Decoding the therapeutic potential of empon-empon: a bioinformatics expedition unraveling mechanisms against COVID-19 and atherosclerosis

Hasanah et al., International Journal of Applied Pharmaceutics, doi:10.22159/ijap.2024v16i2.50128, Mar 2024
Quercetin for COVID-19
27th treatment shown to reduce risk in July 2021, now with p = 0.002 from 12 studies.
Lower risk for ICU, hospitalization, recovery, cases, and viral clearance.
No treatment is 100% effective. Protocols combine treatments.
6,300+ studies for 210+ treatments. c19early.org
Meta Analysis
In silico study of compounds in empon-empon showing that quercetin may be beneficial for treating COVID-19 and atherosclerosis by inhibiting key signaling targets. Authors found that quercetin exhibits strong binding affinity to EP300 and HSP90AA1, which are involved in upregulating profibrotic genes, inflammatory cytokine production, and facilitating viral entry into cells.
89 preclinical studies support the efficacy of quercetin for COVID-19:
53 in silico studies1-53
30 in vitro studies1,2,4,5,7-9,12,22,27,29,33,50,54-70
6 in vivo animal studies12,27,62,65,71,72
In silico studies predict inhibition of SARS-CoV-2, or minimization of side effects, with quercetin or metabolites via binding to the spikeA,9,10,16,17,30,32,33,35,38,46,47,49,50,73 (and specifically the receptor binding domainB,6), MproC,5,6,9,10,14,16,18,20,22,24,26,28,31,32,35,38,42,44-46,50-53,70, RNA-dependent RNA polymeraseD,6,8-10,16,40, PLproE,10,45,53, ACE2F,25,30,31,35,36,45,49, TMPRSS2G,30, nucleocapsidH,10, helicaseI,10,37,42, endoribonucleaseJ,47, NSP16/10K,13, cathepsin LL,34, Wnt-3M,30, FZDN,30, LRP6O,30, ezrinP,48, ADRPQ,46, NRP1R,49, EP300S,23, PTGS2T,31, HSP90AA1U,23,31, matrix metalloproteinase 9V,39, IL-6W,29,43, IL-10X,29, VEGFAY,43, and RELAZ,43 proteins, and inhibition of spike-ACE2 interactionAA,7. In vitro studies demonstrate inhibition of the MproC,22,56,61,69 protein, and inhibition of spike-ACE2 interactionAA,57. In vitro studies demonstrate efficacy in Calu-3AB,60, A549AC,29, HEK293-ACE2+AD,68, Huh-7AE,33, Caco-2AF,59, Vero E6AG,27,50,59, mTECAH,62, RAW264.7AI,62, and HLMECAJ,7 cells. Animal studies demonstrate efficacy in K18-hACE2 miceAK,65, db/db miceAL,62,72, BALB/c miceAM,71, and rats27. Quercetin reduced proinflammatory cytokines and protected lung and kidney tissue against LPS-induced damage in mice71, inhibits LPS-induced cytokine storm by modulating key inflammatory and antioxidant pathways in macrophages12, may block ACE2-spike interaction and NLRP3 inflammasome, limiting viral entry and inflammation3, and inhibits SARS-CoV-2 ORF3a ion channel activity, which contributes to viral pathogenicity and cytotoxicity64.
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a. The trimeric spike (S) protein is a glycoprotein that mediates viral entry by binding to the host ACE2 receptor, is critical for SARS-CoV-2's ability to infect host cells, and is a target of neutralizing antibodies. Inhibition of the spike protein prevents viral attachment, halting infection at the earliest stage.
b. The receptor binding domain is a specific region of the spike protein that binds ACE2 and is a major target of neutralizing antibodies. Focusing on the precise binding site allows highly specific disruption of viral attachment with reduced potential for off-target effects.
c. The main protease or Mpro, also known as 3CLpro or nsp5, is a cysteine protease that cleaves viral polyproteins into functional units needed for replication. Inhibiting Mpro disrupts the SARS-CoV-2 lifecycle within the host cell, preventing the creation of new copies.
d. RNA-dependent RNA polymerase (RdRp), also called nsp12, is the core enzyme of the viral replicase-transcriptase complex that copies the positive-sense viral RNA genome into negative-sense templates for progeny RNA synthesis. Inhibiting RdRp blocks viral genome replication and transcription.
e. The papain-like protease (PLpro) has multiple functions including cleaving viral polyproteins and suppressing the host immune response by deubiquitination and deISGylation of host proteins. Inhibiting PLpro may block viral replication and help restore normal immune responses.
f. The angiotensin converting enzyme 2 (ACE2) protein is a host cell transmembrane protein that serves as the cellular receptor for the SARS-CoV-2 spike protein. ACE2 is expressed on many cell types, including epithelial cells in the lungs, and allows the virus to enter and infect host cells. Inhibition may affect ACE2's physiological function in blood pressure control.
g. Transmembrane protease serine 2 (TMPRSS2) is a host cell protease that primes the spike protein, facilitating cellular entry. TMPRSS2 activity helps enable cleavage of the spike protein required for membrane fusion and virus entry. Inhibition may especially protect respiratory epithelial cells, buy may have physiological effects.
h. The nucleocapsid (N) protein binds and encapsulates the viral genome by coating the viral RNA. N enables formation and release of infectious virions and plays additional roles in viral replication and pathogenesis. N is also an immunodominant antigen used in diagnostic assays.
i. The helicase, or nsp13, protein unwinds the double-stranded viral RNA, a crucial step in replication and transcription. Inhibition may prevent viral genome replication and the creation of new virus components.
j. The endoribonuclease, also known as NendoU or nsp15, cleaves specific sequences in viral RNA which may help the virus evade detection by the host immune system. Inhibition may hinder the virus's ability to mask itself from the immune system, facilitating a stronger immune response.
k. The NSP16/10 complex consists of non-structural proteins 16 and 10, forming a 2'-O-methyltransferase that modifies the viral RNA cap structure. This modification helps the virus evade host immune detection by mimicking host mRNA, making NSP16/10 a promising antiviral target.
l. Cathepsin L is a host lysosomal cysteine protease that can prime the spike protein through an alternative pathway when TMPRSS2 is unavailable. Dual targeting of cathepsin L and TMPRSS2 may maximize disruption of alternative pathways for virus entry.
m. Wingless-related integration site (Wnt) ligand 3 is a host signaling molecule that activates the Wnt signaling pathway, which is important in development, cell growth, and tissue repair. Some studies suggest that SARS-CoV-2 infection may interfere with the Wnt signaling pathway, and that Wnt3a is involved in SARS-CoV-2 entry.
n. The frizzled (FZD) receptor is a host transmembrane receptor that binds Wnt ligands, initiating the Wnt signaling cascade. FZD serves as a co-receptor, along with ACE2, in some proposed mechanisms of SARS-CoV-2 infection. The virus may take advantage of this pathway as an alternative entry route.
o. Low-density lipoprotein receptor-related protein 6 is a cell surface co-receptor essential for Wnt signaling. LRP6 acts in tandem with FZD for signal transduction and has been discussed as a potential co-receptor for SARS-CoV-2 entry.
p. The ezrin protein links the cell membrane to the cytoskeleton (the cell's internal support structure) and plays a role in cell shape, movement, adhesion, and signaling. Drugs that occupy the same spot on ezrin where the viral spike protein would bind may hindering viral attachment, and drug binding could further stabilize ezrin, strengthening its potential natural capacity to impede viral fusion and entry.
q. The Adipocyte Differentiation-Related Protein (ADRP, also known as Perilipin 2 or PLIN2) is a lipid droplet protein regulating the storage and breakdown of fats in cells. SARS-CoV-2 may hijack the lipid handling machinery of host cells and ADRP may play a role in this process. Disrupting ADRP's interaction with the virus may hinder the virus's ability to use lipids for replication and assembly.
r. Neuropilin-1 (NRP1) is a cell surface receptor with roles in blood vessel development, nerve cell guidance, and immune responses. NRP1 may function as a co-receptor for SARS-CoV-2, facilitating viral entry into cells. Blocking NRP1 may disrupt an alternative route of viral entry.
s. EP300 (E1A Binding Protein P300) is a transcriptional coactivator involved in several cellular processes, including growth, differentiation, and apoptosis, through its acetyltransferase activity that modifies histones and non-histone proteins. EP300 facilitates viral entry into cells and upregulates inflammatory cytokine production.
t. Prostaglandin G/H synthase 2 (PTGS2, also known as COX-2) is an enzyme crucial for the production of inflammatory molecules called prostaglandins. PTGS2 plays a role in the inflammatory response that can become severe in COVID-19 and inhibitors (like some NSAIDs) may have benefits in dampening harmful inflammation, but note that prostaglandins have diverse physiological functions.
u. Heat Shock Protein 90 Alpha Family Class A Member 1 (HSP90AA1) is a chaperone protein that helps other proteins fold correctly and maintains their stability. HSP90AA1 plays roles in cell signaling, survival, and immune responses. HSP90AA1 may interact with numerous viral proteins, but note that it has diverse physiological functions.
v. Matrix metalloproteinase 9 (MMP9), also called gelatinase B, is a zinc-dependent enzyme that breaks down collagen and other components of the extracellular matrix. MMP9 levels increase in severe COVID-19. Overactive MMP9 can damage lung tissue and worsen inflammation. Inhibition of MMP9 may prevent excessive tissue damage and help regulate the inflammatory response.
w. The interleukin-6 (IL-6) pro-inflammatory cytokine (signaling molecule) has a complex role in the immune response and may trigger and perpetuate inflammation. Elevated IL-6 levels are associated with severe COVID-19 cases and cytokine storm. Anti-IL-6 therapies may be beneficial in reducing excessive inflammation in severe COVID-19 cases.
x. The interleukin-10 (IL-10) anti-inflammatory cytokine helps regulate and dampen immune responses, preventing excessive inflammation. IL-10 levels can also be elevated in severe COVID-19. IL-10 could either help control harmful inflammation or potentially contribute to immune suppression.
y. Vascular Endothelial Growth Factor A (VEGFA) promotes the growth of new blood vessels (angiogenesis) and has roles in inflammation and immune responses. VEGFA may contribute to blood vessel leakiness and excessive inflammation associated with severe COVID-19.
z. RELA is a transcription factor subunit of NF-kB and is a key regulator of inflammation, driving pro-inflammatory gene expression. SARS-CoV-2 may hijack and modulate NF-kB pathways.
aa. The interaction between the SARS-CoV-2 spike protein and the human ACE2 receptor is a primary method of viral entry, inhibiting this interaction can prevent the virus from attaching to and entering host cells, halting infection at an early stage.
ab. Calu-3 is a human lung adenocarcinoma cell line with moderate ACE2 and TMPRSS2 expression and SARS-CoV-2 susceptibility. It provides a model of the human respiratory epithelium, but many not be ideal for modeling early stages of infection due to the moderate expression levels of ACE2 and TMPRSS2.
ac. A549 is a human lung carcinoma cell line with low ACE2 expression and SARS-CoV-2 susceptibility. Viral entry/replication can be studied but the cells may not replicate all aspects of lung infection.
ad. HEK293-ACE2+ is a human embryonic kidney cell line engineered for high ACE2 expression and SARS-CoV-2 susceptibility.
ae. Huh-7 cells were derived from a liver tumor (hepatoma).
af. Caco-2 cells come from a colorectal adenocarcinoma (cancer). They are valued for their ability to form a polarized cell layer with properties similar to the intestinal lining.
ag. Vero E6 is an African green monkey kidney cell line with low/no ACE2 expression and high SARS-CoV-2 susceptibility. The cell line is easy to maintain and supports robust viral replication, however the monkey origin may not accurately represent human responses.
ah. mTEC is a mouse tubular epithelial cell line.
ai. RAW264.7 is a mouse macrophage cell line.
aj. HLMEC (Human Lung Microvascular Endothelial Cells) are primary endothelial cells derived from the lung microvasculature. They are used to study endothelial function, inflammation, and viral interactions, particularly in the context of lung infections such as SARS-CoV-2. HLMEC express ACE2 and are susceptible to SARS-CoV-2 infection, making them a relevant model for studying viral entry and endothelial responses in the lung.
ak. A mouse model expressing the human ACE2 receptor under the control of the K18 promoter.
al. A mouse model of obesity and severe insulin resistance leading to type 2 diabetes due to a mutation in the leptin receptor gene that impairs satiety signaling.
am. A mouse model commonly used in infectious disease and cancer research due to higher immune response and susceptibility to infection.
Hasanah et al., 7 Mar 2024, peer-reviewed, 5 authors. Contact: arry.yanuar@ui.ac.id.
In silico studies are an important part of preclinical research, however results may be very different in vivo.
DECODING THE THERAPEUTIC POTENTIAL OF EMPON-EMPON: A BIOINFORMATICS EXPEDITION UNRAVELING MECHANISMS AGAINST COVID-19 AND ATHEROSCLEROSIS
Nur Hasanah, Fadlina Chany Saputri, Alhadi Bustamam, Vannajan Sanghiran Lee, Arry Yanuar
International Journal of Applied Pharmaceutics, doi:10.22159/ijap.2024v16i2.50128
Objective: This study aims to elucidate the main compounds and mechanisms of action of Empon-empon (EE), a traditional Indonesian herb used for treating COVID-19 and atherosclerosis, utilizing an integrated network pharmacology and molecular docking approach. Methods: Active compounds in EE were obtained through the KNApSAcK, screening active compounds using parameters: oral bioavailability (OB) ≥ 30% and drug-likeness (DL) ≥ 0.18. Compound-related target genes were collected from GeneCard, ChemBL, and Traditional Chinese Medicine Systems Pharmacology (TCMSP). Disease targets were obtained from the GeneCard database. The protein-protein interaction (PPI) network was built using STRING and visualized using Cytoscape. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis using ShinyGO. Molecular docking analysis using Autodock Vina in PyRx. Results: We identified 18 main compounds in EE. PPI analysis obtained 5 central EE targets involved in treating COVID-19 and atherosclerosis, namely E1A Binding Protein P300 (EP300), Heat Shock Protein 90 Alpha Family Class A Member 1 (HSP90AA1), SRC Proto-Oncogene (SRC), Estrogen Receptor 1 (ESR1), and RELA Proto-Oncogene (RELA). GO and KEGG analysis illustrated EE's pharmacological effects through pathways in cancer, lipid and atherosclerosis, and PI3K-Akt signaling, including Coronavirus disease. Catechin and quercetin exhibited the strongest binding affinity to EP300; licarin B and delphinidin to HSP90AA1; epicatechin and delphinidin to SRC; galangin and ellagic acid to ESR1; and guaiacin and licarin B to RELA. Conclusion: This research provides a strong foundation regarding the main compound and mechanism action of EE in treating atherosclerosis and COVID-19, suggesting potential as a novel therapeutic agent.
AUTHORS CONTRIBUTIONS The manuscript was written through the contributions of all authors, and all authors have approved the final version. CONFLICT OF INTERESTS The authors declare no conflict of interest.
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DOI record: { "DOI": "10.22159/ijap.2024v16i2.50128", "ISSN": [ "0975-7058" ], "URL": "http://dx.doi.org/10.22159/ijap.2024v16i2.50128", "abstract": "<jats:p>Objective: This study aims to elucidate the main compounds and mechanisms of action of Empon-empon (EE), a traditional Indonesian herb used for treating COVID-19 and atherosclerosis, utilizing an integrated network pharmacology and molecular docking approach.\nMethods: Active compounds in EE were obtained through the KNApSAcK, screening active compounds using parameters: oral bioavailability (OB) ≥ 30% and drug-likeness (DL) ≥ 0.18. Compound-related target genes were collected from GeneCard, ChemBL, and Traditional Chinese Medicine Systems Pharmacology (TCMSP). Disease targets were obtained from the GeneCard database. The protein-protein interaction (PPI) network was built using STRING and visualized using Cytoscape. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis using ShinyGO. Molecular docking analysis using Autodock Vina in PyRx.\nResults: We identified 18 main compounds in EE. PPI analysis obtained 5 central EE targets involved in treating COVID-19 and atherosclerosis, namely E1A Binding Protein P300 (EP300), Heat Shock Protein 90 Alpha Family Class A Member 1 (HSP90AA1), SRC Proto-Oncogene (SRC), Estrogen Receptor 1 (ESR1), and RELA Proto-Oncogene (RELA). GO and KEGG analysis illustrated EE's pharmacological effects through pathways in cancer, lipid and atherosclerosis, and PI3K-Akt signaling, including Coronavirus disease. Catechin and quercetin exhibited the strongest binding affinity to EP300; licarin B and delphinidin to HSP90AA1; epicatechin and delphinidin to SRC; galangin and ellagic acid to ESR1; and guaiacin and licarin B to RELA.\nConclusion: This research provides a strong foundation regarding the main compound and mechanism action of EE in treating atherosclerosis and COVID-19, suggesting potential as a novel therapeutic agent.</jats:p>", "author": [ { "ORCID": "http://orcid.org/0000-0001-9436-5745", "affiliation": [], "authenticated-orcid": false, "family": "HASANAH", "given": "NUR", "sequence": "first" }, { "ORCID": "http://orcid.org/0000-0002-6668-8915", "affiliation": [], "authenticated-orcid": false, "family": "SAPUTRI", "given": "FADLINA CHANY", "sequence": "additional" }, { "affiliation": [], "family": "BUSTAMAM", "given": "ALHADI", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0002-2911-7726", "affiliation": [], "authenticated-orcid": false, "family": "SANGHIRAN LEE", "given": "VANNAJAN", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0001-8895-9010", "affiliation": [], "authenticated-orcid": false, "family": "YANUAR", "given": "ARRY", "sequence": "additional" } ], "container-title": "International Journal of Applied Pharmaceutics", "container-title-short": "Int J App Pharm", "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2024, 3, 11 ] ], "date-time": "2024-03-11T10:39:43Z", "timestamp": 1710153583000 }, "deposited": { "date-parts": [ [ 2024, 3, 11 ] ], "date-time": "2024-03-11T10:40:19Z", "timestamp": 1710153619000 }, "indexed": { "date-parts": [ [ 2024, 3, 12 ] ], "date-time": "2024-03-12T00:30:29Z", "timestamp": 1710203429039 }, "is-referenced-by-count": 0, "issued": { "date-parts": [ [ 2024, 3, 7 ] ] }, "license": [ { "URL": "https://creativecommons.org/licenses/by/4.0", "content-version": "unspecified", "delay-in-days": 0, "start": { "date-parts": [ [ 2024, 3, 7 ] ], "date-time": "2024-03-07T00:00:00Z", "timestamp": 1709769600000 } } ], "link": [ { "URL": "https://journals.innovareacademics.in/index.php/ijap/article/download/50128/29749", "content-type": "application/pdf", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "https://journals.innovareacademics.in/index.php/ijap/article/download/50128/29820", "content-type": "text/html", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "https://journals.innovareacademics.in/index.php/ijap/article/download/50128/29749", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "9422", "original-title": [], "page": "215-223", "prefix": "10.22159", "published": { "date-parts": [ [ 2024, 3, 7 ] ] }, "published-online": { "date-parts": [ [ 2024, 3, 7 ] ] }, "publisher": "Innovare Academic Sciences Pvt Ltd", "reference": [ { "key": "1180544", "unstructured": "WHO. Situation by Region, Country, Territory and Area. WHO Coronavirus (COVID-19) Dashboard. Vol. 35(17); 2023. p. 2104. Available from: https://covid19.who.int. [Last accessed on 10 Feb 2024]" }, { "key": "1180545", "unstructured": "Ronconi G, Tete G, Kritas SK, Gallenga CE, Caraffa Al, Ross R. SARS-CoV-2, which induces COVID-19, causes kawasaki-like disease in children: role of pro-inflammatory and anti-inflammatory cytokines. J Biol Regul Homeost Agents. 2020;34(3):767-73. doi: 10.23812/editorial-ronconi-e-59, PMID 32476380." }, { "DOI": "10.1093/nsr/nwaa041", "doi-asserted-by": "crossref", "key": "1180546", "unstructured": "Zhou Y, Fu B, Zheng X, Wang D, Zhao C, Qi Y. Pathogenic T-cells and inflammatory monocytes incite inflammatory storms in severe COVID-19 patients. Natl Sci Rev. 2020;7(6):998-1002. doi: 10.1093/nsr/nwaa041, PMID 34676125." }, { "DOI": "10.22159/ajpcr.2021.v14i6.41491", "doi-asserted-by": "crossref", "key": "1180547", "unstructured": "Zageer Ds, Hantoosh Sf, QSh. Ali W. Association between elevated high sensitivity cardiac-troponin I levels and increase in levels of C-reactive protein, interleukin-6, D-dimer, and consequent cardiac injury and mortality for patients with coronavirus disease 2019: a meta-analysis. Asian J Pharm Clin Res. 2021;14(6):160-6." }, { "DOI": "10.3390/ijerph19116865", "doi-asserted-by": "crossref", "key": "1180548", "unstructured": "Ma Y, Deng J, Liu Q, Du M, Liu M, Liu J. Long-term consequences of COVID-19 at 6 mo and above: A systematic review and meta-analysis. Int J Environ Res Public Health. 2022;19(11)." }, { "DOI": "10.3390/diseases9030047", "doi-asserted-by": "crossref", "key": "1180549", "unstructured": "Lee CCE, Ali K, Connell D, Mordi IR, George J, Lang EMSL. COVID-19-associated cardiovascular complications. Diseases. 2021;9(3). doi: 10.3390/diseases9030047, PMID 34209705." }, { "DOI": "10.3390/ijms22041659", "doi-asserted-by": "crossref", "key": "1180550", "unstructured": "Seeherman S, Suzuki YJ. Viral infection and cardiovascular disease: implications for the molecular basis of COVID-19 pathogenesis. Int J Mol Sci. 2021;22(4):1-13. doi: 10.3390/ijms22041659, PMID 33562193." }, { "key": "1180551", "unstructured": "Madjid M, Aboshady I, Awan I, Litovsky S, Casscells SW. Influenza and cardiovascular disease: is there a causal relationship? Tex Heart Inst J. 2004;31(1):4-13. PMID 15061620." }, { "key": "1180552", "unstructured": "Ramanathan K, Antognini D, Combes A, Paden M, Zakhary B, Ogino M. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-research that is available on the COVID-19 resource centre-including this for unrestricted research re-use a (January); 2020. p. 19-21." }, { "DOI": "10.1016/S0140-6736(20)30183-5", "doi-asserted-by": "crossref", "key": "1180553", "unstructured": "Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5." }, { "DOI": "10.22159/ajpcr.2021.v14i12.43085", "doi-asserted-by": "crossref", "key": "1180554", "unstructured": "Pavan Kumar M, Revathi G, Supraja K, sechana K. Study of demographic analysis, clinical characteristics, diagnosis, management and complications in Covid-19 patients. Asian J Pharm Clin Res. 2021;14(12):64-8. doi: 10.22159/ajpcr.2021.v14i12.43085." }, { "DOI": "10.3389/fmed.2020.629413", "doi-asserted-by": "crossref", "key": "1180555", "unstructured": "Liu Y, Zhang HG. Vigilance on new-onset atherosclerosis following SARS-CoV-2 Infection. Front Med (Lausanne). 2020;7:629413. doi: 10.3389/fmed.2020.629413, PMID 33553222." }, { "DOI": "10.17925/EE.2014.10.02.157", "doi-asserted-by": "crossref", "key": "1180556", "unstructured": "Duntas LH, Chiovato L. Cardiovascular risk in patients with subclinical hypothyroidism. Eur Endocrinol. 2014;10(2):157-60. doi: 10.17925/EE.2014.10.02.157, PMID 29872482." }, { "DOI": "10.3390/jcdd8100130", "doi-asserted-by": "crossref", "key": "1180557", "unstructured": "Vinciguerra M, Romiti S, Sangiorgi GM, Rose D, Miraldi F, Greco E. Sars-cov-2 and atherosclerosis: should COVID-19 be recognized as a new predisposing cardiovascular risk factor? J Cardiovasc Dev Dis. 2021;8(10). doi: 10.3390/jcdd8100130, PMID 34677199." }, { "key": "1180558", "unstructured": "Kumar S, Singh S, Singh P. Detrimental effect of diabetes and hypertension on the severity and mortality of COVID-19 infection (January); 2020." }, { "DOI": "10.3111/13696998.2010.506348", "doi-asserted-by": "crossref", "key": "1180559", "unstructured": "Ohsfeldt RL, Gandhi SK, Fox KM, Bullano MF, Davidson M. Medical and cost burden of atherosclerosis among patients treated in routine clinical practice. J Med Econ. 2010;13(3):500-7. doi: 10.3111/13696998.2010.506348, PMID 20673198." }, { "DOI": "10.1016/j.eclinm.2022.101373", "doi-asserted-by": "crossref", "key": "1180560", "unstructured": "Zhou Q, Zhao S, Gan L, Wang Z, Peng S, Li Q. Use of non-steroidal anti-inflammatory drugs and adverse outcomes during the COVID-19 pandemic: a systematic review and meta-analysis. E Clinical Medicine. 2022;46:101373. doi: org/10.1016/j.eclinm.2022.101373, PMID 35434582." }, { "DOI": "10.1007/s40264-021-01089-5", "doi-asserted-by": "crossref", "key": "1180561", "unstructured": "Moore N, Bosco Levy P, Thurin N, Blin P, Droz Perroteau C. NSAIDs and COVID-19: a systematic review and meta-analysis. Drug Saf. 2021;44(9):929-38. doi: org/10.1007/s40264-021-01089-5, PMID 34339037." }, { "DOI": "10.1007/s40256-021-00490-w", "doi-asserted-by": "crossref", "key": "1180562", "unstructured": "Kow CS, Hasan SS. The association between the use of statins and clinical outcomes in patients with COVID-19: a systematic review and meta-analysis. Am J Cardiovasc Drugs. 2022;22(2):167-81. doi: 10.1007/s40256-021-00490-w, PMID 34341972." }, { "key": "1180563", "unstructured": "Hasanah N, Chany F, Bustamam A, Yanuar A. Traditional Indonesian medication combats COVID-19; 2023. p. 1-24." }, { "key": "1180564", "unstructured": "Yanuar A, Muni’m A, Lagho ABA, Syahdi RR, Rahmat M, Suhartanto H. Medicinal plants database and three-dimensional structure of the chemical compounds from the medicinal plants in Indonesia. Int J Computer Sci. 2011;8(5):180–3." }, { "DOI": "10.1186/s12906-022-03662-6", "doi-asserted-by": "crossref", "key": "1180565", "unstructured": "Fu S, Zhou Y, Hu C, Xu Z, Hou J. Network pharmacology and molecular docking technology-based predictive study of the active ingredients and potential targets of rhubarb for the treatment of diabetic nephropathy. BMC Complement Med. 2022;22(1):210. doi: 10.1186/s12906-022-03662-6, PMID 35932042." }, { "DOI": "10.3390/ijms241210370", "doi-asserted-by": "crossref", "key": "1180566", "unstructured": "Liu L, Jiao Y, Yang M, Wu L, Long G, Hu W. Network pharmacology, molecular docking and Molecular Dynamics to explore the potential immunomodulatory mechanisms of deer antler. Int J Mol Sci. 2023;24(12):10370. doi: 10.3390/ijms241210370, PMID 37373516." }, { "DOI": "10.22159/ijap.2022v14i2.43784", "doi-asserted-by": "crossref", "key": "1180567", "unstructured": "Nurhidayah M, Fadilah F, Arsianti A, Bahtiar A. Identification of Fgfr inhibitor as St2 receptor/interleukin-1 receptor-like 1 inhibitor in chronic obstructive pulmonary disease due to exposure to E-cigarettes by network pharmacology and molecular docking prediction. Int J App Pharm. 2022;14(2):256-66. doi: 10.22159/ijap.2022v14i2.43784." }, { "DOI": "10.22159/ijap.2023v15i5.48416", "doi-asserted-by": "crossref", "key": "1180568", "unstructured": "Nahir CF, Putra MY, Wibowo JT, Lee VS, Yanuar A. The potential of indonesian marine natural product with dual targeting activity through Sars-Cov-2 3Clpro and PLpro: an in silico studies. Int J App Pharm. 2023;15(5):171-80. doi: 10.22159/ijap.2023v15i5.48416." }, { "DOI": "10.3389/fphar.2023.1237454", "doi-asserted-by": "crossref", "key": "1180569", "unstructured": "Giner-soriano M, Dominguez A, Morros R, Pericas C, Dolores A. Vilaplana-carnerero C. Narrative Rev. 2023;2:1-14." }, { "DOI": "10.1371/journal.pcbi.0030059", "doi-asserted-by": "crossref", "key": "1180570", "unstructured": "Yu H, Kim PM, Sprecher E, Trifonov V, Gerstein M. The importance of bottlenecks in protein networks: correlation with gene essentiality and expression dynamics. PLoS Comput Biol. 2007;3(4):e59. doi: 10.1371/journal.pcbi.0030059, PMID 17447836." }, { "DOI": "10.1142/S0219720013410023", "doi-asserted-by": "crossref", "key": "1180571", "unstructured": "Li M, Wang JX, Wang H, Pan Y. Identification of essential proteins from weighted protein-protein interaction networks. J Bioinform Comput Biol. 2013;11(3):1341002. doi: 10.1142/S0219720013410023, PMID 23796179." }, { "DOI": "10.1371/journal.pone.0195410", "doi-asserted-by": "crossref", "key": "1180572", "unstructured": "Zhang X, Xiao W, Hu X. Predicting essential proteins by integrating orthology, gene expressions, and PPI networks. PLOS ONE. 2018;13(4):e0195410. doi: 10.1371/journal.pone.0195410, PMID 29634727." }, { "DOI": "10.3390/ijms241512302", "doi-asserted-by": "crossref", "key": "1180573", "unstructured": "Rubio K, Molina Herrera A, Perez Gonzalez A, Hernandez Galdamez HV, Piña-Vazquez C, Araujo Ramos T. EP300 as a molecular integrator of fibrotic transcriptional programs. Int J Mol Sci. 2023;24(15):1-23. doi: 10.3390/ijms241512302, PMID 37569677." }, { "DOI": "10.1016/j.biopha.2018.07.132", "doi-asserted-by": "crossref", "key": "1180574", "unstructured": "Tao J, Zhang M, Wen Z, Wang B, Zhang L, Ou Y. Inhibition of EP300 and DDR1 synergistically alleviates pulmonary fibrosis in vitro and in vivo. Biomed Pharmacother. 2018;106(May):1727-33. doi: 10.1016/j.biopha.2018.07.132, PMID 30119248." }, { "DOI": "10.4314/tjpr.v19i9.22", "doi-asserted-by": "crossref", "key": "1180575", "unstructured": "Liu C, Fan FF, Li XH, Wang WX, Tu Y, Zhang Y. Elucidation of the mechanisms underlying the anticholecystitis effect of the tibetan medicine ”Dida” using network pharmacology. Trop J Pharm Res. 2020;19(9):1953-61. doi: 10.4314/tjpr.v19i9.22." }, { "DOI": "10.1155/2012/502813", "doi-asserted-by": "crossref", "key": "1180576", "unstructured": "Kilic A, Mandal K. Heat shock proteins: pathogenic role in atherosclerosis and potential therapeutic implications. Autoimmune Dis. 2012;2012(1):502813. doi: 10.1155/2012/502813, PMID 23304456." }, { "DOI": "10.1093/cvr/cvq046", "doi-asserted-by": "crossref", "key": "1180577", "unstructured": "Madrigal Matute J, Lopez Franco O, Blanco Colio LM, Munoz Garcia B, Ramos-Mozo P, Ortega L. Heat shock protein 90 inhibitors attenuate inflammatory responses in atherosclerosis. Cardiovasc Res. 2010;86(2):330-7. doi: 10.1093/cvr/cvq046, PMID 20154064." }, { "DOI": "10.3390/ijms22179366", "doi-asserted-by": "crossref", "key": "1180578", "unstructured": "Lubkowska A, Pluta W, Stronska A, Lalko A. Role of heat shock proteins (Hsp70 and hsp90) in viral infection. Int J Mol Sci. 2021;22(17). doi: 10.3390/ijms22179366, PMID 34502274." }, { "DOI": "10.1253/circj.CJ-15-1039", "doi-asserted-by": "crossref", "key": "1180579", "unstructured": "Wang JG, Aikawa M. Toll-like receptors and src-family kinases in atherosclerosis–Focus on macrophages. Circ J. 2015;79(11):2332-4. doi: 10.1253/circj.CJ-15-1039, PMID 26467082." }, { "DOI": "10.1155/2012/512926", "doi-asserted-by": "crossref", "key": "1180580", "unstructured": "Byeon SE, Yi YS, Oh J, Yoo BC, Hong S, Cho JY. The role of Src kinase in macrophage-mediated inflammatory responses. Mediators Inflamm. 2012;2012:512926. doi: 10.1155/2012/512926, PMID 23209344." }, { "DOI": "10.7150/ijbs.74864", "doi-asserted-by": "crossref", "key": "1180581", "unstructured": "Chen W, Zheng W, Liu S, Su Q, Ding K, Zhang Z. SRC-3 deficiency prevents atherosclerosis development by decreasing endothelial ICAM-1 expression to attenuate macrophage recruitment. Int J Biol Sci. 2022;18(15):5978-93. doi: 10.7150/ijbs.74864, PMID 36263184." }, { "DOI": "10.1038/s41598-022-13585-4", "doi-asserted-by": "crossref", "key": "1180582", "unstructured": "Li F, Boon ACM, Michelson AP, Foraker RE, Zhan M, Payne PRO. Estrogen hormone is an essential sex factor inhibiting inflammation and immune response in COVID-19. Sci Rep. 2022;12(1):9462. doi: org/10.1038/s41598-022-13585-4, PMID 35676404." }, { "DOI": "10.1111/j.1399-0039.2007.00865.x", "doi-asserted-by": "crossref", "key": "1180583", "unstructured": "Hirankarn N, Manonom C, Tangkijvanich P, Poovorawan Y. Association of interleukin-18 gene polymorphism (−607A/A genotype) with susceptibility to chronic hepatitis B virus infection. Tissue Antigens. 2007;70(2):160-3. doi: 10.1111/j.1399-0039.2007.00865.x, PMID 17610422." }, { "DOI": "10.1186/s12906-023-04148-9", "doi-asserted-by": "crossref", "key": "1180584", "unstructured": "Xiao W, Xu Y, Baak JP, Dai J, Jing L, Zhu H. Network module analysis and molecular docking-based study on the mechanism of astragali radix against non-small cell lung cancer. BMC Complement Med. 2023;23(1):345. doi: 10.1186/s12906-023-04148-9, PMID 37770919." }, { "key": "1180585", "unstructured": "Jimi E, Fei Huang CN. NF-κB signaling regulates; 2019. p. 3-11." }, { "DOI": "10.1161/CIRCRESAHA.110.233841", "doi-asserted-by": "crossref", "key": "1180586", "unstructured": "Cuhlmann S, Van Der Heiden K, Saliba D, Tremoleda JL, Khalil M, Zakkar M. Disturbed blood flow induces rela expression via c-Jun N-terminal kinase 1: a novel mode of NF-κB regulation that promotes arterial inflammation. Circ Res. 2011;108(8):950-9. doi: 10.1161/circresaha.110.233841, PMID 21350211." } ], "reference-count": 43, "references-count": 43, "relation": {}, "resource": { "primary": { "URL": "https://journals.innovareacademics.in/index.php/ijap/article/view/50128" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [ "Pharmaceutical Science" ], "subtitle": [], "title": "DECODING THE THERAPEUTIC POTENTIAL OF EMPON-EMPON: A BIOINFORMATICS EXPEDITION UNRAVELING MECHANISMS AGAINST COVID-19 AND ATHEROSCLEROSIS", "type": "journal-article" }
Please send us corrections, updates, or comments. c19early involves the extraction of 200,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. IMA and WCH provide treatment protocols.
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