL12/miR-6873-3p/FRS2 axis.


Subject(s)
Adaptor Proteins, Signal Transducing/drug effects , Endothelial Cells/drug effects , Kaempferols/pharmacology , Membrane Proteins/drug effects , MicroRNAs/drug effects , Nuclear Proteins/drug effects , RNA-Binding Proteins/drug effects , Signal Transduction/drug effects , Anti-Inflammatory Agents/pharmacology , Antioxidants/pharmacology , Apoptosis/drug effects , Female , Human Umbilical Vein Endothelial Cells , Humans , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolism
3.
Eur J Pharm Sci ; 160: 105771, 2021 May 01.
Article in English | MEDLINE | ID: covidwho-1091850

ABSTRACT

AIMS: Cell surface binding immunoglobin protein (csBiP) is predicted to be susceptible to SARS-CoV-2 binding. With a substrate-binding domain (SBD) that binds to polypeptides and a nucleotide-binding domain (NBD) that can initiate extrinsic caspase-dependent apoptosis, csBiP may be a promising therapeutic target for COVID-19. This study aims to identify FDA-approved drugs that can neutralize viral binding and prevent viral replication by targeting the functional domains of csBiP. METHODS: In silico screening of 1999 FDA-approved drugs against the functional domains of BiP were performed using three molecular docking programs to avoid bias from individual docking programs. Top ligands were selected by averaging the ligand rankings from three programs. Interactions between top ligands and functional domains of BiP were analyzed. KEY FINDINGS: The top 10 SBD-binding candidates are velpatasvir, irinotecan, netupitant, lapatinib, doramectin, conivaptan, fenoverine, duvelisib, irbesartan, and pazopanib. The top 10 NBD-binding candidates are nilotinib, eltrombopag, grapiprant, topotecan, acetohexamide, vemurafenib, paritaprevir, pixantrone, azosemide, and piperaquine-phosphate. Among them, Velpatasvir and paritaprevir are antiviral agents that target the protease of hepatitis C virus. Netupitant is an anti-inflammatory drug that inhibits neurokinin-1 receptor, which contributes to acute inflammation. Grapiprant is an anti-inflammatory drug that inhibits the prostaglandin E2 receptor protein subtype 4, which is expressed on immune cells and triggers inflammation. These predicted SBD-binding drugs could disrupt SARS-CoV-2 binding to csBiP, and NBD-binding drugs may falter viral attachment and replication by locking the SBD in closed conformation and triggering apoptosis in infected cells. SIGNIFICANCE: csBiP appears to be a novel therapeutic target against COVID-19 by preventing viral attachment and replication. These identified drugs could be repurposed to treat COVID-19 patients.


Subject(s)
Antiviral Agents/pharmacology , Membrane Proteins/drug effects , SARS-CoV-2/physiology , Virus Attachment/drug effects , Antiviral Agents/chemistry , Drug Repositioning , Immunoglobulins/drug effects , Models, Molecular , Molecular Structure , Protein Conformation , SARS-CoV-2/drug effects , Structure-Activity Relationship , Virus Internalization
4.
Nature ; 589(7843): 630-632, 2021 01.
Article in English | MEDLINE | ID: covidwho-1049956
5.
Biochimie ; 177: 50-52, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-713261

ABSTRACT

Various interferon (IFN)-inducible transmembrane (IFITM) proteins are known to be expressed in human tissues though only IFITM 1-3 are inducible by IFN. Numerous studies have shown that activation of IFITM3 could suppress infection by influenza and coronaviruses such as the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). In view of the potential application of IFITM proteins' induction to target SARS-CoV-2 infection that causes COVID-19, this article layout insights into the known antiviral mechanisms and therapeutic agents related to IFITM. Blocking viral entry through various mechanisms and the potential application of the FDA approved immunosuppressant agent, mycophenolic acid, as inducer of IFITM3 are among those discussed.


Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Interferons/pharmacology , Membrane Proteins/drug effects , Mycophenolic Acid/pharmacology , Pneumonia, Viral/drug therapy , RNA-Binding Proteins/drug effects , Animals , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/metabolism , Humans , Immunosuppressive Agents/pharmacology , Membrane Proteins/immunology , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/metabolism , RNA-Binding Proteins/immunology , SARS-CoV-2
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