Herpesviruses are DNA viruses that infect humans and animals with the ability to induce latent and lytic infections in their hosts, causing critical health complications. The enrolment of nutraceutical anti-herpesvirus drugs in clinical investigations with promising levels of reduced resistance, free or minimal cellular toxicity, and diverse mechanisms of action might be an effective way to defeat challenges that hurdle the progress of anti-herpesvirus drug development, including the problems with drug resistance and recurrent infections. Therefore, in this review, we aim to hunt down all investigations that feature the curative properties of curcumin, a principal bioactive phenolic compound of the spice turmeric, in regard to various human and animal herpesvirus infections and inflammation connected with these diseases. Curcumin was explored with potent antiherpetic actions against herpes simplex virus type 1 and type 2, human cytomegalovirus, Kaposi's sarcoma-associated herpesvirus, Epstein-Barr virus, bovine herpesvirus 1, and pseudorabies virus. The mechanisms and pathways by which curcumin inhibits anti-herpesvirus activities by targeting multiple steps in herpesvirus life/infectious cycle are emphasized. Improved strategies to overcome bioavailability challenges that limit its use in clinical practice, along with approaches and new directions to enhance the anti-herpesvirus efficacy of this compound, are also reviewed. According to the reviewed studies, this paper presents curcumin as a promising natural drug for the prevention and treatment of herpesvirus infections and their associated inflammatory diseases.

Department of Applied Ecology Faculty of Environmental Sciences Czech University of Life Sciences Prague Kamýcká 129 6 Suchdol 16500 Prague Czech Republic

Museum of Literature in Moravia Klášter 1 66461 Rajhrad Czech Republic

Zobrazit více v PubMed

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

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

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

Roizman B., Pellett P.E. The family Herpesviridae: A brief introduction. In: Knipe D.M., editor. Fields—Virology. 4th ed. Lippincott Williams & Wilkins; Philadelphia, PA, USA: 2001. pp. 2381–2397.

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

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

Pellett P., Roizman B. Herpesviridae. In: Knipe D., Howley P., editors. Fields Virology. Lippincott, Wil-liams and Wilkins; Philadelphia, PA, USA: 2013. pp. 1802–1822.

Savva R. The Essential Co-Option of Uracil-DNA Glycosylases by Herpesviruses Invites Novel Antiviral Design. Microorganisms. 2020;8:461. doi: 10.3390/microorganisms8030461. PubMed DOI PMC

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

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

Zheng W., Xu Q., Zhang Y., Xiaofei E., Gao W., Zhang M., Zhai W., Rajkumar R.S., Liu Z. Toll-like receptor-mediated innate immunity against herpesviridae infection: A current perspective on viral infection signaling pathways. Virol. J. 2020;17:192. doi: 10.1186/s12985-020-01463-2. PubMed DOI PMC

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

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

Andreu S., Ripa I., Bello-Morales R., López-Guerrero J.A. Valproic Acid and Its Amidic Derivatives as New Antivirals against Alphaherpesviruses. Viruses. 2020;12:1356. doi: 10.3390/v12121356. 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

Aggarwal B.B., Kumar A., Bharti A.C. Anticancer potential of curcumin: Preclinical and clinical studies. Anticancer Res. 2003;23:363–398. PubMed

Tsuda T. Curcumin as a functional food-derived factor: Degradation products, metabolites, bioactivity, and future perspectives. Food Funct. 2018;9:705–714. doi: 10.1039/C7FO01242J. PubMed DOI

Milobedeska J., Kostanecki S., Lampe V. Zur kenntnis des curcumins. Ber. Deut. Chem. Ges. 1910;43:2163–2170. doi: 10.1002/cber.191004302168. DOI

Lampe V., Milobedeska J. Studien über curcumin. Eur. J. Pharm. Biopharm. 1913;46:2235–2240. doi: 10.1002/cber.191304602149. DOI

Zhou Y., Xie M., Song Y., Wang W., Zhao H., Tian Y., Wang Y., Bai S., Zhao Y., Chen X., et al. Two traditional Chinese medicines Curcumae radix and Curcumae Rhizoma: An ethnopharmacology, phytochemistry, and pharmacology review. Evid. Based Complement. Altern. Med. 2016;2016:4973128. doi: 10.1155/2016/4973128. PubMed DOI PMC

Seidi Damyeh M., Mereddy R., Netzel M.E., Sultanbawa Y. An insight into curcumin-based photosensitization as a promising and green food preservation technology. Compr. Rev. Food Sci. Food Saf. 2020;19:1727–1759. doi: 10.1111/1541-4337.12583. PubMed DOI

Soleimani V., Sahebkar A., Hosseinzadeh H. Turmeric (Curcuma longa) and its major constituent (curcumin) as nontoxic and safe substances: Review. Phytother. Res. 2018;32:985–995. doi: 10.1002/ptr.6054. PubMed DOI

Praditya D., Kirchhoff L., Brüning J., Rachmawati H., Steinmann J., Steinmann E. Anti-infective Properties of the Golden Spice Curcumin. Front Microbiol. 2019;10:912. doi: 10.3389/fmicb.2019.00912. PubMed DOI PMC

Hewlings S.J., Kalman D.S. Curcumin: A Review of Its’ Effects on Human Health. Foods. 2017;6:92. doi: 10.3390/foods6100092. PubMed DOI PMC

Kotha R.R., Luthria D.L. Curcumin: Biological, Pharmaceutical, Nutraceutical, and Analytical Aspects. Molecules. 2019;24:2930. doi: 10.3390/molecules24162930. PubMed DOI PMC

Moghadamtousi S.Z., Kadir H.A., Hassandarvish P., Tajik H., Abubakar S., Zandi K. A review on antibacterial, antiviral, and antifungal activity of curcumin. Biomed Res Int. 2014;2014:186864. PubMed PMC

Jha A., Mohapatra P.P., AlHarbi S.A., Jahan N. Curcumin: Not So Spicy After All. Mini Rev. Med. Chem. 2017;17:1425–1434. doi: 10.2174/1389557517666170228114234. PubMed DOI

Di Meo F., Margarucci S., Galderisi U., Crispi S., Peluso G. Curcumin, Gut Microbiota, and Neuroprotection. Nutrients. 2019;11:2426. doi: 10.3390/nu11102426. PubMed DOI PMC

Birkmann A., Zimmermann H. HSV antivirals—Current and future treatment options. Curr. Opin. Virol. 2016;18:9–13. doi: 10.1016/j.coviro.2016.01.013. PubMed DOI

Kenny K., Leung W., Stephanson K., Ross S. Clinical practice in prevention of neonatal HSV infection: A survey of obstetrical care providers in Alberta. J. Obstet. Gynaecol. Can. 2013;35:131–137. doi: 10.1016/S1701-2163(15)31017-3. PubMed DOI

Piret J., Boivin G. Antiviral resistance in herpes simplex virus and varicella-zoster virus infections: Diagnosis and management. Curr. Opin. Infect Dis. 2016;29:654–662. doi: 10.1097/QCO.0000000000000288. PubMed DOI

Rechenchoski D.Z., Faccin-Galhardi L.C., Linhares R.E.C., Nozawa C. Herpesvirus: An underestimated virus. Folia Microbiol. 2017;62:151–156. doi: 10.1007/s12223-016-0482-7. PubMed DOI

Britt W.J., Prichard M.N. New therapies for human cytomegalovirus infections. Antivir. Res. 2018;159:153–174. doi: 10.1016/j.antiviral.2018.09.003. PubMed DOI

Maple P.A.C. Cytomegalovirus and Epstein-Barr Virus Associations with Neurological Diseases and the Need for Vaccine Development. Vaccines. 2020;8:35. doi: 10.3390/vaccines8010035. PubMed DOI PMC

Bonizzoli M., Arvia R., di Valvasone S., Liotta F., Zakrzewska K., Azzi A., Peris A. Human herpesviruses respiratory infections in patients with acute respiratory distress (ARDS) Med. Microbiol. Immunol. 2016;205:371–379. doi: 10.1007/s00430-016-0456-z. PubMed DOI PMC

Annunziata G., Maisto M., Schisano C., Ciampaglia R., Narciso V., Tenore G.C., Novellino E. Resveratrol as a Novel Anti-Herpes Simplex Virus Nutraceutical Agent: An Overview. Viruses. 2018;10:473. doi: 10.3390/v10090473. PubMed DOI PMC

Zinser E., Krawczyk A., Mühl-Zürbes P., Aufderhorst U., Draßner C., Stich L., Zaja M., Strobl S., Steinkasserer A., Heilingloh C.S. A new promising candidate to overcome drug resistant herpes simplex virus infections. Antivir. Res. 2018;149:202–210. doi: 10.1016/j.antiviral.2017.11.012. 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

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

Memish Z.A., Almasri M., Chentoufi A.A., Al-Tawfiq J.A., Al-Shangiti A.M., Al-Kabbani K.M., Otaibi B., Assirri A., Yezli S. Seroprevalence of Herpes Simplex Virus Type 1 and Type 2 and Coinfection with HIV and Syphilis: The First National Seroprevalence Survey in Saudi Arabia. Sex. Trans. Dis. 2015;42:526–532. doi: 10.1097/OLQ.0000000000000336. PubMed DOI

Ma W., He H., Wang H. Oncolytic herpes simplex virus and immunotherapy. BMC Immunol. 2018;19:40. doi: 10.1186/s12865-018-0281-9. PubMed DOI PMC

Hassan S.T.S., Švajdlenka E., Berchová-Bímová K. Hibiscus sabdariffa L. and Its Bioactive Constituents Exhibit Antiviral Activity against HSV-2 and Anti-enzymatic Properties against Urease by an ESI-MS Based Assay. Molecules. 2017;22:722. doi: 10.3390/molecules22050722. 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

Widener R.W., Whitley R.J. Herpes simplex virus. Handb. Clin. Neurol. 2014;123:251–263. PubMed

Goins W.F., Hall B., Cohen J.B., Glorioso J.C. Retargeting of herpes simplex virus (HSV) vectors. Curr. Opin. Virol. 2016;21:93–101. doi: 10.1016/j.coviro.2016.08.007. PubMed DOI PMC

Joe B., Vijaykumar M., Lokesh B.R. Biological properties of curcumin-cellular and molecular mechanisms of action. Crit. Rev. Food Sci. Nutr. 2004;44:97–111. doi: 10.1080/10408690490424702. PubMed DOI

Sharma R.A., Gescher A.J., Steward W.P. Curcumin: The story so far. Eur. J. Cancer. 2005;41:1955–1968. doi: 10.1016/j.ejca.2005.05.009. PubMed DOI

Dai J., Gu L., Su Y., Wang Q., Zhao Y., Chen X., Deng H., Li W., Wang G., Li K. Inhibition of curcumin on influenza A virus infection and influenzal pneumonia via oxidative stress, TLR2/4, p38/JNK MAPK and NF-κB pathways. Int. Immunopharmacol. 2018;54:177–187. doi: 10.1016/j.intimp.2017.11.009. PubMed DOI

Kutluay S.B., Doroghazi J., Roemer M.E., Triezenberg S.J. Curcumin inhibits herpes simplex virus immediate-early gene expression by a mechanism independent of p300/CBP histone acetyltransferase activity. Virology. 2008;373:239–247. doi: 10.1016/j.virol.2007.11.028. PubMed DOI PMC

Bourne K.Z., Bourne N., Reising S.F., Stanberry L.R. Plant products as topical microbicide candidates: Assessment of in vitro and in vivo activity against herpes simplex virus type 2. Antivir. Res. 1999;42:219–226. doi: 10.1016/S0166-3542(99)00020-0. PubMed DOI

Ferreira V.H., Nazli A., Dizzell S.E., Mueller K., Kaushic C. The anti-inflammatory activity of curcumin protects the genital mucosal epithelial barrier from disruption and blocks replication of HIV-1 and HSV-2. PLoS ONE. 2015;10:e0124903. doi: 10.1371/journal.pone.0124903. PubMed DOI PMC

Flores D.J., Lee L.H., Adams S.D. Inhibition of Curcumin-Treated Herpes Simplex Virus 1 and 2 in Vero Cells. Adv. Microbiol. 2016;6:276–287. doi: 10.4236/aim.2016.64027. DOI

Vitali D., Bagri P., Wessels J.M., Arora M., Ganugula R., Parikh A., Mandur T., Felker A., Garg S., Kumar M.R., et al. Curcumin Can Decrease Tissue Inflammation and the Severity of HSV-2 Infection in the Female Reproductive Mucosa. Int. J. Mol. Sci. 2020;21:337. doi: 10.3390/ijms21010337. PubMed DOI PMC

Zandi K., Ramedani E., Mohammadi K., Tajbakhsh S., Deilami I., Rastian Z., Fouladvand M., Yousefi F., Farshadpour F. Evaluation of antiviral activities of curcumin derivatives against HSV-1 in Vero cell line. Nat. Prod. Commun. 2010;5:1935–1938. doi: 10.1177/1934578X1000501220. PubMed DOI

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

Hannigan B.M., Barnett Y.A., Armstrong D.B., McKelvey-Martin V.J., McKenna P.G. Thymidine kinases: The enzymes and their clinical usefulness. Cancer Biother. 1993;8:189–197. doi: 10.1089/cbr.1993.8.189. PubMed DOI

Fujii H., Harada S., Yoshikawa T., Yamada S., Omura N., Shibamura M., Inagaki T., Kato H., Fukushi S., Saijo M. Differences in the Likelihood of Acyclovir Resistance-Associated Mutations in the Thymidine Kinase Genes of Herpes Simplex Virus 1 and Varicella-Zoster Virus. Antimicrob. Agents Chemother. 2019;63:e00017–e00019. doi: 10.1128/AAC.00017-19. PubMed DOI PMC

Coen N., Duraffour S., Haraguchi K., Balzarini J., van den Oord J.J., Snoeck R., Andrei G. Antiherpesvirus activities of two novel 4′-thiothymidine derivatives, KAY-2-41 and KAH-39-149, are dependent on viral and cellular thymidine kinases. Antimicrob. Agents Chemother. 2014;58:4328–4340. doi: 10.1128/AAC.02825-14. PubMed DOI PMC

Topalis D., Gillemot S., Snoeck R., Andrei G. Thymidine kinase and protein kinase in drug-resistant herpesviruses: Heads of a Lernaean Hydra. Drug Resist. Updat. 2018;37:1–16. doi: 10.1016/j.drup.2018.01.003. PubMed DOI

Xie Y., Wu L., Wang M., Cheng A., Yang Q., Wu Y., Jia R., Zhu D., Zhao X., Chen S., et al. Alpha-Herpesvirus Thymidine Kinase Genes Mediate Viral Virulence and Are Potential Therapeutic Targets. Front. Microbiol. 2019;10:941. doi: 10.3389/fmicb.2019.00941. PubMed DOI PMC

El-Halim S.M.A., Mamdouh M.A., El-Haddad A.E., Soliman S.M. Fabrication of Anti-HSV-1 Curcumin Stabilized Nanostructured Proniosomal Gel: Molecular Docking Studies on Thymidine Kinase Proteins. Sci. Pharm. 2020;88:9. doi: 10.3390/scipharm88010009. DOI

Li H., Du H., Zhang G., Wu Y., Qiu P., Liu J., Guo J., Liu X., Sun L., Du B., et al. Curcumin plays a synergistic role in combination with HSV-TK/GCV in inhibiting growth of murine B16 melanoma cells and melanoma xenografts. PeerJ. 2019;7:e7760. doi: 10.7717/peerj.7760. PubMed DOI PMC

Griffiths P., Baraniak I., Reeves M. The pathogenesis of human cytomegalovirus. J. Pathol. 2015;235:288–297. doi: 10.1002/path.4437. PubMed DOI

Dooley A.L., O’Connor C.M. Regulation of the MIE Locus during HCMV Latency and Reactivation. Pathogens. 2020;9:869. doi: 10.3390/pathogens9110869. PubMed DOI PMC

Lv Y., An Z., Chen H., Wang Z., and Liu L. Mechanism of curcumin resistance to human cytomegalovirus in HELF cells. BMC Complement. Altern. Med. 2014;14:284. doi: 10.1186/1472-6882-14-284. PubMed DOI PMC

Lv Y., Gong L., Wang Z., Han F., Liu H., Lu X., Liu L. Curcumin inhibits human cytomegalovirus by downregulating heat shock protein 90. Mol. Med. Rep. 2015;12:4789–4793. doi: 10.3892/mmr.2015.3983. PubMed DOI

Lv Y., Lei N., Wang D., An Z., Li G., Han F., Liu H., Liu L. Protective effect of curcumin against cytomegalovirus infection in Balb/c mice. Environ. Toxicol. Pharmacol. 2014;37:140–147. doi: 10.1016/j.etap.2014.04.017. PubMed DOI

Guito J., Lukac D.M. KSHV Rta Promoter Specification and Viral Reactivation. Front. Microbiol. 2012;3:30. doi: 10.3389/fmicb.2012.00030. PubMed DOI PMC

Hussein H.A.M., Alfhili M.A., Pakala P., Simon S., Hussain J., McCubrey J.A., Akula S.M. miRNAs and their roles in KSHV pathogenesis. Virus Res. 2019;266:15–24. doi: 10.1016/j.virusres.2019.03.024. PubMed DOI

Zhong C., Xu M., Wang Y., Xu J., Yuan Y. An APE1 inhibitor reveals critical roles of the redox function of APE1 in KSHV replication and pathogenic phenotypes. PLoS Pathog. 2017;13:e1006289. doi: 10.1371/journal.ppat.1006289. PubMed DOI PMC

Hu J., Wang Y., Yuan Y. Inhibitors of APE1 redox function effectively inhibit γ-herpesvirus replication in vitro and in vivo. Antivir. Res. 2020;185:104985. doi: 10.1016/j.antiviral.2020.104985. PubMed DOI

Li H., Zhong C., Wang Q., Chen W., Yuan Y. Curcumin is an APE1 redox inhibitor and exhibits an antiviral activity against KSHV replication and pathogenesis. Antivir. Res. 2019;167:98–103. doi: 10.1016/j.antiviral.2019.04.011. PubMed DOI PMC

Kanda T. EBV-Encoded Latent Genes. Adv. Exp. Med. Biol. 2018;1045:377–394. PubMed

Farina A., Cirone M., York M., Lenna S., Padilla C., Mclaughlin S., Faggioni A., Lafyatis R., Trojanowska M., Farina G.A. Epstein-Barr virus infection induces aberrant TLR activation pathway and fibroblast-myofibroblast conversion in scleroderma. J. Investig. Dermatol. 2014;134:954–964. doi: 10.1038/jid.2013.423. PubMed DOI PMC

Ascherio A., Munger K.L. EBV and Autoimmunity. Curr. Top. Microbiol. Immunol. 2015;390:365–385. PubMed

Hergenhahn M., Soto U., Weninger A., Polack A., Hsu C.H., Cheng A.L., Rosl F. The chemopreventive compound curcumin is an efficient inhibitor of Epstein-Barr virus BZLF1 transcription in Raji DR-LUC cells. Mol. Carcinog. 2002;33:137–145. doi: 10.1002/mc.10029. PubMed DOI

Zhu L., Ding X., Tao J., Wang J., Zhao X., Zhu G. Critical role of cholesterol in bovine herpesvirus type 1infection of MDBK cells. Vet. Microbiol. 2010;144:51–57. doi: 10.1016/j.vetmic.2009.12.031. PubMed DOI PMC

Teles A.V., Oliveira T.M.A., Bezerra F.C., Alonso L., Alonso A., Borissevitch I.E., Gonçalves P.J., Souza G.R.L. Photodynamic inactivation of Bovine herpesvirus type 1 (BoHV-1) by porphyrins. J. Gen. Virol. 2018;99:1301–1306. doi: 10.1099/jgv.0.001121. PubMed DOI

Zhu L., Ding X., Zhang D., Yuan C., Wang J., Ndegwa E., Zhu G. Curcumin inhibits bovine herpesvirus type 1 entry into MDBK cells. Acta Virol. 2015;59:221–227. doi: 10.4149/av_2015_03_221. PubMed DOI

Reolon J.B., Brustolin M., Accarini T., Viçozzi G.P., Sari M.H.M., Bender E.A., Haas S.E., Brum M.C.S., Gündel A., Colomé L.M. Co-encapsulation of acyclovir and curcumin into microparticles improves the physicochemical characteristics and potentiates in vitro antiviral action: Influence of the polymeric composition. Eur. J. Pharm. Sci. 2019;131:167–176. doi: 10.1016/j.ejps.2019.02.019. PubMed DOI

Pomeranz L.E., Reynolds A.E., Hengartner C.J. Molecular biology of pseudorabies virus: Impact on neurovirology and veterinary medicine. Microbiol. Mol. Biol. Rev. 2005;69:462–500. doi: 10.1128/MMBR.69.3.462-500.2005. PubMed DOI PMC

Freuling C.M., Müller T.F., Mettenleiter T.C. Vaccines against pseudorabies virus (PrV) Vet. Microbiol. 2017;206:3–9. doi: 10.1016/j.vetmic.2016.11.019. PubMed DOI

Chen T.Y., Chen D.Y., Wen H.W., Ou J.L., Chiou S.S., Chen J.M., Wong M.L., Hsu W.L. Inhibition of enveloped viruses infectivity by curcumin. PLoS ONE. 2013;8:e62482. doi: 10.1371/journal.pone.0062482. PubMed DOI PMC

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

Prasad S., Gupta S.C., Tyagi A.K., Aggarwal B.B. Curcumin, a component of golden spice: From bedside to bench and back. Biotechnol. Adv. 2014;32:1053–1064. doi: 10.1016/j.biotechadv.2014.04.004. PubMed DOI

Ghosh S., Banerjee S., Sil P.C. The beneficial role of curcumin on inflammation, diabetes and neurodegenerative disease: A recent update. Food Chem. Toxicol. 2015;83:111–124. doi: 10.1016/j.fct.2015.05.022. PubMed DOI

Aggarwal B.B., Sung B. Pharmacological basis for the role of curcumin in chronic diseases: An age-old spice with modern targets. Trends Pharmacol. Sci. 2009;30:85–94. doi: 10.1016/j.tips.2008.11.002. PubMed DOI

Boyanapalli S.S.S., Huang Y., Su Z., Cheng D., Zhang C., Guo Y., Rao R., Androulakis I.P., Kong A.N. Pharmacokinetics and Pharmacodynamics of Curcumin in regulating anti-inflammatory and epigenetic gene expression. Biopharm. Drug Dispos. 2018;39:289–297. doi: 10.1002/bdd.2136. PubMed DOI PMC

Gupta S.C., Patchva S., Aggarwal B.B. Therapeutic Roles of Curcumin: Lessons Learned from Clinical Trials. AAPS J. 2013;5:195–218. doi: 10.1208/s12248-012-9432-8. PubMed DOI PMC

Yang Z., Liu W., Zhou X., Zhu X., Suo F., Yao S. The effectiveness and safety of curcumin as a complementary therapy in inflammatory bowel disease: A protocol of systematic review and meta-analysis. Medicine. 2020;99:e22916. doi: 10.1097/MD.0000000000022916. PubMed DOI PMC

Lao C.D., Ruffin M.T., Normolle D., Heath D.D., Murray S.I., Bailey J.M., Boggs M.E., Crowell J., Rock C.L., Brenner D.E. Dose escalation of a curcuminoid formulation. BMC Complement. Altern. Med. 2006;6:10. doi: 10.1186/1472-6882-6-10. PubMed DOI PMC

Kocaadam B., Sanlier N. Curcumin, an active component of turmeric (Curcuma longa), and its effects on health. Crit. Rev. Food Sci. Nutr. 2017;57:2889–2895. doi: 10.1080/10408398.2015.1077195. PubMed DOI

Sharma R.A., Euden S.A., Platton S.L., Cooke D.N., Shafayat A., Hewitt H.R., Marczylo T.H., Morgan B., Hemingway D., Plummer S.M. Phase I clinical trial of oral curcumin: Biomarkers of systemic activity and compliance. Clin. Cancer Res. 2004;10:6847–6854. doi: 10.1158/1078-0432.CCR-04-0744. PubMed DOI

Jennings M.R., Parks R.J. Curcumin as an Antiviral Agent. Viruses. 2020;12:1242. doi: 10.3390/v12111242. PubMed DOI PMC

Yang B., Luo G., Zhang C., Feng L., Luo X., Gan L. Curcumin protects rat hippocampal neurons against pseudorabies virus by regulating the BDNF/TrkB pathway. Sci. Rep. 2020;10:22204. doi: 10.1038/s41598-020-78903-0. PubMed DOI PMC

Liu W., Zhai Y., Heng X., Che F.Y., Chen W., Sun D., Zhai G. Oral bioavailability of curcumin: Problems and advancements. Drug Target. 2016;24:694–702. doi: 10.3109/1061186X.2016.1157883. PubMed DOI

Lopresti A.L. The Problem of Curcumin and Its Bioavailability: Could Its Gastrointestinal Influence Contribute to Its Overall Health-Enhancing Effects? Adv. Nutr. 2018;9:41–50. doi: 10.1093/advances/nmx011. PubMed DOI PMC

Antony B., Merina B., Iyer V.S., Judy N., Lennertz K., Joyal S. A pilot crossover study to evaluate human oral bioavailability of BCM-95CG (Biocurcumax), a novel bioenhanced preparation of curcumin. Indian J. Pharm. Sci. 2008;70:445–449. doi: 10.4103/0250-474X.44591. PubMed DOI PMC

Allegri P., Mastromarino A., Neri P. Management of chronic anterior uveitis relapses: Efficacy of oral phospholipidic curcumin treatment. Long-term follow-up. Clin. Ophthalmol. 2010;4:1201–1206. PubMed PMC

Kurita T., Makino Y. Novel curcumin oral delivery systems. Anticancer Res. 2013;33:2807–2821. PubMed

McFarlin B.K., Venable A.S., Henning A.L., Sampson J.N., Pennel K., Vingren J.L., Hill D.W. Reduced inflammatory and muscle damage biomarkers following oral supplementation with bioavailable curcumin. BBA Clin. 2016;5:72–78. doi: 10.1016/j.bbacli.2016.02.003. PubMed DOI PMC

Mathew D., Hsu W.L. Antiviral potential of curcumin. J. Funct. Foods. 2018;40:692–699. doi: 10.1016/j.jff.2017.12.017. DOI

Li X., Chen S., Zhang B., Li M., Diao K., Zhang Z., Li J., Xu Y., Wang X., Chen H. In situ injectable nano-composite hydrogel composed of curcumin, N,O-carboxymethyl chitosan and oxidized alginate for wound healing application. Int. J. Pharm. 2012;437:110–119. doi: 10.1016/j.ijpharm.2012.08.001. PubMed DOI

Misra R., Sahoo S.K. Coformulation of doxorubicin and curcumin in poly(D, Llactide- co-glycolide) nanoparticles suppresses the development of multidrug resistance in K562 cells. Mol. Pharm. 2011;8:852–866. doi: 10.1021/mp100455h. PubMed DOI

Sun M., Gao Y., Guo C.Y., Cao F.L., Song Z.M., Xi Y.W., Yu A., Li A., Zhai G. Enhancement of transport of curcumin to brain in mice by poly(n-butylcyanoacrylate) nanoparticle. J. Nanopart. Res. 2010;12:3111–3122. doi: 10.1007/s11051-010-9907-4. DOI

Onoue S., Takahashi H., Kawabata Y., Seto Y., Hatanaka J., Timmermann B., Yamada S. Formulation design and photochemical studies on nanocrystal solid dispersion of curcumin with improved oral bioavailability. J. Pharm. Sci. 2010;99:1871–1881. doi: 10.1002/jps.21964. PubMed DOI

Gou M., Men K., Shi H., Xiang M., Zhang J., Song J., Long J., Wan Y., Luo F., Zhao X., et al. Curcumin loaded biodegradable polymeric micelles for colon cancer therapy in vitro and in vivo. Nanoscale. 2011;3:1558–1567. doi: 10.1039/c0nr00758g. PubMed DOI

Thangapazham R.L., Puri A., Tele S., Blumenthal R., Maheshwari R.K. Evaluation of a nanotechnology-based carrier for delivery of curcumin in prostate cancer cells. Int. J. Oncol. 2008;32:1119–1123. doi: 10.3892/ijo.32.5.1119. PubMed DOI PMC

Aboali F.A., Habib D.A., Elbedaiwy H.M., Farid R.M. Curcumin-loaded proniosomal gel as a biofreindly alternative for treatment of ocular inflammation: In-vitro and in-vivo assessment. Int. J. Pharm. 2020;589:119835. doi: 10.1016/j.ijpharm.2020.119835. PubMed DOI

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

Anti-Epstein-Barr Virus Activities of Flavones and Flavonols with Effects on Virus-Related Cancers

Herpesvirus Diseases in Humans and Animals: Recent Developments, Challenges, and Charting Future Paths

Flavonoids with Anti-Herpes Simplex Virus Properties: Deciphering Their Mechanisms in Disrupting the Viral Life Cycle

Molecular Mechanisms of Flavonoids against Tumor Gamma-Herpesviruses and Their Correlated Cancers-A Focus on EBV and KSHV Life Cycles and Carcinogenesis

Insights into Antiviral Properties and Molecular Mechanisms of Non-Flavonoid Polyphenols against Human Herpesviruses

Flavonoids Target Human Herpesviruses That Infect the Nervous System: Mechanisms of Action and Therapeutic Insights

Tumor Viruses and Their Associated Cancers: Remain on the Track with the Latest Advances

Targeting phytoprotection in the COVID-19-induced lung damage and associated systemic effects-the evidence-based 3PM proposition to mitigate individual risks

Berberine in Human Oncogenic Herpesvirus Infections and Their Linked Cancers