{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T10:53:22Z","timestamp":1788951202010,"version":"build-2803163510"},"reference-count":60,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2018,8,9]],"date-time":"2018-08-09T00:00:00Z","timestamp":1533772800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004396","name":"Thailand Research Fund","doi-asserted-by":"publisher","award":["TRG5780086"],"award-info":[{"award-number":["TRG5780086"]}],"id":[{"id":"10.13039\/501100004396","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Neuroscience Research and Development Group at Khon Kaen University","award":["012\/2559"],"award-info":[{"award-number":["012\/2559"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>5-fluorouracil or 5-FU (a chemotherapeutic medication) has been revealed to induce memory deficits in many cancer patients. Asiatic acid (AA) is a triterpenoid extract from Centella asiatica. This compound can ameliorate intracellular oxidative stress caused by chemotherapy drugs. Recent studies have shown that AA is capable of inhibiting neuronal generation and memory deficit produced by 5-FU chemotherapy. This study aimed to assess the molecular mechanisms of AA related to hippocampal neurogenesis and memory in rats receiving 5-FU. Male Sprague Dawley rats were given AA (30 mg\/kg) orally and given 5-FU (25 mg\/kg) by i.v. injection 5 times. Some rats were given AA for 20 days before and during 15-FU treatment (preventive), some received AA for 20 days after 5-FU treatment (recovery), and some underwent treatment with AA throughout the time of the experiment (throughout) for 40 days. Treatment with 5-FU caused significant reductions in Notch1, sex determining region Y-box 2 (SOX2), nestin, doublecortin (DCX), and nuclear factor erythroid 2-related factor 2 (Nrf2) levels within the hippocampus. In addition, 5-FU significantly increased p21 positive cell number in the subgranular zone (SGZ) and malondialdehyde (MDA) levels in the hippocampus. Administration with both AA and 5-FU in prevention and throughout was able to prevent decreases in Notch1 SOX2, nestin, DCX, and Nrf2 caused by 5-FU. Treatment with AA also led to decreases in p21 positive cells and MDA levels in the hippocampus. These findings exhibit that AA has the ability to counteract the down-regulation of neurogenesis within the hippocampus and memory deficits caused by 5-FU via inhibiting oxidative stress and increasing neuroprotective properties.<\/jats:p>","DOI":"10.3390\/nu10081053","type":"journal-article","created":{"date-parts":[[2018,8,9]],"date-time":"2018-08-09T10:36:31Z","timestamp":1533810991000},"page":"1053","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Neuroprotective Properties of Asiatic Acid against 5-Fluorouracil Chemotherapy in the Hippocampus in an Adult Rat Model"],"prefix":"10.3390","volume":"10","author":[{"given":"Jariya Umka","family":"Welbat","sequence":"first","affiliation":[{"name":"Department of Anatomy, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand"},{"name":"Neuroscience Research and Development Group, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pornthip","family":"Chaisawang","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanassanun","family":"Pannangrong","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Wigmore","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Medical School, Queen\u2019s Medical Centre, Nottingham University, Nottingham NG7 2RD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,8,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Lyons, L., ElBeltagy, M., Bennett, G., and Wigmore, P. (2012). Fluoxetine counteracts the cognitive and cellular effects of 5-fluorouracil in the rat hippocampus by a mechanism of prevention rather than recovery. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0030010"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1111\/j.1460-9568.2008.06325.x","article-title":"5-fluorouracil chemotherapy affects spatial working memory and newborn neurons in the adult rat hippocampus","volume":"28","author":"Mustafa","year":"2008","journal-title":"Eur. J. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1188\/09.CJON.413-421","article-title":"Chemotherapy-related cognitive impairment","volume":"13","author":"Myers","year":"2009","journal-title":"Clin. J. Oncol. Nurs."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.taap.2011.11.013","article-title":"Chrysin protects against cisplatin-induced colon. Toxicity via amelioration of oxidative stress and apoptosis: Probable role of p38mapk and p53","volume":"258","author":"Khan","year":"2012","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"306","DOI":"10.4048\/jbc.2012.15.3.306","article-title":"Impact of breast cancer and combination chemotherapy on oxidative stress, hepatic and cardiac markers","volume":"15","author":"Amin","year":"2012","journal-title":"J. Breast Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1007\/s10549-010-1158-7","article-title":"Individual responses to chemotherapy-induced oxidative stress","volume":"125","author":"Kennedy","year":"2011","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1016\/j.redox.2014.04.011","article-title":"Biochemical responses and mitochondrial mediated activation of apoptosis on long-term effect of aspartame in rat brain","volume":"2","author":"Ashok","year":"2014","journal-title":"Redox Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"26","DOI":"10.4161\/oxim.2.1.7901","article-title":"Metallothionein induction reduces caspase-3 activity and TNF alpha levels with preservation of cognitive function and intact hippocampal neurons in carmustine-treated rats","volume":"2","author":"Helal","year":"2009","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.ejphar.2016.08.003","article-title":"Edaravone alleviates cisplatin-induced neurobehavioral deficits via modulation of oxidative stress and inflammatory mediators in the rat hippocampus","volume":"791","author":"Jangra","year":"2016","journal-title":"Eur. J. Pharmacol."},{"key":"ref_10","unstructured":"Chen, C., Zhang, H., Xu, H., Zheng, Y., Wu, T., and Lian, Y. (2017). Ginsenoside Rb1 ameliorates cisplatin-induced learning and memory impairments. J. Ginseng Res., in press."},{"key":"ref_11","first-page":"304","article-title":"Antioxidants in cancer therapy; their actions and interactions with oncologic therapies","volume":"4","author":"Lamson","year":"1999","journal-title":"Altern. Med. Rev. J. Clin. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1055\/s-0030-1267852","article-title":"Chemotherapy agents: A primer for the interventional radiologist","volume":"27","author":"Mihlon","year":"2010","journal-title":"Semin. Interv. Radiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"81880","DOI":"10.18632\/oncotarget.11980","article-title":"Determining the optimal 5-FU therapeutic dosage in the treatment of colorectal cancer patients","volume":"7","author":"Fang","year":"2016","journal-title":"Oncotarget"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"S80","DOI":"10.1007\/s00280-003-0625-9","article-title":"Thymidylate synthase inhibitors as anticancer agents: From bench to bedside","volume":"52","author":"Chu","year":"2003","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/nrc1074","article-title":"5-fluorouracil: Mechanisms of action and clinical strategies","volume":"3","author":"Longley","year":"2003","journal-title":"Nat. Rev. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1016\/j.brainresbull.2012.05.005","article-title":"The effect of 5-fluorouracil on the long term survival and proliferation of cells in the rat hippocampus","volume":"88","author":"ELBeltagy","year":"2012","journal-title":"Brain Res. Bull."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1007\/978-1-4419-6306-2_20","article-title":"Effects of 5-FU","volume":"678","author":"Wigmore","year":"2010","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.bbr.2009.11.017","article-title":"Fluoxetine improves the memory deficits caused by the chemotherapy agent 5-fluorouracil","volume":"208","author":"ElBeltagy","year":"2010","journal-title":"Behav. Brain Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0378-8741(98)00141-X","article-title":"In vitro and in vivo wound healing activity of asiaticoside isolated from Centella asiatica","volume":"65","author":"Shukla","year":"1999","journal-title":"J. Ethnopharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"895857","DOI":"10.1155\/2011\/895857","article-title":"Antinociceptive activities and the mechanisms of anti-inflammation of asiatic acid in mice","volume":"2011","author":"Huang","year":"2011","journal-title":"Evid.-Based Complement. Altern. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2541","DOI":"10.1002\/jnr.22071","article-title":"Asiatic acid, a pentacyclic triterpene from Centella asiatica, is neuroprotective in a mouse model of focal cerebral ischemia","volume":"87","author":"Krishnamurthy","year":"2009","journal-title":"J. Neurosci. Res."},{"key":"ref_22","first-page":"1735","article-title":"Kinetics of entry and distribution of 5-fluorouracil in cerebrospinal fluid and brain following intravenous injection in a primate","volume":"33","author":"Bourke","year":"1973","journal-title":"Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1007\/s00280-005-0159-4","article-title":"5-fluorouracil can cross brain-blood barrier and cause encephalopathy: Should we expect the same from capecitabine? A case report on capecitabine-induced central neurotoxicity progressing to coma","volume":"58","author":"Formica","year":"2006","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1002\/ptr.5156","article-title":"Asiatic acid reduces blood pressure by enhancing nitric oxide bioavailability with modulation of eNOS and p47phox expression in l-NAME-induced hypertensive rats","volume":"28","author":"Bunbupha","year":"2014","journal-title":"Phytother. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1111\/1440-1681.12472","article-title":"Asiatic acid alleviates cardiovascular remodelling in rats with l-name-induced hypertension","volume":"42","author":"Bunbupha","year":"2015","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1007\/s12012-017-9424-0","article-title":"Asiatic acid ameliorates doxorubicin-induced cardiac and hepato-renal toxicities with Nrf2 transcriptional factor activation in rats","volume":"18","author":"Kamble","year":"2017","journal-title":"Cardiovasc. Toxicol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"8413","DOI":"10.3390\/nu7105401","article-title":"Effects of asiatic acid on spatial working memory and cell proliferation in the adult rat hippocampus","volume":"7","author":"Sirichoat","year":"2015","journal-title":"Nutrients"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Umka Welbat, J., Sirichoat, A., Chaijaroonkhanarak, W., Prachaney, P., Pannangrong, W., Pakdeechote, P., Sripanidkulchai, B., and Wigmore, P. (2016). Asiatic acid prevents the deleterious effects of valproic acid on cognition and hippocampal cell proliferation and survival. Nutrients, 8.","DOI":"10.3390\/nu8050303"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Chaisawang, P., Sirichoat, A., Chaijaroonkhanarak, W., Pannangrong, W., Sripanidkulchai, B., Wigmore, P., and Welbat, J.U. (2017). Asiatic acid protects against cognitive deficits and reductions in cell proliferation and survival in the rat hippocampus caused by 5-fluorouracil chemotherapy. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0180650"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1002\/(SICI)1097-0215(19980316)75:6<873::AID-IJC9>3.0.CO;2-S","article-title":"Pre-clinical evaluation of the gastrimmune immunogen alone and in combination with 5-fluorouracil\/leucovorin in a rat colorectal cancer model","volume":"75","author":"Watson","year":"1998","journal-title":"Int. J. Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.3390\/cancers2031717","article-title":"5-fu metabolism in cancer and orally-administrable 5-fu drugs","volume":"2","author":"Miura","year":"2010","journal-title":"Cancers"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1517\/13543780902729412","article-title":"S-1: A promising new oral fluoropyrimidine derivative","volume":"18","author":"Saif","year":"2009","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1523\/JNEUROSCI.22-03-00619.2002","article-title":"Neurogenesis in adult mammals: Some progress and problems","volume":"22","author":"Gould","year":"2002","journal-title":"J. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"12237","DOI":"10.1523\/JNEUROSCI.2195-06.2006","article-title":"Integration of new neurons into functional neural networks","volume":"26","author":"Marrone","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/j.neuron.2011.05.001","article-title":"Adult neurogenesis in the mammalian brain: Significant answers and significant questions","volume":"70","author":"Ming","year":"2011","journal-title":"Neuron"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"13427","DOI":"10.1073\/pnas.96.23.13427","article-title":"Running enhances neurogenesis, learning, and long-term potentiation in mice","volume":"96","author":"Christie","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.neubiorev.2008.08.007","article-title":"Adult hippocampal neurogenesis: Regulation, functional implications, and contribution to disease pathology","volume":"33","author":"Balu","year":"2009","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/nrn3024","article-title":"Not(ch) just development: Notch signalling in the adult brain","volume":"12","author":"Ables","year":"2011","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1016\/j.neuron.2011.02.031","article-title":"Notch in the vertebrate nervous system: An old dog with new tricks","volume":"69","author":"Pierfelice","year":"2011","journal-title":"Neuron"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/j.neuron.2011.01.004","article-title":"Activity-induced notch signaling in neurons requires Arc\/Arg3.1 and is essential for synaptic plasticity in hippocampal networks","volume":"69","author":"Alberi","year":"2011","journal-title":"Neuron"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"20558","DOI":"10.1073\/pnas.0710156104","article-title":"Notch regulates cell fate and dendrite morphology of newborn neurons in the postnatal dentate gyrus","volume":"104","author":"Breunig","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.neuroscience.2011.12.013","article-title":"Expression of doublecortin, a neuronal migration protein, in unipolar brush cells of the vestibulocerebellum and dorsal cochlear nucleus of the adult rat","volume":"202","author":"Manohar","year":"2012","journal-title":"Neuroscience"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1111\/j.0953-816X.2003.03123.x","article-title":"Efficacy of doublecortin as a marker to analyse the absolute number and dendritic growth of newly generated neurons in the adult dentate gyrus","volume":"19","author":"Rao","year":"2004","journal-title":"Eur. J. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.neulet.2008.07.030","article-title":"Doublecortin expression continues into adulthood in horizontal cells in the rat retina","volume":"442","author":"Wakabayashi","year":"2008","journal-title":"Neurosci. Lett."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.neuroscience.2009.11.073","article-title":"Valproic acid reduces spatial working memory and cell proliferation in the hippocampus","volume":"166","author":"Umka","year":"2010","journal-title":"Neuroscience"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/j.stem.2013.02.001","article-title":"Opposing regulation of Sox2 by cell-cycle effectors E2f3a and E2f3b in neural stem cells","volume":"12","author":"Julian","year":"2013","journal-title":"Cell Stem Cell"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.stem.2012.12.007","article-title":"The sox family of transcription factors: Versatile regulators of stem and progenitor cell fate","volume":"12","author":"Sarkar","year":"2013","journal-title":"Cell Stem cell"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.freeradbiomed.2016.11.046","article-title":"Cisplatin-induced mitochondrial dysfunction is associated with impaired cognitive function in rats","volume":"102","author":"Lomeli","year":"2017","journal-title":"Free Radic. Biol. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1038\/35089085","article-title":"Purification of a pluripotent neural stem cell from the adult mouse brain","volume":"412","author":"Rietze","year":"2001","journal-title":"Nature"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2162","DOI":"10.1002\/stem.541","article-title":"Nestin is required for the proper self-renewal of neural stem cells","volume":"28","author":"Park","year":"2010","journal-title":"Stem Cells"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Chen, H.L., Yuh, C.H., and Wu, K.K. (2010). Nestin is essential for zebrafish brain and eye development through control of progenitor cell apoptosis. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0009318"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/1756-9966-31-60","article-title":"5-fluorouracil induces apoptosis in rat cardiocytes through intracellular oxidative stress","volume":"31","author":"Lamberti","year":"2012","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"129","DOI":"10.2306\/scienceasia1513-1874.2012.38.129","article-title":"Preventive role of mirtazapine in methotrexate induced nephrotoxicity in rats","volume":"38","author":"Uzkeser","year":"2012","journal-title":"Scienceasia"},{"key":"ref_54","first-page":"81","article-title":"Oncoprotein expression of E6 and E7 does not prevent 5-fluorouracil (5FU) mediated G(1)\/S arrest and apoptosis in 5FU resistant carcinoma cell lines","volume":"23","author":"Didelot","year":"2003","journal-title":"Int. J. Oncol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1111\/j.1460-9568.2005.03875.x","article-title":"New neurons in the dentate gyrus are involved in the expression of enhanced long-term memory following environmental enrichment","volume":"21","author":"Laroche","year":"2005","journal-title":"Eur. J. Neurosci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.aanat.2016.04.029","article-title":"Kaempferia parviflora extract ameliorates the cognitive impairments and the reduction in cell proliferation induced by valproic acid treatment in rats","volume":"206","author":"Welbat","year":"2016","journal-title":"Ann. Anat."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.phymed.2012.09.023","article-title":"Efficacy of asiatic acid, a pentacyclic triterpene on attenuating the key enzymes activities of carbohydrate metabolism in streptozotocin-induced diabetic rats","volume":"20","author":"Ramachandran","year":"2013","journal-title":"Phytomedicine"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"785","DOI":"10.3389\/fimmu.2017.00785","article-title":"Asiatic acid exhibits anti-inflammatory and antioxidant activities against lipopolysaccharide and d-galactosamine-induced fulminant hepatic failure","volume":"8","author":"Lv","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3255","DOI":"10.4161\/cc.8.20.9565","article-title":"Nrf2 and p21 regulate the fine balance between life and death by controlling ROS levels","volume":"8","author":"Villeneuve","year":"2009","journal-title":"Cell Cycle"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1904","DOI":"10.1002\/stem.1666","article-title":"Nrf2 regulates neurogenesis and protects neural progenitor cells against Abeta toxicity","volume":"32","author":"Karkkainen","year":"2014","journal-title":"Stem Cells"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/10\/8\/1053\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:17:41Z","timestamp":1760195861000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/10\/8\/1053"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,8,9]]},"references-count":60,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2018,8]]}},"alternative-id":["nu10081053"],"URL":"https:\/\/doi.org\/10.3390\/nu10081053","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,8,9]]}}}