Honeysuckle Aqueous Extracts Induced let-7a Suppress EV71 Replication and Pathogenesis In Vitro and In Vivo and Is Predicted to Inhibit SARS-CoV-2
Abstract
:1. Introduction
2. Materials and Methods
2.1. Preparation of Honeysuckle Aqueous Extract Preparation and Analysis of Blood miRNA Expression Profiles in Human Participants and Mice after Ingestion
2.2. Prediction of Honeysuckle-Induced miRNA and Pathway Analysis
2.3. Cell Culture and Viruses
2.4. Plaque Assay
2.5. Western Blot Analysis
2.6. Reporter Plasmids and Luciferase Assay
2.7. RT-PCR and Real-Time PCR
2.8. Suckling Mouse Model for EV71 Infection
3. Results
3.1. Honeysuckle-Induced Host miRNAs Both in Mice and Humans Were Predicted to Be Capable of Targeting Genome Sequences of SARS-CoV-2, DENV and EV71
3.2. In Silico Prediction of Honeysuckle-Related Pathways Are Highly Correlated to Diverse Virus Infections and Regulation of Cytokines
3.3. Let-7a Bound with Two EV71 Replicon Clones and Attenuated Luciferase Activity
3.4. Let-7a Was Confirmed to Specifically Target the EV71 Genome at Two Regions, 5′UTR 233–254 and VP2 1234–1256
3.5. Let-7a Suppressed EV71 RNA Expression and Viral Titer in Various Infected Cell Lines
3.6. Honeysuckle Ingestion Attenuated Disease Symptoms, Prolonged Survival Time and Suppressed Viral Replication as Well as Viral Titer in EV71 MP4-Infected Suckling Mice
3.7. Let-7a Treatment Alleviated Clinical Scores, Prolonged Survival Time and Suppressed Viral Replication and Viral Titer in EV71 MP4-Infected Suckling Mice
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Enriched Pathway-Based Sets | q-Value # | Source |
---|---|---|
Interleukin-4 and Interleukin-13 signaling | 4.82E-29 | Wikipathways |
Human cytomegalovirus infection | 2.40E-22 | KEGG |
Kaposi sarcoma-associated herpesvirus infection | 6.30E-20 | KEGG |
Human T-cell leukemia virus 1 infection | 1.94E-18 | KEGG |
Epstein–Barr virus infection | 2.43E-18 | KEGG |
IL-17 signaling pathway | 4.20E-17 | KEGG |
IL-2 receptor beta chain in t cell activation | 4.41E-12 | BioCarta |
Validated transcriptional targets of AP1 family members Fra1 and Fra2 | 5.32E-12 | PID |
Human immunodeficiency virus 1 infection | 8.74E-11 | KEGG |
Human papillomavirus infection | 1.41E-10 | KEGG |
IL-2-mediated signaling events | 3.35E-10 | PID |
IL-2 Signaling Pathway | 4.95E-10 | Wikipathways |
Interleukin-10 signaling | 4.18E-09 | Wikipathways |
IL-5 Signaling Pathway | 6.59E-09 | Wikipathways |
IL-6 | 8.49E-09 | NetPath |
IL-3 Signaling Pathway | 3.56E-08 | Wikipathways |
IL-11 | 4.30E-08 | NetPath |
IL-23-mediated signaling events | 6.36E-08 | PID |
IL-7 Signaling Pathway | 7.65E-08 | Wikipathways |
IL-4 Signaling Pathway | 7.99E-08 | Wikipathways |
Interleukin-11 Signaling Pathway | 2.44E-07 | Wikipathways |
IL-2 signaling events mediated by STAT5 | 2.80E-07 | PID |
IL-6-mediated signaling events | 3.97E-07 | PID |
Regulation of Telomerase | 5.31E-07 | PID |
IL-1 | 1.08E-06 | NetPath |
IL-2 signaling events mediated by PI3K | 1.11E-06 | PID |
Signal transduction through il1r | 1.11E-06 | BioCarta |
IL-1 signaling pathway | 1.22E-06 | Wikipathways |
IL-2 | 1.29E-06 | NetPath |
Ras signaling in the CD4+ TCR pathway | 1.91E-06 | PID |
IL-27-mediated signaling events | 2.20E-06 | PID |
Ras signaling pathway | 2.82E-06 | KEGG |
Fc-epsilon receptor I signaling in mast cells | 2.83E-06 | PID |
IL-4 | 3.16E-06 | NetPath |
Human cytomegalovirus and map kinase pathways | 3.74E-06 | BioCarta |
Ras Signaling | 7.25E-06 | Wikipathways |
Signaling by Interleukins | 7.27E-06 | Reactome |
Natural killer cell-mediated cytotoxicity | 1.17E-05 | KEGG |
Activation of the AP-1 family of transcription factors | 1.39E-05 | Reactome |
IL-6 signaling pathway | 3.54E-05 | Wikipathways |
IL-4-mediated signaling events | 3.66E-05 | PID |
IL-12-mediated signaling events | 3.66E-05 | PID |
IL-7 signaling | 3.76E-05 | INOH |
IL-10 anti-inflammatory signaling pathway | 4.00E-05 | BioCarta |
Fc epsilon RI signaling pathway | 4.30E-05 | KEGG |
IL8- and CXCR1-mediated signaling events | 5.36E-05 | PID |
Fc epsilon receptor i signaling in mast cells | 6.24E-05 | BioCarta |
Nfkb activation by nontypeable hemophilus influenzae | 6.24E-05 | BioCarta |
IL-3 | 8.49E-05 | NetPath |
IL-12 signaling mediated by STAT4 | 9.82E-05 | PID |
IL-8- and CXCR2-mediated signaling events | 0.000129 | PID |
West Nile virus | 0.000231 | BioCarta |
MAPK family signaling cascades | 0.000287 | Reactome |
Ccr3 signaling in eosinophils | 0.000346 | BioCarta |
Ebola Virus Pathway on Host | 0.00037 | Wikipathways |
Structural Pathway of Interleukin 1 (IL-1) | 0.000392 | Wikipathways |
IL-1 and megakaryocytes in obesity | 0.0004 | Wikipathways |
Signaling pathway from g-protein families | 0.000528 | BioCarta |
IL-5 | 0.000562 | NetPath |
IL-7 | 0.000607 | NetPath |
IL-17 signaling pathway | 0.000985 | Wikipathways |
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors | 0.00113 | Wikipathways |
Regulation of Ras family activation | 0.00123 | PID |
Calcium signaling by hbx of hepatitis b virus | 0.00162 | BioCarta |
IL-1-mediated signaling events | 0.00162 | PID |
IL-1 NFkB | 0.00181 | INOH |
IL-9 Signaling Pathway | 0.00187 | Wikipathways |
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors | 0.00228 | Reactome |
TFAP2 (AP-2) family regulates transcription of cell cycle factors | 0.00246 | Reactome |
Ras signaling pathway | 0.0028 | BioCarta |
Fc epsilon receptor (FCERI) signaling | 0.00348 | Reactome |
Interleukin-1 processing | 0.00467 | Reactome |
FoxO family signaling | 0.00467 | PID |
IPA Canonical Pathways | −log (p-Value) |
---|---|
IL-12 signaling and production in macrophages | 17.4 |
IL-8 signaling | 14.8 |
IL-6 signaling | 12.7 |
Role of PKR in interferon induction and antiviral response | 12.2 |
IL-10 signaling | 12 |
Role of pattern recognition receptors in recognition of bacteria and viruses | 12 |
IL-7 signaling pathway | 10.1 |
TNFR1 signaling | 9.79 |
ILK signaling | 9.45 |
IL-17A signaling in fibroblasts | 8.9 |
IL-3 signaling | 8.23 |
TNFR2 signaling | 7.5 |
NF-κB activation by viruses | 6.61 |
Differential regulation of cytokine production in macrophages and T helper cells by IL-17A and IL-17F | 6.55 |
IL-23 signaling pathway | 6.55 |
Differential regulation of cytokine production in intestinal epithelial cells by IL-17A and IL-17F | 6.1 |
IL-15 signaling | 5.5 |
IL-17 signaling | 5.25 |
Regulation of IL-2 expression in activated and anergic T lymphocytes | 5.04 |
IL-17A signaling in airway cells | 4.28 |
LPS/IL-1-mediated inhibition of RXR function | 4.25 |
IL-1 signaling | 3.69 |
Mechanisms of viral exit from host cells | 3.52 |
Natural killer cell signaling | 3.27 |
IL-2 signaling | 3.01 |
Virus entry via endocytic pathways | 2.31 |
IL-9 signaling | 2.3 |
IL-15 production | 2.19 |
Role of RIG1-like receptors in antiviral innate immunity | 2.1 |
IL-4 signaling | 1.55 |
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Lee, Y.-R.; Chang, C.-M.; Yeh, Y.-C.; Huang, C.-Y.F.; Lin, F.-M.; Huang, J.-T.; Hsieh, C.-C.; Wang, J.-R.; Liu, H.-S. Honeysuckle Aqueous Extracts Induced let-7a Suppress EV71 Replication and Pathogenesis In Vitro and In Vivo and Is Predicted to Inhibit SARS-CoV-2. Viruses 2021, 13, 308. https://doi.org/10.3390/v13020308
Lee Y-R, Chang C-M, Yeh Y-C, Huang C-YF, Lin F-M, Huang J-T, Hsieh C-C, Wang J-R, Liu H-S. Honeysuckle Aqueous Extracts Induced let-7a Suppress EV71 Replication and Pathogenesis In Vitro and In Vivo and Is Predicted to Inhibit SARS-CoV-2. Viruses. 2021; 13(2):308. https://doi.org/10.3390/v13020308
Chicago/Turabian StyleLee, Ying-Ray, Chia-Ming Chang, Yuan-Chieh Yeh, Chi-Ying F. Huang, Feng-Mao Lin, Juan-Ting Huang, Chang-Chi Hsieh, Jen-Ren Wang, and Hsiao-Sheng Liu. 2021. "Honeysuckle Aqueous Extracts Induced let-7a Suppress EV71 Replication and Pathogenesis In Vitro and In Vivo and Is Predicted to Inhibit SARS-CoV-2" Viruses 13, no. 2: 308. https://doi.org/10.3390/v13020308
APA StyleLee, Y. -R., Chang, C. -M., Yeh, Y. -C., Huang, C. -Y. F., Lin, F. -M., Huang, J. -T., Hsieh, C. -C., Wang, J. -R., & Liu, H. -S. (2021). Honeysuckle Aqueous Extracts Induced let-7a Suppress EV71 Replication and Pathogenesis In Vitro and In Vivo and Is Predicted to Inhibit SARS-CoV-2. Viruses, 13(2), 308. https://doi.org/10.3390/v13020308