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Therapeutic effect and potential mechanism of curcumin, an active ingredient in Tongnao Decoction, on COVID-19 combined with stroke: a network pharmacology study and GEO database mining

Yunze et al., Research Square, doi:10.21203/rs.3.rs-4329762/v1

May 2024

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Curcumin for COVID-19

15th treatment shown to reduce risk in February 2021, now with p = 0.0000000096 from 27 studies.

Lower risk for mortality, ventilation, hospitalization, progression, recovery, and viral clearance.

No treatment is 100% effective. Protocols combine treatments.

5,100+ studies for 112 treatments. c19early.org

In Silico study showing that curcumin, the active ingredient in Tongnao Decoction, may be beneficial for COVID-19 combined with stroke through the CCNA2, JAK2, MMP9, PPARG, PTGS2, and STAT3 target pathways, with MMP9 being the most important target. Authors used network pharmacology and GEO database mining to identify 205 overlapping differentially expressed genes between COVID-19 and stroke datasets. Enrichment analysis showed these genes were involved in immune response, inflammation, and signaling pathways. Curcumin was predicted as a candidate treatment and molecular docking showed strong binding of curcumin to the 6 core target proteins.

51 preclinical studies support the efficacy of curcumin for COVID-19:

26 In Silico studies1-26

24 In Vitro studies1,3,7,9,13,19,23,27-43

1 In Vivo animal study7

In Silico studies predict inhibition of SARS-CoV-2 with curcumin or metabolites via binding to the spikeA,2,7,12,14,20,23,44 (and specifically the receptor binding domainB,10,13,16), M^proC,2,7,9,11-13,15,16,18,21,23,24,26,40,44, RNA-dependent RNA polymeraseD,2,13,22,44, PLproE,2, ACE2F,14,15,17, nucleocapsidG,8,25, nsp10H,25, and helicaseI,29 proteins. In Vitro studies demonstrate inhibition of the spikeA,34 (and specifically the receptor binding domainB,43), M^proC,19,34,40,42, ACE2F,43, and TMPRSS2J,43 proteins, and inhibition of spike-ACE2 interactionK,27. In Vitro studies demonstrate efficacy in Calu-3L,41, A549M,34, 293TN,3, HEK293-hACE2O,19,32, 293T/hACE2/TMPRSS2P,33, Vero E6Q,9,13,23,32,34,36,37,39,41, and SH-SY5YR,31 cells. Curcumin is predicted to inhibit the interaction between the SARS-CoV-2 spike protein receptor binding domain and the human ACE2 receptor for the delta and omicron variants10, decreases pro-inflammatory cytokines induced by SARS-CoV-2 in peripheral blood mononuclear cells39, alleviates SARS-CoV-2 spike protein-induced mitochondrial membrane damage and oxidative stress3, may limit COVID-19 induced cardiac damage by inhibiting the NF-κB signaling pathway which mediates the profibrotic effects of the SARS-CoV-2 spike protein on cardiac fibroblasts45, and inhibits SARS-CoV-2 ORF3a ion channel activity, which contributes to viral pathogenicity and cytotoxicity35.

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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 M^pro, also known as 3CL^pro or nsp5, is a cysteine protease that cleaves viral polyproteins into functional units needed for replication. Inhibiting M^pro 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. 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.

h. Non-structural protein 10 (nsp10) serves as an RNA chaperone and stabilizes conformations of nsp12 and nsp14 in the replicase-transcriptase complex, which synthesizes new viral RNAs. Nsp10 disruption may destabilize replicase-transcriptase complex activity.

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. 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.

k. 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.

l. 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.

m. 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.

n. 293T is a human embryonic kidney cell line that can be engineered for high ACE2 expression and SARS-CoV-2 susceptibility. 293T cells are easily transfected and support high protein expression.

o. HEK293-hACE2 is a human embryonic kidney cell line with high ACE2 expression and SARS-CoV-2 susceptibility. Cells have been transfected with a plasmid to express the human ACE2 (hACE2) protein.

p. 293T/hACE2/TMPRSS2 is a human embryonic kidney cell line engineered for high ACE2 and TMPRSS2 expression, which mimics key aspects of human infection. 293T/hACE2/TMPRSS2 cells are very susceptible to SARS-CoV-2 infection.

q. 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.

r. SH-SY5Y is a human neuroblastoma cell line that exhibits neuronal phenotypes. It is commonly used as an in vitro model for studying neurotoxicity, neurodegenerative diseases, and neuronal differentiation.

Yunze et al., 29 May 2024, preprint, 10 authors.

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

This Paper Curcumin All

Therapeutic effect and potential mechanism of curcumin, an active ingredient in Tongnao Decoction, on COVID-19 combined with stroke: a network pharmacology study and GEO database mining

Li Yunze, Yao Yangjing, Mao Rui, Wu Jiacheng, Liu Yan, Feng Qinghua, Hu Manyan, Chen Weiwei, Wu Minghua, Li Jianjun

doi:10.21203/rs.3.rs-4329762/v1

Background The onset of severe acute respiratory syndrome coronavirus type 2 at the end of 2019 led to a global pandemic of acute respiratory diseases, commonly known as COVID-19, caused by this highly infectious and pathogenic coronavirus. As members of the Fifth-batch National TCM Medical Team sent by the A liated Hospital of Nanjing University of Chinese Medicine to assist Wuhan Jiangxia Mobile Cabin Hospital, it was observed that patients with COVID-19 had an elevated incidence of stroke and are prone to progression. The possible mechanisms included neuroinvasion by the virus, an imbalance between ACE1 and ACE2, hypercoagulability, and a pre-thrombotic state. However, effective treatment options are not yet available. Developed by the Department of Neurology, A liated Hospital of Nanjing University of Chinese Medicine, Tongnao Decoction (TND) is a prescribed medication. The chemical components within the TND extract were previously examined using Waters ACQUITY UPLC ultra-performance liquid chromatography. Notably, identi ed chemical constituents, including curcumin, exhibited protective effects on brain cells. In the current investigation, bioinformatics techniques were employed to mine the GEO database, aiming to assess the functional role and potential action mechanism of curcumin as a therapeutic agent for COVID-19 combined with stroke.Tongnao Decoction Methods The datasets of COVID-19 and stroke were retrieved from the GEO database to identify the differentially intersecting genes (DIGs) between the two diseases. These DIGs were then exposed to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses employing

Declarations 6 Data availability The data used to support the results of this study are available from the rst and corresponding authors. of interest: The authors declare that they have no known competing nancial interests or personal relationships that could have appeared to in uence the work reported in this paper. The owchart of the analysis process.

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{ 'institution': [{'name': 'Research Square'}], 'indexed': {'date-parts': [[2024, 5, 29]], 'date-time': '2024-05-29T02:10:36Z', 'timestamp': 1716948636665}, 'posted': {'date-parts': [[2024, 5, 29]]}, 'group-title': 'In Review', 'reference-count': 0, 'publisher': 'Research Square Platform LLC', 'license': [ { 'start': { 'date-parts': [[2024, 5, 29]], 'date-time': '2024-05-29T00:00:00Z', 'timestamp': 1716940800000}, 'content-version': 'unspecified', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0/'}], 'content-domain': {'domain': [], 'crossmark-restriction': False}, 'accepted': {'date-parts': [[2024, 4, 26]]}, 'abstract': '<title>Abstract</title>\n' ' <p>Background\n' ' The onset of severe acute respiratory syndrome coronavirus type 2 at the end of 2019 led to ' 'a global pandemic of acute respiratory diseases, commonly known as COVID-19, caused by this ' 'highly infectious and pathogenic coronavirus. As members of the Fifth-batch National TCM ' 'Medical Team sent by the Affiliated Hospital of Nanjing University of Chinese Medicine to ' 'assist Wuhan Jiangxia Mobile Cabin Hospital, it was observed that patients with COVID-19 had ' 'an elevated incidence of stroke and are prone to progression. The possible mechanisms ' 'included neuroinvasion by the virus, an imbalance between ACE1 and ACE2, hypercoagulability, ' 'and a pre-thrombotic state. However, effective treatment options are not yet available. ' 'Developed by the Department of Neurology, Affiliated Hospital of Nanjing University of ' 'Chinese Medicine, Tongnao Decoction (TND) is a prescribed medication. The chemical components ' 'within the TND extract were previously examined using Waters ACQUITY UPLC ultra-performance ' 'liquid chromatography. Notably, identified chemical constituents, including curcumin, ' 'exhibited protective effects on brain cells. In the current investigation, bioinformatics ' 'techniques were employed to mine the GEO database, aiming to assess the functional role and ' 'potential action mechanism of curcumin as a therapeutic agent for COVID-19 combined with ' 'stroke.Tongnao Decoction\n' 'Methods\n' ' The datasets of COVID-19 and stroke were retrieved from the GEO database to identify the ' 'differentially intersecting genes (DIGs) between the two diseases. These DIGs were then ' 'exposed to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway ' 'enrichment analyses employing the clusterProfiler to extract TF genes in the Trrust database ' '(TF in TRRUST). Core TF genes were found to be target genes in DEGs-related TF in Stroke and ' 'DEGs-related TF in COVID. The overlapping set of these target genes yielded intersected ' 'target genes, which were then imported into the DGIdb website for drug prediction. ' 'Subsequently, the selected core drugs were subjected to drug validation on the cMAP website. ' 'Target prediction was performed on four online platforms: SEA, SwissTargetPrediction, ' 'TargetNet, and TCMSP. Subsequently, the obtained results were imported into the String ' 'database to create an interaction network comprising core target genes and enriched pathways. ' 'Additionally, molecular docking was performed using AutoDock software. Finally, molecular ' 'docking scoring was applied to the core targets.\n' 'Results\n' ' The intersection of DEGs from stroke dataset GSE16561 with DEGs from COVID dataset GSE211979 ' 'yielded 205 intersected genes. These intersected genes, including E2F3, BCL6, ETS2, CEBPD, ' 'STAT1, MXD1, NFIL3, HDAC4, MMP9, CD163, FCGR1A, IFIT3, LY96, PLSCR1, TNFSF10:E2F3, BCL6, ' 'ETS2, CEBPD, STAT1, MXD1, NFIL3, HDAC4, MMP9, CD163, FCGR1A, IFIT3, LY96, PLSCR1, and ' 'TNFSF10, were subjected to GO and KEGG pathway enrichment analyses utilizing the ' 'clusterProfiler. Subsequently, the core drug curcumin was selected from the 17 intersected ' 'drugs. Curcumin inhibits NF-κb and MAPKs and possesses various pharmacological effects ' 'encompassing anti-proliferative, anti-oxidant, anti-inflammatory, and anti-angiogenic ' 'effects. The six core targets CCNA2, JAK2, MMP9, PPARG, PTGS2, and STAT3 had molecular ' 'docking scores of -2.86, -2.98, -5.01, -2.42, -3.83, and −\u20092.28, respectively.\n' 'Conclusion\n' ' Curcumin, the active ingredient in TND, can effectively intervene in COVID-19 combined with ' 'stroke through CCNA2, JAK2, MMP9, PPARG, PTGS2, and STAT3 target pathways, of which the most ' 'important target is MMP9.</p>', 'DOI': '10.21203/rs.3.rs-4329762/v1', 'type': 'posted-content', 'created': {'date-parts': [[2024, 5, 29]], 'date-time': '2024-05-29T01:55:37Z', 'timestamp': 1716947737000}, 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'Therapeutic effect and potential mechanism of curcumin, an active ingredient in Tongnao ' 'Decoction, on COVID-19 combined with stroke: a network pharmacology study and GEO database ' 'mining', 'prefix': '10.21203', 'author': [ { 'given': 'Li', 'family': 'Yunze', 'sequence': 'first', 'affiliation': [ { 'name': 'Affiliated Hospital of Nanjing University of Chinese Medicine, ' 'Nanjing University of Chinese Medicine'}]}, { 'given': 'Yao', 'family': 'Yangjing', 'sequence': 'additional', 'affiliation': [ { 'name': 'Affiliated Hospital of Nanjing University of Chinese Medicine, ' 'Nanjing University of Chinese Medicine'}]}, { 'given': 'Mao', 'family': 'Rui', 'sequence': 'additional', 'affiliation': [{'name': 'Lianyungang Food and Drug Inspection Center'}]}, { 'given': 'Wu', 'family': 'Jiacheng', 'sequence': 'additional', 'affiliation': [{'name': 'Nanjing Medical University Friendship Plastic Surgery Hospital'}]}, { 'given': 'Liu', 'family': 'Yan', 'sequence': 'additional', 'affiliation': [ { 'name': 'Affiliated Hospital of Nanjing University of Chinese Medicine, ' 'Nanjing University of Chinese Medicine'}]}, { 'given': 'Feng', 'family': 'Qinghua', 'sequence': 'additional', 'affiliation': [ { 'name': 'Affiliated Hospital of Nanjing University of Chinese Medicine, ' 'Nanjing University of Chinese Medicine'}]}, { 'given': 'Hu', 'family': 'Manyan', 'sequence': 'additional', 'affiliation': [ { 'name': 'Affiliated Hospital of Nanjing University of Chinese Medicine, ' 'Nanjing University of Chinese Medicine'}]}, { 'given': 'Chen', 'family': 'Weiwei', 'sequence': 'additional', 'affiliation': [ { 'name': 'Affiliated Hospital of Nanjing University of Chinese Medicine, ' 'Nanjing University of Chinese Medicine'}]}, { 'given': 'Wu', 'family': 'Minghua', 'sequence': 'additional', 'affiliation': [ { 'name': 'Affiliated Hospital of Nanjing University of Chinese Medicine, ' 'Nanjing University of Chinese Medicine'}]}, { 'given': 'Li', 'family': 'Jianjun', 'sequence': 'additional', 'affiliation': [{'name': 'Lianyungang Hospital of Traditional Chinese Medicine'}]}], 'member': '8761', 'container-title': [], 'original-title': [], 'link': [ { 'URL': 'https://www.researchsquare.com/article/rs-4329762/v1', 'content-type': 'text/html', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://www.researchsquare.com/article/rs-4329762/v1.html', 'content-type': 'unspecified', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2024, 5, 29]], 'date-time': '2024-05-29T01:55:37Z', 'timestamp': 1716947737000}, 'score': 1, 'resource': {'primary': {'URL': 'https://www.researchsquare.com/article/rs-4329762/v1'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2024, 5, 29]]}, 'references-count': 0, 'URL': 'http://dx.doi.org/10.21203/rs.3.rs-4329762/v1', 'relation': {}, 'subject': [], 'published': {'date-parts': [[2024, 5, 29]]}, 'subtype': 'preprint'}

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