{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T22:30:48Z","timestamp":1788388248652,"version":"build-2803163510"},"reference-count":60,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2018,1,17]],"date-time":"2018-01-17T00:00:00Z","timestamp":1516147200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Despite the introduction of new therapies for multiple myeloma (MM), many patients are still dying from this disease and novel treatments are urgently needed. We have designed a novel hybrid molecule, called NEO214, that was generated by covalent conjugation of the natural monoterpene perillyl alcohol (POH), an inducer of endoplasmic reticulum (ER) stress, to rolipram (Rp), an inhibitor of phosphodiesterase-4 (PDE4). Its potential anticancer effects were investigated in a panel of MM cell lines. We found that NEO214 effectively killed MM cells in vitro with a potency that was over an order of magnitude stronger than that of its individual components, either alone or in combination. The cytotoxic mechanism of NEO214 involved severe ER stress and prolonged induction of CCAAT\/enhancer-binding protein homologous protein (CHOP), a key pro-apoptotic component of the ER stress response. These effects were prevented by salubrinal, a pharmacologic inhibitor of ER stress, and by CHOP gene knockout. Conversely, combination of NEO214 with bortezomib, a drug in clinical use for patients with MM, resulted in synergistic enhancement of MM cell death. Combination with the adenylate cyclase stimulant forskolin did not enhance NEO214 impact, indicating that cyclic adenosine 3\u2032,5\u2032-monophosphate (AMP) pathways might play a lesser role. Our study introduces the novel agent NEO214 as a potent inducer of ER stress with significant anti-MM activity in vitro. It should be further investigated as a potential MM therapy aimed at exploiting this tumor\u2019s distinct sensitivity to ER stress.<\/jats:p>","DOI":"10.3390\/ijms19010277","type":"journal-article","created":{"date-parts":[[2018,1,17]],"date-time":"2018-01-17T12:17:11Z","timestamp":1516191431000},"page":"277","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Induction of Pro-Apoptotic Endoplasmic Reticulum Stress in Multiple Myeloma Cells by NEO214, Perillyl Alcohol Conjugated to Rolipram"],"prefix":"10.3390","volume":"19","author":[{"given":"Thomas","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nymph","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shirin","family":"Labib","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiali","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hee-Yeon","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florence","family":"Hofman","sequence":"additional","affiliation":[{"name":"Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0662-5653","authenticated-orcid":false,"given":"Axel","family":"Sch\u00f6nthal","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,1,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1111\/boc.201100055","article-title":"The unfolded protein response at the crossroads of cellular life and death during endoplasmic reticulum stress","volume":"104","author":"Bertrand","year":"2012","journal-title":"Biol. Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1093\/abbs\/gmu048","article-title":"New insights into the roles of CHOP-induced apoptosis in ER stress","volume":"46","author":"Li","year":"2014","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Rutkowski, D.T., Arnold, S.M., Miller, C.N., Wu, J., Li, J., Gunnison, K.M., Mori, K., Sadighi Akha, A.A., Raden, D., and Kaufman, R.J. (2006). Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteins. PLoS Biol., 4.","DOI":"10.1371\/journal.pbio.0040374"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1146\/annurev-biochem-072909-095555","article-title":"Endoplasmic reticulum stress and type 2 diabetes","volume":"81","author":"Back","year":"2012","journal-title":"Annu. Rev. Biochem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1038\/nrd2755","article-title":"Cell death and endoplasmic reticulum stress: Disease relevance and therapeutic opportunities","volume":"7","author":"Kim","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/j.bcp.2012.09.012","article-title":"Pharmacological targeting of endoplasmic reticulum stress signaling in cancer","volume":"85","year":"2013","journal-title":"Biochem. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1158\/0008-5472.CAN-06-2258","article-title":"Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition","volume":"67","author":"Meister","year":"2007","journal-title":"Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"10748","DOI":"10.18632\/oncotarget.13314","article-title":"Magic year for multiple myeloma therapeutics: Key takeaways from the ASH 2015 annual meeting","volume":"8","author":"Zhang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Scott, K., Hayden, P.J., Will, A., Wheatley, K., and Coyne, I. (2013). Bortezomib for the treatment of multiple myeloma. Cochrane Database Syst. Rev., 4.","DOI":"10.1002\/14651858.CD010816"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1007\/s12185-016-2016-0","article-title":"Endoplasmic-reticulum stress pathway-associated mechanisms of action of proteasome inhibitors in multiple myeloma","volume":"104","author":"Ri","year":"2016","journal-title":"Int. J. Hematol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4907","DOI":"10.1182\/blood-2005-08-3531","article-title":"Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells","volume":"107","author":"Obeng","year":"2006","journal-title":"Blood"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1158\/1535-7163.MCT-12-0782","article-title":"Endoplasmic reticulum stress and the unfolded protein response: Targeting the Achilles heel of multiple myeloma","volume":"12","author":"Vincenz","year":"2013","journal-title":"Mol. Cancer Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2428","DOI":"10.2174\/138161211797249242","article-title":"Preclinical development of novel anti-tumor drugs targeting the endoplasmic reticulum stress response","volume":"17","author":"Chen","year":"2011","journal-title":"Curr. Pharm. Des."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"8435","DOI":"10.1158\/0008-5472.CAN-07-5555","article-title":"Aggravated endoplasmic reticulum stress as a basis for enhanced glioblastoma cell killing by bortezomib in combination with celecoxib or its non-coxib analogue, 2,5-dimethyl-celecoxib","volume":"68","author":"Kardosh","year":"2008","journal-title":"Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"346","DOI":"10.3324\/haematol.2015.135780","article-title":"Treatment with the HIV protease inhibitor nelfinavir triggers the unfolded protein response and may overcome proteasome inhibitor resistance of multiple myeloma in combination with bortezomib: A phase I trial (SAKK 65\/08)","volume":"101","author":"Driessen","year":"2016","journal-title":"Haematologica"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5183","DOI":"10.1158\/1078-0432.CCR-07-0161","article-title":"Nelfinavir, A lead HIV protease inhibitor, is a broad-spectrum, anticancer agent that induces endoplasmic reticulum stress, autophagy, and apoptosis in vitro and in vivo","volume":"13","author":"Gills","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1111\/j.1527-3458.2001.tb00206.x","article-title":"The antidepressant and antiinflammatory effects of rolipram in the central nervous system","volume":"7","author":"Zhu","year":"2001","journal-title":"CNS Drug Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"268","DOI":"10.4161\/cbt.80","article-title":"The type IV phosphodiesterase inhibitor rolipram induces expression of the cell cycle inhibitors p21(Cip1) and p27(Kip1), resulting in growth inhibition, increased differentiation, and subsequent apoptosis of malignant A-172 glioma cells","volume":"1","author":"Chen","year":"2002","journal-title":"Cancer Biol. Ther"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5248","DOI":"10.1158\/0008-5472.CAN-07-0097","article-title":"Chemoresistant KM12C colon cancer cells are addicted to low cyclic AMP levels in a phosphodiesterase 4-regulated compartment via effects on phosphoinositide 3-kinase","volume":"67","author":"McEwan","year":"2007","journal-title":"Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4733","DOI":"10.1021\/jm981021v","article-title":"Synthesis of 7-benzylamino-6-chloro-2-piperazino-4-pyrrolidinopteridine and novel derivatives free of positional isomers. Potent inhibitors of cAMP-specific phosphodiesterase and of malignant tumor cell growth","volume":"41","author":"Merz","year":"1998","journal-title":"J. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1038\/nsmb.2022","article-title":"ERK and PDE4 cooperate to induce RAF isoform switching in melanoma","volume":"18","author":"Marquette","year":"2011","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5401","DOI":"10.4049\/jimmunol.0804255","article-title":"Chronic lymphocytic leukemia and B and T cells differ in their response to cyclic nucleotide phosphodiesterase inhibitors","volume":"182","author":"Meyers","year":"2009","journal-title":"J. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"7717","DOI":"10.1158\/1078-0432.CCR-08-0827","article-title":"Targeted inhibition of cyclic AMP phosphodiesterase-4 promotes brain tumor regression","volume":"14","author":"Goldhoff","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"26","DOI":"10.3389\/fnmol.2015.00026","article-title":"Looking downstream: The role of cyclic AMP-regulated genes in axonal regeneration","volume":"8","author":"Siddiq","year":"2015","journal-title":"Front. Mol. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Wildman, R.E.C. (2001). Isoprenoids, Health and Disease. Nutraceuticals and Functional Foods, CRC Press.","DOI":"10.1201\/9781420036695"},{"key":"ref_26","first-page":"1580","article-title":"Preclinical development and clinical use of perillyl alcohol for chemoprevention and cancer therapy","volume":"5","author":"Chen","year":"2015","journal-title":"Am. J. Cancer Res."},{"key":"ref_27","first-page":"5625","article-title":"Long-term outcome in patients with recurrent malignant glioma treated with Perillyl alcohol inhalation","volume":"33","author":"Teixeira","year":"2013","journal-title":"Anticancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"17508","DOI":"10.1074\/jbc.270.29.17508","article-title":"Differential effects of monoterpenes and lovastatin on RAS processing","volume":"270","author":"Hohl","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_29","first-page":"823","article-title":"Effects of the antitumor agent perillyl alcohol on H-Ras vs. K-Ras farnesylation and signal transduction in pancreatic cells","volume":"18","author":"Stayrook","year":"1998","journal-title":"Anticancer Res"},{"key":"ref_30","first-page":"4494","article-title":"Anti-leukemia effect of perillyl alcohol in Bcr\/Abl-transformed cells indirectly inhibits signaling through Mek in a Ras- and Raf-independent fashion","volume":"9","author":"Clark","year":"2003","journal-title":"Clin. Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1097\/00001813-199606000-00008","article-title":"Inhibition of tumor cell growth by monoterpenes in vitro: Evidence of a Ras-independent mechanism of action","volume":"7","author":"Karlson","year":"1996","journal-title":"Anticancer Drugs"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1093\/carcin\/15.4.787","article-title":"Growth inhibition of rat liver epithelial tumor cells by monoterpenes does not involve Ras plasma membrane association","volume":"15","author":"Ruch","year":"1994","journal-title":"Carcinogenesis"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1957","DOI":"10.1093\/carcin\/20.10.1957","article-title":"Induction of AP-1 activity by perillyl alcohol in breast cancer cells","volume":"20","author":"Satomi","year":"1999","journal-title":"Carcinogenesis"},{"key":"ref_34","first-page":"1917","article-title":"Activation of the transforming growth factor beta signaling pathway and induction of cytostasis and apoptosis in mammary carcinomas treated with the anticancer agent perillyl alcohol","volume":"59","author":"Ariazi","year":"1999","journal-title":"Cancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"8558","DOI":"10.1158\/0008-5472.CAN-04-4072","article-title":"Perillyl alcohol inhibits a calcium-dependent constitutive nuclear factor-\u03baB pathway","volume":"65","author":"Berchtold","year":"2005","journal-title":"Cancer Res."},{"key":"ref_36","first-page":"97","article-title":"Disruption of an hTERT-mTOR-RAPTOR protein complex by a phytochemical perillyl alcohol and rapamycin","volume":"375","author":"Sundin","year":"2013","journal-title":"Mol. Cell Biochem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/01635589809514708","article-title":"Monoterpenes inhibit cell growth, cell cycle progression, and cyclin D1 gene expression in human breast cancer cell lines","volume":"32","author":"Bardon","year":"1998","journal-title":"Nutr. Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1124\/jpet.106.111666","article-title":"Cell cycle arrest by the isoprenoids perillyl alcohol, geraniol, and farnesol is mediated by p21(Cip1) and p27(Kip1) in human pancreatic adenocarcinoma cells","volume":"320","author":"Wiseman","year":"2007","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2103","DOI":"10.1016\/j.yexcr.2013.05.029","article-title":"eIF4E-Overexpression imparts perillyl alcohol and rapamycin-mediated regulation of telomerase reverse transcriptase","volume":"319","author":"Sundin","year":"2013","journal-title":"Exp. Cell Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2639","DOI":"10.1016\/j.biochi.2012.07.028","article-title":"The isoprenoid perillyl alcohol inhibits telomerase activity in prostate cancer cells","volume":"94","author":"Sundin","year":"2012","journal-title":"Biochimie"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s11010-010-0556-9","article-title":"The anticancer drug perillyl alcohol is a Na\/K-ATPase inhibitor","volume":"345","author":"Garcia","year":"2010","journal-title":"Mol. Cell Biochem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2462","DOI":"10.1158\/1535-7163.MCT-12-0321","article-title":"Perillyl alcohol for the treatment of temozolomide-resistant gliomas","volume":"11","author":"Cho","year":"2012","journal-title":"Mol. Cancer Ther."},{"key":"ref_43","first-page":"979","article-title":"Induction of apoptosis in liver tumors by the monoterpene perillyl alcohol","volume":"55","author":"Mills","year":"1995","journal-title":"Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/S0031-6997(25)06847-4","article-title":"The search for synergy: A critical review from a response surface perspective","volume":"47","author":"Greco","year":"1995","journal-title":"Pharmacol. Rev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1007\/s40262-012-0010-0","article-title":"Pharmacokinetic, pharmacodynamic and covariate analysis of subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma","volume":"51","author":"Moreau","year":"2012","journal-title":"Clin. Pharmacokinet."},{"key":"ref_46","first-page":"232","article-title":"Clinical effects of the neurotropic selective cAMP phosphodiesterase inhibitor rolipram in depressed patients: Global evaluation of the preliminary reports","volume":"38","author":"Horowski","year":"1985","journal-title":"Curr. Ther. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.taap.2012.06.017","article-title":"Inhibition of chlorine-induced lung injury by the type 4 phosphodiesterase inhibitor rolipram","volume":"263","author":"Chang","year":"2012","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Chen, T.C., da Fonseca, C.O., and Schonthal, A.H. (2016). Perillyl Alcohol and Its Drug-Conjugated Derivatives as Potential Novel Methods of Treating Brain Metastases. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17091463"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"230","DOI":"10.3389\/fphar.2015.00230","article-title":"Effect of cAMP signaling on expression of glucocorticoid receptor, Bim and Bad in glucocorticoid-sensitive and resistant leukemic and multiple myeloma cells","volume":"6","author":"Dong","year":"2015","journal-title":"Front. Pharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3390","DOI":"10.1182\/blood.V99.9.3390","article-title":"Inhibition of PDE4 phosphodiesterase activity induces growth suppression, apoptosis, glucocorticoid sensitivity, p53, and p21(WAF1\/CIP1) proteins in human acute lymphoblastic leukemia cells","volume":"99","author":"Ogawa","year":"2002","journal-title":"Blood"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.bcp.2004.10.009","article-title":"Type 4 cAMP phosphodiesterase (PDE4) inhibitors augment glucocorticoid-mediated apoptosis in B cell chronic lymphocytic leukemia (B-CLL) in the absence of exogenous adenylyl cyclase stimulation","volume":"69","author":"Tiwari","year":"2005","journal-title":"Biochem. Pharmacol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.ceb.2010.11.003","article-title":"Signaling cell death from the endoplasmic reticulum stress response","volume":"23","author":"Shore","year":"2011","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1093\/jb\/mvr143","article-title":"CHOP is a multifunctional transcription factor in the ER stress response","volume":"151","author":"Nishitoh","year":"2012","journal-title":"J. Biochem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1126\/science.1101902","article-title":"A selective inhibitor of eIF2\u03b1 dephosphorylation protects cells from ER stress","volume":"307","author":"Boyce","year":"2005","journal-title":"Science"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.molmed.2005.06.011","article-title":"A new pharmacology\u2014drugging stressed folding pathways","volume":"11","author":"Wiseman","year":"2005","journal-title":"Trends Mol. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"16275","DOI":"10.3390\/ijms160716275","article-title":"Experimental Evidence Shows Salubrinal, an eIF2\u03b1 Dephosphorylation Inhibitor, Reduces Xenotoxicant-Induced Cellular Damage","volume":"16","author":"Matsuoka","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_57","first-page":"5125","article-title":"Characterization of a new drug-resistant human myeloma cell line that expresses P-glycoprotein","volume":"46","author":"Dalton","year":"1986","journal-title":"Cancer Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"575","DOI":"10.2353\/ajpath.2008.071079","article-title":"Increased survivin expression confers chemoresistance to tumor-associated endothelial cells","volume":"173","author":"Virrey","year":"2008","journal-title":"Am. J. Pathol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.canlet.2010.11.008","article-title":"Green tea epigallocatechin gallate enhances therapeutic efficacy of temozolomide in orthotopic mouse glioblastoma models","volume":"302","author":"Chen","year":"2011","journal-title":"Cancer Lett."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/1476-4598-5-19","article-title":"Downregulation of survivin expression and concomitant induction of apoptosis by celecoxib and its non-cyclooxygenase-2-inhibitory analog, dimethyl-celecoxib (DMC), in tumor cells in vitro and in vivo","volume":"5","author":"Pyrko","year":"2006","journal-title":"Mol. Cancer"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/1\/277\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T14:51:40Z","timestamp":1760194300000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/1\/277"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,1,17]]},"references-count":60,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,1]]}},"alternative-id":["ijms19010277"],"URL":"https:\/\/doi.org\/10.3390\/ijms19010277","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,1,17]]}}}