{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T13:08:30Z","timestamp":1790341710727,"version":"4.1.0"},"reference-count":90,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2024,12,16]],"date-time":"2024-12-16T00:00:00Z","timestamp":1734307200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"MUR-FISR COVID-miRNAPNA Project","award":["FISR2020IP_04128"],"award-info":[{"award-number":["FISR2020IP_04128"]}]},{"name":"MUR-FISR COVID-miRNAPNA Project","award":["CIB-Unife-2020"],"award-info":[{"award-number":["CIB-Unife-2020"]}]},{"name":"MUR-FISR COVID-miRNAPNA Project","award":["MARZ_CARIVARI20_01 C94I20002500007"],"award-info":[{"award-number":["MARZ_CARIVARI20_01 C94I20002500007"]}]},{"name":"MUR-FISR COVID-miRNAPNA Project","award":["25528"],"award-info":[{"award-number":["25528"]}]},{"name":"Interuniversity Consortium for Biotechnologies","award":["FISR2020IP_04128"],"award-info":[{"award-number":["FISR2020IP_04128"]}]},{"name":"Interuniversity Consortium for Biotechnologies","award":["CIB-Unife-2020"],"award-info":[{"award-number":["CIB-Unife-2020"]}]},{"name":"Interuniversity Consortium for Biotechnologies","award":["MARZ_CARIVARI20_01 C94I20002500007"],"award-info":[{"award-number":["MARZ_CARIVARI20_01 C94I20002500007"]}]},{"name":"Interuniversity Consortium for Biotechnologies","award":["25528"],"award-info":[{"award-number":["25528"]}]},{"name":"CARIPARO Foundation","award":["FISR2020IP_04128"],"award-info":[{"award-number":["FISR2020IP_04128"]}]},{"name":"CARIPARO Foundation","award":["CIB-Unife-2020"],"award-info":[{"award-number":["CIB-Unife-2020"]}]},{"name":"CARIPARO Foundation","award":["MARZ_CARIVARI20_01 C94I20002500007"],"award-info":[{"award-number":["MARZ_CARIVARI20_01 C94I20002500007"]}]},{"name":"CARIPARO Foundation","award":["25528"],"award-info":[{"award-number":["25528"]}]},{"name":"FIRC-AIRC \u201cMichele e Carlo Ardizzone\u201d","award":["FISR2020IP_04128"],"award-info":[{"award-number":["FISR2020IP_04128"]}]},{"name":"FIRC-AIRC \u201cMichele e Carlo Ardizzone\u201d","award":["CIB-Unife-2020"],"award-info":[{"award-number":["CIB-Unife-2020"]}]},{"name":"FIRC-AIRC \u201cMichele e Carlo Ardizzone\u201d","award":["MARZ_CARIVARI20_01 C94I20002500007"],"award-info":[{"award-number":["MARZ_CARIVARI20_01 C94I20002500007"]}]},{"name":"FIRC-AIRC \u201cMichele e Carlo Ardizzone\u201d","award":["25528"],"award-info":[{"award-number":["25528"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Garlic (Allium sativum L.) is a species of the onion family (Alliaceae) widely used as a food and a folk medicine. The objective of this study was to determine the effects of AGE (aged garlic extract) on pro-inflammatory genes relevant to COVID-19. To this aim, we treated bronchial epithelial IB3-1 cells with SARS-CoV-2 spike protein (S-protein) or with the COVID-19 BNT162b2 vaccine in the absence or in the presence of AGE. The results obtained demonstrated that AGE is a potent inhibitor of the S-protein-induced expression of the IL-1\u03b2, IL-6 and IL-8 genes. Bio-Plex analysis demonstrated that AGE reduced release of IL-6 and IL-8, which were highly induced by S-protein. No inhibition of cells\u2019 growth, toxicity and pro-apoptotic effects were found in AGE-treated cells. The effects of one of the major AGE constituents (S-allyl cysteine, SAC) were studied on the same experimental model systems. SAC was able to inhibit the S-protein-induced expression of IL-1\u03b2, IL-6 and IL-8 genes and extracellular release of IL-6 and IL-8, confirming that S-allyl-cysteine is one of the constituents of AGE that is responsible for inhibiting S-protein-induced pro-inflammatory genes. Docking experiments suggest that a possible mechanism of action of SAC is an interference with the activity of Toll-like receptors (TLRs), particularly TLR4, thereby inhibiting NF-\u03baB- and NF-\u03baB-regulated genes, such as IL-1\u03b2, IL-6 and IL-8 genes. These results suggest that both AGE and SAC deserve further experimental efforts to verify their effects on pro-inflammatory genes in SARS-CoV-2-infected cells.<\/jats:p>","DOI":"10.3390\/molecules29245938","type":"journal-article","created":{"date-parts":[[2024,12,16]],"date-time":"2024-12-16T12:09:28Z","timestamp":1734350968000},"page":"5938","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Aged Garlic Extract (AGE) and Its Constituent S-Allyl-Cysteine (SAC) Inhibit the Expression of Pro-Inflammatory Genes Induced in Bronchial Epithelial IB3-1 Cells by Exposure to the SARS-CoV-2 Spike Protein and the BNT162b2 Vaccine"],"prefix":"10.3390","volume":"29","author":[{"given":"Jessica","family":"Gasparello","sequence":"first","affiliation":[{"name":"Department of Life Sciences and Biotechnology, Ferrara University, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9242-1766","authenticated-orcid":false,"given":"Chiara","family":"Papi","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Biotechnology, Ferrara University, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5892-5992","authenticated-orcid":false,"given":"Giovanni","family":"Marzaro","sequence":"additional","affiliation":[{"name":"Department of Diagnostics and Public Health, University of Verona, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0455-1400","authenticated-orcid":false,"given":"Alberto","family":"Macone","sequence":"additional","affiliation":[{"name":"Department of Biochemical Sciences \u2018A. Rossi Fanelli\u2019, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Zurlo","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Biotechnology, Ferrara University, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7638-515X","authenticated-orcid":false,"given":"Alessia","family":"Finotti","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Biotechnology, Ferrara University, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2508-8868","authenticated-orcid":false,"given":"Enzo","family":"Agostinelli","sequence":"additional","affiliation":[{"name":"Department of Sensory Organs, Sapienza University of Rome, Policlinico Umberto I, Viale del Policlinico 155, 00161 Rome, Italy"},{"name":"International Polyamines Foundation \u2018ETS-ONLUS\u2019, Via del Forte Tiburtino 98, 00159 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9205-6033","authenticated-orcid":false,"given":"Roberto","family":"Gambari","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Biotechnology, Ferrara University, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,16]]},"reference":[{"key":"ref_1","unstructured":"Koch, H.P., and Lawson, L.D. (1996). History, folk medicine, and legendary uses of garlic. Garlic: The Science and Therapeutic Application of Allium sativum L. and Related Species, Williams & Wilkins."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"949554","DOI":"10.3389\/fnut.2022.929554","article-title":"Traditional uses, phytochemistry, pharmacology and toxicology of garlic (Allium sativum), a storehouse of diverse phytochemicals: A review of research from the last decade focusing on health and nutritional implications","volume":"9","author":"Tudu","year":"2022","journal-title":"Front. Nutr."},{"key":"ref_3","first-page":"e42484","article-title":"Traditional Vietnamese Medicine Containing Garlic Extract for Patients with Non-severe COVID-19: A Phase-II, Double-Blind, Randomized Controlled Trial","volume":"15","author":"Giang","year":"2023","journal-title":"Cureus"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s13002-022-00513-z","article-title":"Traditional uses and practices of edible cultivated Allium species (fam. Amaryllidaceae) in Sweden","volume":"18","author":"Svanberg","year":"2022","journal-title":"J. Ethnobiol. Ethnomed."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2415","DOI":"10.1039\/D1FO03180E","article-title":"Biological properties and therapeutic applications of garlic and its components","volume":"13","author":"Ruiz","year":"2022","journal-title":"Food Funct."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"115452","DOI":"10.1016\/j.jep.2022.115452","article-title":"Insight into drug sensitizing effect of diallyl disulfide and diallyl trisulfide from Allium sativum L. on paclitaxel-resistant triple-negative breast cancer cells","volume":"29","author":"Marni","year":"2022","journal-title":"J. Ethnopharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4041","DOI":"10.1002\/ptr.7556","article-title":"A systematic review of randomized controlled trials related to the effects of garlic supplementation on platelet aggregation","volume":"36","author":"Mollahosseini","year":"2022","journal-title":"Phytother. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"113835","DOI":"10.1016\/j.colsurfb.2024.113835","article-title":"Evaluating the hypolipidemic effect of garlic essential oil encapsulated in a novel double-layer delivery system","volume":"237","author":"Zhang","year":"2024","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"213592","DOI":"10.1016\/j.bioadv.2023.213592","article-title":"Garlic-derived exosome-like nanovesicles as a hepatoprotective agent alleviating acute liver failure by inhibiting CCR2\/CCR5 signaling and inflammation","volume":"154","author":"Zhao","year":"2023","journal-title":"Biomater. Adv."},{"key":"ref_10","first-page":"1257","article-title":"The antioxidant, aged garlic extract, exerts cytotoxic effects on wild-type and multidrug-resistant human cancer cells by altering mitochondrial permeability","volume":"53","author":"Ohkubo","year":"2018","journal-title":"Int. J. Oncol."},{"key":"ref_11","first-page":"1511","article-title":"Aged garlic extract and its constituent, S-allyl-L-cysteine, induce the apoptosis of neuroblastoma cancer cells due to mitochondrial membrane depolarization","volume":"19","author":"Kanamori","year":"2020","journal-title":"Exp. Ther. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1055\/s-2006-959522","article-title":"Antioxidant and radical scavenging effects of aged garlic extract and its constituents","volume":"60","author":"Imai","year":"1994","journal-title":"Planta Medica"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Serrano, J.C.E., Castro-Boqu\u00e9, E., Garc\u00eda-Carrasco, A., Mor\u00e1n-Valero, M.I., Gonz\u00e1lez-Hedstr\u00f6m, D., Berm\u00fadez-L\u00f3pez, M., Valdivielso, J.M., Espinel, A.E., and Portero-Ot\u00edn, M. (2023). Antihypertensive Effects of an Optimized Aged Garlic Extract in Subjects with Grade I Hypertension and Antihypertensive Drug Therapy: A Randomized, Triple-Blind Controlled Trial. Nutrients, 15.","DOI":"10.3390\/nu15173691"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e0286454","DOI":"10.1371\/journal.pone.0286454","article-title":"Aged black garlic extract inhibits the growth of estrogen receptor-positive breast cancer cells by downregulating MCL-1 expression through the ROS-JNK pathway","volume":"18","author":"Yang","year":"2023","journal-title":"PLoS ONE"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"146","DOI":"10.2174\/2772432819666230504093227","article-title":"A Review on the Efficacy of Plant-derived Bio-active Compounds Curcumin and Aged Garlic Extract in Modulating Cancer and Age-related Diseases","volume":"19","author":"Das","year":"2024","journal-title":"Curr. Rev. Clin. Exp. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e26681","DOI":"10.1016\/j.heliyon.2024.e26681","article-title":"Diallyl trisulfide inhibits osteosarcoma 143B cell migration, invasion and EMT by inducing autophagy","volume":"10","author":"Liu","year":"2024","journal-title":"Heliyon"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Ferguson, D.T., Taka, E., Messeha, S., Flores-Rozas, H., Reed, S.L., Redmond, B.V., Soliman, K.F.A., Kanga, K.J.W., and Darling-Reed, S.F. (2024). The Garlic Compound, Diallyl Trisulfide, Attenuates Benzo[a]Pyrene-Induced Precancerous Effect through Its Antioxidant Effect, AhR Inhibition, and Increased DNA Repair in Human Breast Epithelial Cells. Nutrients, 16.","DOI":"10.3390\/nu16020300"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Bentke-Imiolek, A., Szl\u0119zak, D., Zarzycka, M., Wr\u00f3bel, M., and Bronowicka-Adamska, P. (2024). S-Allyl-L-Cysteine Affects Cell Proliferation and Expression of H2S-Synthetizing Enzymes in MCF-7 and MDA-MB-231 Adenocarcinoma Cell Lines. Biomolecules, 14.","DOI":"10.3390\/biom14020188"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1186\/s12931-020-01511-z","article-title":"Inflammatory phenotyping predicts clinical outcome in COVID-19","volume":"21","author":"Burke","year":"2020","journal-title":"Respir. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1186\/s13054-020-03255-0","article-title":"Longitudinal changes of inflammatory parameters and their correlation with disease severity and outcomes in patients with COVID-19 from Wuhan, China","volume":"24","author":"Zeng","year":"2020","journal-title":"Crit. Care"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1038\/s41591-020-1051-9","article-title":"An inflammatory cytokine signature predicts COVID-19 severity and survival","volume":"26","author":"Huang","year":"2020","journal-title":"Nat. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1007\/s10067-020-05190-5","article-title":"Cytokine in COVID-19: Pathogenesis and overview of anti-inflammatory agents used in treatment","volume":"39","author":"Soy","year":"2020","journal-title":"Clin. Rheumatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1111\/joim.13091","article-title":"COVID-19 diagnosis and management: A comprehensive review","volume":"288","author":"Pascarella","year":"2020","journal-title":"J. Intern. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1753466620933508","DOI":"10.1177\/1753466620933508","article-title":"Lung under attack by COVID-19-induced cytokine storm: Pathogenic mechanisms and therapeutic implications","volume":"14","author":"Pelaia","year":"2020","journal-title":"Ther. Adv. Respir. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1007\/s12015-020-10010-z","article-title":"SARS-CoV-2 entry receptor ACE2 is expressed on very small CD45(-) precursors of hematopoietic and endothelial cells and in response to virus Spike protein activates the Nlrp3 inflammasome","volume":"17","author":"Ratajczak","year":"2021","journal-title":"Stem Cell Rev. Rep."},{"key":"ref_26","first-page":"100789","article-title":"Pulmonary embolism among critically ill patients with ARDS due to COVID-19","volume":"78","author":"Soumagne","year":"2020","journal-title":"Respir. Med. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1016\/S2213-2600(20)30370-2","article-title":"Pathophysiology of COVID-19-associated acute respiratory distress syndrome: A multicentre prospective observational study","volume":"8","author":"Grasselli","year":"2020","journal-title":"Lancet Respir. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1164\/rccm.202009-3629ED","article-title":"Biological mechanisms of COVID-19 Acute Respiratory Distress Syndrome","volume":"202","author":"Matthay","year":"2020","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"110698","DOI":"10.1016\/j.biopha.2020.110698","article-title":"The role of Interleukin 6 inhibitors in therapy of severe COVID-19","volume":"131","author":"Nasonov","year":"2020","journal-title":"Biomed. Pharmacother."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2710","DOI":"10.1038\/s41375-021-01299-x","article-title":"Siltuximab downregulates interleukin-8 and pentraxin 3 to improve ventilatory status and survival in severe COVID-19","volume":"35","author":"Gritti","year":"2021","journal-title":"Leukemia"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.ijid.2020.09.1454","article-title":"Finding the right time for anti-inflammatory therapy in COVID-19","volume":"101","author":"Mancusi","year":"2020","journal-title":"Int. J. Infect. Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"153311","DOI":"10.1016\/j.phymed.2020.153311","article-title":"Screening for natural and derived bio-active compounds in preclinical and clinical studies: One of the frontlines of fighting the coronaviruses pandemic","volume":"85","author":"Khalifa","year":"2021","journal-title":"Phytomedicine"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"589998","DOI":"10.3389\/fpls.2020.589998","article-title":"In search of herbal anti-SARS-Cov2 compounds","volume":"11","author":"Matveeva","year":"2020","journal-title":"Front. Plant Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"153310","DOI":"10.1016\/j.phymed.2020.153310","article-title":"Caffeic acid derivatives (CAFDs) as inhibitors of SARS-CoV-2: CAFDs-based functional foods as a potential alternative approach to combat COVID-19","volume":"85","author":"Adem","year":"2021","journal-title":"Phytomedicine"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Ngwa, W., Kumar, R., Thompson, D., Lyerly, W., Moore, R., Reid, T.E., Lowe, H., and Toyang, N. (2020). Potential of flavonoid-inspired phytomedicines against COVID-19. Molecules, 25.","DOI":"10.3390\/molecules25112707"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1089\/omi.2020.0122","article-title":"Coronavirus Disease-2019 treatment strategies targeting interleukin-6 signaling and herbal medicine","volume":"25","author":"Dzobo","year":"2020","journal-title":"OMICS"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e9533","DOI":"10.7717\/peerj.9533","article-title":"Small molecule therapeutics for COVID-19: Repurposing of inhaled furosemide","volume":"8","author":"Wang","year":"2020","journal-title":"Peer J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"153583","DOI":"10.1016\/j.phymed.2021.153583","article-title":"Sulforaphane inhibits the expression of interleukin-6 and interleukin-8 induced in bronchial epithelial IB3-1 cells by exposure to the SARS-CoV-2 Spike protein","volume":"87","author":"Gasparello","year":"2021","journal-title":"Phytomedicine"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"108201","DOI":"10.1016\/j.intimp.2021.108201","article-title":"In vitro induction of interleukin-8 by SARS-CoV-2 Spike protein is inhibited in bronchial epithelial IB3-1 cells by a miR-93-5p agomiR","volume":"101","author":"Gasparello","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"113853","DOI":"10.1016\/j.yexcr.2023.113853","article-title":"The anti-SARS-CoV-2 BNT162b2 vaccine suppresses mithramycin-induced erythroid differentiation and expression of embryo-fetal globin genes in human erythroleukemia K562 cells","volume":"433","author":"Zurlo","year":"2023","journal-title":"Exp. Cell Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"104128","DOI":"10.1016\/j.exphem.2023.11.002","article-title":"Inhibitory effects of SARS-CoV-2 spike protein and BNT162b2 vaccine on erythropoietin-induced globin gene expression in erythroid precursor cells from patients with \u03b2-thalassemia","volume":"129","author":"Cosenza","year":"2024","journal-title":"Exp. Hematol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.ejmech.2018.03.080","article-title":"Design, synthesis and biological evaluation of novel trimethylangelicin analogues targeting nuclear factor kB (NF-kB)","volume":"151","author":"Marzaro","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2255","DOI":"10.1056\/NEJMra2026131","article-title":"Cytokine Storm","volume":"383","author":"Fajgenbaum","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.immuni.2020.06.017","article-title":"Cytokine Storms: Understanding COVID-19","volume":"53","author":"Mangalmurti","year":"2020","journal-title":"Immunity"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"200160","DOI":"10.1098\/rsob.200160","article-title":"Cytokine storm and COVID-19: A chronicle of pro-inflammatory cytokines","volume":"10","author":"Fara","year":"2020","journal-title":"Open Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e68563","DOI":"10.7554\/eLife.68563","article-title":"SARS-CoV-2 spike protein induces inflammation via TLR2-dependent activation of the NF-\u03baB pathway","volume":"10","author":"Khan","year":"2021","journal-title":"Elife"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1089\/nat.2019.0825","article-title":"High Levels of Apoptosis Are Induced in the Human Colon Cancer HT-29 Cell Line by Co-Administration of Sulforaphane and a Peptide Nucleic Acid Targeting miR-15b-5p","volume":"30","author":"Gasparello","year":"2020","journal-title":"Nucleic Acid Ther."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Gasparello, J., Papi, C., Zurlo, M., Gambari, L., Rozzi, A., Manicardi, A., Corradini, R., Gambari, R., and Finotti, A. (2022). Treatment of Human Glioblastoma U251 Cells with Sulforaphane and a Peptide Nucleic Acid (PNA) Targeting miR-15b-5p: Synergistic Effects on Induction of Apoptosis. Molecules, 27.","DOI":"10.3390\/molecules27041299"},{"key":"ref_49","first-page":"907162","article-title":"The antioxidant mechanisms underlying the aged garlic extract- and S-allylcysteine-induced protection","volume":"2012","author":"Santana","year":"2012","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.cellbi.2007.08.030","article-title":"Evaluation of chemokine and cytokine profiles in osteoblast progenitors from umbilical cord blood stem cells by BIO-PLEX technology","volume":"32","author":"Penolazzi","year":"2008","journal-title":"Cell Biol. Int."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"76","DOI":"10.3892\/ijmm.2023.5279","article-title":"Effects of Sulforaphane on SARS-CoV-2 infection and NF-\u03baB dependent expression of genes involved in the COVID-19 \u2018cytokine storm\u2019","volume":"52","author":"Gasparello","year":"2023","journal-title":"Int. J. Mol. Med."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Forsyth, C.B., Zhang, L., Bhushan, A., Swanson, B., Zhang, L., Mamede, J.I., Voigt, R.M., Shaikh, M., Engen, P.A., and Keshavarzian, A. (2022). The SARS-CoV-2 S1 Spike Protein Promotes MAPK and NF-kB Activation in Human Lung Cells and Inflammatory Cytokine Production in Human Lung and Intestinal Epithelial Cells. Microorganisms, 10.","DOI":"10.20944\/preprints202206.0010.v1"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Van Tin, H., Rethi, L., Higa, S., Kao, Y.H., and Chen, Y.J. (2024). Spike Protein of SARS-CoV-2 Activates Cardiac Fibrogenesis through NLRP3 Inflammasomes and NF-kappaB Signaling. Cells, 13.","DOI":"10.3390\/cells13161331"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.3727\/096504017X14928634401187","article-title":"Corilagin Induces High Levels of Apoptosis in the Temozolomide-Resistant T98G Glioma Cell Line","volume":"26","author":"Milani","year":"2018","journal-title":"Oncol. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/nri1391","article-title":"Toll-like receptor signalling","volume":"4","author":"Akira","year":"2004","journal-title":"Nat. Rev. Immunol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3792","DOI":"10.1021\/acsbiomaterials.8b00613","article-title":"Toll-like Receptor 2-Dependent NF-\u03baB\/AP-1 Activation by Damage-Associated Molecular Patterns Adsorbed on Polymeric Surfaces","volume":"4","author":"McKiel","year":"2018","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"107087","DOI":"10.1016\/j.intimp.2020.107087","article-title":"Toll-like receptors in sepsis-associated cytokine storm and their endogenous negative regulators as future immunomodulatory targets","volume":"89","author":"Kumar","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"ref_58","first-page":"3875","article-title":"NF-\u03baB inhibitor on Toll-like receptor 4 signal-induced expression of angiotensinogen and AT1a receptor in neonatal rat left ventricular myocytes","volume":"16","author":"Jiang","year":"2018","journal-title":"Exp. Ther. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3891","DOI":"10.1021\/acs.jcim.1c00203","article-title":"AutoDock Vina 1.2.0: New Docking Methods, Expanded Force Field, and Python Bindings","volume":"61","author":"Eberhardt","year":"2021","journal-title":"J. Chem. Inf. Model."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1038\/s41422-021-00495-9","article-title":"SARS-CoV-2 spike protein interacts with and activates TLR4","volume":"31","author":"Zhao","year":"2021","journal-title":"Cell Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"e21893","DOI":"10.1016\/j.heliyon.2023.e21893","article-title":"SARS-CoV-2 activates the TLR4\/MyD88 pathway in human macrophages: A possible correlation with strong pro-inflammatory responses in severe COVID-19","volume":"9","author":"Sahanic","year":"2023","journal-title":"Heliyon"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.heliyon.2021.e06187","article-title":"SARS-CoV-2 spike protein S1 subunit induces pro-inflammatory responses via toll-like receptor 4 signaling in murine and human macrophages","volume":"7","author":"Shirato","year":"2021","journal-title":"Heliyon"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"5077","DOI":"10.2147\/JIR.S474707","article-title":"Interplay of TLR4 and SARS-CoV-2: Unveiling the Complex Mechanisms of Inflammation and Severity in COVID-19 Infections","volume":"17","author":"Asaba","year":"2024","journal-title":"J. Inflamm. Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1038\/s41392-022-00968-2","article-title":"Aptamer blocking S-TLR4 interaction selectively inhibits SARS-CoV-2 induced inflammation","volume":"7","author":"Yang","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"989664","DOI":"10.3389\/fphar.2022.989664","article-title":"Toll-like receptor (TLRs) agonists and antagonists for COVID-19 treatments","volume":"13","author":"Liu","year":"2022","journal-title":"Front Pharmacol."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Zelkoski, A., Mitre, E., and Malloy, A. (2024). TLR4 recognizes the BNT162b2 vaccine\u2019s empty lipid nanoparticle to induce NF-\u03baB and IRF responses. J. Immunol., 212.","DOI":"10.4049\/jimmunol.210.Supp.160.18"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Pelaia, C., Calabrese, C., Garofalo, E., Bruni, A., Vatrella, A., and Pelaia, G. (2021). Therapeutic Role of Tocilizumab in SARS-CoV-2-Induced Cytokine Storm: Rationale and Current Evidence. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22063059"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"11","DOI":"10.2478\/rir-2022-0002","article-title":"Interleukin-6 blocking therapy for COVID-19: From immune pathogenesis to clinical outcomes","volume":"3","author":"Xiao","year":"2022","journal-title":"Rheumatol. Immunol. Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/s41577-021-00553-8","article-title":"Is IL-6 a key cytokine target for therapy in COVID-19?","volume":"21","author":"Jones","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1993","DOI":"10.1016\/j.immuni.2022.10.014","article-title":"Innate immune mechanisms of mRNA vaccines","volume":"55","author":"Verbeke","year":"2022","journal-title":"Immunity"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1038\/s41541-021-00391-8","article-title":"Exploiting viral sensing mediated by Toll-like receptors to design innovative vaccines","volume":"6","author":"Sartorius","year":"2021","journal-title":"NPJ Vaccines"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Delehedde, C., Even, L., Midoux, P., Pichon, C., and Perche, F. (2021). Intracellular Routing and Recognition of Lipid-Based mRNA Nanoparticles. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13070945"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.jcf.2008.06.002","article-title":"Anti-inflammatory effect of miglustat in bronchial epithelial cells","volume":"7","author":"Dechecchi","year":"2008","journal-title":"J. Cyst. Fibros."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.intimp.2012.04.010","article-title":"Corilagin is a potent inhibitor of NF-kappaB activity and downregulates TNF-alpha induced expression of IL-8 gene in cystic fibrosis IB3-1 cells","volume":"13","author":"Gambari","year":"2012","journal-title":"Int. Immunopharmacol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1002\/jgm.1546","article-title":"Sustained inhibition of IL-6 and IL-8 expression by decoy ODN to NF-kappaB delivered through respirable large porous particles in LPS-stimulated cystic fibrosis bronchial cells","volume":"13","author":"Ungaro","year":"2011","journal-title":"J. Gene Med."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Paranga, T.G., Mitu, I., Pavel-Tanasa, M., Rosu, M.F., Miftode, I.L., Constantinescu, D., Obreja, M., Plesca, C.E., and Miftode, E. (2024). Cytokine Storm in COVID-19: Exploring IL-6 Signaling and Cytokine-Microbiome Interactions as Emerging Therapeutic Approaches. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252111411"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2395","DOI":"10.1002\/ptr.7761","article-title":"Traditional Vietnamese medicine Kovir capsule for non-severe COVID-19 patients: A phase III double-blind randomized controlled trial","volume":"37","author":"Loc","year":"2023","journal-title":"Phytother Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1093\/cvr\/cvq076","article-title":"The nuclear factor-kappaB-interleukin-6 signalling pathway mediating vascular inflammation","volume":"86","author":"Brasier","year":"2010","journal-title":"Cardiovasc. Res."},{"key":"ref_79","first-page":"2327","article-title":"Activation of Interleukin-6 Gene Expression through the NF-KB Transcription Factor","volume":"10","author":"Libermann","year":"1990","journal-title":"Mol. Cell. Biol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"6069","DOI":"10.4049\/jimmunol.1100821","article-title":"Mapping the transcriptional machinery of the IL-8 gene in human bronchial epithelial cells","volume":"187","author":"Bezzerri","year":"2011","journal-title":"J. Immunol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"125","DOI":"10.4049\/jimmunol.208.Supp.125.30","article-title":"TLR2 senses spike protein of SARS-CoV-2 to trigger inflammation","volume":"208","author":"Zaki","year":"2022","journal-title":"J. Immunol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2456","DOI":"10.1021\/jf2052338","article-title":"Gas chromatography-mass spectrometry method for the determination of free amino acids as their dimethyl-tert-butylsilyl (TBDMS) derivatives in animal source food","volume":"60","author":"Ruiz","year":"2012","journal-title":"J. Agric. Food Chem."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1016\/j.omtn.2019.09.029","article-title":"Efficient Delivery of MicroRNA and AntimiRNA Molecules Using an Argininocalix[4]arene Macrocycle","volume":"18","author":"Gasparello","year":"2019","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"489","DOI":"10.3389\/fimmu.2018.00489","article-title":"Computational Insight Into the Structural Organization of Full-Length Toll-Like Receptor 4 Dimer in a Model Phospholipid Bilayer","volume":"9","author":"Patra","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/1758-2946-4-17","article-title":"Avogadro: An advanced semantic chemical editor, visualization, and analysis platform","volume":"4","author":"Hanwell","year":"2012","journal-title":"J. Cheminform."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers","volume":"1\u20132","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1961","DOI":"10.1016\/j.cpc.2009.05.011","article-title":"PLUMED: A portable plugin for free-energy calculations with molecular dynamics","volume":"180","author":"Bonomi","year":"2009","journal-title":"Comput. Phys. Commun."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2135","DOI":"10.1002\/jcc.23354","article-title":"CHARMM36 all-atom additive protein force field: Validation based on comparison to NMR data","volume":"34","author":"Huang","year":"2013","journal-title":"J. Comput. Chem."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1177\/01410768211032850","article-title":"Symptoms, complications and management of long COVID: A review","volume":"114","author":"Aiyegbusi","year":"2021","journal-title":"J. R. Soc. Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1007\/s42399-022-01167-4","article-title":"Post-acute sequelae of COVID-19 (PASC): A meta-narrative review of pathophysiology, prevalence, and management","volume":"4","author":"Munipalli","year":"2022","journal-title":"SN Compr. Clin. Med."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/24\/5938\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:53:16Z","timestamp":1760115196000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/24\/5938"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,16]]},"references-count":90,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["molecules29245938"],"URL":"https:\/\/doi.org\/10.3390\/molecules29245938","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,16]]}}}