A Computational Approach Identified Andrographolide as a Potential Drug for Suppressing COVID-19-Induced Cytokine Storm

Rehan et al., Frontiers in Immunology, doi:10.3389/fimmu.2021.648250

Jun 2021

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In Silico study showing that andrographolide, a compound from Andrographis paniculata, may reduce cytokine storm in COVID-19 by targeting the TNF signaling pathway. Authors found that andrographolide binds to TNF and NFkB1 proteins, potentially blocking the pathway responsible for elevated inflammatory cytokines in severe COVID-19. Molecular docking analysis showed andrographolide formed a covalent bond with Cys-62 of NFkB1 and hydrogen bonds with the TNF homodimer. The compound had suitable drug-like properties, suggesting it could be a promising therapeutic candidate to combat cytokine storm and severe disease.

22 preclinical studies support the efficacy of andrographolide for COVID-19:

12 In Silico studies1-12

8 In Vitro studies1,13-19

2 In Vivo animal studies16,19

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1. Zhang et al., Effects and Mechanisms of Andrographolide for COVID-19: A Network Pharmacology-Based and Experimentally Validated Study, Natural Product Communications, doi:10.1177/1934578X241288428.sagepub.com, doi.org.

2. Thomas et al., Cheminformatics approach to identify andrographolide derivatives as dual inhibitors of methyltransferases (nsp14 and nsp16) of SARS-CoV-2, Scientific Reports, doi:10.1038/s41598-024-58532-7.nature.com, doi.org.

3. Bhattarai et al., Investigating the binding affinity of andrographolide against human SARS-CoV-2 spike receptor-binding domain through docking and molecular dynamics simulations, Journal of Biomolecular Structure and Dynamics, doi:10.1080/07391102.2023.2174596.tandfonline.com, doi.org.

4. Nguyen et al., The Potential of Ameliorating COVID-19 and Sequelae From Andrographis paniculata via Bioinformatics, Bioinformatics and Biology Insights, doi:10.1177/11779322221149622.sagepub.com, doi.org.

5. Dassanayake et al., Molecular Docking and In-Silico Analysis of Natural Biomolecules against Dengue, Ebola, Zika, SARS-CoV-2 Variants of Concern and Monkeypox Virus, International Journal of Molecular Sciences, doi:10.3390/ijms231911131.mdpi.com, doi.org.

6. Ningrum et al., Potency Of Andrographolide, L-Mimosine And Asiaticoside Compound As Antiviral For Covid-19 Based On In Silico Method, Proceedings Universitas Muhammadiyah Yogyakarta Undergraduate Conference, doi:10.18196/umygrace.v2i2.418.ac.id, doi.org.

7. Ravichandran et al., Identification of Potential Semisynthetic Andrographolide Derivatives to Combat COVID-19 by Targeting the SARS-COV-2 Spike Protein and Human ACE2 Receptor– An In-silico Approach, Biointerface Research in Applied Chemistry, doi:10.33263/BRIAC132.155.biointerfaceresearch.com, doi.org.

8. Saeheng et al., In Silico Prediction of Andrographolide Dosage Regimens for COVID-19 Treatment, The American Journal of Chinese Medicine, doi:10.1142/S0192415X22500732.worldscientific.com, doi.org.

9. Khanal et al., Combination of system biology to probe the anti-viral activity of andrographolide and its derivative against COVID-19, RSC Advances, doi:10.1039/D0RA10529E.rsc.org, doi.org.

10. Rehan et al., A Computational Approach Identified Andrographolide as a Potential Drug for Suppressing COVID-19-Induced Cytokine Storm, Frontiers in Immunology, doi:10.3389/fimmu.2021.648250.frontiersin.org, doi.org.

11. Rajagopal et al., Activity of phytochemical constituents of Curcuma longa (turmeric) and Andrographis paniculata against coronavirus (COVID-19): an in silico approach, Future Journal of Pharmaceutical Sciences, doi:10.1186/s43094-020-00126-x.springeropen.com, doi.org.

12. Dey et al., The role of andrographolide and its derivative in COVID-19 associated proteins and immune system, Research Square, doi:10.21203/rs.3.rs-35800/v1.researchsquare.com, doi.org.

13. Chaopreecha et al., Proteomic Analysis Identifies the Glutathione Synthesizing Enzyme Gclc as an Andrographolide Target and a Protective Factor Against Sars-Cov-2 Infection, Elsevier BV, doi:10.2139/ssrn.4876852.ssrn.com, doi.org.

14. Li et al., Andrographolide suppresses SARS-CoV-2 infection by downregulating ACE2 expression: A mechanistic study, Antiviral Therapy, doi:10.1177/13596535241259952.sagepub.com, doi.org.

15. Low et al., The wide spectrum anti-inflammatory activity of andrographolide in comparison to NSAIDs: a promising therapeutic compound against the cytokine storm, bioRxiv, doi:10.1101/2024.02.21.581396.biorxiv.org, doi.org.

16. Wan et al., Synergistic inhibition effects of andrographolide and baicalin on coronavirus mechanisms by downregulation of ACE2 protein level, Scientific Reports, doi:10.1038/s41598-024-54722-5.nature.com, doi.org.

17. Siridechakorn et al., Inhibitory efficiency of Andrographis paniculata extract on viral multiplication and nitric oxide production, Scientific Reports, doi:10.1038/s41598-023-46249-y.nature.com, doi.org.

18. Mohd Abd Razak et al., In Vitro Anti-SARS-CoV-2 Activities of Curcumin and Selected Phenolic Compounds, Natural Product Communications, doi:10.1177/1934578X231188861.sagepub.com, doi.org.

19. Pu et al., The effects and mechanisms of the anti-COVID-19 traditional Chinese medicine, Dehydroandrographolide from Andrographis paniculata (Burm.f.) Wall, on acute lung injury by the inhibition of NLRP3-mediated pyroptosis, Phytomedicine, doi:10.1016/j.phymed.2023.154753.sciencedirect.com, doi.org.

Rehan et al., 24 Jun 2021, Saudi Arabia, peer-reviewed, 8 authors. Contact: mrehan786@gmail.com, fahmed1@uj.edu.sa.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

This Paper Andrographol..All

A Computational Approach Identified Andrographolide as a Potential Drug for Suppressing COVID-19-Induced Cytokine Storm

Mohd Rehan, Firoz Ahmed, Saad M Howladar, Mohammed Y Refai, Hanadi M Baeissa, Torki A Zughaibi, Khalid Mohammed Kedwa, Mohammad Sarwar Jamal

Frontiers in Immunology, doi:10.3389/fimmu.2021.648250

Background: The newly identified betacoronavirus SARS-CoV-2 is the causative pathogen of the coronavirus disease of 2019 that killed more than 3.5 million people till now. The cytokine storm induced in severe COVID-19 patients causes hyper-inflammation, is the primary reason for respiratory and multi-organ failure and fatality. This work uses a rational computational strategy to identify the existing drug molecules to target host pathways to reduce the cytokine storm. Results: We used a "host response signature network" consist of 36 genes induced by SARS-CoV-2 infection and associated with cytokine storm. In order to attenuate the cytokine storm, potential drug molecules were searched against "host response signature network". Our study identified that drug molecule andrographolide, naturally present in a medicinal plant Andrographis paniculata, has the potential to bind with crucial proteins to block the TNF-induced NFkB1 signaling pathway responsible for cytokine storm in COVID-19 patients. The molecular docking method showed the binding of andrographolide with TNF and covalent binding with NFkB1 proteins of the TNF signaling pathway. Conclusion: We used a rational computational approach to repurpose existing drugs targeting host immunomodulating pathways. Our study suggests that andrographolide could bind with TNF and NFkB1 proteins, block TNF-induced cytokine storm in COVID-19 patients, and warrant further experimental validation.

AUTHOR CONTRIBUTIONS FA conceived the idea, generated the data, analyzed and interpreted the results, wrote and revised the manuscript, and designed and guided the project. MR improved the idea, The interacting residues of both chains (A and B) are listed with a number of interactions (hydrogen bonds and non-bonded contacts). SUPPLEMENTARY MATERIAL The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2021. 648250/full#supplementary-material Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

Ahmed, A Network-Based Analysis Reveals the Mechanism Underlying Vitamin D in Suppressing Cytokine Storm and Virus in SARS-Cov-2 Infection, Front Immunol, doi:10.3389/fimmu.2020.590459

Ahmed, Integrated Network Analysis Reveals FOXM1 and MYBL2 as Key Regulators of Cell Proliferation in Non-Small Cell Lung Cancer, Front Oncol, doi:10.3389/fonc.2019.01011

Ahmed, Raghava, Designing of Highly Effective Complementary and Mismatch SiRNAs for Silencing a Gene, PloS One, doi:10.1371/journal.pone.0023443

Ahmed, Sharma, Al-Ghamdi, Sm, Am et al., A Comprehensive Analysis of Cis-Acting RNA Elements in the SARS-Cov-2 Genome by a Bioinformatics Approach, Front Genet, doi:10.3389/fgene.2020.572702

Akbar, Andrographis Paniculata: A Review of Pharmacological Activities and Clinical Effects, Altern Med Rev

Ariga, Namekawa, Matsumoto, Inoue, Umezawa, Inhibition of Tumor Necrosis Factor-Alpha -Induced Nuclear Translocation and Activation of NF-Kappa B by Dehydroxymethylepoxyquinomicin, J Biol Chem, doi:10.1074/jbc.M112063200

Ashburn, Thor, Drug Repositioning: Identifying and Developing New Uses for Existing Drugs, Nat Rev Drug Discovery, doi:10.1038/nrd1468

Betts, Mayer, Tal-Singer, Warnock, Clayton et al., Gene Expression Changes Caused by the P38 MAPK Inhibitor Dilmapimod in COPD Patients: Analysis of Blood and Sputum Samples From a Randomized, Placebo-Controlled Clinical Trial, Pharmacol Res Perspect, doi:10.1002/prp2.94

Blanco-Melo, Nilsson-Payant, Liu, Uhl, Hoagland et al., Imbalanced Host Response to SARS-Cov-2 Drives Development of COVID-19, Cell, doi:10.1016/j.cell.2020.04.026

Carter, Knudtson, Monick, Hunninghake, The P38 Mitogen-Activated Protein Kinase Is Required for NF-Kappab-Dependent Gene Expression. The Role of TATA-Binding Protein (TBP), J Biol Chem, doi:10.1074/jbc.274.43.30858

Chen, Xue, Ye, Fang, Liu et al., Activity of Andrographolide and Its Derivatives Against Influenza Virus In Vivo and In Vitro, Biol Pharm Bull, doi:10.1248/bpb.32.1385

Choudhry, Bakhrebah, Abdulaal, Zamzami, Baothman et al., Middle East Respiratory Syndrome: Pathogenesis and Therapeutic Developments, Future Virol, doi:10.2217/fvl-2018-0201

Enmozhi, Raja, Sebastine, Joseph, Andrographolide as a Potential Inhibitor of SARS-CoV-2 Main Protease: An In Silico Approach, J Biol Chem, doi:10.1080/07391102.2020.1760136

Ewing, Makino, Skillman, Kuntz, DOCK 4.0: Search Strategies for Automated Molecular Docking of Flexible Molecule Databases, J Comput Aided Mol Des, doi:10.1023/a:1011115820450

Ferreira, Santos, Oliva, Andricopulo, Molecular Docking and Structure-Based Drug Design Strategies, Molecules, doi:10.3390/molecules200713384

Gopalaswamy, Subbian, Corticosteroids for COVID-19 Therapy: Potential Implications on Tuberculosis, Int J Mol Sci, doi:10.3390/ijms22073773

Gupta, Khan, Choudhury, Mukhopadhyay, Sakshi et al., Coronavr: A Computational Resource and Analysis of Epitopes and Therapeutics for Severe Acute Respiratory Syndrome Coronavirus-2, Front Microbiol, doi:10.3389/fmicb.2020.01858

Kale, Habib, Chitren, Patel, Pramanik et al., Old Drugs, New Uses: Drug Repurposing in Hematological Malignancies, Semin Cancer Biol, doi:10.1016/j.semcancer.2020.03.005

Khanal, Dey, Patil, Chikhale, Wanjari et al., Combination of System Biology to Probe the Anti-Viral Activity of Andrographolide and Its Derivative Against COVID-19, RSC Adv, doi:10.1039/D0RA10529E

Kumar, Harilal, Gupta, Jose, Parambi et al., Exploring the New Horizons of Drug Repurposing: A Vital Tool for Turning Hard Work Into Smart Work, Eur J Med Chem, doi:10.1016/j.ejmech.2019.111602

Laskowski, Swindells, Ligplot+: Multiple Ligand-Protein Interaction Diagrams for Drug Discovery, J Chem Inf Model, doi:10.1021/ci200227u

Lee, Chang, Wen, Huang, Chang, Modulation of Thioacetamide-Induced Hepatic Inflammations, Angiogenesis and Fibrosis by Andrographolide in Mice, J Ethnopharmacol, doi:10.1016/j.jep.2014.10.056

Lee, Tseng, Young, Sun, Wang et al., Andrographolide Exerts Anti-Hepatitis C Virus Activity by Up-Regulating Haeme Oxygenase-1 via the P38 MAPK/Nrf2 Pathway in Human Hepatoma Cells, Br J Pharmacol, doi:10.1111/bph.12440

Lin, Ukaji, Koide, Umezawa, Inhibition of Late and Early Phases of Cancer Metastasis by the NF-kb Inhibitor DHMEQ Derived From Microbial Bioactive Metabolite Epoxyquinomicin: A Review, Int J Mol Sci, doi:10.3390/ijms19030729

Liu, Zhang, Joo, Sun, Nf-kb Signaling in Inflammation, Signal Transduct Target Ther, doi:10.1038/sigtrans.2017.23

Luo, Luo, Lin, Zhang, Li, Andrographolide Inhibits Proliferation of Human Lung Cancer Cells and the Related Mechanisms, Int J Clin Exp Med

Moore, June, Cytokine Release Syndrome in Severe COVID-19, Science, doi:10.1126/science.abb8925

Morris, Huey, Lindstrom, Sanner, Belew et al., Autodock4 and Autodocktools4: Automated Docking With Selective Receptor Flexibility, J Comput Chem, doi:10.1002/jcc.21256

Nishioka, Ikezoe, Jing, Umezawa, Yokoyama, DHMEQ, a Novel Nuclear Factor-Kappab Inhibitor, Induces Selective Depletion of Alloreactive or Phytohaemagglutinin-Stimulated Peripheral Blood Mononuclear Cells, Decreases Production of T Helper Type 1 Cytokines, and Blocks Maturation of Dendritic Cells, Immunology, doi:10.1111/j.1365-2567.2007.02755.x

Patra, Ray, IL-6 Induction and Signaling: Horizons of COVID-19-Related Pathogenesis, DNA Cell Biol, doi:10.1089/dna.2021.0152

Pelaia, Vatrella, Gallelli, Lombardo, Sciacqua et al., Role of P38 Mitogen-Activated Protein Kinase in Asthma and COPD: Pathogenic Aspects and Potential Targeted Therapies, Drug Des Devel Ther, doi:10.2147/DDDT.S300988

Peng, Hu, Wu, Zhang, Chen et al., Andrographolide Suppresses Proliferation of Nasopharyngeal Carcinoma Cells via Attenuating NF-kB Pathway, BioMed Res Int, doi:10.1155/2015/735056

Pettersen, Goddard, Huang, Couch, Greenblatt et al., UCSF Chimera-A Visualization System for Exploratory Research and Analysis, J Comput Chem, doi:10.1002/jcc.20084

Pires, Blundell, Ascher, Pkcsm: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures, J Med Chem, doi:10.1021/acs.jmedchem.5b00104

Pratt, Chen, Pillich, Rynkov, Gary et al., Ndex 2.0: A Clearinghouse for Research on Cancer Pathways, Cancer Res, doi:10.1158/0008-5472.CAN-17-0606

Pratt, Chen, Welker, Rivas, Pillich et al., Ndex, the Network Data Exchange, Cell Syst, doi:10.1016/j.cels.2015.10.001

Pushpakom, Iorio, Eyers, Escott, Hopper et al., Drug Repurposing: Progress, Challenges and Recommendations, Nat Rev Drug Discov, doi:10.1038/nrd.2018.168

Rehan, A Structural Insight Into the Inhibitory Mechanism of an Orally Active PI3K/Mtor Dual Inhibitor, PKI-179 Using Computational Approaches, J Mol Graph Model, doi:10.1016/j.jmgm.2015.10.005

Rehan, Anticancer Compound XL765 as PI3K/mTOR Dual Inhibitor: A Structural Insight Into the Inhibitory Mechanism Using Computational Approaches, PloS One, doi:10.1371/journal.pone.0219180

Rehan, Mahmoud, Tabrez, Hassan, Ashraf, Exploring Flavonoids for Potential Inhibitors of a Cancer Signaling Protein PI3Kg Kinase Using Computational Methods, Anticancer Res, doi:10.21873/anticanres.14460

Rehan, Mostafa, Virtual Screening of 1,4-Naphthoquinone Derivatives for Inhibition of a Key Cancer Signaling Protein, AKT1 Kinase, Anticancer Res, doi:10.21873/anticanres.13532

Ren, Wang, Wu, Xiang, Guo et al., Identification of a Novel Coronavirus Causing Severe Pneumonia in Human: A Descriptive Study, Med J (Engl), doi:10.1097/CM9.0000000000000722

Seubsasana, Pientong, Ekalaksananan, Thongchai, Aromdee, A Potential Andrographolide Analogue Against the Replication of Herpes Simplex Virus Type 1 in Vero Cells, Med Chem, doi:10.2174/157340611795564268

Shimizu, Konno, Ozaki, Umezawa, Yamashita et al., Dehydroxymethylepoxyquinomicin (DHMEQ), A Novel NF-Kappab Inhibitor, Inhibits Allergic Inflammation and Airway Remodelling in Murine Models of Asthma, Clin Exp Allergy, doi:10.1111/j.1365-2222.2012.04007.x

Singh, Smyth, Borrill, Sweeney, Singer, A Randomized, Placebo-Controlled Study of the Effects of the P38 MAPK Inhibitor SB-681323 on Blood Biomarkers of Inflammation in COPD Patients, J Clin Pharmacol, doi:10.1177/0091270009347873

Tang, Wu, Li, Song, Yao et al., On the Origin and Continuing Evolution of SARS-Cov-2, Natl Sci Rev, doi:10.1093/nsr/nwaa036

Trott, Olson, Autodock Vina: Improving the Speed and Accuracy of Docking With a New Scoring Function, Efficient Optimization, and Multithreading, J Comput Chem, doi:10.1002/jcc.21334

Tyagi, Ahmed, Thakur, Sharma, Raghava et al., Hivsirdb: A Database of HIV Inhibiting SiRNAs, PloS One, doi:10.1371/journal.pone.0025917

Wang, Du, Zhu, Cao, An et al., Comorbidities and Multi-Organ Injuries in the Treatment of COVID-19, Lancet, doi:10.1016/S0140-6736(20)30558-4

Wang, Lai, Wang, Further Development and Validation of Empirical Scoring Functions for Structure-Based Binding Affinity Prediction, J Comput Aided Mol Des, doi:10.1023/a:1016357811882

Wang, Tan, Nguyen, Yang, Zhou et al., A Quantitative Chemical Proteomics Approach to Profile the Specific Cellular Targets of Andrographolide, a Promising Anticancer Agent That Suppresses Tumor Metastasis, Mol Cell Proteomics, doi:10.1074/mcp.M113.029793

Wintachai, Kaur, Lee, Ramphan, Kuadkitkan et al., Activity of Andrographolide Against Chikungunya Virus Infection, Sci Rep, doi:10.1038/srep14179

Wu, Liu, Yang, Zhang, Zhong et al., Analysis of Therapeutic Targets for SARS-Cov-2 and Discovery of Potential Drugs by Computational Methods, Acta Pharm Sin B, doi:10.1016/j.apsb.2020.02.008

Xia, Ye, Li, Wang, He et al., Andrographolide Attenuates Inflammation by Inhibition of NF-Kappa B Activation Through Covalent Modification of Reduced Cysteine 62 of P50, J Immunol, doi:10.4049/jimmunol.173.6.4207

Yang, Yu, Xu, Shu, Xia et al., Clinical Course and Outcomes of Critically Ill Patients With SARS-Cov-2 Pneumonia in Wuhan, China: A Single-Centered, Retrospective, Observational Study, Lancet Respir Med, doi:10.1016/S2213-2600(20)30079-5

Yu, Chen, Fu, Lin, Lee et al., Andrographolide Enhances the Anti-Metastatic Effect of Radiation in RAS-Transformed Cells via Suppression of ERK-Mediated MMP-2 Activity, PloS One, doi:10.1371/journal.pone.0205666

Yu, Dai, Jiang, Li, Chen et al., Andrographolide as an Anti-H1N1 Drug and the Mechanism Related to Retinoic Acid-Inducible Gene-I-Like Receptors Signaling Pathway, Chin J Integr Med, doi:10.1007/s11655-014-1860-0

Zhang, Wu, Li, Zhao, Wang, Cytokine Release Syndrome in Severe COVID-19: Interleukin-6 Receptor Antagonist Tocilizumab May Be the Key to Reduce Mortality, Int J Antimicrob Agents, doi:10.1016/j.ijantimicag.2020.105954

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'doi-asserted-by': 'publisher', 'DOI': '10.2174/157340611795564268', 'article-title': 'A Potential Andrographolide Analogue Against the Replication of Herpes ' 'Simplex Virus Type 1 in Vero Cells', 'volume': '7', 'author': 'Seubsasana', 'year': '2011', 'journal-title': 'Med Chem'}, { 'key': 'B41', 'doi-asserted-by': 'publisher', 'first-page': '14179', 'DOI': '10.1038/srep14179', 'article-title': 'Activity of Andrographolide Against Chikungunya Virus Infection', 'volume': '5', 'author': 'Wintachai', 'year': '2015', 'journal-title': 'Sci Rep'}, { 'key': 'B42', 'article-title': 'Andrographolide Inhibits Proliferation of Human Lung Cancer Cells and ' 'the Related Mechanisms', 'volume': '7', 'author': 'Luo', 'year': '2014', 'journal-title': 'Int J Clin Exp Med'}, { 'key': 'B43', 'doi-asserted-by': 'publisher', 'first-page': '735056', 'DOI': '10.1155/2015/735056', 'article-title': 'Andrographolide Suppresses Proliferation of Nasopharyngeal Carcinoma ' 'Cells via Attenuating NF-κB Pathway', 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'year': '2002', 'journal-title': 'J Biol Chem'}, { 'key': 'B47', 'doi-asserted-by': 'publisher', 'DOI': '10.1080/07391102.2020.1760136', 'article-title': 'Andrographolide as a Potential Inhibitor of SARS-CoV-2 Main Protease: ' 'An In Silico Approach', 'volume': '39', 'author': 'Enmozhi', 'year': '2021', 'journal-title': 'J Biol Chem'}, { 'key': 'B48', 'doi-asserted-by': 'publisher', 'DOI': '10.1039/D0RA10529E', 'article-title': 'Combination of System Biology to Probe the Anti-Viral Activity of ' 'Andrographolide and Its Derivative Against COVID-19', 'volume': '11', 'author': 'Khanal', 'year': '2021', 'journal-title': 'RSC Adv'}, { 'key': 'B49', 'doi-asserted-by': 'publisher', 'first-page': 'e17023', 'DOI': '10.1038/sigtrans.2017.23', 'article-title': 'Nf-κb Signaling in Inflammation', 'volume': '2', 'author': 'Liu', 'year': '2017', 'journal-title': 'Signal Transduct Target Ther'}, { 'key': 'B50', 'doi-asserted-by': 'publisher', 'DOI': '10.2147/DDDT.S300988', 'article-title': 'Role of 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The Role of TATA-Binding Protein ' '(TBP)', 'volume': '274', 'author': 'Carter', 'year': '1999', 'journal-title': 'J Biol Chem'}, { 'key': 'B52', 'doi-asserted-by': 'publisher', 'first-page': '94', 'DOI': '10.1177/0091270009347873', 'article-title': 'A Randomized, Placebo-Controlled Study of the Effects of the P38 MAPK ' 'Inhibitor SB-681323 on Blood Biomarkers of Inflammation in COPD ' 'Patients', 'volume': '50', 'author': 'Singh', 'year': '2010', 'journal-title': 'J Clin Pharmacol'}, { 'key': 'B53', 'doi-asserted-by': 'publisher', 'first-page': 'e00094', 'DOI': '10.1002/prp2.94', 'article-title': 'Gene Expression Changes Caused by the P38 MAPK Inhibitor Dilmapimod in ' 'COPD Patients: Analysis of Blood and Sputum Samples From a Randomized, ' 'Placebo-Controlled Clinical Trial', 'volume': '3', 'author': 'Betts', 'year': '2015', 'journal-title': 'Pharmacol Res Perspect'}, { 'key': 'B54', 'doi-asserted-by': 'publisher', 'DOI': '10.1089/dna.2021.0152', 'article-title': 'IL-6 Induction and Signaling: Horizons of COVID-19-Related Pathogenesis', 'volume': '40', 'author': 'Patra', 'year': '2021', 'journal-title': 'DNA Cell Biol'}, { 'key': 'B55', 'doi-asserted-by': 'publisher', 'first-page': '3773', 'DOI': '10.3390/ijms22073773', 'article-title': 'Corticosteroids for COVID-19 Therapy: Potential Implications on ' 'Tuberculosis', 'volume': '22', 'author': 'Gopalaswamy', 'year': '2021', 'journal-title': 'Int J Mol Sci'}, { 'key': 'B56', 'doi-asserted-by': 'publisher', 'first-page': '198', 'DOI': '10.1111/j.1365-2567.2007.02755.x', 'article-title': 'DHMEQ, a Novel Nuclear Factor-Kappab Inhibitor, Induces Selective ' 'Depletion of Alloreactive or Phytohaemagglutinin-Stimulated Peripheral ' 'Blood Mononuclear Cells, Decreases Production of T Helper Type 1 ' 'Cytokines, and Blocks Maturation of Dendritic Cells', 'volume': '124', 'author': 'Nishioka', 'year': '2008', 'journal-title': 'Immunology'}, { 'key': 'B57', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/ijms19030729', 'article-title': 'Inhibition of Late and Early Phases of Cancer Metastasis by the NF-κb ' 'Inhibitor DHMEQ Derived From Microbial Bioactive Metabolite ' 'Epoxyquinomicin: A Review', 'volume': '19', 'author': 'Lin', 'year': '2018', 'journal-title': 'Int J Mol Sci'}, { 'key': 'B58', 'doi-asserted-by': 'publisher', 'DOI': '10.1111/j.1365-2222.2012.04007.x', 'article-title': 'Dehydroxymethylepoxyquinomicin (DHMEQ), A Novel NF-Kappab Inhibitor, ' 'Inhibits Allergic Inflammation and Airway Remodelling in Murine Models ' 'of Asthma', 'volume': '42', 'author': 'Shimizu', 'year': '2012', 'journal-title': 'Clin Exp Allergy'}], 'container-title': 'Frontiers in Immunology', 'original-title': [], 'link': [ { 'URL': 'https://www.frontiersin.org/articles/10.3389/fimmu.2021.648250/full', 'content-type': 'unspecified', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2021, 6, 24]], 'date-time': '2021-06-24T06:09:04Z', 'timestamp': 1624514944000}, 'score': 1, 'resource': {'primary': {'URL': 'https://www.frontiersin.org/articles/10.3389/fimmu.2021.648250/full'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2021, 6, 24]]}, 'references-count': 58, 'alternative-id': ['10.3389/fimmu.2021.648250'], 'URL': 'http://dx.doi.org/10.3389/fimmu.2021.648250', 'relation': {}, 'ISSN': ['1664-3224'], 'subject': [], 'container-title-short': 'Front. Immunol.', 'published': {'date-parts': [[2021, 6, 24]]}}

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