{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:43:49Z","timestamp":1790189029439,"version":"4.1.0"},"reference-count":67,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,10,22]],"date-time":"2021-10-22T00:00:00Z","timestamp":1634860800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Autophagy has been demonstrated to have a beneficial effect on diabetic nephropathy (DN). Rapamycin, an inhibitor of mTOR, was shown to stimulate \u03b2-cell autophagy. However, its effects on preventing or ameliorating DN is unclear, and its effects are worth studying. As fasting is now an attractive protective strategy, we aim to compare its effect to rapamycin effects on pancreatic and renal cells. Twenty-eight adult male Wistar Albino rats were randomly divided into four groups, using streptozotocin (STZ) to induce diabetes mellitus (DM). Autophagy was induced by two ways; rapamycin or fasting. The extent of autophagy and apoptosis were investigated by measuring the level of LC3B and p53 proteins, respectively, in pancreatic and kidney tissues using Western blotting (WB) technique and imaging the renal cells under transmission electron microscope. The efflux transporter P-glycoprotein was quantified by WB as well. Rapamycin-induced autophagy occurred concurrently with apoptosis. On the other hand, fasting supported P-glycoprotein recovery and renal cell survival together with disabling \u03b2-cells apoptosis. In conclusion, this study provides a potential link between rapamycin or fasting for the cross-regulation of apoptosis and autophagy in the setting of cell stress as DN. Unlike rapamycin, fasting enhanced the active expression of ABCB1 efflux protein, providing insights on the potential ameliorative effects of fasting in DN that require further elucidation.<\/jats:p>","DOI":"10.3390\/cimb43030120","type":"journal-article","created":{"date-parts":[[2021,10,25]],"date-time":"2021-10-25T21:44:31Z","timestamp":1635198271000},"page":"1698-1714","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Amelioration of Diabetic Nephropathy by Targeting Autophagy via Rapamycin or Fasting: Relation to Cell Apoptosis\/Survival"],"prefix":"10.3390","volume":"43","author":[{"given":"Khaled","family":"Gouda","sequence":"first","affiliation":[{"name":"Biochemistry Department, Faculty of Pharmacy, Modern University for Technology and Information, Cairo 12055, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4900-3715","authenticated-orcid":false,"given":"Sherihan","family":"AbdelHamid","sequence":"additional","affiliation":[{"name":"Biochemistry Department, Faculty of Pharmacy, Ain-Shams University, Cairo 11566, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed","family":"Mansour","sequence":"additional","affiliation":[{"name":"Pharmacology and Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11651, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nesreen","family":"Omar","sequence":"additional","affiliation":[{"name":"Biochemistry Department, Faculty of Pharmacy, Modern University for Technology and Information, Cairo 12055, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hala","family":"El-Mesallamy","sequence":"additional","affiliation":[{"name":"Biochemistry Department, Faculty of Pharmacy, Ain-Shams University, Cairo 11566, Egypt"},{"name":"Dean of Faculty of Pharmacy, Sinai University, North Sinai 45518, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S92","DOI":"10.1016\/j.molmet.2019.06.014","article-title":"\u03b2-cell autophagy: Mechanism and role in \u03b2-cell dysfunction","volume":"27","author":"Lee","year":"2019","journal-title":"Mol. Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1111\/j.1463-1326.2010.01278.x","article-title":"Role of autophagy in \u03b2-cell function and mass","volume":"12","author":"Hur","year":"2010","journal-title":"Diabetes Obes. Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"R1","DOI":"10.1530\/EC-14-0092","article-title":"Mitochondrial dysfunction and insulin resistance: An update","volume":"4","author":"Montgomery","year":"2015","journal-title":"Endocr. Connect."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1002\/path.2697","article-title":"Autophagy: Cellular and molecular mechanisms","volume":"221","author":"Glick","year":"2010","journal-title":"J. Pathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1055\/s-0043-101700","article-title":"Effects of A One-week Fasting Therapy in Patients with Type-2 Diabetes Mellitus and Metabolic Syndrome\u2014A Randomized Controlled Explorative Study","volume":"125","author":"Li","year":"2017","journal-title":"Exp. Clin. Endocrinol. Diabetes"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.cmet.2013.12.008","article-title":"Fasting: Molecular mechanisms and clinical applications","volume":"19","author":"Longo","year":"2014","journal-title":"Cell Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2541","DOI":"10.1056\/NEJMra1905136","article-title":"Effects of intermittent fasting on health, aging, and disease","volume":"381","author":"Mattson","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1126\/science.aau2095","article-title":"A time to fast","volume":"362","author":"Bernier","year":"2018","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s12263-019-0650-x","article-title":"Metabolic regulation of lifespan from a C. Elegans perspective","volume":"14","author":"Dall","year":"2019","journal-title":"Genes Nutr."},{"key":"ref_10","first-page":"709","article-title":"Is autophagy associated with diabetes mellitus and its complications? A review","volume":"17","author":"Bhattacharya","year":"2018","journal-title":"EXCLI J."},{"key":"ref_11","first-page":"102","article-title":"Rapamycin Causes Upregulation of Autophagy and Impairs Islets Function Both In Vitro and In Vivo","volume":"12","author":"Tanemura","year":"2012","journal-title":"Arab. Archaeol. Epigr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"11061","DOI":"10.1074\/jbc.R109.072181","article-title":"Chemical Inducers of Autophagy That Enhance the Clearance of Mutant Proteins in Neurodegenerative Diseases","volume":"285","author":"Renna","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1146\/annurev-genet-102808-114910","article-title":"Regulation Mechanisms and Signaling Pathways of Autophagy","volume":"43","author":"He","year":"2009","journal-title":"Annu. Rev. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.cell.2012.03.017","article-title":"mTOR signaling in growth control and disease","volume":"149","author":"Laplante","year":"2012","journal-title":"Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s12154-008-0003-5","article-title":"Rapamycin and mTOR kinase inhibitors","volume":"1","author":"Ballou","year":"2008","journal-title":"J. Chem. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.cmet.2014.01.001","article-title":"Rapamycin: One drug, many effects","volume":"19","author":"Li","year":"2014","journal-title":"Cell Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/ncb2940","article-title":"Lipidation of the LC3\/GABARAP family of autophagy proteins relies on a membrane-curvature-sensing domain in Atg3","volume":"16","author":"Nath","year":"2014","journal-title":"Nat. Cell Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1996","DOI":"10.1158\/0008-5472.CAN-11-2291","article-title":"p53\/HMGB1 Complexes Regulate Autophagy and Apoptosis","volume":"72","author":"Livesey","year":"2012","journal-title":"Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.ceb.2009.12.001","article-title":"Autophagy regulation by p53","volume":"22","author":"Maiuri","year":"2010","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2012\/628978","article-title":"Autophagy as a Therapeutic Target in Diabetic Nephropathy","volume":"2012","author":"Tanaka","year":"2012","journal-title":"Exp. Diabetes Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"R15","DOI":"10.1530\/JOE-14-0437","article-title":"Autophagy in diabetic nephropathy","volume":"224","author":"Ding","year":"2014","journal-title":"J. Endocrinol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1159\/000324941","article-title":"Obesity, Metabolic Syndrome and Diabetic Nephropathy","volume":"170","author":"Maric","year":"2011","journal-title":"Contrib. Nephrol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"(2003). USRDS: The United States Renal Data System. Am. J. Kidney Dis., 42, 1\u2013230.","DOI":"10.1053\/j.ajkd.2003.09.004"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1208\/s12248-012-9404-z","article-title":"Regulatory Pathways for ATP-binding Cassette Transport Proteins in Kidney Proximal Tubules","volume":"14","author":"Masereeuw","year":"2012","journal-title":"AAPS J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/j.cell.2011.10.026","article-title":"Autophagy: Renovation of Cells and Tissues","volume":"147","author":"Mizushima","year":"2011","journal-title":"Cell"},{"key":"ref_26","first-page":"865","article-title":"Receptor-mediated endocytosis and cytoskeleton","volume":"79","author":"Kornilova","year":"2014","journal-title":"Biochemistry"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0169-409X(02)00169-2","article-title":"Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: An overview","volume":"55","author":"Schinkel","year":"2003","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.brainres.2006.09.061","article-title":"Impaired function and expression of P-glycoprotein in blood\u2013brain barrier of streptozotocin-induced diabetic rats","volume":"1123","author":"Liu","year":"2006","journal-title":"Brain Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/nrm3025","article-title":"MTOR: From growth signal integration to cancer, diabetes and ageing","volume":"12","author":"Zoncu","year":"2011","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"23","DOI":"10.2337\/db11-0555","article-title":"Nutrient sensing, autophagy, and diabetic nephropathy","volume":"61","author":"Kume","year":"2012","journal-title":"Diabetes"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1016\/j.cmet.2017.09.020","article-title":"System-wide Benefits of Intermeal Fasting by Autophagy","volume":"26","author":"Tarabra","year":"2017","journal-title":"Cell Metab."},{"key":"ref_32","unstructured":"Benevenga, N.J., Calvert, C., Eckhert, C.D., Fahey, G.C., Greger, J.L., Keen, C.L., Knapka, J.J., Magalhaes, H., Oftedal, O.T., and Reeves, P.G. (1995). Nutrient Requirements of the Laboratory Rat, The National Academic Press."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Lu, Z., Liu, F., Chen, L., Zhang, H., Ding, Y., Liu, J., Wong, M., and Zeng, L.-H. (2015). Effect of Chronic Administration of Low Dose Rapamycin on Development and Immunity in Young Rats. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0135256"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e814s","DOI":"10.6061\/clinics\/2018\/e814s","article-title":"Autophagy and intermittent fasting: The connection for cancer therapy?","volume":"73","author":"Antunes","year":"2018","journal-title":"Clinics"},{"key":"ref_35","unstructured":"Norecopa (2009). Fasting in Rodents. Norecopa Vet. Inst., 1\u201311. Available online: https:\/\/norecopa.no\/media\/6351\/food-deprivation.pdf."},{"key":"ref_36","unstructured":"(2021, September 29). Food Regulation and Restriction in Rodents | Research Support. [Online]. Available online: https:\/\/www.bu.edu\/researchsupport\/compliance\/animal-care\/working-with-animals\/food-regulation-and-restriction-in-rodents\/."},{"key":"ref_37","unstructured":"(2020, March 21). Guidelines on Use of Streptozotocin in Rodents|Research A to Z. Available online: https:\/\/az.research.umich.edu\/animalcare\/guidelines\/guidelines-use-streptozotocin-rodents."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1111\/j.1476-5381.2012.01911.x","article-title":"The use of animal models in diabetes research","volume":"166","author":"King","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"ref_39","first-page":"91","article-title":"Revised guides for organ sampling and trimming in rats and Mice\u2014Part 1: A joint publication of the RITA and NACAD groups","volume":"55","author":"Kittel","year":"2003","journal-title":"Exp. Toxicol. Pathol."},{"key":"ref_40","first-page":"433","article-title":"Revised guides for organ sampling and trimming in rats and Mice\u2014Part 3","volume":"55","author":"Kittel","year":"2003","journal-title":"Exp. Toxicol. Pathol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/S0076-6879(08)03610-0","article-title":"Monitoring autophagy by electron microscopy in Mammalian cells","volume":"452","author":"Vihinen","year":"2009","journal-title":"Methods Enzym."},{"key":"ref_42","unstructured":"Bancroft, J.D., and Gamble, M. (2008). Theory and Practice of Histological Techniques, Elsevier Health Sciences."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"429","DOI":"10.4103\/1947-2714.100998","article-title":"Western blot: Technique, theory, and trouble shooting","volume":"4","author":"Mahmood","year":"2012","journal-title":"N. Am. J. Med. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Ayache, J., Beaunier, L., Boumendil, J., Ehret, G., and Laub, D. (2010). Sample Preparation Handbook for Transmission Electron Microscopy, Springer.","DOI":"10.1007\/978-1-4419-5975-1"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"BSR20181822","DOI":"10.1042\/BSR20181822","article-title":"Rapamycin inhibits proliferation and induces autophagy in human neuroblastoma cells","volume":"38","author":"Lin","year":"2018","journal-title":"Biosci. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1007\/s00018-017-2639-1","article-title":"Autophagy in diabetic kidney disease: Regulation, pathological role and therapeutic potential","volume":"75","author":"Yang","year":"2018","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1126\/science.aaa2628","article-title":"Insulin secretory granules control autophagy in Pancreatic \u03b2 cells","volume":"347","author":"Goginashvili","year":"2015","journal-title":"Science"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1952","DOI":"10.1080\/15548627.2017.1368596","article-title":"Intermittent fasting preserves beta-cell mass in obesity-induced diabetes via the autophagy-lysosome pathway","volume":"13","author":"Liu","year":"2017","journal-title":"Autophagy"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"266","DOI":"10.11613\/BM.2013.033","article-title":"Diabetes and beta cell function: From mechanisms to evaluation and clinical implications","volume":"23","author":"Cernea","year":"2013","journal-title":"Biochem. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1038\/nrd4231","article-title":"Targeting the pancreatic \u03b2-cell to treat diabetes","volume":"13","author":"Vetere","year":"2014","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/0891-5849(96)02051-5","article-title":"Low antioxidant enzyme gene expression in pancreatic islets compared with various other mouse tissues","volume":"20","author":"Lenzen","year":"1996","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Lin, T.-A., Wu, V.C.-C., and Wang, C.-Y. (2019). Autophagy in Chronic Kidney Diseases. Cells, 8.","DOI":"10.3390\/cells8010061"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2014\/315494","article-title":"Role of Nutrient-Sensing Signals in the Pathogenesis of Diabetic Nephropathy","volume":"2014","author":"Kume","year":"2014","journal-title":"BioMed Res. Int."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.ejphar.2012.06.013","article-title":"Hyperglycemia induced down-regulation of renal P-glycoprotein expression","volume":"690","author":"Yeh","year":"2012","journal-title":"Eur. J. Pharmacol."},{"key":"ref_55","first-page":"10723","article-title":"Rapamycin, an mTOR inhibitor, induced apoptosis via independent mitochondrial and death receptor pathway in retinoblastoma Y79 cell","volume":"8","author":"Wang","year":"2015","journal-title":"Int. J. Clin. Exp. Med."},{"key":"ref_56","first-page":"15","article-title":"mTOR Inhibitors at a Glance","volume":"7","author":"Zheng","year":"2016","journal-title":"Mol. Cell. Pharmacol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2495","DOI":"10.1016\/j.jacc.2013.02.058","article-title":"The P-glycoprotein transport system and cardiovascular drugs","volume":"61","author":"Wessler","year":"2013","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"7024","DOI":"10.1073\/pnas.95.12.7024","article-title":"The drug efflux protein, P-glycoprotein, additionally protects drug-resistant tumor cells from multiple forms of caspase-dependent apoptosis","volume":"95","author":"Smyth","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.transproceed.2008.10.032","article-title":"Rapamycin Induces Autophagy in Islets: Relevance in Islet Transplantation","volume":"41","author":"Tanemura","year":"2009","journal-title":"Transplant. Proc."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3120","DOI":"10.18632\/aging.101117","article-title":"Rapamycin treatment benefits glucose metabolism in mouse models of type 2 diabetes","volume":"8","author":"PReifsnyder","year":"2016","journal-title":"Aging"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2674","DOI":"10.2337\/db13-0106","article-title":"Evidence for Rapamycin Toxicity in Pancreatic \u03b2-Cells and a Review of the Underlying Molecular Mechanisms","volume":"62","author":"Barlow","year":"2013","journal-title":"Diabetes"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.prp.2016.02.001","article-title":"Sirt1 is essential for resveratrol enhancement of hypoxia-induced autophagy in the type 2 diabetic nephropathy rat","volume":"212","author":"Ma","year":"2016","journal-title":"Pathol. Res. Pract."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2557","DOI":"10.1111\/bph.13079","article-title":"Glucose modulation induces reactive oxygen species and increases P-glycoprotein-mediated multidrug resistance to chemotherapeutics","volume":"172","author":"Seebacher","year":"2015","journal-title":"Br. J. Pharmacol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"3796","DOI":"10.1074\/jbc.M115.682450","article-title":"Glucose Modulation Induces Lysosome Formation and Increases Lysosomotropic Drug Sequestration via the P-Glycoprotein Drug Transporter","volume":"291","author":"Seebacher","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Rojas-Morales, P., Tapia, E., Le\u00f3n-Contreras, J.C., Gonz\u00e1lez-Reyes, S., Jim\u00e9nez-Osorio, A.S., Trujillo, J., Pav\u00f3n, N., Granados-Pineda, J., Hern\u00e1ndez-Pando, R., and S\u00e1nchez-Lozada, L.G. (2019). Mechanisms of Fasting-Mediated Protection against Renal Injury and Fibrosis Development after Ischemic Acute Kidney Injury. Biomolecules, 9.","DOI":"10.3390\/biom9090404"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s11906-017-0721-6","article-title":"The Gut Microbiome, Energy Homeostasis, and Implications for Hypertension","volume":"19","author":"Riedl","year":"2017","journal-title":"Curr. Hypertens. Rep."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1080\/07853890.2020.1770849","article-title":"Unravelling the health effects of fasting: A long road from obesity treatment to healthy life span increase and improved cognition","volume":"52","author":"Grundler","year":"2020","journal-title":"Ann. Med."}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/43\/3\/120\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:21:09Z","timestamp":1760167269000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/43\/3\/120"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,22]]},"references-count":67,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["cimb43030120"],"URL":"https:\/\/doi.org\/10.3390\/cimb43030120","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,22]]}}}