{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T21:27:24Z","timestamp":1790890044234,"version":"4.1.0"},"reference-count":83,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T00:00:00Z","timestamp":1632700800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004242","name":"Princess Nourah Bint Abdulrahman University","doi-asserted-by":"publisher","award":["Fast-tract Research Funding program."],"award-info":[{"award-number":["Fast-tract Research Funding program."]}],"id":[{"id":"10.13039\/501100004242","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>In response to the urgent need to control Coronavirus disease 19 (COVID-19), this study aims to explore potential anti-SARS-CoV-2 agents from natural sources. Moreover, cytokine immunological responses to the viral infection could lead to acute respiratory distress which is considered a critical and life-threatening complication associated with the infection. Therefore, the anti-viral and anti-inflammatory agents can be key to the management of patients with COVID-19. Four bioactive compounds, namely ferulic acid 1, rutin 2, gallic acid 3, and chlorogenic acid 4 were isolated from the leaves of Pimenta dioica (L.) Merr (ethyl acetate extract) and identified using spectroscopic evidence. Furthermore, molecular docking and dynamics simulations were performed for the isolated and identified compounds (1\u20134) against SARS-CoV-2 main protease (Mpro) as a proposed mechanism of action. Furthermore, all compounds were tested for their half-maximal cytotoxicity (CC50) and SARS-CoV-2 inhibitory concentrations (IC50). Additionally, lung toxicity was induced in rats by mercuric chloride and the effects of treatment with P. dioca aqueous extract, ferulic acid 1, rutin 2, gallic acid 3, and chlorogenic acid 4 were recorded through measuring TNF-\u03b1, IL-1\u03b2, IL-2, IL-10, G-CSF, and genetic expression of miRNA 21-3P and miRNA-155 levels to assess their anti-inflammatory effects essential for COVID-19 patients. Interestingly, rutin 2, gallic acid 3, and chlorogenic acid 4 showed remarkable anti-SARS-CoV-2 activities with IC50 values of 31 \u00b5g\/mL, 108 \u03bcg\/mL, and 360 \u00b5g\/mL, respectively. Moreover, the anti-inflammatory effects were found to be better in ferulic acid 1 and rutin 2 treatments. Our results could be promising for more advanced preclinical and clinical studies especially on rutin 2 either alone or in combination with other isolates for COVID-19 management.<\/jats:p>","DOI":"10.3390\/molecules26195844","type":"journal-article","created":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T21:40:30Z","timestamp":1632778830000},"page":"5844","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":77,"title":["Pimenta dioica (L.) Merr. Bioactive Constituents Exert Anti-SARS-CoV-2 and Anti-Inflammatory Activities: Molecular Docking and Dynamics, In Vitro, and In Vivo Studies"],"prefix":"10.3390","volume":"26","author":[{"given":"Heba A.","family":"El Gizawy","sequence":"first","affiliation":[{"name":"Department of Pharmacognosy, Faculty of Pharmacy, October 6 University (O6U), October 6 City, Giza 12585, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4059-2912","authenticated-orcid":false,"given":"Sylvia A.","family":"Boshra","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Pharmacy, October 6 University (O6U), October 6 City, Giza 12585, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2878-5714","authenticated-orcid":false,"given":"Ahmed","family":"Mostafa","sequence":"additional","affiliation":[{"name":"Center of Scientific Excellence for Influenza Viruses, National Research Centre (NRC), Dokki, Giza 12622, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara H.","family":"Mahmoud","sequence":"additional","affiliation":[{"name":"Center of Scientific Excellence for Influenza Viruses, National Research Centre (NRC), Dokki, Giza 12622, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2562-4357","authenticated-orcid":false,"given":"Muhammad I.","family":"Ismail","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, The British University in Egypt, Al-Sherouk City, Cairo-Suez Desert Road, Cairo 11837, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4497-5013","authenticated-orcid":false,"given":"Aisha A.","family":"Alsfouk","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh 84428, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Azza T.","family":"Taher","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt"},{"name":"Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, October 6 University (O6U), October 6 City, Giza 12585, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8173-6073","authenticated-orcid":false,"given":"Ahmed A.","family":"Al-Karmalawy","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"138996","DOI":"10.1016\/j.scitotenv.2020.138996","article-title":"Evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as coronavirus disease 2019 (COVID-19) pandemic: A global health emergency","volume":"730","author":"Acter","year":"2020","journal-title":"Sci. Total. Environ."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"100604","DOI":"10.1016\/j.imu.2021.100604","article-title":"The journey of antimalarial drugs against SARS-CoV-2: Review article","volume":"24","author":"Sarhan","year":"2021","journal-title":"Inform. Med. Unlocked"},{"key":"ref_3","unstructured":"(2021, August 01). Worldometer. Available online: https:\/\/www.worldometers.info\/coronavirus\/."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2838","DOI":"10.1039\/D0RA09632F","article-title":"Inhibitory activity of quercetin, its metabolite, and standard antiviral drugs towards enzymes essential for SARS-CoV-2: The role of acid\u2013base equilibria","volume":"11","author":"Avdovic","year":"2021","journal-title":"Rsc Adv."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"29267","DOI":"10.1039\/D1RA05268C","article-title":"Anti-SARS-CoV-2 activities of tanshinone IIA, carnosic acid, rosmarinic acid, salvianolic acid, baicalein, and glycyrrhetinic acid between computational and in vitro insights","volume":"11","author":"Elebeedy","year":"2021","journal-title":"RSC Adv."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/S0140-6736(21)00424-4","article-title":"Future scenarios for the COVID-19 pandemic","volume":"397","author":"Skegg","year":"2021","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.cca.2020.06.017","article-title":"Cytokine storm induced by SARS-CoV-2","volume":"509","author":"Song","year":"2020","journal-title":"Clin Chim Acta"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"303","DOI":"10.15517\/rbt.v63i1.14580","article-title":"Leaf and fruit essential oil compositions of Pimenta guatemalensis (Myrtaceae) from Costa Rica","volume":"63","author":"Chaverri","year":"2014","journal-title":"Revista de Biolog\u00eda Tropical"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1080\/14786419.2010.526606","article-title":"Composition and antioxidant activity of essential oil of pimento (Pimenta dioica(L) Merr.) from Jamaica","volume":"25","author":"Padmakumari","year":"2011","journal-title":"Nat. Prod. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1900","DOI":"10.2174\/138945012804545641","article-title":"Medicinal properties of the Jamaican pepper plant Pimenta dioica and Allspice","volume":"13","author":"Zhang","year":"2012","journal-title":"Curr. Drug Targets"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1515\/opag-2018-0033","article-title":"Phytochemical profile and bioactivity of essential oil from Pimenta dioica leaves on cowpea beetle, Callosobruchus maculatus (F.) (Coleoptera: Bruchidae): A farmer friendly solution for postharvest pest management","volume":"3","author":"Tenne","year":"2018","journal-title":"Open Agric."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"420715","DOI":"10.1155\/2012\/420715","article-title":"Phytochemical analysis and antimicrobial, antinociceptive, and anti-inflammatory activities of two chemotypes of Pimenta pseudocaryophyllus (Myrtaceae)","volume":"2012","author":"Paula","year":"2012","journal-title":"Evid.-Based Complementary Altern. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.fct.2013.12.024","article-title":"Ferulic acid: Pharmacological and toxicological aspects","volume":"65","author":"Mancuso","year":"2014","journal-title":"Food Chem. Toxicol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.cbi.2006.03.004","article-title":"Membrane cholesterol contents influence the protective effects of quercetin and rutin in erythrocytes damaged by oxidative stress","volume":"161","author":"Gallego","year":"2006","journal-title":"Chem. Interact."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.freeradbiomed.2014.01.028","article-title":"Rutin decreases lipopolysaccharide-induced acute lung injury via inhibition of oxidative stress and the MAPK\u2013NF-\u03baB pathway","volume":"69","author":"Yeh","year":"2014","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s11671-018-2720-1","article-title":"Enhanced Effect of Combining Chlorogenic Acid on Selenium Nanoparticles in Inhibiting Amyloid \u03b2 Aggregation and Reactive Oxygen Species Formation In Vitro","volume":"13","author":"Yang","year":"2018","journal-title":"Nanoscale Res. Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1016\/j.pharep.2017.03.011","article-title":"Anti-inflammatory and ameliorative effects of gallic acid on fluoxetine-induced oxidative stress and liver damage in rats","volume":"69","author":"Heidarian","year":"2017","journal-title":"Pharmacol. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1038\/s41586-020-2223-y","article-title":"Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors","volume":"582","author":"Jin","year":"2020","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.ijantimicag.2018.03.005","article-title":"Corrigendum to \u2018Panton-Valentine Leucocidin (PVL) Staphylococcus aureus a position statement from the International Society of Chemotherapy","volume":"52","author":"Saeed","year":"2018","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Sharma, N., Ojha, H., Raghav, P.K., and Goyal, R.K. (2021). Chapter 2\u2014Structure- and ligand-based drug design: Concepts, approaches, and challenges. Chemoinformatics and Bioinformatics in the Pharmaceutical Sciences, Academic Press.","DOI":"10.1016\/B978-0-12-821748-1.00004-X"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"501","DOI":"10.2174\/1389450119666181022153016","article-title":"Molecular docking: Challenges, advances and its use in drug discovery perspective","volume":"20","author":"Saikia","year":"2019","journal-title":"Curr. Drug Targets"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Soltan, M.A., Eldeen, M.A., Elbassiouny, N., Mohamed, I., El-Damasy, D.A., Fayad, E., Abu Ali, O.A., Raafat, N., Eid, R.A., and Al-Karmalawy, A.A. (2021). Proteome Based Approach Defines Candidates for Designing a Multitope Vaccine against the Nipah Virus. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22179330"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Brogi, S. (2019). Computational Approaches for Drug Discovery. Multidiscip. Digit. Publ. Institute, 24.","DOI":"10.3390\/molecules24173061"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/s12272-016-0849-y","article-title":"Synthesis and cytotoxic activity of certain trisubstituted azetidin-2-one derivatives as a cis-restricted combretastatin A-4 analogues","volume":"40","author":"Elmeligie","year":"2017","journal-title":"Arch. Pharmacal Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1007\/s12272-013-0081-y","article-title":"Synthesis of new 1,3,4-benzotriazepin-5-one derivatives and their biological evaluation as antitumor agents","volume":"36","author":"Taher","year":"2013","journal-title":"Arch. Pharmacal Res."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Al-Karmalawy, A.A., Alnajjar, R., Dahab, M.A., Metwaly, A., and Eissa, I.H. (2021). Molecular docking and dynamics simulations reveal the potential of anti-HCV drugs to inhibit COVID-19 main protease. Pharm. Sci.","DOI":"10.34172\/PS.2021.3"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e05641","DOI":"10.1016\/j.heliyon.2020.e05641","article-title":"Molecular docking, molecular dynamics, and in vitro studies reveal the potential of angiotensin II receptor blockers to inhibit the COVID-19 main protease","volume":"6","author":"Alnajjar","year":"2020","journal-title":"Heliyon"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"16752","DOI":"10.1039\/D0NJ03611K","article-title":"Molecular docking reveals the potential of Cleome amblyocarpa isolated compounds to inhibit COVID-19 virus main protease","volume":"44","author":"Zaki","year":"2020","journal-title":"New J. Chem."},{"key":"ref_29","first-page":"227","article-title":"Molecular docking and dynamics simulation revealed the potential inhibitory activity of ACEIs against SARS-CoV-2 targeting hACE2 receptor","volume":"9","author":"Dahab","year":"2021","journal-title":"Front. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Elmaaty, A.A., Darwish, K.M., Khattab, M., Elhady, S.S., Salah, M., Hamed, M.I.A., Al-Karmalawy, A.A., and Saleh, M.M. (2021). In a search for potential drug candidates for combating COVID-19: Computational study revealed salvianolic acid B as a potential therapeutic targeting 3CLpro and spike proteins. J. Biomol. Struct. Dyn., 1\u201328.","DOI":"10.1080\/07391102.2021.1918256"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"10027","DOI":"10.1039\/D0RA10674G","article-title":"Revisiting activity of some glucocorticoids as a potential inhibitor of SARS-CoV-2 main protease: Theoretical study","volume":"11","author":"Elmaaty","year":"2021","journal-title":"RSC Adv."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Zaki, A.A., Ashour, A., Elhady, S.S., Darwish, K.M., and Al-Karmalawye, A.A. (2021). Calendulaglycoside A Showing Potential Activity Against SARS-CoV-2 Main Protease: Molecular Docking, Molecular Dynamics, and SAR Studies. J. Tradit. Complementary Med.","DOI":"10.1016\/j.jtcme.2021.05.001"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Soltane, R., Chrouda, A., Mostafa, A., Al-Karmalawy, A., Choua\u00efb, K., Dhahri, A., Pashameah, R., Alasiri, A., Kutkat, O., and Shehata, M. (2021). Strong Inhibitory Activity and Action Modes of Synthetic Maslinic Acid Derivative on Highly Pathogenic Coronaviruses: COVID-19 Drug Candidate. Pathogens, 10.","DOI":"10.3390\/pathogens10050623"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Kandeil, A., Mostafa, A., Kutkat, O., Moatasim, Y., Al-Karmalawy, A.A., Rashad, A.A., Kayed, A.E., Kayed, A.E., El-Shesheny, R., and Kayali, G. (2021). Bioactive Polyphenolic Compounds Showing Strong Antiviral Activities against Severe Acute Respiratory Syndrome Coronavirus 2. Pathogens, 10.","DOI":"10.3390\/pathogens10060758"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Elmaaty, A.A., Hamed, M., Ismail, M., Elkaeed, E.B., Abulkhair, H.S., Khattab, M., and Al-Karmalawy, A. (2021). Computational Insights on the Potential of Some NSAIDs for Treating COVID-19: Priority Set and Lead Optimization. Molecules, 26.","DOI":"10.3390\/molecules26123772"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.ijid.2020.05.085","article-title":"Lack of antiviral activity of darunavir against SARS-CoV-2","volume":"97","author":"Bojkova","year":"2020","journal-title":"Int. J. Infect. Dis."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Chen, F. (2004). In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds. J. Clin. Virol.","DOI":"10.1016\/S1386-6532(04)00055-1"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.fct.2014.04.016","article-title":"Protective effect of curcumin against heavy metals-induced liver damage","volume":"69","year":"2014","journal-title":"Food Chem. Toxicol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Smiechowicz, J., Skoczynska, A., Nieckula-Szwarc, A., Kulpa, K., and K\u00fcbler, A. (2017). Occupational mercury vapour poisoning with a respiratory failure, pneumomediastinum and severe quadriparesis. SAGE Open Med Case Rep., 5.","DOI":"10.1177\/2050313X17695472"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Pateda, S.M., Sakakibara, M., and Sera, K. (2018). Lung Function Assessment as an Early Biomonitor of Mercury-Induced Health Disorders in Artisanal and Small-Scale Gold Mining Areas in Indonesia. Int. J. Environ. Res. Public Health, 15.","DOI":"10.3390\/ijerph15112480"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"185","DOI":"10.21608\/ajps.2012.7145","article-title":"Design, Synthesis, Molecular Docking and Biological Evaluation of Some Novel Quinazolin-4(3h)-One Derivatives As Anti-Inflammatory Agents","volume":"46","author":"Ibrahim","year":"2012","journal-title":"Al-Azhar J. Pharm. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/j.envres.2019.01.026","article-title":"Prenatal exposure to mercury in relation to infant infections and respiratory symptoms in the New Hampshire Birth Cohort Study","volume":"171","author":"Emeny","year":"2019","journal-title":"Environ. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1016\/j.foodchem.2010.03.041","article-title":"Anti-inflammatory activity of extracts from fruits, herbs and spices","volume":"122","author":"Mueller","year":"2010","journal-title":"Food Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1111\/j.2042-7158.2011.01440.x","article-title":"Clove and eugenol in noncytotoxic concentrations exert immunomodulatory\/anti-inflammatory action on cytokine production by murine macrophages","volume":"64","author":"Bachiega","year":"2012","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"5375","DOI":"10.1021\/jf060899p","article-title":"Impact of Alkyl Esters of Caffeic and Ferulic Acids on Tumor Cell Proliferation, Cyclooxygenase Enzyme, and Lipid Peroxidation","volume":"54","author":"Jayaprakasam","year":"2006","journal-title":"J. Agric. Food Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1093\/toxsci\/kfj063","article-title":"Gallic Acid Inhibits Histamine Release and Pro-inflammatory Cytokine Production in Mast Cells","volume":"91","author":"Kim","year":"2005","journal-title":"Toxicol. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"666","DOI":"10.3109\/15376516.2014.961215","article-title":"Effect of rutin against gastric esophageal reflux in experimental animals","volume":"24","author":"Kumar","year":"2014","journal-title":"Toxicol. Mech. Methods"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"38.8","DOI":"10.4049\/jimmunol.182.Supp.38.8","article-title":"Insight into mechanism of IL-2-induced toxicity provides rationale for improved treatment strategy using IL-2\/mAb complexes (38.8)","volume":"182","author":"Boyman","year":"2009","journal-title":"J. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"121","DOI":"10.2754\/avb200978010121","article-title":"Anti-Inflammatory Effects of Rosmarinus officinalis Essential Oil in Mice","volume":"78","author":"Fabian","year":"2009","journal-title":"Acta Veter\u2013Brno"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1089\/jmf.2007.0524","article-title":"Anti-Inflammatory and Antinociceptive Effects of Rosmarinus officinalis L. Essential Oil in Experimental Animal Models","volume":"11","author":"Takaki","year":"2008","journal-title":"J. Med. Food"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1089\/wound.2019.1032","article-title":"The Role of the Anti-Inflammatory Cytokine Interleukin-10 in Tissue Fibrosis","volume":"9","author":"Steen","year":"2020","journal-title":"Adv. Wound Care"},{"key":"ref_52","first-page":"133","article-title":"Heavy Metal Toxicity and the Environment","volume":"101","author":"Tchounwou","year":"2012","journal-title":"Front. Environ. Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"23399","DOI":"10.18632\/oncotarget.4351","article-title":"High copy number variation of cancer-related microRNA genes and frequent amplification of DICER1 and DROSHA in lung cancer","volume":"6","author":"Czubak","year":"2015","journal-title":"Oncotarget"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1016\/j.ejca.2012.09.031","article-title":"High expression of miR-21 and miR-155 predicts recurrence and unfavourable survival in non-small cell lung cancer","volume":"49","author":"Yang","year":"2013","journal-title":"Eur. J. Cancer"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s11010-012-1443-3","article-title":"MicroRNA-21 (miR-21) expression promotes growth, metastasis, and chemo-or radioresistance in non-small cell lung cancer cells by targeting PTEN","volume":"372","author":"Liu","year":"2013","journal-title":"Mol. Cell. Biochem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1165\/rcmb.2011-0005OC","article-title":"The Role of Cyclooxygenase-2 in Mechanical Ventilation\u2013Induced Lung Injury","volume":"47","author":"Robertson","year":"2012","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/1756-3305-5-9","article-title":"Anti-inflammatory\/anti-fibrotic effects of the hepatoprotective silymarin and the schistosomicide praziquantel against Schistosoma mansoni-induced liver fibrosis","volume":"5","author":"Hammam","year":"2012","journal-title":"Parasites Vectors"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/s11010-008-9741-5","article-title":"Silymarin downregulates COX-2 expression and attenuates hyperlipidemia during NDEA-induced rat hepatocellular carcinoma","volume":"313","author":"Ramakrishnan","year":"2008","journal-title":"Mol. Cell. Biochem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1089\/jmf.2019.0209","article-title":"Resveratrol Modulates miR-34a in Cardiotoxicity Induced by Isoproterenol","volume":"23","author":"Boshra","year":"2020","journal-title":"J. Med. Food"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"51","DOI":"10.4142\/jvs.2014.15.1.51","article-title":"Protective effects of silymarin on fumonisin B1-induced hepatotoxicity in mice","volume":"15","author":"Sozmen","year":"2014","journal-title":"J. Vete\u2013Sci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.ejphar.2012.06.027","article-title":"Ferulic acid, a dietary phenolic acid, modulates radiation effects in Swiss albino mice","volume":"691","author":"Shanthakumar","year":"2012","journal-title":"Eur. J. Pharmacol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12894-018-0421-9","article-title":"Ameliorative effects of rutin against cisplatin-induced reproductive toxicity in male rats","volume":"18","author":"Jahan","year":"2018","journal-title":"BMC Urol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2013\/297154","article-title":"Roles of Chlorogenic Acid on Regulating Glucose and Lipids Metabolism: A Review","volume":"2013","author":"Meng","year":"2013","journal-title":"Evidence-Based Complement. Altern. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1515\/znc-2007-7-811","article-title":"Anticancer and Antioxidant Tannins from Pimenta dioica Leaves","volume":"62","author":"Marzouk","year":"2007","journal-title":"Zeitschrift f\u00fcr Naturforschung C"},{"key":"ref_65","unstructured":"Chemical Computing Group Inc. (2016). Molecular Operating Environment (MOE), Chemical Computing Group Inc."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"13990","DOI":"10.1039\/D0NJ02844D","article-title":"Molecular modelling of mebendazole polymorphs as a potential colchicine binding site inhibitor","volume":"44","author":"Khattab","year":"2020","journal-title":"New J. Chem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.sajb.2021.02.007","article-title":"Bioassay-guided isolation of a new cytotoxic ceramide from Cyperus rotundus L.","volume":"139","author":"Samra","year":"2021","journal-title":"South Afr. J. Bot."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Gaber, A.A., El-Morsy, A.M., Sherbiny, F.F., Bayoumi, A.H., El-Gamal, K.M., El-Adl, K., Al-Karmalawy, A.A., Ezz Eldin, R.R., Saleh, M.A., and Abulkhair, H.S. (2021). Pharmacophore-linked pyrazolo [3,4-d]pyrimidines as EGFR-TK inhibitors: Synthesis, anticancer evaluation, pharmacokinetics, and in silico mechanistic studies. Arch. Der Pharmazie., e2100258.","DOI":"10.1002\/ardp.202100258"},{"key":"ref_69","unstructured":"Al-Karmalawy, A., Nissa, Y.M., Ismail, N.S.M., Dalal, A., Ella, A.E., Khojah, S.M., and Abouzid, K.A.M. (2021). Synthesis of New Quinoxaline Derivatives as Potential Histone Deacetylase Inhibitors Targeting Hepatocellular Carcinoma: In Silico, In Vitro, and SAR Studies. Front. Chem., 648."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"El-Shershaby, M.H., Ghiaty, A., Bayoumi, A.H., Al-Karmalawy, A.A., Husseiny, E.M., El-Zoghbi, M.S., and Abulkhair, H.S. (2021). The antimicrobial potential and pharmacokinetic profiles of novel quinoline-based scaffolds: Synthesis and in silico mechanistic studies as dual DNA gyrase and DHFR inhibitors. New J. Chem.","DOI":"10.1039\/D1NJ02838C"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1038\/s41586-020-2223-y","article-title":"Structure of Mpro from COVID-19 virus and discovery of its inhibitors","volume":"582","author":"Wang","year":"2020","journal-title":"Nature"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"17374","DOI":"10.1039\/D0NJ04088F","article-title":"Tanshinone IIA synergistically enhances the antitumor activity of doxorubicin by interfering with the PI3K\/AKT\/mTOR pathway and inhibition of topoisomerase II: In Vitro and molecular docking studies","volume":"44","author":"Ghanem","year":"2020","journal-title":"New J. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"92","DOI":"10.3389\/fchem.2021.628398","article-title":"Revisiting Activity of Some Nocodazole Analogues as a Potential Anticancer Drugs Using Molecular Docking and DFT Calculations","volume":"9","author":"Khattab","year":"2021","journal-title":"Front. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Alesawy, M.S., Al-Karmalawy, A.A., Elkaeed, E.B., Alswah, M., Belal, A., Taghour, M.S., and Eissa, I.H. (2020). Design and discovery of new 1,2,4-triazolo [4,3-c] quinazolines as potential DNA intercalators and topoisomerase II inhibitors. Archiv Der Pharmazie, e2000237.","DOI":"10.1002\/ardp.202000237"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1021\/acsptsci.0c00144","article-title":"Empagliflozin and Doxorubicin Synergistically Inhibit the Survival of Triple-Negative Breast Cancer Cells via Interfering with the mTOR Pathway and Inhibition of Calmodulin: In Vitro and Molecular Docking Studies","volume":"3","author":"Eliaa","year":"2020","journal-title":"ACS Pharmacol. Transl. Sci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"116266","DOI":"10.1016\/j.bmc.2021.116266","article-title":"From triazolophthalazines to triazoloquinazolines: A bioisosterism-guided approach toward the identification of novel PCAF inhibitors with potential anticancer activity","volume":"42","author":"Ghiaty","year":"2021","journal-title":"Bioorganic Med. Chem."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Soltan, M.A., Elbassiouny, N., Gamal, H., Elkaeed, E.B., Eid, R.A., Eldeen, M.A., and Al-Karmalawy, A.A. (2021). In Silico Prediction of a Multitope Vaccine against Moraxella catarrhalis: Reverse Vaccinology and Immunoinformatics. Vaccines, 9.","DOI":"10.3390\/vaccines9060669"},{"key":"ref_78","unstructured":"McConkey, B.J., Sobolev, V., and Edelman, M. (2002). The Performance of Current Methods In Ligand\u2013Protein Dockin. Curr. Sci., 845\u2013856."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Abdallah, A.E., Alesawy, M.S., Eissa, S.I., El-Fakharany, E.M., Kalaba, M.H., Sharaf, M.H., Shama, N.M.A., Mahmoud, S.H., Mostafa, A., and Al-Karmalawy, A.A. (2021). Design and synthesis of new 4-(2-nitrophenoxy)benzamide derivatives as potential antiviral agents: Molecular modeling and in vitro antiviral screening. New J. Chem.","DOI":"10.1039\/D1NJ02710G"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0022-1759(83)90303-4","article-title":"Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays","volume":"65","author":"Mosmann","year":"1983","journal-title":"J. Immunol. Methods"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Mostafa, A., Kandeil, A., Elshaier, Y.A.M.M., Kutkat, O., Moatasim, Y., Rashad, A.A., Shehata, M., Gomaa, M.R., Mahrous, N., and Mahmoud, S.H. (2020). FDA-Approved Drugs with Potent In Vitro Antiviral Activity against Severe Acute Respiratory Syndrome Coronavirus 2. Pharmaceuticals, 13.","DOI":"10.3390\/ph13120443"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2\u2212\u0394\u0394CT method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_83","unstructured":"Bancroft, J., Stevens, A., and Turner, D. (1996). Theory and Practice of Histological Techniques, Churchill Living Stone. [4th ed.]."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/19\/5844\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:05:33Z","timestamp":1760166333000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/19\/5844"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,27]]},"references-count":83,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["molecules26195844"],"URL":"https:\/\/doi.org\/10.3390\/molecules26195844","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,27]]}}}