Human herpesviruses are known to induce a broad spectrum of diseases, ranging from common cold sores to cancer, and infections with some types of these viruses, known as human oncogenic herpesviruses (HOHVs), can cause cancer. Challenges with viral latency, recurrent infections, and drug resistance have generated the need for finding new drugs with the ability to overcome these barriers. Berberine (BBR), a naturally occurring alkaloid, is known for its multiple biological activities, including antiviral and anticancer effects. This paper comprehensively compiles all studies that have featured anti-HOHV properties of BBR along with promising preventive effects against the associated cancers. The mechanisms and pathways induced by BBR via targeting the herpesvirus life cycle and the pathogenesis of the linked malignancies are reviewed. Approaches to enhance the therapeutic efficacy of BBR and its use in clinical practice as an anti-herpesvirus drug are also discussed.

Department of Applied Ecology Faculty of Environmental Sciences Czech University of Life Sciences Prague Kamýcká 129 16500 Prague Czech Republic

Department of Medical Biology Jessenius Faculty of Medicine Comenius University in Bratislava 03601 Martin Slovakia

Department of Obstetrics and Gynecology Jessenius Faculty of Medicine Comenius University in Bratislava 03601 Martin Slovakia

Department of Pharmacy University of Salerno 84084 Fisciano SA Italy

Museum of Literature in Moravia Klášter 1 66461 Rajhrad Czech Republic

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Hassan S.T., Masarčíková R., Berchová K. Bioactive natural products with anti-herpes simplex virus properties. J. Pharm. Pharmacol. 2015;67:1325–1336. doi: 10.1111/jphp.12436. PubMed DOI

Treml J., Gazdová M., Šmejkal K., Šudomová M., Kubatka P., Hassan S.T.S. Natural Products-Derived Chemicals: Breaking Barriers to Novel Anti-HSV Drug Development. Viruses. 2020;12:154. doi: 10.3390/v12020154. PubMed DOI PMC

Manners O., Murphy J.C., Coleman A., Hughes D.J., Whitehouse A. Contribution of the KSHV and EBV lytic cycles to tumourigenesis. Curr. Opin. Virol. 2018;32:60–70. doi: 10.1016/j.coviro.2018.08.014. PubMed DOI PMC

Dittmer D.P., Damania B., Sin S.H. Animal models of tumorigenic herpesviruses--An update. Curr. Opin. Virol. 2015;14:145–150. doi: 10.1016/j.coviro.2015.09.006. PubMed DOI PMC

Wołącewicz M., Becht R., Grywalska E., Niedźwiedzka-Rystwej P. Herpesviruses in Head and Neck Cancers. Viruses. 2020;12:172. doi: 10.3390/v12020172. PubMed DOI PMC

Tomkins A., White C., Higgins S.P. Primary herpes simplex virus infection mimicking cervical cancer. BMJ Case Rep. 2015;2015:bcr2015210194. doi: 10.1136/bcr-2015-210194. PubMed DOI PMC

Herbein G. The Human Cytomegalovirus, from Oncomodulation to Oncogenesis. Viruses. 2018;10:408. doi: 10.3390/v10080408. PubMed DOI PMC

Glaunsinger B.A. Modulation of the Translational Landscape During Herpesvirus Infection. Annu. Rev. Virol. 2015;2:311–333. doi: 10.1146/annurev-virology-100114-054839. PubMed DOI PMC

Asha K., Sharma-Walia N. Targeting Host Cellular Factors as a Strategy of Therapeutic Intervention for Herpesvirus Infections. Front. Cell Infect. Microbiol. 2021;11:603309. doi: 10.3389/fcimb.2021.603309. PubMed DOI PMC

Poole C.L., James S.H. Antiviral Therapies for Herpesviruses: Current Agents and New Directions. Clin. Ther. 2018;40:1282–1298. doi: 10.1016/j.clinthera.2018.07.006. PubMed DOI PMC

Hassan S.T.S. Brassicasterol with Dual Anti-Infective Properties against HSV-1 and Mycobacterium tuberculosis, and Cardiovascular Protective Effect: Nonclinical In Vitro and In Silico Assessments. Biomedicines. 2020;8:132. doi: 10.3390/biomedicines8050132. PubMed DOI PMC

Brezáni V., Leláková V., Hassan S.T.S., Berchová-Bímová K., Nový P., Klouček P., Maršík P., Dall’Acqua S., Hošek J., Šmejkal K. Anti-Infectivity against Herpes Simplex Virus and Selected Microbes and Anti-Inflammatory Activities of Compounds Isolated from Eucalyptus globulus Labill. Viruses. 2018;10:360. doi: 10.3390/v10070360. PubMed DOI PMC

Hassan S.T.S., Šudomová M., Berchová-Bímová K., Šmejkal K., Echeverría J. Psoromic Acid, a Lichen-Derived Molecule, Inhibits the Replication of HSV-1 and HSV-2, and Inactivates HSV-1 DNA Polymerase: Shedding Light on Antiherpetic Properties. Molecules. 2019;24:2912. doi: 10.3390/molecules24162912. PubMed DOI PMC

Čulenová M., Sychrová A., Hassan S.T.S., Berchová-Bímová K., Svobodová P., Helclová A., Michnová H., Hošek J., Vasilev H., Suchý P., et al. Multiple In vitro biological effects of phenolic compounds from Morus alba root bark. J. Ethnopharmacol. 2020;248:112296. doi: 10.1016/j.jep.2019.112296. PubMed DOI

Hassan S.T.S., Švajdlenka E. Biological Evaluation and Molecular Docking of Protocatechuic Acid from Hibiscus sabdariffa L. as a Potent Urease Inhibitor by an ESI-MS Based Method. Molecules. 2017;22:1696. doi: 10.3390/molecules22101696. PubMed DOI PMC

Feng X., Sureda A., Jafari S., Memariani Z., Tewari D., Annunziata G., Barrea L., Hassan S.T.S., Šmejkal K., Malaník M., et al. Berberine in Cardiovascular and Metabolic Diseases: From Mechanisms to Therapeutics. Theranostics. 2019;9:1923–1951. doi: 10.7150/thno.30787. PubMed DOI PMC

Wang K., Feng X., Chai L., Cao S., Qiu F. The metabolism of berberine and its contribution to the pharmacological effects. Drug Metab. Rev. 2017;49:139–157. doi: 10.1080/03602532.2017.1306544. PubMed DOI

Warowicka A., Nawrot R., Goździcka-Józefiak A. Antiviral activity of berberine. Arch. Virol. 2020;165:1935–1945. doi: 10.1007/s00705-020-04706-3. PubMed DOI PMC

Zeng Q., Deng H., Li Y., Fan T., Liu Y., Tang S., Wei W., Liu X., Guo X., Jiang J., et al. Berberine Directly Targets the NEK7 Protein to Block the NEK7-NLRP3 Interaction and Exert Anti-inflammatory Activity. J. Med. Chem. 2021;64:768–781. doi: 10.1021/acs.jmedchem.0c01743. PubMed DOI

Liu D., Meng X., Wu D., Qiu Z., Luo H. A Natural Isoquinoline Alkaloid with Antitumor Activity: Studies of the Biological Activities of Berberine. Front. Pharmacol. 2019;10:9. doi: 10.3389/fphar.2019.00009. PubMed DOI PMC

Hassan S.T.S. Shedding Light on the Effect of Natural Anti-Herpesvirus Alkaloids on SARS-CoV-2: A Treatment Option for COVID-19. Viruses. 2020;12:476. doi: 10.3390/v12040476. PubMed DOI PMC

Johnston B.P., McCormick C. Herpesviruses and the Unfolded Protein Response. Viruses. 2019;12:17. doi: 10.3390/v12010017. PubMed DOI PMC

Stempel M., Chan B., Brinkmann M.M. Coevolution pays off: Herpesviruses have the license to escape the DNA sensing pathway. Med. Microbiol. Immunol. 2019;208:495–512. doi: 10.1007/s00430-019-00582-0. PubMed DOI

Adler B., Sattler C., Adler H. Herpesviruses and Their Host Cells: A Successful Liaison. Trends Microbiol. 2017;25:229–241. doi: 10.1016/j.tim.2016.11.009. PubMed DOI

Jarosinski K.W. Interindividual Spread of Herpesviruses. Adv. Anat. Embryol. Cell Biol. 2017;223:195–224. PubMed

Azab W., Dayaram A., Greenwood A.D., Osterrieder N. How Host Specific Are Herpesviruses? Lessons from Herpesviruses Infecting Wild and Endangered Mammals. Annu. Rev. Virol. 2018;5:53–68. doi: 10.1146/annurev-virology-092917-043227. PubMed DOI

Lomonte P. Herpesvirus Latency: On the Importance of Positioning Oneself. Adv. Anat. Embryol. Cell Biol. 2017;223:95–117. PubMed

Cohen J.I. Herpesvirus latency. J. Clin. Investig. 2020;130:3361–3369. doi: 10.1172/JCI136225. PubMed DOI PMC

Connolly S.A., Jardetzky T.S., Longnecker R. The structural basis of herpesvirus entry. Nat. Rev. Microbiol. 2021;19:110–121. doi: 10.1038/s41579-020-00448-w. PubMed DOI PMC

Sadeghipour S., Mathias R.A. Herpesviruses hijack host exosomes for viral pathogenesis. Semin. Cell. Dev. Biol. 2017;67:91–100. doi: 10.1016/j.semcdb.2017.03.005. PubMed DOI

Choi U.Y., Park A., Jung J.U. Double the Trouble When Herpesviruses Join Hands. Cell Host Microbe. 2017;22:5–7. doi: 10.1016/j.chom.2017.06.016. PubMed DOI PMC

Ho D.Y., Enriquez K., Multani A. Herpesvirus Infections Potentiated by Biologics. Infect. Dis. Clin. N. Am. 2020;34:311–339. doi: 10.1016/j.idc.2020.02.006. PubMed DOI

Koyuncu O.O., MacGibeny M.A., Enquist L.W. Latent versus productive infection: The alpha herpesvirus switch. Future Virol. 2018;13:431–443. doi: 10.2217/fvl-2018-0023. PubMed DOI PMC

Lagunoff M. Activation of cellular metabolism during latent Kaposi’s Sarcoma herpesvirus infection. Curr. Opin. Virol. 2016;19:45–49. doi: 10.1016/j.coviro.2016.06.012. PubMed DOI PMC

Šudomová M., Hassan S.T.S. Nutraceutical Curcumin with Promising Protection against Herpesvirus Infections and Their Associated Inflammation: Mechanisms and Pathways. Microorganisms. 2021;9:292. doi: 10.3390/microorganisms9020292. PubMed DOI PMC

Thorley-Lawson D.A. EBV Persistence--Introducing the Virus. Curr. Top. Microbiol. Immunol. 2015;390:151–209. PubMed PMC

Zaman A., Rahaman M.H., Razzaque S. Kaposi’s sarcoma: A computational approach through protein-protein interaction and gene regulatory networks analysis. Virus Genes. 2013;46:242–254. doi: 10.1007/s11262-012-0865-z. PubMed DOI

Li R., Liao G., Nirujogi R.S., Pinto S.M., Shaw P.G., Huang T.C., Wan J., Qian J., Gowda H., Wu X., et al. Phosphoproteomic Profiling Reveals Epstein-Barr Virus Protein Kinase Integration of DNA Damage Response and Mitotic Signaling. PLoS Pathog. 2015;11:e1005346. doi: 10.1371/journal.ppat.1005346. PubMed DOI PMC

Baquero-Pérez B., Whitehouse A. Hsp70 Isoforms Are Essential for the Formation of Kaposi’s Sarcoma-Associated Herpesvirus Replication and Transcription Compartments. PLoS Pathog. 2015;11:e1005274. doi: 10.1371/journal.ppat.1005274. PubMed DOI PMC

Li D.J., Verma D., Mosbruger T., Swaminathan S. CTCF and Rad21 act as host cell restriction factors for Kaposi’s sarcoma-associated herpesvirus (KSHV) lytic replication by modulating viral gene transcription. PLoS Pathog. 2014;10:e1003880. doi: 10.1371/journal.ppat.1003880. PubMed DOI PMC

Li Q., Wilkie A.R., Weller M., Liu X., Cohen J.I. THY-1 Cell Surface Antigen (CD90) Has an Important Role in the Initial Stage of Human Cytomegalovirus Infection. PLoS Pathog. 2015;11:e1004999. doi: 10.1371/journal.ppat.1004999. PubMed DOI PMC

Weekes M.P., Tomasec P., Huttlin E.L., Fielding C.A., Nusinow D., Stanton R.J., Wang E.C.Y., Aicheler R., Murrell I., Wilkinson G.W.G., et al. Quantitative temporal viromics: An approach to investigate host-pathogen interaction. Cell. 2014;157:1460–1472. doi: 10.1016/j.cell.2014.04.028. PubMed DOI PMC

Griffiths S.J., Koegl M., Boutell C., Zenner H.L., Crump C.M., Pica F., Gonzalez O., Friedel C.C., Barry G., Martin K., et al. A systematic analysis of host factors reveals a Med23-interferon-λ regulatory axis against herpes simplex virus type 1 replication. PLoS Pathog. 2013;9:e1003514. doi: 10.1371/journal.ppat.1003514. PubMed DOI PMC

Griffiths S.J. Screening for host proteins with pro- and antiviral activity using high-throughput RNAi. Methods Mol. Biol. 2013;1064:71–90. PubMed

Münz C. Latency and lytic replication in Epstein-Barr virus-associated oncogenesis. Nat. Rev. Microbiol. 2019;17:691–700. doi: 10.1038/s41579-019-0249-7. PubMed DOI

Charostad J., Nakhaie M., Dehghani A., Faghihloo E. The interplay between EBV and KSHV viral products and NF-κB pathway in oncogenesis. Infect. Agents Cancer. 2020;15:62. doi: 10.1186/s13027-020-00317-4. PubMed DOI PMC

Young L.S., Yap L.F., Murray P.G. Epstein-Barr virus: More than 50 years old and still providing surprises. Nat. Rev. Cancer. 2016;16:789–802. doi: 10.1038/nrc.2016.92. PubMed DOI

Epstein M.A., Achong B.G., Barr Y.M. Virus particles in cultured lymphoblasts from Burkitt’s lymphoma. Lancet. 1964;1:702–703. doi: 10.1016/S0140-6736(64)91524-7. PubMed DOI

Epstein M.A., Henle G., Achong B.G., Barr Y.M. Morphological and biological studies on a virus in cultured lymphoblasts from Burkitt’s lymphoma. J. Exp. Med. 1964;121:761–770. doi: 10.1084/jem.121.5.761. PubMed DOI PMC

Farrell P.J. Epstein–Barr virus and cancer. Annu. Rev. Pathol. 2019;14:29–53. doi: 10.1146/annurev-pathmechdis-012418-013023. PubMed DOI

Ciccarese G., Trave I., Herzum A., Parodi A., Drago F. Dermatological manifestations of Epstein-Barr virus systemic infection: A case report and literature review. Int. J. Dermatol. 2020;59:1202–1209. doi: 10.1111/ijd.14887. PubMed DOI

Cui Q., Feng F.T., Xu M., Liu W.S., Yao Y.Y., Xie S.H., Li X.Z., Ye Z.L., Feng Q.S., Chen L.Z., et al. Nasopharyngeal carcinoma risk prediction via salivary detection of host and Epstein-Barr virus genetic variants. Oncotarget. 2016;8:95066–95074. doi: 10.18632/oncotarget.11144. PubMed DOI PMC

Xu M., Cheung C.C., Chow C., Lun S.W., Cheung S.T., Lo K.W. Overexpression of PIN1 enhances cancer growth and aggressiveness with cyclin D1 induction in EBV-associated nasopharyngeal carcinoma. PLoS ONE. 2016;11:e0156833. doi: 10.1371/journal.pone.0156833. PubMed DOI PMC

Wang F.W., Wu X.R., Liu W.J., Liang Y.J., Huang Y.F., Liao Y.J., Shao C.K., Zong Y.S., Mai S.J., Xie D. The nucleotide polymorphisms within the Epstein-Barr virus C and Q promoters from nasopharyngeal carcinoma affect transcriptional activity in vitro. Eur. Arch. Otorhinolaryngol. 2012;269:931–938. doi: 10.1007/s00405-011-1862-x. PubMed DOI

Shen Y., Zhang S., Sun R., Wu T., Qian J. Understanding the interplay between host immunity and Epstein-Barr virus in NPC patients. Emerg. Microbes Infect. 2015;4:20. doi: 10.1038/emi.2015.20. PubMed DOI PMC

Kelly G.L., Stylianou J., Rasaiyaah J., Wei W., Thomas W., Croom-Carter D., Kohler C., Spang R., Woodman C., Kellam P., et al. Different patterns of Epstein-Barr virus latency in endemic Burkitt lymphoma (BL) lead to distinct variants within the BL-associated gene expression signature. J. Virol. 2013;87:2882–2894. doi: 10.1128/JVI.03003-12. PubMed DOI PMC

Kempkes B., Ling P.D. EBNA2 and Its Coactivator EBNA-LP. Curr. Top. Microbiol. Immunol. 2015;391:35–59. PubMed

Frappier L. Contributions of Epstein-Barr nuclear antigen 1 (EBNA1) to cell immortalization and survival. Viruses. 2012;4:1537–1547. doi: 10.3390/v4091537. PubMed DOI PMC

Wang C., Wang H., Zhang Y., Guo W., Long C., Wang J., Liu L., Sun X. Berberine inhibits the proliferation of human nasopharyngeal carcinoma cells via an Epstein-Barr virus nuclear antigen 1-dependent mechanism. Oncol. Rep. 2017;37:2109–2120. doi: 10.3892/or.2017.5489. PubMed DOI

Tsang C.M., Cheung Y.C., Lui V.W., Yip Y.L., Zhang G., Lin V.W., Cheung K.C., Feng Y., Tsao S.W. Berberine suppresses tumorigenicity and growth of nasopharyngeal carcinoma cells by inhibiting STAT3 activation induced by tumor associated fibroblasts. BMC Cancer. 2013;13:619. doi: 10.1186/1471-2407-13-619. PubMed DOI PMC

Tao D., Zhang N., Huang Q., Ge C., Li Q., Li S., Weng K., Guo Q., Sui J., Wang C., et al. Association of Epstein-Barr virus infection with peripheral immune parameters and clinical outcome in advanced nasopharyngeal carcinoma. Sci. Rep. 2020;10:21976. doi: 10.1038/s41598-020-78892-0. PubMed DOI PMC

Hassan S.T.S., Berchová-Bímová K., Petráš J., Hassan K.T.S. Cucurbitacin B interacts synergistically with antibiotics against Staphylococcus aureus clinical isolates and exhibits antiviral activity against HSV-1. S. Afr. J. Bot. 2017;108:90–94. doi: 10.1016/j.sajb.2016.10.001. DOI

Zhou F., Hu J., Dai N., Song L., Lin T., Liu J., Li K., Peng Z., He Y., Liao D.-F. Berberine and ginsenoside Rg3 act synergistically via the MAPK/ERK pathway in nasopharyngeal carcinoma cells. J. Funct. Foods. 2020;66:103802. doi: 10.1016/j.jff.2020.103802. DOI

Park G.B., Park S.H., Kim D., Kim Y.S., Yoon S.H., Hur D.Y. Berberine induces mitochondrial apoptosis of EBV-transformed B cells through p53-mediated regulation of XAF1 and GADD45α. Int. J. Oncol. 2016;49:411–421. doi: 10.3892/ijo.2016.3502. PubMed DOI

Kumar B., Roy A., Veettil M.V., Chandran B. Insight into the Roles of E3 Ubiquitin Ligase c-Cbl, ESCRT Machinery, and Host Cell Signaling in Kaposi’s Sarcoma-Associated Herpesvirus Entry and Trafficking. J. Virol. 2018;92:e01317, e01376. doi: 10.1128/JVI.01376-17. PubMed DOI PMC

Minhas V., Wood C. Epidemiology and transmission of Kaposi’s sarcoma-associated herpesvirus. Viruses. 2014;6:4178–4194. doi: 10.3390/v6114178. PubMed DOI PMC

Ueda K. KSHV Genome Replication and Maintenance in Latency. Adv. Exp. Med. Biol. 2018;1045:299–320. PubMed

Li S., Bai L., Dong J., Sun R., Lan K. Kaposi’s Sarcoma-Associated Herpesvirus: Epidemiology and Molecular Biology. Adv. Exp. Med. Biol. 2017;1018:91–127. PubMed

Schneider J.W., Dittmer D.P. Diagnosis and Treatment of Kaposi Sarcoma. Am. J. Clin. Dermatol. 2017;18:529–539. doi: 10.1007/s40257-017-0270-4. PubMed DOI PMC

Watanabe T., Sugimoto A., Hosokawa K., Fujimuro M. Signal Transduction Pathways Associated with KSHV-Related Tumors. Adv. Exp. Med. Biol. 2018;1045:321–355. PubMed

Abere B., Mamo T.M., Hartmann S., Samarina N., Hage E., Rückert J., Hotop S.K., Büsche G., Schulz T.F. The Kaposi’s sarcoma-associated herpesvirus (KSHV) non-structural membrane protein K15 is required for viral lytic replication and may represent a therapeutic target. PLoS Pathog. 2017;13:e1006639. doi: 10.1371/journal.ppat.1006639. PubMed DOI PMC

Cesarman E., Damania B., Krown S.E., Martin J., Bower M., Whitby D. Kaposi sarcoma. Nat. Rev. Dis. Primers. 2019;5:9. doi: 10.1038/s41572-019-0060-9. PubMed DOI PMC

Shimada K., Hayakawa F., Kiyoi H. Biology and management of primary effusion lymphoma. Blood. 2018;132:1879–1888. doi: 10.1182/blood-2018-03-791426. PubMed DOI

Goto H., Kariya R., Shimamoto M., Kudo E., Taura M., Katano H., Okada S. Antitumor effect of berberine against primary effusion lymphoma via inhibition of NF-κB pathway. Cancer Sci. 2012;103:775–781. doi: 10.1111/j.1349-7006.2012.02212.x. PubMed DOI PMC

Damania B., Münz C. Immunodeficiencies that predispose to pathologies by human oncogenic γ-herpesViruses. FEMS Microbiol. Rev. 2019;43:181–192. doi: 10.1093/femsre/fuy044. PubMed DOI PMC

Tada S., Hamada M., Yura Y. Proteomic Analysis of Secretomes of Oncolytic Herpes Simplex Virus-Infected Squamous Cell Carcinoma Cells. Cancers. 2018;10:28. doi: 10.3390/cancers10020028. PubMed DOI PMC

Liljeqvist J.Å., Tunbäck P., Norberg P. Asymptomatically shed recombinant herpes simplex virus type 1 strains detected in saliva. J. Gen. Virol. 2009;90:559–566. doi: 10.1099/vir.0.007070-0. PubMed DOI

Kameyama T., Haikata K., Nakamura Y., Murase H., Yamamoto S. Shedding of herpes simplex virus type 1 into saliva after surgery for oral and genital or urological cancer patients. Kurume Med. J. 1989;36:117–121. doi: 10.2739/kurumemedj.36.117. PubMed DOI

Nolan A. Interventions for prevention and treatment of herpes simplex virus in cancer patients. Evid. Based Dent. 2009;10:116–117. doi: 10.1038/sj.ebd.6400689. PubMed DOI

Correia A.V., Coêlho M.R., de Oliveira Mendes Cahú G.G., de Almeida Silva J.L., da Mota Vasconcelos Brasil C., de Castro J.F. Seroprevalence of HSV-1/2 and correlation with aggravation of oral mucositis in patients with squamous cell carcinoma of the head and neck region submitted to antineoplastic treatment. Support Care Cancer. 2015;23:2105–2111. doi: 10.1007/s00520-014-2558-8. PubMed DOI

Smith J.W., Torres J.E., Holmquist N.D. Association of Herpes simplex virus (HSV) with cervical cancer by lymphocyte reactivity with HSV-1 and HSV-2 antigens. Am. J. Epidemiol. 1979;110:141–147. doi: 10.1093/oxfordjournals.aje.a112798. PubMed DOI

Thomas F., Elguero E., Brodeur J., Le Goff J., Missé D. Herpes simplex virus type 2 and cancer: A medical geography approach. Infect. Genet. Evol. 2011;11:1239–1242. doi: 10.1016/j.meegid.2011.04.009. PubMed DOI

Parker T.M., Smith E.M., Ritchie J.M., Haugen T.H., Vonka V., Turek L.P., Hamsikova E. Head and neck cancer associated with herpes simplex virus 1 and 2 and other risk factors. Oral Oncol. 2006;42:288–296. doi: 10.1016/j.oraloncology.2005.08.003. PubMed DOI

Schildt E.B., Eriksson M., Hardell L., Magnuson A. Oral infections and dental factors in relation to oral cancer: A Swedish case--control study. Eur. J. Cancer Prev. 1998;7:201–206. doi: 10.1097/00008469-199806000-00004. PubMed DOI

Starr J.R., Daling J.R., Fitzgibbons E.D., Madeleine M.M., Ashley R., Galloway D.A., Schwartz S.M. Serologic evidence of herpes simplex virus 1 infection and oropharyngeal cancer risk. Cancer Res. 2001;61:8459–8464. PubMed

Michaelis M., Doerr H.W., Cinatl J. The story of human cytomegalovirus and cancer: Increasing evidence and open questions. Neoplasia. 2009;11:1–9. doi: 10.1593/neo.81178. PubMed DOI PMC

Ahmed H.G., Suliman R.S.A., Ashankyty I.M., Albieh Z.A., Warille A.A. Role of human Cytomegalovirus in the etiology of nasopharyngeal carcinoma. J. Cancer Res. Ther. 2018;14:583–586. doi: 10.4103/0973-1482.176175. PubMed DOI

Kiprian D., Czarkowska-Paczek B., Wyczalkowska-Tomasik A., Paczek L. Human cytomegalovirus and Epstein-Barr virus infections increase the risk of death in patients with head and neck cancers receiving radiotherapy or radiochemotherapy. Medicine. 2018;97:e13777. doi: 10.1097/MD.0000000000013777. PubMed DOI PMC

Richardson A.K., Walker L.C., Cox B., Rollag H., Robinson B.A., Morrin H., Pearson J.F., Potter J.D., Paterson M., Surcel H.M., et al. Breast cancer and cytomegalovirus. Clin. Transl. Oncol. 2020;22:585–602. doi: 10.1007/s12094-019-02164-1. PubMed DOI

Zhang L., Guo G., Xu J., Sun X., Chen W., Jin J., Hu C., Zhang P., Shen X., Xue X. Human cytomegalovirus detection in gastric cancer and its possible association with lymphatic metastasis. Diagn. Microbiol. Infect. Dis. 2017;88:62–68. doi: 10.1016/j.diagmicrobio.2017.02.001. PubMed DOI

Lawler S.E. Cytomegalovirus and glioblastoma; controversies and opportunities. J. Neurooncol. 2015;123:465–471. doi: 10.1007/s11060-015-1734-0. PubMed DOI

Teo W.H., Chen H.P., Huang J.C., Chan Y.J. Human cytomegalovirus infection enhances cell proliferation, migration and upregulation of EMT markers in colorectal cancer-derived stem cell-like cells. Int. J. Oncol. 2017;51:1415–1426. doi: 10.3892/ijo.2017.4135. PubMed DOI PMC

Golais F., Mrázová V. Human alpha and beta herpesviruses and cancer: Passengers or foes? Folia Microbiol. 2020;65:439–449. doi: 10.1007/s12223-020-00780-x. PubMed DOI

Dziurzynski K., Chang S.M., Heimberger A.B., Kalejta R.F., McGregor Dallas S.R., Smit M., Soroceanu L., Cobbs C.S. HCMV and Gliomas Symposium. Consensus on the role of human cytomegalovirus in glioblastoma. Neuro Oncol. 2012;14:246–255. doi: 10.1093/neuonc/nor227. PubMed DOI PMC

Blaylock R.L. Accelerated cancer aggressiveness by viral oncomodulation: New targets and newer natural treatments for cancer control and treatment. Surg. Neurol. Int. 2019;10:199. doi: 10.25259/SNI_361_2019. PubMed DOI PMC

Chen H.P., Chan Y.J. The oncomodulatory role of human cytomegalovirus in colorectal cancer: Implications for clinical trials. Front. Oncol. 2014;4:314. doi: 10.3389/fonc.2014.00314. PubMed DOI PMC

Hassan S.T.S., Šudomová M., Masarčíková R. Herpes simplex virus infection: An overview of the problem, pharmacologic therapy and dietary measures. Ceska Slov. Farm. 2017;66:95–102. PubMed

Zhao J., Qin C., Liu Y., Rao Y., Feng P. Herpes Simplex Virus and Pattern Recognition Receptors: An Arms Race. Front. Immunol. 2021;11:613799. doi: 10.3389/fimmu.2020.613799. PubMed DOI PMC

Sawtell N.M., Thompson R.L. Alphaherpesvirus Latency and Reactivation with a Focus on Herpes Simplex Virus. Curr. Issues Mol. Biol. 2021;41:267–356. doi: 10.21775/cimb.041.267. PubMed DOI

Song S., Qiu M., Chu Y., Chen D., Wang X., Su A., Wu Z. Downregulation of cellular c-Jun N-terminal protein kinase and NF-κB activation by berberine may result in inhibition of herpes simplex virus replication. Antimicrob. Agents Chemother. 2014;58:5068–5078. doi: 10.1128/AAC.02427-14. PubMed DOI PMC

Chin L.W., Cheng Y.W., Lin S.S., Lai Y.Y., Lin L.Y., Chou M.Y., Chou M.C., Yang C.C. Anti-herpes simplex virus effects of berberine from Coptidis rhizoma, a major component of a Chinese herbal medicine, Ching-Wei-San. Arch. Virol. 2010;155:1933–1941. doi: 10.1007/s00705-010-0779-9. PubMed DOI

Duan Q., Liu T., Yuan P., Huang C., Shao Q., Xu L., Sun J., Huang G., Chen Z. Antiviral effect of Chinese herbal prescription JieZe-1 on adhesion and penetration of VK2/E6E7 with herpes simplex viruses type 2. J. Ethnopharmacol. 2020;249:112405. doi: 10.1016/j.jep.2019.112405. PubMed DOI PMC

Kim J.H., Weeratunga P., Kim M.S., Nikapitiya C., Lee B.H., Uddin M.B., Kim T.H., Yoon J.E., Park C., Ma J.Y., et al. Inhibitory effects of an aqueous extract from Cortex Phellodendri on the growth and replication of broad-spectrum of viruses in vitro and in vivo. BMC Complement. Altern. Med. 2016;16:265. doi: 10.1186/s12906-016-1206-x. PubMed DOI PMC

Wu J.B., Zheng J.R., Lin Z., Li X.Y., Cui P.G. In vitro antiviral activity of a berberine derivant HB-13 against herpes simplex virus. Chin. J. Dermatol. 2007;40:671–673.

Wei H.L., Wang S., Xu F., Xu L.F., Zheng J.R., Chen Y. Evaluation of a 13-hexyl-berberine hydrochloride topical gel formulation. Drug Dev. Ind. Pharm. 2013;39:534–539. doi: 10.3109/03639045.2012.687746. PubMed DOI

Luganini A., Mercorelli B., Messa L., Palù G., Gribaudo G., Loregian A. The isoquinoline alkaloid berberine inhibits human cytomegalovirus replication by interfering with the viral Immediate Early-2 (IE2) protein transactivating activity. Antiviral Res. 2019;164:52–60. doi: 10.1016/j.antiviral.2019.02.006. PubMed DOI

Pignoloni B., Fionda C., Dell’Oste V., Luganini A., Cippitelli M., Zingoni A., Landolfo S., Gribaudo G., Santoni A., Cerboni C. Distinct Roles for Human Cytomegalovirus Immediate Early Proteins IE1 and IE2 in the Transcriptional Regulation of MICA and PVR/CD155 Expression. J. Immunol. 2016;197:4066–4078. doi: 10.4049/jimmunol.1502527. PubMed DOI

Hayashi K., Minoda K., Nagaoka Y., Hayashi T., Uesato S. Antiviral activity of berberine and related compounds against human cytomegalovirus. Bioorg. Med. Chem. Lett. 2007;17:1562–1564. doi: 10.1016/j.bmcl.2006.12.085. PubMed DOI

Bennett J.M., Glaser R., Malarkey W.B., Beversdorf D.Q., Peng J., Kiecolt-Glaser J.K. Inflammation and reactivation of latent herpesviruses in older adults. Brain Behav. Immun. 2012;26:739–746. doi: 10.1016/j.bbi.2011.11.007. PubMed DOI PMC

Cruz-Muñoz M.E., Fuentes-Pananá E.M. Beta and Gamma Human Herpesviruses: Agonistic and Antagonistic Interactions with the Host Immune System. Front Microbiol. 2018;8:2521. doi: 10.3389/fmicb.2017.02521. PubMed DOI PMC

Lobo A.M., Agelidis A.M., Shukla D. Pathogenesis of herpes simplex keratitis: The host cell response and ocular surface sequelae to infection and inflammation. Ocul. Surf. 2019;17:40–49. doi: 10.1016/j.jtos.2018.10.002. PubMed DOI PMC

Islam S.M.S., Sohn S. HSV-Induced Systemic Inflammation as an Animal Model for Behçet’s Disease and Therapeutic Applications. Viruses. 2018;10:511. doi: 10.3390/v10090511. PubMed DOI PMC

Johnston C., Corey L. Current Concepts for Genital Herpes Simplex Virus Infection: Diagnostics and Pathogenesis of Genital Tract Shedding. Clin. Microbiol. Rev. 2016;29:149–161. doi: 10.1128/CMR.00043-15. PubMed DOI PMC

Alomari N., Totonchy J. Cytokine-Targeted Therapeutics for KSHV-Associated Disease. Viruses. 2020;12:1097. doi: 10.3390/v12101097. PubMed DOI PMC

Polizzotto M.N., Uldrick T.S., Wyvill K.M., Aleman K., Marshall V., Wang V., Whitby D., Pittaluga S., Jaffe E.S., Millo C., et al. Clinical Features and Outcomes of Patients with Symptomatic Kaposi Sarcoma Herpesvirus (KSHV)-associated Inflammation: Prospective Characterization of KSHV Inflammatory Cytokine Syndrome (KICS) Clin. Infect. Dis. 2016;62:730–738. doi: 10.1093/cid/civ996. PubMed DOI PMC

Shrivastava G., León-Juárez M., García-Cordero J., Meza-Sánchez D.E., Cedillo-Barrón L. Inflammasomes and its importance in viral infections. Immunol. Res. 2016;64:1101–1117. doi: 10.1007/s12026-016-8873-z. PubMed DOI

Liu T., Zhang L., Joo D., Sun S.C. NF-κB signaling in inflammation. Signal Transduct. Target. Ther. 2017;2:17023. doi: 10.1038/sigtrans.2017.23. PubMed DOI PMC

Carty M., Guy C., Bowie A.G. Detection of viral infections by innate immunity. Biochem. Pharmacol. 2020;183:114316. doi: 10.1016/j.bcp.2020.114316. PubMed DOI

Crusz S.M., Balkwill F.R. Inflammation and cancer: Advance and new agents. Nat. Rev. Clin. Oncol. 2015;12:584–596. doi: 10.1038/nrclinonc.2015.105. PubMed DOI

Murata M. Inflammation and cancer. Environ. Health Prev. Med. 2018;23:50. doi: 10.1186/s12199-018-0740-1. PubMed DOI PMC

Zou K., Li Z., Zhang Y., Zhang H.Y., Li B., Zhu W.L., Shi J.Y., Jia Q., Li Y.M. Advances in the study of berberine and its derivatives: A focus on anti-inflammatory and anti-tumor effects in the digestive system. Acta Pharmacol. Sin. 2017;38:157–167. doi: 10.1038/aps.2016.125. PubMed DOI PMC

Ehteshamfar S.M., Akhbari M., Afshari J.T., Seyedi M., Nikfar B., Shapouri-Moghaddam A., Ghanbarzadeh E., Momtazi-Borojeni A.A. Anti-inflammatory and immune-modulatory impacts of berberine on activation of autoreactive T cells in autoimmune inflammation. J. Cell. Mol. Med. 2020;24:13573–13588. doi: 10.1111/jcmm.16049. PubMed DOI PMC

Di Pierro F., Bertuccioli A., Giuberti R., Saponara M., Ivaldi L. Role of a berberine-based nutritional supplement in reducing diarrhea in subjects with functional gastrointestinal disorders. Minerva Gastroenterol. Dietol. 2020;66:29–34. doi: 10.23736/S1121-421X.19.02649-7. PubMed DOI

Funk R.S., Singh R.K., Winefield R.D., Kandel S.E., Ruisinger J.F., Moriarty P.M., Backes J.M. Variability in Potency among Commercial Preparations of Berberine. J. Diet. Suppl. 2018;15:343–351. doi: 10.1080/19390211.2017.1347227. PubMed DOI PMC

Lan J., Zhao Y., Dong F., Yan Z., Zheng W., Fan J., Sun G. Meta-analysis of the effect and safety of berberine in the treatment of type 2 diabetes mellitus, hyperlipemia and hypertension. J. Ethnopharmacol. 2015;161:69–81. doi: 10.1016/j.jep.2014.09.049. PubMed DOI

Dong H., Wang N., Zhao L., Lu F. Berberine in the treatment of type 2 diabetes mellitus: A systemic review and meta-analysis. Evid. Based Complement. Alternat. Med. 2012;2012:591654. doi: 10.1155/2012/591654. PubMed DOI PMC

Gupta P.K., Gurley B.J., Barone G., Hendrickson H.P. Clinical Pharmacokinetics and Metabolism of Berberine and Hydrastine Following an Oral Dose of Goldenseal Supplement. Planta Med. 2010;76:110. doi: 10.1055/s-0030-1251872. DOI

Gupta P.K., Hubbard M., Gurley B., Hendrickson H.P. Validation of a liquid chromatography-tandem mass spectrometric assay for the quantitative determination of hydrastine and berberine in human serum. J. Pharm. Biomed. Anal. 2009;49:1021–1026. doi: 10.1016/j.jpba.2009.01.036. PubMed DOI

Domitrović R., Cvijanović O., Pernjak-Pugel E., Skoda M., Mikelić L., Crnčević-Orlić Z. Berberine exerts nephroprotective effect against cisplatin-induced kidney damage through inhibition of oxidative/nitrosative stress, inflammation, autophagy and apoptosis. Food Chem. Toxicol. 2013;62:397–406. doi: 10.1016/j.fct.2013.09.003. PubMed DOI

Germoush M.O., Mahmoud A.M. Berberine mitigates cyclophosphamide-induced hepatotoxicity by modulating antioxidant status and inflammatory cytokines. J. Cancer Res. Clin. Oncol. 2014;140:1103–1109. doi: 10.1007/s00432-014-1665-8. PubMed DOI PMC

Hao G., Yu Y., Gu B., Xing Y., Xue M. Protective effects of berberine against doxorubicin-induced cardiotoxicity in rats by inhibiting metabolism of doxorubicin. Xenobiotica. 2015;45:1024–1029. doi: 10.3109/00498254.2015.1034223. PubMed DOI

Chitra P., Saiprasad G., Manikandan R., Sudhandiran G. Berberine attenuates bleomycin induced pulmonary toxicity and fibrosis via suppressing NF-κB dependant TGF-β activation: A biphasic experimental study. Toxicol. Lett. 2013;219:178–193. doi: 10.1016/j.toxlet.2013.03.009. PubMed DOI

Yin J., Xing H., Ye J. Efficacy of berberine in patients with type 2 diabetes mellitus. Metabolism. 2008;57:712–717. doi: 10.1016/j.metabol.2008.01.013. PubMed DOI PMC

Zhi D., Feng P.F., Sun J.L., Guo F., Zhang R., Zhao X., Li B.X. The enhancement of cardiac toxicity by concomitant administration of Berberine and macrolides. Eur. J. Pharm. Sci. 2015;76:149–155. doi: 10.1016/j.ejps.2015.05.009. PubMed DOI

Feng P., Zhao L., Guo F., Zhang B., Fang L., Zhan G., Xu X., Fang Q., Liang Z., Li B. The enhancement of cardiotoxicity that results from inhibition of CYP 3A4 activity and hERG channel by berberine in combination with statins. Chem. Biol. Interact. 2018;293:115–123. doi: 10.1016/j.cbi.2018.07.022. PubMed DOI

Singh N., Sharma B. Toxicological Effects of Berberine and Sanguinarine. Front. Mol. Biosci. 2018;5:21. doi: 10.3389/fmolb.2018.00021. PubMed DOI PMC

Habtemariam S. Berberine pharmacology and the gut microbiota: A hidden therapeutic link. Pharmacol Res. 2020;155:104722. doi: 10.1016/j.phrs.2020.104722. PubMed DOI

Hou Q., He W.J., Wu Y.S., Hao H.J., Xie X.Y., Fu X.B. Berberine: A Traditional Natural Product with Novel Biological Activities. Altern. Ther. Health Med. 2020;26:20–27. PubMed

Gaba S., Saini A., Singh G., Monga V. An insight into the medicinal attributes of berberine derivatives: A review. Bioorg. Med. Chem. 2021;38:116143. doi: 10.1016/j.bmc.2021.116143. PubMed DOI

Wang L., Li H., Wang S., Liu R., Wu Z., Wang C., Wang Y., Chen M. Enhancing the antitumor activity of berberine hydrochloride by solid lipid nanoparticle encapsulation. AAPS PharmSciTech. 2014;15:834–844. doi: 10.1208/s12249-014-0112-0. PubMed DOI PMC

Wang Z.P., Wu J.B., Chen T.S., Zhou Q., Wang Y.F. Biophotonics and Immune Responses X. SIPE; Bellingham, WA, USA: 2015. In vitro and in vivo antitumor efficacy of berberine-nanostructured lipid carriers against H22 tumor.

Lin Y.C., Kuo J.Y., Hsu C.C., Tsai W.C., Li W.C., Yu M.C., Wen H.W. Optimizing manufacture of liposomal berberine with evaluation of its antihepatoma effects in a murine xenograft model. Int. J. Pharm. 2013;441:381–388. doi: 10.1016/j.ijpharm.2012.11.017. PubMed DOI

Nguyen T.X., Huang L., Liu L., Elamin Abdalla A.M., Gauthier M., Yang G. Chitosan-coated nano-liposomes for the oral delivery of berberine hydrochloride. J. Mater. Chem. B. 2014;2:7149–7159. doi: 10.1039/C4TB00876F. PubMed DOI

Mirhadi E., Rezaee M., Malaekeh-Nikouei B. Nano strategies for berberine delivery, a natural alkaloid of Berberis. Biomed. Pharmacother. 2018;104:465–473. doi: 10.1016/j.biopha.2018.05.067. PubMed DOI

Majidzadeh H., Araj-Khodaei M., Ghaffari M., Torbati M., Ezzati Nazhad Dolatabadi J., Hamblin M.R. Nano-based delivery systems for berberine: A modern anti-cancer herbal medicine. Colloids Surf. B Biointerfaces. 2020;194:111188. doi: 10.1016/j.colsurfb.2020.111188. PubMed DOI

Gao J., Fan D., Song P., Zhang S., Liu X. Preparation and application of pH-responsive composite hydrogel beads as potential delivery carrier candidates for controlled release of berberine hydrochloride. R. Soc. Open Sci. 2020;7:200676. doi: 10.1098/rsos.200676. PubMed DOI PMC

Yan C., Liang J., Fang H., Meng X., Chen J., Zhong Z., Liu Q., Hu H., Zhang X. Fabrication and Evaluation of Silk Sericin-Derived Hydrogel for the Release of the Model Drug Berberine. Gels. 2021;7:23. doi: 10.3390/gels7010023. PubMed DOI PMC

Brandariz-Nuñez A., Liu T., Du T., Evilevitch A. Pressure-driven release of viral genome into a host nucleus is a mechanism leading to herpes infection. Elife. 2019;8:e47212. doi: 10.7554/eLife.47212. PubMed DOI PMC

Bauer D.W., Li D., Huffman J., Homa F.L., Wilson K., Leavitt J.C., Casjens S.R., Baines J., Evilevitch A. Exploring the Balance between DNA Pressure and Capsid Stability in Herpesviruses and Phages. J. Virol. 2015;89:9288–9298. doi: 10.1128/JVI.01172-15. PubMed DOI PMC

Brandariz-Nuñez A., Robinson S.J., Evilevitch A. Pressurized DNA state inside herpes capsids-A novel antiviral target. PLoS Pathog. 2020;16:e1008604. doi: 10.1371/journal.ppat.1008604. PubMed DOI PMC

Van Diemen F.R., Kruse E.M., Hooykaas M.J., Bruggeling C.E., Schürch A.C., van Ham P.M., Imhof S.M., Nijhuis M., Wiertz E.J., Lebbink R.J. CRISPR/Cas9-Mediated Genome Editing of Herpesviruses Limits Productive and Latent Infections. PLoS Pathog. 2016;12:e1005701. doi: 10.1371/journal.ppat.1005701. PubMed DOI PMC

Van Diemen F.R., Lebbink R.J. CRISPR/Cas9, a powerful tool to target human herpesViruses. Cell Microbiol. 2017;19:2. doi: 10.1111/cmi.12694. PubMed DOI

Chen Y.C., Sheng J., Trang P., Liu F. Potential Application of the CRISPR/Cas9 System against Herpesvirus Infections. Viruses. 2018;10:291. doi: 10.3390/v10060291. PubMed DOI PMC

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