Rapid and Effective Vitamin D Supplementation May Present Better Clinical Outcomes in COVID-19 (SARS-CoV-2) Patients by Altering Serum INOS1, IL1B, IFNg, Cathelicidin-LL37, and ICAM1
Mustafa Sait Gönen, Merve Alaylıoğlu, Emre Durcan, Yusuf Özdemir, Serdar Şahin, Dildar Konukoğlu, Okan Kadir Nohut, Seval Ürkmez, Berna Küçükece, İlker İnanç Balkan, H Volkan Kara, Şermin Börekçi, Hande Özkaya, Zekayi Kutlubay, Yalım Dikmen, Yılmaz Keskindemirci, Spyridon N Karras, Cedric Annweiler, Duygu Gezen-Ak, Erdinç Dursun
Nutrients, doi:10.3390/nu13114047
Background: We aimed to establish an acute treatment protocol to increase serum vitamin D, evaluate the effectiveness of vitamin D3 supplementation, and reveal the potential mechanisms in COVID-19. Methods: We retrospectively analyzed the data of 867 COVID-19 cases. Then, a prospective study was conducted, including 23 healthy individuals and 210 cases. A total of 163 cases had vitamin D supplementation, and 95 were followed for 14 days. Clinical outcomes, routine blood biomarkers, serum levels of vitamin D metabolism, and action mechanism-related parameters were evaluated. Results: Our treatment protocol increased the serum 25OHD levels significantly to above
Institutional Review Board Statement: The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by, and the study was approved by the Ethics Committee of ISTANBUL UNIVERSITY-CERRAHPASA, and the REPUBLIC OF TURKEY MINISTRY OF HEALTH (Approval Number: Mustafa Sait Gönen-2020-05-06T19_51_05). Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.
Conflicts of Interest: All authors declare that they have no conflict of interest.
References
Aceti, Margarucci, Scaramucci, Orsini, Salerno et al., Serum S100B protein as a marker of severity in COVID-19 patients, Sci. Rep,
doi:10.1038/s41598-020-75618-0Alipio, Vitamin D Supplementation Could Possibly Improve Clinical Outcomes of Patients Infected with Coronavirus
Alsafar, Grant, Hijazi, Uddin, Alkaabi et al., COVID-19 disease severity and death in relation to vitamin d status among SARS-CoV-2-positive uae residents, Nutrients,
doi:10.3390/nu13051714Amrein, Schnedl, Holl, Riedl, Christopher et al., Effect of high-dose vitamin d3 on hospi-tal length of stay in critically ill patients with vitamin d deficiency: The vitdal-icu randomized clinical trial, JAMA,
doi:10.1001/jama.2014.13204Andrukhova, Slavic, Zeitz, Riesen, Heppelmann et al., Vitamin d is a regulator of endothelial nitric oxide syn-thase and arterial stiffness in mice, Mol. Endocrinol,
doi:10.1210/me.2013-1252Annweiler, Dursun, Feron, Gezen-Ak, Kalueff et al., Vitamin d and cognition in older adults: Internation-al consensus guidelines, Geriatr. Psychol. Neuropsychiatr. Vieil,
doi:10.1684/pnv.2016.0613Azevedo, Zanchettin, Vaz De Paula, Motta Junior, Malaquias et al., Lung neutro-philic recruitment and il-8/il-17a tissue expression in COVID-19, Front. Immunol,
doi:10.3389/fimmu.2021.656350Azizi-Soleiman, Vafa, Abiri, Safavi, Effects of iron on Vitamin D metabolism: A systematic review, Int. J. Prev. Med,
doi:10.4103/2008-7802.195212Bauer, Ulke, Galtung, Strasser-Marsik, Neuwinger et al., Role of Cell Adhesion Molecules for Prognosis of Disease Development of Patients with and Without COVID-19 in the Emergency Department, J. Infect. Dis,
doi:10.1093/infdis/jiab042Blanco-Rojo, Pérez-Granados, Toxqui, Zazo, De La Piedra et al., Relationship between vitamin D deficiency, bone remodelling and iron status in iron-deficient young women consuming an iron-fortified food, Eur. J. Nutr,
doi:10.1007/s00394-012-0375-8Bodnar, Krohn, Simhan, Maternal Vitamin D Deficiency Is Associated with Bacterial Vaginosis in the First Trimester of Pregnancy, J. Nutr,
doi:10.3945/jn.108.103168Corwin, Gettinger, Pearl, Fink, Levy et al., The CRIT Study: Anemia and blood transfusion in the critically ill-Current clinical practice in the United States *, Crit. Care Med,
doi:10.1097/01.CCM.0000104112.34142.79Dursun, Alaylioglu, Bilgic, Hanagasi, Lohmann et al., Vitamin d deficiency might pose a greater risk for apo-evarepsilon4 non-carrier alzheimer's disease patients, Neurol. Sci,
doi:10.1007/s10072-016-2647-1Dursun, Gezen-Ak, Yilmazer, A new mechanism for amyloid-beta induction of inos: Vitamin d-vdr pathway disruption, J. Alzheimer's Dis,
doi:10.3233/JAD-130416Dursun, Gezen-Ak, Yilmazer, The influence of vitamin d treatment on the inducible nitric oxide synthase (inos) expression in primary hippocampal neurons, Noro. Psikiyatr. Ars,
doi:10.4274/npa.y7089Elham, Azam, Azam, Mostafa, Nasrin et al., Serum vitamin D, calcium, and zinc levels in patients with COVID-19, Clin. Nutr. ESPEN,
doi:10.1016/j.clnesp.2021.03.040Fernandes De Abreu, Eyles, Féron, Vitamin d, a neuro-immunomodulator: Implications for neurodegenerative and autoimmune diseases, Psychoneuroendocrinology,
doi:10.1016/j.psyneuen.2009.05.023Gezen-Ak, Alaylıo Glu, Genç, Şengül, Keskin et al., Altered Transcriptional Profile of Mitochondrial DNA-Encoded OXPHOS Subunits, Mitochondria Quality Control Genes, and Intracellular ATP Levels in Blood Samples of Patients with Parkinson's Disease, J. Alzheimer's Dis,
doi:10.3233/JAD-191164Gezen-Ak, Dursun, Molecular basis of vitamin D action in neurodegeneration: The story of a team perspective, Hormones,
doi:10.1007/s42000-018-0087-4Gezen-Ak, Yilmazer, Dursun, Why vitamin d in alzheimer's disease? The hypothesis, J. Alzheimers Dis
Golpour, Bereswill, Heimesaat, Antimicrobial and immune-modulatory effects of vitamin D provide promising antibiotics-independent approaches to tackle bacterial infections-lessons learnt from a literature survey, Eur. J. Microbiol. Immunol,
doi:10.1556/1886.2019.00014Grant, Lahore, Mcdonnell, Baggerly, French et al., Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths, Nutrients,
doi:10.3390/nu12040988Hayden, Albert, Watkins, Swenson, Anemia in critical illness: Insights into etiology, consequences, and management, Am. J. Respir. Crit. Care Med,
doi:10.1164/rccm.201110-1915CIHeldenberg, Tenenbaum, Weisman, Effect of iron on serum 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D concentrations, Am. J. Clin. Nutr,
doi:10.1093/ajcn/56.3.533Joshi, Pantalena, Liu, Gaffen, Liu et al., 1,25-dihydroxyvitamin d(3) ameliorates th17 autoimmunity via transcriptional modulation of interleukin-17a, Mol. Cell Biol,
doi:10.1128/MCB.05020-11Kazemi, Mohammadi, Aghababaee, Golzarand, Clark et al., Association of vitamin d status with SARS-CoV-2 infection or COVID-19 severity: A systematic review and meta-analysis, Adv. Nutr,
doi:10.1093/advances/nmab012Kessel, Vollenberg, Masjosthusmann, Hinze, Wittkowski et al., Discrimination of COVID-19 from inflam-mation-induced cytokine storm syndromes by disease-related blood biomarkers, Arthritis Rheumatol,
doi:10.1002/art.41763Kumar, Rathi, Haq, Wimalawansa, Sharma, Putative roles of vitamin D in modulating immune response and immunopathology associated with COVID-19, Virus Res,
doi:10.1016/j.virusres.2020.198235Lakkireddy, Gadiga, Malathi, Karra, Raju et al., Impact of daily high dose oral vitamin d therapy on the inflammatory markers in patients with COVID 19 disease, Sci. Rep
Li, Duan, Li, Li, Gao et al., Differentially expressed immune response genes in COVID-19 patients based on disease severity, Aging,
doi:10.18632/aging.202877Li, Huang, Shen, Wang, Wang et al., Serum Levels of Soluble Platelet Endothelial Cell Adhesion Molecule 1 in COVID-19 Patients Are Associated with Disease Severity, J. Infect. Dis,
doi:10.1093/infdis/jiaa642Lorente, Gómez-Bernal, Martín, Navarro-Gonzálvez, Argueso et al., High serum nitrates levels in non-survivor COVID-19 patients, Med. Intensiva,
doi:10.1016/j.medin.2020.10.003Mazziotti, Lavezzi, Brunetti, Mirani, Favacchio et al., Vitamin d deficiency, secondary hyperpara-thyroidism and respiratory insufficiency in hospitalized patients with COVID-19, J. Endocrinol. Investig,
doi:10.1007/s40618-021-01535-2Osman, Al Fahdi, Al Salmi, Al Khalili, Gokhale et al., Serum Calcium and Vitamin D levels: Correlation with severity of COVID-19 in hospitalized patients in Royal Hospital, Oman, Int. J. Infect. Dis,
doi:10.1016/j.ijid.2021.04.050Perrin, Collongues, Baloglu, Bedo, Bassand et al., Cytokine release syndrome-associated encephalo-pathy in patients with COVID-19, Eur. J. Neurol,
doi:10.1111/ene.14491Pizzini, Aichner, Sahanic, Bohm, Egger et al., Impact of vitamin d deficiency on COVID-19-a pro-spective analysis from the covild registry, Nutrients,
doi:10.3390/nu12092775Radujkovic, Hippchen, Tiwari-Heckler, Dreher, Boxberger et al., Vitamin D Deficiency and Outcome of COVID-19 Patients, Nutrients,
doi:10.3390/nu12092757Rodríguez, Daniels, Gunawardene, Robbins, High Frequency of Vitamin D Deficiency in Ambulatory HIV-Positive Patients, AIDS Res. Hum. Retrovir,
doi:10.1089/aid.2008.0183Sanchez-Zuno, Gonzalez-Estevez, Matuz-Flores, Macedo-Ojeda, Hernandez-Bello et al., Vitamin d levels in COVID-19 outpatients from western mexico: Clinical correlation and effect of its supplementation, J. Clin. Med,
doi:10.3390/jcm10112378Smith, Jones, Han, Alvarez, Sloan et al., High-dose vitamin d3 administration is associated with increases in hemoglobin concentrations in mechanically ventilated critically ill adults: A pilot double-blind, randomized, placebo-controlled trial, J. Parenter Enter. Nutr,
doi:10.1177/0148607116678197Spadaro, Fogagnolo, Campo, Zucchetti, Verri et al., Markers of endothelial and epithelial pulmonary injury in mechanically ventilated COVID-19 ICU patients, Crit. Care,
doi:10.1186/s13054-021-03499-4Vincent, Baron, Reinhart, Gattinoni, Thijs et al., For the ABC Investigators Anemia and Blood Transfusion in Critically Ill Patients, JAMA,
doi:10.1001/jama.288.12.1499Visweswaran, Lekha, Extraskeletal effects and manifestations of Vitamin D deficiency, Indian J. Endocrinol. Metab,
doi:10.4103/2230-8210.113750Wan, Yi, Fan, Lv, Zhang et al., Relationships among lymphocyte subsets, cytokines, and the pulmonary inflammation index in coronavirus (COVID-19) infected patients, Br. J. Haematol,
doi:10.1111/bjh.16659Wright, Blanco-Rojo, Fernández, Toxqui, Moreno et al., Bone remodelling is reduced by recovery from iron-deficiency anaemia in premenopausal women, J. Physiol. Biochem,
doi:10.1007/s13105-013-0266-3Yamasaki, Blood nitrate and nitrite modulating nitric oxide bioavailability: Potential therapeutic functions in COVID-19, Nitric Oxide,
doi:10.1016/j.niox.2020.07.005Yang, Liu, Wan, Zhonghua, Zhong et al., Role and mechanism of vitamin D in sepsis, Jiu Yi Xue
Yardan, Erenler, Baydin, Aydin, Cokluk, Usefulness of S100B protein in neurological disorders, J. Pak. Med. Assoc
Zawawi, Naser, Alwafi, Minshawi, Profile of Circulatory Cytokines and Chemokines in Human Coronaviruses: A Systematic Review and Meta-Analysis, Front. Immunol,
doi:10.3389/fimmu.2021.666223{ 'indexed': {'date-parts': [[2024, 3, 26]], 'date-time': '2024-03-26T23:09:23Z', 'timestamp': 1711494563507},
'reference-count': 62,
'publisher': 'MDPI AG',
'issue': '11',
'license': [ { 'start': { 'date-parts': [[2021, 11, 12]],
'date-time': '2021-11-12T00:00:00Z',
'timestamp': 1636675200000},
'content-version': 'vor',
'delay-in-days': 0,
'URL': 'https://creativecommons.org/licenses/by/4.0/'}],
'funder': [{'name': 'Istanbul University Cerrahpaşa', 'award': ['TSG-2020-34998']}],
'content-domain': {'domain': [], 'crossmark-restriction': False},
'abstract': '<jats:p>Background: We aimed to establish an acute treatment protocol to increase serum '
'vitamin D, evaluate the effectiveness of vitamin D3 supplementation, and reveal the potential '
'mechanisms in COVID-19. Methods: We retrospectively analyzed the data of 867 COVID-19 cases. '
'Then, a prospective study was conducted, including 23 healthy individuals and 210 cases. A '
'total of 163 cases had vitamin D supplementation, and 95 were followed for 14 days. Clinical '
'outcomes, routine blood biomarkers, serum levels of vitamin D metabolism, and action '
'mechanism-related parameters were evaluated. Results: Our treatment protocol increased the '
'serum 25OHD levels significantly to above 30 ng/mL within two weeks. COVID-19 cases (no '
'comorbidities, no vitamin D treatment, 25OHD <30 ng/mL) had 1.9-fold increased risk of '
'having hospitalization longer than 8 days compared with the cases with comorbidities and '
'vitamin D treatment. Having vitamin D treatment decreased the mortality rate by 2.14 times. '
'The correlation analysis of specific serum biomarkers with 25OHD indicated that the vitamin D '
'action in COVID-19 might involve regulation of INOS1, IL1B, IFNg, cathelicidin-LL37, and '
'ICAM1. Conclusions: Vitamin D treatment shortened hospital stay and decreased mortality in '
'COVID-19 cases, even in the existence of comorbidities. Vitamin D supplementation is '
'effective on various target parameters; therefore, it is essential for COVID-19 '
'treatment.</jats:p>',
'DOI': '10.3390/nu13114047',
'type': 'journal-article',
'created': { 'date-parts': [[2021, 11, 15]],
'date-time': '2021-11-15T01:51:53Z',
'timestamp': 1636941113000},
'page': '4047',
'source': 'Crossref',
'is-referenced-by-count': 45,
'title': 'Rapid and Effective Vitamin D Supplementation May Present Better Clinical Outcomes in COVID-19 '
'(SARS-CoV-2) Patients by Altering Serum INOS1, IL1B, IFNg, Cathelicidin-LL37, and ICAM1',
'prefix': '10.3390',
'volume': '13',
'author': [ { 'ORCID': 'http://orcid.org/0000-0002-1089-623X',
'authenticated-orcid': False,
'given': 'Mustafa Sait',
'family': 'Gönen',
'sequence': 'first',
'affiliation': []},
{'given': 'Merve', 'family': 'Alaylıoğlu', 'sequence': 'additional', 'affiliation': []},
{'given': 'Emre', 'family': 'Durcan', 'sequence': 'additional', 'affiliation': []},
{'given': 'Yusuf', 'family': 'Özdemir', 'sequence': 'additional', 'affiliation': []},
{'given': 'Serdar', 'family': 'Şahin', 'sequence': 'additional', 'affiliation': []},
{'given': 'Dildar', 'family': 'Konukoğlu', 'sequence': 'additional', 'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0002-8111-8072',
'authenticated-orcid': False,
'given': 'Okan Kadir',
'family': 'Nohut',
'sequence': 'additional',
'affiliation': []},
{'given': 'Seval', 'family': 'Ürkmez', 'sequence': 'additional', 'affiliation': []},
{'given': 'Berna', 'family': 'Küçükece', 'sequence': 'additional', 'affiliation': []},
{'given': 'İlker İnanç', 'family': 'Balkan', 'sequence': 'additional', 'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0001-7702-9731',
'authenticated-orcid': False,
'given': 'H. Volkan',
'family': 'Kara',
'sequence': 'additional',
'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0002-0089-1312',
'authenticated-orcid': False,
'given': 'Şermin',
'family': 'Börekçi',
'sequence': 'additional',
'affiliation': []},
{'given': 'Hande', 'family': 'Özkaya', 'sequence': 'additional', 'affiliation': []},
{'given': 'Zekayi', 'family': 'Kutlubay', 'sequence': 'additional', 'affiliation': []},
{'given': 'Yalım', 'family': 'Dikmen', 'sequence': 'additional', 'affiliation': []},
{'given': 'Yılmaz', 'family': 'Keskindemirci', 'sequence': 'additional', 'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0002-4225-2746',
'authenticated-orcid': False,
'given': 'Spyridon N.',
'family': 'Karras',
'sequence': 'additional',
'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0002-7199-8109',
'authenticated-orcid': False,
'given': 'Cedric',
'family': 'Annweiler',
'sequence': 'additional',
'affiliation': []},
{'given': 'Duygu', 'family': 'Gezen-Ak', 'sequence': 'additional', 'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0003-3701-6674',
'authenticated-orcid': False,
'given': 'Erdinç',
'family': 'Dursun',
'sequence': 'additional',
'affiliation': []}],
'member': '1968',
'published-online': {'date-parts': [[2021, 11, 12]]},
'reference': [ {'key': 'ref1', 'doi-asserted-by': 'publisher', 'DOI': '10.1111/bjh.16659'},
{'key': 'ref2', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/S0140-6736(20)30183-5'},
{'key': 'ref3', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41422-020-0327-4'},
{'key': 'ref4', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.biopha.2020.110493'},
{'key': 'ref5', 'doi-asserted-by': 'publisher', 'DOI': '10.1007/s10072-016-2647-1'},
{'key': 'ref6', 'doi-asserted-by': 'publisher', 'DOI': '10.1002/jcb.10338'},
{'key': 'ref7', 'doi-asserted-by': 'publisher', 'DOI': '10.2478/v10011-012-0031-z'},
{'key': 'ref8', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.jcte.2014.10.001'},
{'key': 'ref9', 'doi-asserted-by': 'publisher', 'DOI': '10.4103/2230-8210.113750'},
{'key': 'ref10', 'doi-asserted-by': 'publisher', 'DOI': '10.1007/s42000-018-0087-4'},
{'key': 'ref11', 'doi-asserted-by': 'publisher', 'DOI': '10.3233/JAD-131970'},
{'key': 'ref12', 'doi-asserted-by': 'publisher', 'DOI': '10.1684/pnv.2016.0613'},
{'key': 'ref13', 'doi-asserted-by': 'publisher', 'DOI': '10.1007/s42000-018-0086-5'},
{'key': 'ref14', 'doi-asserted-by': 'publisher', 'DOI': '10.2310/JIM.0b013e31821b8755'},
{'key': 'ref15', 'doi-asserted-by': 'publisher', 'DOI': '10.1017/S0950268806007175'},
{'key': 'ref16', 'doi-asserted-by': 'publisher', 'DOI': '10.3945/jn.108.103168'},
{ 'key': 'ref17',
'doi-asserted-by': 'publisher',
'DOI': '10.1111/j.1753-4887.2006.tb00205.x'},
{'key': 'ref18', 'doi-asserted-by': 'publisher', 'DOI': '10.1089/aid.2008.0183'},
{'key': 'ref19', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/MCB.05020-11'},
{'key': 'ref20', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.psyneuen.2009.05.023'},
{'key': 'ref21', 'doi-asserted-by': 'publisher', 'DOI': '10.1556/1886.2019.00014'},
{'key': 'ref22', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.virusres.2020.198235'},
{'key': 'ref23', 'doi-asserted-by': 'publisher', 'DOI': '10.4103/2008-7802.195212'},
{'key': 'ref24', 'doi-asserted-by': 'publisher', 'DOI': '10.1007/s00394-012-0375-8'},
{'key': 'ref25', 'doi-asserted-by': 'publisher', 'DOI': '10.1093/ajcn/56.3.533'},
{'key': 'ref26', 'doi-asserted-by': 'publisher', 'DOI': '10.1007/s13105-013-0266-3'},
{'key': 'ref27', 'doi-asserted-by': 'publisher', 'DOI': '10.1164/rccm.201110-1915CI'},
{ 'key': 'ref28',
'first-page': '1170',
'article-title': 'Role and mechanism of vitamin D in sepsis',
'volume': '31',
'author': 'Yang',
'year': '2019',
'journal-title': 'Zhonghua Wei Zhong Bing Ji Jiu Yi Xue'},
{'key': 'ref29', 'doi-asserted-by': 'publisher', 'DOI': '10.1097/CCM.0000000000002095'},
{ 'key': 'ref30',
'series-title': 'Vitamin D Supplementation Could Possibly Improve Clinical Outcomes of '
'Patients Infected with Coronavirus-2019 (COVID-2019)',
'author': 'Alipio',
'year': '2020'},
{'key': 'ref31', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/nu12092757'},
{'key': 'ref32', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/nu13051714'},
{'key': 'ref33', 'doi-asserted-by': 'publisher', 'DOI': '10.1093/advances/nmab012'},
{'key': 'ref34', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/jcm10112378'},
{'key': 'ref35', 'doi-asserted-by': 'publisher', 'DOI': '10.1093/jpepsy/jsp004'},
{'key': 'ref36', 'doi-asserted-by': 'publisher', 'DOI': '10.3233/JAD-191164'},
{ 'key': 'ref37',
'doi-asserted-by': 'publisher',
'DOI': '10.1097/01.CCM.0000104112.34142.79'},
{'key': 'ref38', 'doi-asserted-by': 'publisher', 'DOI': '10.1001/jama.288.12.1499'},
{'key': 'ref39', 'doi-asserted-by': 'publisher', 'DOI': '10.1001/jama.2014.13204'},
{'key': 'ref40', 'doi-asserted-by': 'publisher', 'DOI': '10.1177/0148607116678197'},
{'key': 'ref41', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/nu12092775'},
{'key': 'ref42', 'doi-asserted-by': 'publisher', 'DOI': '10.1007/s40618-021-01535-2'},
{'key': 'ref43', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.clnesp.2021.03.040'},
{'key': 'ref44', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.ijid.2021.04.050'},
{'key': 'ref45', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/nu12040988'},
{'key': 'ref46', 'doi-asserted-by': 'publisher', 'DOI': '10.3389/fimmu.2021.656350'},
{'key': 'ref47', 'doi-asserted-by': 'publisher', 'DOI': '10.18632/aging.202877'},
{'key': 'ref48', 'doi-asserted-by': 'publisher', 'DOI': '10.3389/fimmu.2021.666223'},
{'key': 'ref49', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41598-021-90189-4'},
{'key': 'ref50', 'doi-asserted-by': 'publisher', 'DOI': '10.1002/art.41763'},
{'key': 'ref51', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.intimp.2021.107615'},
{'key': 'ref52', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.niox.2020.07.005'},
{'key': 'ref53', 'doi-asserted-by': 'publisher', 'DOI': '10.3233/JAD-130416'},
{'key': 'ref54', 'doi-asserted-by': 'publisher', 'DOI': '10.4274/npa.y7089'},
{'key': 'ref55', 'doi-asserted-by': 'publisher', 'DOI': '10.1210/me.2013-1252'},
{'key': 'ref56', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.medin.2020.10.003'},
{ 'key': 'ref57',
'first-page': '276',
'article-title': 'Usefulness of S100B protein in neurological disorders',
'volume': '61',
'author': 'Yardan',
'year': '2011',
'journal-title': 'J. Pak. Med. Assoc.'},
{'key': 'ref58', 'doi-asserted-by': 'publisher', 'DOI': '10.1111/ene.14491'},
{'key': 'ref59', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41598-020-75618-0'},
{'key': 'ref60', 'doi-asserted-by': 'publisher', 'DOI': '10.1093/infdis/jiab042'},
{'key': 'ref61', 'doi-asserted-by': 'publisher', 'DOI': '10.1093/infdis/jiaa642'},
{'key': 'ref62', 'doi-asserted-by': 'publisher', 'DOI': '10.1186/s13054-021-03499-4'}],
'container-title': 'Nutrients',
'original-title': [],
'language': 'en',
'link': [ { 'URL': 'https://www.mdpi.com/2072-6643/13/11/4047/pdf',
'content-type': 'unspecified',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2021, 11, 15]],
'date-time': '2021-11-15T02:09:10Z',
'timestamp': 1636942150000},
'score': 1,
'resource': {'primary': {'URL': 'https://www.mdpi.com/2072-6643/13/11/4047'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2021, 11, 12]]},
'references-count': 62,
'journal-issue': {'issue': '11', 'published-online': {'date-parts': [[2021, 11]]}},
'alternative-id': ['nu13114047'],
'URL': 'http://dx.doi.org/10.3390/nu13114047',
'relation': {},
'ISSN': ['2072-6643'],
'subject': ['Food Science', 'Nutrition and Dietetics'],
'container-title-short': 'Nutrients',
'published': {'date-parts': [[2021, 11, 12]]}}
