{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T05:19:11Z","timestamp":1790745551307,"version":"4.1.0"},"reference-count":54,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2021,8,14]],"date-time":"2021-08-14T00:00:00Z","timestamp":1628899200000},"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>Nearly 40\u201350% of infertility problems are estimated to be of female origin. Previous studies dedicated to the analysis of metabolites in follicular fluid (FF) produced contrasting results, although some valuable indexes capable to discriminate control groups (CTRL) from infertile females (IF) and correlate with outcome measures of assisted reproduction techniques were in some instances found. In this study, we analyzed in blind FF of 35 control subjects (CTRL = patients in which inability to obtain pregnancy was exclusively due to a male factor) and 145 IF (affected by: endometriosis, n = 19; polycystic ovary syndrome, n = 14; age-related reduced ovarian reserve, n = 58; reduced ovarian reserve, n = 29; unexplained infertility, n = 14; genetic infertility, n = 11) to determine concentrations of 55 water- and fat-soluble low molecular weight compounds (antioxidants, oxidative\/nitrosative stress-related compounds, purines, pyrimidines, energy-related metabolites, and amino acids). Results evidenced that 27\/55 of them had significantly different values in IF with respect to those measured in CTRL. The metabolic pattern of these potential biomarkers of infertility was cumulated (in both CTRL and IF) into a Biomarker Score index (incorporating the metabolic anomalies of FF), that fully discriminated CTRL (mean Biomarker Score value = 4.00 \u00b1 2.30) from IF (mean Biomarker Score value = 14.88 \u00b1 3.09, p &lt; 0.001). The Biomarker Score values were significantly higher than those of CTRL in each of the six subgroups of IF. Posterior probability curves and ROC curve indicated that values of the Biomarker Score clustered CTRL and IF into two distinct groups, based on the individual FF metabolic profile. Furthermore, Biomarker Score values correlated with outcome measures of ovarian stimulation, in vitro fertilization, number and quality of blastocysts, clinical pregnancy, and healthy offspring. These results strongly suggest that the biochemical quality of FF deeply influences not only the effectiveness of IVF procedures but also the following embryonic development up to healthy newborns. The targeted metabolomic analysis of FF (using empowered Redox Energy Test) and the subsequent calculation of the Biomarker Score evidenced a set of 27 low molecular weight infertility biomarkers potentially useful in the laboratory managing of female infertility and to predict the success of assisted reproduction techniques.<\/jats:p>","DOI":"10.3390\/ijms22168735","type":"journal-article","created":{"date-parts":[[2021,8,15]],"date-time":"2021-08-15T21:43:55Z","timestamp":1629063835000},"page":"8735","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Altered Follicular Fluid Metabolic Pattern Correlates with Female Infertility and Outcome Measures of In Vitro Fertilization"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1639-0966","authenticated-orcid":false,"given":"Giacomo","family":"Lazzarino","sequence":"first","affiliation":[{"name":"UniCamillus\u2014Saint Camillus International University of Health Sciences, Via di Sant\u2019Alessandro 8, 00131 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romina","family":"Pallisco","sequence":"additional","affiliation":[{"name":"Alma Res Fertility Center, Laboratory of Andrology and Embriology, Via Parenzo 12, 00198 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Bilotta","sequence":"additional","affiliation":[{"name":"Alma Res Fertility Center, Laboratory of Andrology and Embriology, Via Parenzo 12, 00198 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Listorti","sequence":"additional","affiliation":[{"name":"Alma Res Fertility Center, Laboratory of Andrology and Embriology, Via Parenzo 12, 00198 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renata","family":"Mangione","sequence":"additional","affiliation":[{"name":"Department of Basic Biotechnological Sciences, Intensive and Perioperative Clinics, Catholic University of Rome, Largo F. Vito 1, 00168 Rome, Italy"},{"name":"Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Saab","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, Division of Medical Biochemistry, University of Catania, Viale A. Doria 6, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1571-5327","authenticated-orcid":false,"given":"Giuseppe","family":"Caruso","sequence":"additional","affiliation":[{"name":"Department of Drug and Health Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3525-9955","authenticated-orcid":false,"given":"Angela","family":"Amorini","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, Division of Medical Biochemistry, University of Catania, Viale A. Doria 6, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5146-3564","authenticated-orcid":false,"given":"Maria","family":"Brundo","sequence":"additional","affiliation":[{"name":"Department of Biology, Geology and Environmental Sciences, Section of Animal Biology, University of Catania, Via Androne 81, 95124 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5917-7279","authenticated-orcid":false,"given":"Giuseppe","family":"Lazzarino","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, Division of Medical Biochemistry, University of Catania, Viale A. Doria 6, 95125 Catania, Italy"},{"name":"Department of Biomedical and Biotechnological Sciences, LTA-Biotech srl, Viale Don Orione 3D, 95047 Patern\u00f2, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8743-0895","authenticated-orcid":false,"given":"Barbara","family":"Tavazzi","sequence":"additional","affiliation":[{"name":"Department of Basic Biotechnological Sciences, Intensive and Perioperative Clinics, Catholic University of Rome, Largo F. Vito 1, 00168 Rome, Italy"},{"name":"Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pasquale","family":"Bilotta","sequence":"additional","affiliation":[{"name":"Alma Res Fertility Center, Obstetrics and Gynecology, Via Parenzo 12, 00198 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.ucl.2013.08.006","article-title":"The epidemiology of male infertility","volume":"41","author":"Winters","year":"2014","journal-title":"Urol. Clin. N. Am."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1210\/jc.2018-01869","article-title":"Genetics and Epigenetics of Infertility and Treatments on Outcomes","volume":"104","author":"Pisarska","year":"2019","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1016\/j.fertnstert.2008.01.003","article-title":"From oocyte to baby: A clinical evaluation of the biological efficiency of in vitro fertilization","volume":"91","author":"Patrizio","year":"2009","journal-title":"Fertil. Steril."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.fertnstert.2014.11.015","article-title":"Oocyte environment: Follicular fluid and cumulus cells are critical for oocyte health","volume":"103","author":"Dumesic","year":"2015","journal-title":"Fertil. Steril."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.freeradbiomed.2015.05.013","article-title":"Metabolism alteration in follicular niche: The nexus among intermediary metabolism, mitochondrial function, and classic polycystic ovary syndrome","volume":"86","author":"Zhao","year":"2015","journal-title":"Free Radic. Biol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.fertnstert.2014.11.002","article-title":"Endometriosis may be associated with mitochondrial dysfunction in cumulus cells from subjects undergoing in vitro fertilization-intracytoplasmic sperm injection, as reflected by decreased adenosine triphosphate production","volume":"103","author":"Hsu","year":"2015","journal-title":"Fertil. Steril."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Xu, W.L., Liu, G.Y., Zhang, N., Ren, J., Li, X.Y., Li, Y.Q., Chen, Y., and Liu, J.Y. (2020). Untargeted metabolomics analysis of serum and follicular fluid samples from women with polycystic ovary syndrome. Minerva Endocrinol.","DOI":"10.23736\/S0391-1977.20.03199-5"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s13048-017-0342-3","article-title":"Follicular Fluid redox involvement for ovarian follicle growth","volume":"10","author":"Freitas","year":"2017","journal-title":"J. Ovarian Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"80472","DOI":"10.18632\/oncotarget.19058","article-title":"Follicular metabolic changes and effects on oocyte quality in polycystic ovary syndrome patients","volume":"8","author":"Zhang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1007\/s00404-020-05609-z","article-title":"Metabolic changes in follicular fluids of patients treated with recombinant versus urinary human chorionic gonadotropin for triggering ovulation in assisted reproductive technologies: A metabolomics pilot study","volume":"302","author":"Iuliano","year":"2020","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1002\/mrd.23415","article-title":"Relationship between the metabolic and lipid profile in follicular fluid of women undergoing in vitro fertilization","volume":"87","author":"Luti","year":"2020","journal-title":"Mol. Reprod. Dev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s12958-019-0490-y","article-title":"Identification of potential metabolic biomarkers of polycystic ovary syndrome in follicular fluid by SWATH mass spectrometry","volume":"17","author":"Sun","year":"2019","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2269","DOI":"10.1093\/humrep\/dex303","article-title":"Targeted metabolomics reveals reduced levels of polyunsaturated choline plasmalogens and a smaller dimethylarginine\/arginine ratio in the follicular fluid of patients with a diminished ovarian reserve","volume":"32","author":"Boueilh","year":"2017","journal-title":"Hum. Reprod."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1039\/C7MB90021J","article-title":"Metabolomic profiling and biochemical evaluation of the follicular fluid of endometriosis patients","volume":"13","author":"Santonastaso","year":"2017","journal-title":"Mol. Biosyst."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1007\/s43032-020-00370-9","article-title":"Metabolic Profile of Patients with Severe Endometriosis: A Prospective Experimental Study","volume":"28","author":"Murgia","year":"2021","journal-title":"Reprod. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1016\/j.fertnstert.2012.01.122","article-title":"An investigation into the relationship between the metabolic profile of follicular fluid, oocyte developmental potential, and implantation outcome","volume":"97","author":"Wallace","year":"2012","journal-title":"Fertil. Steril."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1530\/REP-13-0184","article-title":"Metabolic profiling of human follicular fluid identifies potential biomarkers of oocyte developmental competence","volume":"146","author":"Wallace","year":"2013","journal-title":"Reproduction"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"10291","DOI":"10.1096\/fj.201900318RR","article-title":"A shift in follicular fluid from triacylglycerols to membrane lipids is associated with positive pregnancy outcome","volume":"33","author":"Shehadeh","year":"2019","journal-title":"FASEB J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1093\/humrep\/dey279","article-title":"Low-molecular weight compounds in human seminal plasma as potential biomarkers of male infertility","volume":"33","author":"Lazzarino","year":"2018","journal-title":"Hum. Reprod."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1089\/gte.2006.0511","article-title":"Risk prediction for clinical phenotype in myotonic dystrophy type 1: Data from 2650 patients","volume":"11","author":"Salehi","year":"2007","journal-title":"Genet. Test."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"603167","DOI":"10.1155\/2013\/603167","article-title":"Metabolite Profiling in the Pursuit of Biomarkers for IVF Outcome: The Case for Metabolomics Studies","volume":"2013","author":"McRae","year":"2013","journal-title":"Int. J. Reprod. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1093\/humupd\/dmx023","article-title":"Metabolomics as a tool to identify biomarkers to predict and improve outcomes in reproductive medicine: A systematic review","volume":"23","author":"Saso","year":"2017","journal-title":"Hum. Reprod. Update"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1016\/j.fertnstert.2019.10.011","article-title":"In vitro fertilization add-ons for the endometrium: It doesn\u2019t add-up","volume":"112","author":"Lensen","year":"2019","journal-title":"Fertil. Steril."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1093\/humrep\/dez099","article-title":"Treatment-independent live birth after in-vitro fertilisation: A retrospective cohort study of 2,133 women","volume":"34","author":"ElMokhallalati","year":"2019","journal-title":"Hum. Reprod."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1016\/j.fertnstert.2020.04.051","article-title":"First effective mHealth nutrition and lifestyle coaching program for subfertile couples undergoing in vitro fertilization treatment: A single-blinded multicenter randomized controlled trial","volume":"114","author":"Oostingh","year":"2020","journal-title":"Fertil. Steril."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Budani, M.C., and Tiboni, G.M. (2020). Effects of Supplementation with Natural Antioxidants on Oocytes and Preimplantation Embryos. Antioxidants, 9.","DOI":"10.3390\/antiox9070612"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1080\/19396368.2018.1478469","article-title":"Metabolomics analysis of follicular fluid in women with ovarian endometriosis undergoing in vitro fertilization","volume":"65","author":"Karaer","year":"2019","journal-title":"Syst. Biol. Reprod. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1007\/s10815-020-01693-x","article-title":"High-resolution (1)H-NMR spectroscopy indicates variations in metabolomics profile of follicular fluid from women with advanced maternal age","volume":"37","author":"Dogan","year":"2020","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1016\/j.fertnstert.2012.06.025","article-title":"Women with reduced ovarian reserve or advanced maternal age have an altered follicular environment","volume":"98","author":"Pacella","year":"2012","journal-title":"Fertil. Steril."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1016\/j.rbmo.2020.09.002","article-title":"The follicular fluid metabolome differs according to the endometriosis phenotype","volume":"41","author":"Santulli","year":"2020","journal-title":"Reprod. Biomed. Online"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"7520","DOI":"10.1007\/s12035-016-0257-9","article-title":"Serum Compounds of Energy Metabolism Impairment Are Related to Disability, Disease Course and Neuroimaging in Multiple Sclerosis","volume":"54","author":"Lazzarino","year":"2017","journal-title":"Mol. Neurobiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.1016\/j.bbadis.2016.08.019","article-title":"An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington\u2019s disease related cardiomyopathy","volume":"1862","author":"Toczek","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.reprotox.2013.08.005","article-title":"Markers of oxidative stress in follicular fluid of women with endometriosis and tubal infertility undergoing IVF","volume":"42","author":"Singh","year":"2013","journal-title":"Reprod. Toxicol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1007\/s10815-014-0396-8","article-title":"Changes of sFas and sFasL, oxidative stress markers in serum and follicular fluid of patients undergoing IVF","volume":"32","author":"Pekel","year":"2015","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1884","DOI":"10.1111\/jog.14040","article-title":"Role of oxidative stress in follicular fluid on embryos of patients undergoing assisted reproductive technology treatment","volume":"45","author":"Terao","year":"2019","journal-title":"J. Obstet. Gynaecol. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1080\/14647273.2018.1551630","article-title":"The role of stimulation protocol, number of oocytes retrieved with respect to follicular fluid oxidative stress and IVF outcome","volume":"23","author":"Thaker","year":"2020","journal-title":"Hum. Fertil."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Zhang, C.M., Zhao, Y., Li, R., Yu, Y., Yan, L.Y., Li, L., Liu, N.N., Liu, P., and Qiao, J. (2014). Metabolic heterogeneity of follicular amino acids in polycystic ovary syndrome is affected by obesity and related to pregnancy outcome. BMC Pregnancy Childbirth, 14.","DOI":"10.1186\/1471-2393-14-11"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2293","DOI":"10.1093\/humrep\/dep069","article-title":"Homocysteine concentrations in follicular fluid are associated with poor oocyte and embryo qualities in polycystic ovary syndrome patients undergoing assisted reproduction","volume":"24","author":"Berker","year":"2009","journal-title":"Hum. Reprod."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e4993","DOI":"10.1002\/bmc.4993","article-title":"Metabolomics and correlation network analysis of follicular fluid reveals associations between l-tryptophan, l-tyrosine and polycystic ovary syndrome","volume":"35","author":"Hou","year":"2021","journal-title":"Biomed. Chromatogr."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1002\/nbm.1488","article-title":"NMR metabolic profile of human follicular fluid","volume":"23","author":"Nunes","year":"2010","journal-title":"NMR Biomed."},{"key":"ref_41","first-page":"7220","article-title":"Metabolomic profiling of human follicular fluid from patients with repeated failure of in vitro fertilization using gas chromatography\/mass spectrometry","volume":"7","author":"Xia","year":"2014","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/j.bbabio.2010.09.003","article-title":"Oxidative phosphorylation in cancer cells","volume":"1807","author":"Solaini","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3195","DOI":"10.1111\/cas.14443","article-title":"Nuclear magnetic resonance-based tissue metabolomic analysis clarifies molecular mechanisms of gastric carcinogenesis","volume":"111","author":"Gu","year":"2020","journal-title":"Cancer Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1177\/153537020422901002","article-title":"DNA methylation, cancer susceptibility, and nutrient interactions","volume":"229","author":"Davis","year":"2004","journal-title":"Exp. Biol. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1016\/j.neubiorev.2009.10.010","article-title":"Histone modifications, DNA methylation, and schizophrenia","volume":"34","author":"Gavin","year":"2010","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1002\/mnfr.201200125","article-title":"The relationship between intracellular and plasma levels of folate and metabolites in the methionine cycle: A model","volume":"57","author":"Duncan","year":"2013","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_47","first-page":"4293","article-title":"A novel biomarker score for the screening and management of patients with plasma cell proliferative disorders","volume":"23","author":"Basile","year":"2019","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.ab.2003.07.013","article-title":"Single-sample preparation for simultaneous cellular redox and energy state determination","volume":"322","author":"Lazzarino","year":"2003","journal-title":"Anal. Biochem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.chroma.2017.10.053","article-title":"Single-step preparation of selected biological fluids for the high performance liquid chromatographic analysis of fat-soluble vitamins and antioxidants","volume":"1527","author":"Lazzarino","year":"2017","journal-title":"J Chromatogr. A"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1016\/j.clinbiochem.2005.08.002","article-title":"Simultaneous high performance liquid chromatographic separation of purines, pyrimidines, N-acetylated amino acids, and dicarboxylic acids for the chemical diagnosis of inborn errors of metabolism","volume":"38","author":"Tavazzi","year":"2005","journal-title":"Clin. Biochem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1038\/jcbfm.2014.112","article-title":"3-Nitropropionic acid-induced ischemia tolerance in the rat brain is mediated by reduced metabolic activity and cerebral blood flow","volume":"34","author":"Bracko","year":"2014","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/s11010-011-1015-y","article-title":"Metabolic profile of amniotic fluid as a biochemical tool to screen for inborn errors of metabolism and fetal anomalies","volume":"359","author":"Amorini","year":"2012","journal-title":"Mol. Cell. Biochem."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Lazzarino, G., Listorti, I., Bilotta, G., Capozzolo, T., Amorini, A.M., Longo, S., Caruso, G., Lazzarino, G., Tavazzi, B., and Bilotta, P. (2019). Water- and Fat-Soluble Antioxidants in Human Seminal Plasma and Serum of Fertile Males. Antioxidants, 8.","DOI":"10.3390\/antiox8040096"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1309\/65UJ-FQ75-DVGC-XX1N","article-title":"A liquid-stable reagent for lactic acid levels. Application to the Hitachi 911 and Beckman CX7","volume":"114","author":"Artiss","year":"2000","journal-title":"Am. J. Clin. Pathol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/16\/8735\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:45:58Z","timestamp":1760165158000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/16\/8735"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,14]]},"references-count":54,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["ijms22168735"],"URL":"https:\/\/doi.org\/10.3390\/ijms22168735","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,14]]}}}