{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T20:40:17Z","timestamp":1791492017047,"version":"4.3.4"},"reference-count":50,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,1,4]],"date-time":"2020-01-04T00:00:00Z","timestamp":1578096000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["126019"],"award-info":[{"award-number":["126019"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["138657"],"award-info":[{"award-number":["138657"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01EY028169"],"award-info":[{"award-number":["R01EY028169"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Herpes Simplex Virus Type 2 (HSV-2) is one of the most prevalent sexually transmitted viruses and is a known risk factor for HIV acquisition in the Female Genital Tract (FGT). Previously, we found that curcumin can block HSV-2 infection and abrogate the production of inflammatory cytokines and chemokines by genital epithelial cells in vitro. In this study, we investigated whether curcumin, encapsulated in nanoparticles and delivered by various in vivo routes, could minimize inflammation and prevent or reduce HSV-2 infection in the FGT. Female mice were pre-treated with curcumin nanoparticles through oral, intraperitoneal and intravaginal routes, and then exposed intravaginally to the tissue inflammation stimulant CpG-oligodeoxynucleotide (ODN). Local intravaginal delivery of curcumin nanoparticles, but not intraperitoneal or oral delivery, reduced CpG-mediated inflammatory histopathology and decreased production of pro-inflammatory cytokines Interleukin (IL)-6, Tumor Necrosis Factor Alpha (TNF-\u03b1) and Monocyte Chemoattractant Protein-1 (MCP-1) in the FGT. However, curcumin nanoparticles did not demonstrate anti-viral activity nor reduce tissue pathology when administered prior to intravaginal HSV-2 infection. In an alternative approach, intravaginal pre-treatment with crude curcumin or solid dispersion formulations of curcumin demonstrated increased survival and delayed pathology following HSV-2 infection. Our results suggest that curcumin nanoparticle delivery in the vaginal tract could reduce local tissue inflammation. The anti-inflammatory properties of curcumin delivered to the vaginal tract could potentially reduce the severity of HSV-2 infection and decrease the risk of HIV acquisition in the FGT of women.<\/jats:p>","DOI":"10.3390\/ijms21010337","type":"journal-article","created":{"date-parts":[[2020,1,6]],"date-time":"2020-01-06T03:48:48Z","timestamp":1578282528000},"page":"337","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["Curcumin Can Decrease Tissue Inflammation and the Severity of HSV-2 Infection in the Female Reproductive Mucosa"],"prefix":"10.3390","volume":"21","author":[{"given":"Danielle","family":"Vitali","sequence":"first","affiliation":[{"name":"Department of Pathology &amp; Molecular Medicine and McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Puja","family":"Bagri","sequence":"additional","affiliation":[{"name":"Department of Pathology &amp; Molecular Medicine and McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jocelyn M.","family":"Wessels","sequence":"additional","affiliation":[{"name":"Department of Pathology &amp; Molecular Medicine and McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meenakshi","family":"Arora","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, Texas A&amp;M University, College Station, TX 77843, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raghu","family":"Ganugula","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, Texas A&amp;M University, College Station, TX 77843, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ankit","family":"Parikh","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Medical Sciences, University of South Australia, Adelaide 5000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Talveer","family":"Mandur","sequence":"additional","affiliation":[{"name":"Department of Pathology &amp; Molecular Medicine and McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison","family":"Felker","sequence":"additional","affiliation":[{"name":"Department of Pathology &amp; Molecular Medicine and McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7253-2629","authenticated-orcid":false,"given":"Sanjay","family":"Garg","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Medical Sciences, University of South Australia, Adelaide 5000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.N.V. Ravi","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, Texas A&amp;M University, College Station, TX 77843, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7088-2569","authenticated-orcid":false,"given":"Charu","family":"Kaushic","sequence":"additional","affiliation":[{"name":"Department of Pathology &amp; Molecular Medicine and McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,4]]},"reference":[{"key":"ref_1","unstructured":"UNAIDS (2016). Global AIDS Update 2016, UNAIDS."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1909","DOI":"10.1097\/QAD.0b013e3283060ea4","article-title":"A new strategy to understand how HIV infects women: Identification of a window of vulnerability during the menstrual cycle","volume":"22","author":"Wira","year":"2008","journal-title":"AIDS"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1038\/nri2302","article-title":"Setting the stage: Host invasion by HIV","volume":"8","author":"Hladik","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Looker, K.J., Magaret, A.S., Turner, K.M.E., Vickerman, P., Gottlieb, S.L., and Newman, L.M. (2015). Global estimates of prevalent and incident herpes simplex virus type 2 infections in 2012. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0128615"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1093\/cid\/civ298","article-title":"Genital inflammation and the risk of HIV acquisition in women","volume":"61","author":"Masson","year":"2015","journal-title":"Clin. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1097\/COH.0000000000000232","article-title":"Genital inflammation, immune activation and risk of sexual HIV acquisition","volume":"11","author":"Passmore","year":"2016","journal-title":"Curr. Opin. HIV AIDS"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.jri.2012.10.010","article-title":"Innate and adaptive anti-HIV immune responses in the female reproductive tract","volume":"97","author":"Patel","year":"2013","journal-title":"J. Reprod. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1093\/infdis\/jir260","article-title":"Endometrial Epithelial Cell Responses to Coinfecting Viral and Bacterial Pathogens in the Genital Tract Can Activate the HIV-1 LTR in an NF\u03baB-and AP-1\u2013Dependent Manner","volume":"204","author":"Ferreira","year":"2011","journal-title":"J. Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Nazli, A., Chan, O., Dobson-Belaire, W.N., Ouellet, M., Tremblay, M.J., Gray-Owen, S.D., Arsenault, A.L., and Kaushic, C. (2010). Exposure to HIV-1 directly impairs mucosal epithelial barrier integrity allowing microbial translocation. PLoS Pathog., 6.","DOI":"10.1371\/journal.ppat.1000852"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4246","DOI":"10.4049\/jimmunol.1301482","article-title":"HIV-1 gp120 Induces TLR2- and TLR4-Mediated Innate Immune Activation in Human Female Genital Epithelium","volume":"191","author":"Nazli","year":"2013","journal-title":"J. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Martinelli, E., Tharinger, H., Frank, I., Arthos, J., Piatak, M., Lifson, J.D., Blanchard, J., Gettie, A., and Robbiani, M. (2011). HSV-2 infection of dendritic cells amplifies a highly susceptible HIV-1 cell target. PLoS Pathog., 7.","DOI":"10.1371\/journal.ppat.1002109"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1128\/JVI.01302-12","article-title":"Herpes simplex virus 2 (HSV-2) prevents dendritic cell maturation, induces apoptosis, and triggers release of proinflammatory cytokines: Potential links to HSV-HIV synergy","volume":"87","author":"Stefanidou","year":"2013","journal-title":"J. Virol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e2354","DOI":"10.1038\/cddis.2016.250","article-title":"HSV-1-induced activation of NF-kappaB protects U937 monocytic cells against both virus replication and apoptosis","volume":"7","author":"Papaianni","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_14","first-page":"186864","article-title":"A review on antibacterial, antiviral, and antifungal activity of curcumin","volume":"2014","author":"Moghadamtousi","year":"2014","journal-title":"BioMed Res. Int."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1002\/mnfr.200700354","article-title":"Multi-targeted therapy by curcumin: How spicy is it?","volume":"52","author":"Goel","year":"2008","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1016\/j.bcp.2007.08.016","article-title":"Curcumin as \u201cCurecumin\u201d: From kitchen to clinic","volume":"75","author":"Goel","year":"2008","journal-title":"Biochem. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1006\/phrs.1998.0404","article-title":"Curcumin inhibition of inflammatory cytokine production by peripheral blood monocytes and alveolar maccrophages","volume":"39","author":"Abe","year":"1999","journal-title":"Pharmacol. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6506","DOI":"10.4049\/jimmunol.168.12.6506","article-title":"Curcumin Inhibits Experimental Allergic Encephalomyelitis by Blocking IL-12 Signaling Through Janus Kinase-STAT Pathway in T Lymphocytes","volume":"168","author":"Natarajan","year":"2002","journal-title":"J. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1002\/cncr.21216","article-title":"Curcumin-induced antiproliferative and proapoptotic effects in melanoma cells are associated with suppression of I\u03baB kinase and nuclear factor \u03baB activity and are independent of the B-Raf\/mitogen-activated\/extracellular signal-regulated protein kinase pathway and the Akt pathway","volume":"104","author":"Siwak","year":"2005","journal-title":"Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/S0027-5107(01)00183-X","article-title":"Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: Down-regulation of COX-2 and iNOS through suppression of NF-\u03baB activation","volume":"480\u2013481","author":"Surh","year":"2001","journal-title":"Mutat. Res. Fundam. Mol. Mech. Mutagen."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Ferreira, V.H., Nazli, A., Dizzell, S.E., Mueller, K., and Kaushic, C. (2015). 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, 10.","DOI":"10.1371\/journal.pone.0124903"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1158\/1940-6207.CAPR-10-0006","article-title":"Advanced drug delivery systems of curcumin for cancer chemoprevention","volume":"4","author":"Bansal","year":"2011","journal-title":"Cancer Prev. Res. (Phila)"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1021\/acs.jafc.6b04815","article-title":"Physical and Chemical Stability of Curcumin in Aqueous Solutions and Emulsions: Impact of pH, Temperature, and Molecular Environment","volume":"65","author":"Kharat","year":"2017","journal-title":"J. Agric. Food Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"7606","DOI":"10.1021\/acs.jafc.5b00244","article-title":"Degradation of Curcumin: From Mechanism to Biological Implications","volume":"63","author":"Schneider","year":"2015","journal-title":"J. Agric. Food Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.ejps.2009.02.019","article-title":"Nanoparticle encapsulation improves oral bioavailability of curcumin by at least 9-fold when compared to curcumin administered with piperine as absorption enhancer","volume":"37","author":"Shaikh","year":"2009","journal-title":"Eur. J. Pharma. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Grama, C.N., Suryanarayana, P., Patil, M.A., Raghu, G., Balakrishna, N., Kumar, M.N.V.R., and Reddy, G.B. (2013). Efficacy of biodegradable curcumin nanoparticles in delaying cataract in diabetic rat model. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0078217"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1007\/s13346-011-0041-3","article-title":"Protective effects of nanoparticulate coenzyme Q10 and curcumin on inflammatory markers and lipid metabolism in streptozotocin-induced diabetic rats: A possible remedy to diabetic complications","volume":"1","author":"Devadasu","year":"2011","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1007\/s13346-018-0570-0","article-title":"Curcumin-loaded self-nanomicellizing solid dispersion system: Part II: In vivo safety and efficacy assessment against behavior deficit in Alzheimer disease","volume":"8","author":"Parikh","year":"2018","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1007\/s13346-018-0543-3","article-title":"Curcumin-loaded self-nanomicellizing solid dispersion system: Part I: Development, optimization, characterization, and oral bioavailability","volume":"8","author":"Parikh","year":"2018","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1086\/425079","article-title":"Toll-Like Receptor (TLR)-3, but Not TLR4, Agonist Protects against Genital Herpes Infection in the Absence of Inflammation Seen with CpG DNA","volume":"190","author":"Ashkar","year":"2004","journal-title":"J. Infect. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1002\/jmv.10518","article-title":"Parameters of CpG oligodeoxynucleotide-induced protection against intravaginal HSV-2 challenge","volume":"71","author":"Sajic","year":"2003","journal-title":"J. Med. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1089\/aid.2016.0187","article-title":"High Levels of Inflammatory Cytokines in the Reproductive Tract of Women with BV and Engaging in Intravaginal Douching: A Cross-Sectional Study of Participants in the Women Interagency HIV Study","volume":"33","author":"Alcaide","year":"2017","journal-title":"AIDS Res. Hum. Retrovir."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1038\/mi.2015.51","article-title":"Increased levels of inflammatory cytokines in the female reproductive tract are associated with altered expression of proteases, mucosal barrier proteins, and an influx of HIV-susceptible target cells","volume":"9","author":"Arnold","year":"2016","journal-title":"Mucosal Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1038\/nature07831","article-title":"Glycerol monolaurate prevents mucosal SIV transmission","volume":"458","author":"Li","year":"2009","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"25479","DOI":"10.1038\/srep25479","article-title":"Triple combination MPT vaginal microbicide using curcumin and efavirenz loaded lactoferrin nanoparticles","volume":"6","author":"Lakshmi","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/S0166-3542(99)00020-0","article-title":"Plant products as topical microbicide candidates: Assessment of in vitro and in vivo activity against herpes simplex virus type 2","volume":"42","author":"Bourne","year":"1999","journal-title":"Antivir. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2","DOI":"10.4143\/crt.2014.46.1.2","article-title":"Recent developments in delivery, bioavailability, absorption and metabolism of curcumin: The golden pigment from golden spice","volume":"46","author":"Prasad","year":"2014","journal-title":"Cancer Res. Treat."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3667","DOI":"10.2147\/IJN.S30428","article-title":"Enhanced bioavailability and efficiency of curcumin for the treatment of asthma by its formulation in solid lipid nanoparticles","volume":"7","author":"Wang","year":"2012","journal-title":"Int. J. Nanomed."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"741","DOI":"10.3892\/ijo.2012.1734","article-title":"Oral or parenteral administration of curcumin does not prevent the growth of high-risk t(4;11) acute lymphoblastic leukemia cells engrafted into a NOD\/SCID mouse model","volume":"42","author":"Zunino","year":"2013","journal-title":"Int. J. Oncol."},{"key":"ref_40","first-page":"196","article-title":"Effect of curcumin, the active constituent of turmeric, on penicillin-induced epileptiform activity in rats","volume":"2","author":"Tamaddonfard","year":"2012","journal-title":"Avicenna J. Phytomed"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"717","DOI":"10.4103\/0971-5916.91009","article-title":"Preventive action of curcumin in experimental acute pancreatitis in mouse","volume":"134","author":"Yu","year":"2011","journal-title":"Indian J. Med. Res."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Young, N.A., Bruss, M.S., Gardner, M., Willis, W.L., Mo, X., Valiente, G.R., Cao, Y., Liu, Z., Jarjour, W.N., and Wu, L.C. (2014). Oral administration of nano-emulsion curcumin in mice suppresses inflammatory-induced NFkappaB signaling and macrophage migration. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0111559"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1007\/s10620-009-0843-z","article-title":"Oral administration of curcumin emulsified in carboxymethyl cellulose has a potent anti-inflammatory effect in the IL-10 gene-deficient mouse model of IBD","volume":"55","author":"Ung","year":"2010","journal-title":"Dig. Dis. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"L614","DOI":"10.1152\/ajplung.90443.2008","article-title":"Curcumin attenuates elastase- and cigarette smoke-induced pulmonary emphysema in mice","volume":"296","author":"Suzuki","year":"2009","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_45","first-page":"1","article-title":"Curcumin: Clinical trial finds no antiviral effect","volume":"242","author":"James","year":"1996","journal-title":"AIDS Treat News"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"695","DOI":"10.2147\/IJWH.S34030","article-title":"Intravaginal rings as delivery systems for microbicides and multipurpose prevention technologies","volume":"5","author":"Thurman","year":"2013","journal-title":"Int. J. Womens Health"},{"key":"ref_47","first-page":"1574","article-title":"Solid dispersion technique for improving solubility of some poorly soluble drugs","volume":"4","author":"Mogal","year":"2012","journal-title":"Der Pharm. Lett."},{"key":"ref_48","first-page":"137","article-title":"Increased solubility, dissolution and physicochemical studies ofcurcumin-polyvinylpyrrolidone K-30 solid dispersions","volume":"3","author":"Kaewnopparat","year":"2009","journal-title":"Int. J. Med. Health Biomed. Bioeng. Pharm. Eng."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4558","DOI":"10.1128\/JVI.77.8.4558-4565.2003","article-title":"Progesterone increases susceptibility and decreases immune responses to genital herpes infection","volume":"77","author":"Kaushic","year":"2003","journal-title":"J. Virol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"6165","DOI":"10.1016\/j.vaccine.2008.08.045","article-title":"Intranasal and subcutaneous immunization under the effect of estradiol leads to better protection against genital HSV-2 challenge compared to progesterone","volume":"26","author":"Bhavanam","year":"2008","journal-title":"Vaccine"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/1\/337\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:42:17Z","timestamp":1760362937000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/1\/337"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,4]]},"references-count":50,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,1]]}},"alternative-id":["ijms21010337"],"URL":"https:\/\/doi.org\/10.3390\/ijms21010337","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,4]]}}}