{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T09:14:45Z","timestamp":1782810885468,"version":"3.54.5"},"reference-count":71,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,6,5]],"date-time":"2023-06-05T00:00:00Z","timestamp":1685923200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Centro de Qu\u00edmica Estrutural Research Unit (RU)","award":["UIDB\/00100\/2020"],"award-info":[{"award-number":["UIDB\/00100\/2020"]}]},{"name":"Centro de Qu\u00edmica Estrutural Research Unit (RU)","award":["UIDP\/00100\/2020"],"award-info":[{"award-number":["UIDP\/00100\/2020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Hypercholesterolemia is a major risk for the development of cardiovascular diseases (CVDs), the main cause of mortality worldwide, and it is characterized by high levels of circulating cholesterol. The drugs currently available for hypercholesterolemia control have several side effects, so it is necessary to develop new effective and safer therapies. Seaweeds serve as sources of several bioactive compounds with claimed beneficial effects. Eisenia bicyclis (Aram\u00e9) and Porphyra tenera (Nori) are edible seaweeds that were previously recognized as rich in bioactive compounds. In the present study, we aim to evaluate the anti-hypercholesterolemia effect of these two seaweed extracts and their health potential. Both extracts, but more efficiently Aram\u00e9 extract, have liver 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) inhibitory activity as well as the capability to reduce approximately 30% of cholesterol permeation through human Caco-2 cells by simulating the intestinal lining, which is a target for hypercholesterolemia treatments. An untargeted metabolomic assay on human intestinal Caco-2 and liver Hep-G2 cell lines exposed to Aram\u00e9 and Nori extracts revealed changes in the cells\u2019 metabolism, indicating the extracts\u2019 health beneficial effects. The metabolic pathways affected by exposure to both extracts were associated with lipid metabolism, such as phospholipids, and fatty acid metabolism, amino acid pathways, cofactors, vitamins, and cellular respiration metabolism. The effects were more profound in Aram\u00e9-treated cells, but they were also observed in Nori-exposed cells. The metabolite modifications were associated with the protection against CVDs and other diseases and to the improvement of the cells\u2019 oxidative stress tolerance. The results obtained for the anti-hypercholesterolemia properties, in addition to the revelation of the positive impact on cell metabolism, offer an important contribution for further evaluation of these seaweed extracts as functional foods or for CVD prevention.<\/jats:p>","DOI":"10.3390\/life13061325","type":"journal-article","created":{"date-parts":[[2023,6,6]],"date-time":"2023-06-06T01:38:26Z","timestamp":1686015506000},"page":"1325","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Anti-Hypercholesterolemia Effects of Edible Seaweed Extracts and Metabolomic Changes in Hep-G2 and Caco-2 Cell Lines"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8168-7267","authenticated-orcid":false,"given":"Mariana","family":"Coelho","sequence":"first","affiliation":[{"name":"Departamento de Engenharia Qu\u00edmica, Instituto Superior de Engenharia de Lisboa (ISEL), Rua. Conselheiro Em\u00eddio Navarro 1, 1959-007 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5192-3006","authenticated-orcid":false,"given":"Rita","family":"Pacheco","sequence":"additional","affiliation":[{"name":"Departamento de Engenharia Qu\u00edmica, Instituto Superior de Engenharia de Lisboa (ISEL), Rua. Conselheiro Em\u00eddio Navarro 1, 1959-007 Lisboa, Portugal"},{"name":"Centro de Qu\u00edmica Estrutural, Institute of Molecular Sciences, Universidade de Lisboa, 1749-016 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Amante, C., Esposito, T., Luccheo, G., Luccheo, L., Russo, P., and Del Gaudio, P. (2022). Recapsoma\u00ae: A Novel Mixture Based on Bergamot, Ipomoea Batatas, Policosanol Extracts and Liposomal Berberine for the Treatment of Hypercholesterolemia. Life, 12.","DOI":"10.3390\/life12081162"},{"key":"ref_2","unstructured":"World Health Organization (2021, April 05). Cardiovascular Diseases. Available online: https:\/\/www.who.int\/cardiovascular_diseases\/about_cvd\/en\/."},{"key":"ref_3","unstructured":"Huhtaniemi, I., and Martini, L. (2019). Encyclopedia of Endocrine Diseases, Academic Press. [2nd ed.]."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/j.jacl.2022.09.006","article-title":"A mechanism-based operational definition and classification of hypercholesterolemia","volume":"16","author":"Civeira","year":"2022","journal-title":"J. Clin. Lipidol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Andr\u00e9, R., Pacheco, R., Bourbon, M., and Serralheiro, M.L. (2021). Brown Algae Potential as a Functional Food against Hypercholesterolemia: Review. Foods, 10.","DOI":"10.3390\/foods10020234"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/nrcardio.2018.3","article-title":"Advances in lipid-lowering therapy through gene-silencing technologies","volume":"15","author":"Nordestgaard","year":"2018","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1016\/j.clinthera.2022.08.013","article-title":"Efficacy and Tolerability of Ezetimibe\/Atorvastatin Fixed-dose Combination Versus Atorvastatin Monotherapy in Hypercholesterolemia: A Phase III, Randomized, Active-controlled Study in Chinese Patients","volume":"44","author":"Qian","year":"2022","journal-title":"Clin. Ther."},{"key":"ref_8","unstructured":"Database, H.M. (2021, April 05). Cholesterol. Available online: https:\/\/hmdb.ca\/metabolites\/HMDB0000067."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1038\/s41580-019-0190-7","article-title":"Mechanisms and regulation of cholesterol homeostasis","volume":"21","author":"Luo","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"103674","DOI":"10.1016\/j.jff.2019.103674","article-title":"Cholesterol transporter proteins in HepG2 cells can be modulated by phenolic compounds present in Opuntia ficus-indica aqueous solutions","volume":"64","author":"Ressaissi","year":"2020","journal-title":"J. Funct. Foods"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1700314","DOI":"10.1002\/ardp.201700314","article-title":"Synthesis and biological evaluation of phloroglucinol derivatives possessing \u03b1-glycosidase, acetylcholinesterase, butyrylcholinesterase, carbonic anhydrase inhibitory activity","volume":"351","author":"Burmaoglu","year":"2018","journal-title":"Archiv. Der Pharm."},{"key":"ref_12","first-page":"415","article-title":"Ezetimibe therapy: Mechanism of action and clinical update","volume":"8","author":"Phan","year":"2012","journal-title":"Vasc. Health Risk Manag."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Battaggia, A., Donzelli, A., Font, M., Molteni, D., and Galvano, A. (2015). Clinical efficacy and safety of Ezetimibe on major cardiovascular endpoints: Systematic review and meta-analysis of randomized controlled trials. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0124587"},{"key":"ref_14","unstructured":"Cardiology, A.C.O. (2021, March 01). Ezetimibe: The Lower the LDL-C, the Better (Even for Total Cardiovascular Events). Available online: https:\/\/www.acc.org\/latest-in-cardiology\/articles\/2016\/03\/09\/06\/50\/ezetimibe-the-lower-the-ldlc-the-better."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1161\/CIRCRESAHA.118.312782","article-title":"Statin Toxicity","volume":"124","author":"Ward","year":"2019","journal-title":"Circ. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2526","DOI":"10.1093\/eurheartj\/ehy182","article-title":"Adverse effects of statin therapy: Perception vs. the evidence\u2014Focus on glucose homeostasis, cognitive, renal and hepatic function, haemorrhagic stroke and cataract","volume":"39","author":"Mach","year":"2018","journal-title":"Eur. Heart J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2532","DOI":"10.1016\/S0140-6736(16)31357-5","article-title":"Interpretation of the evidence for the efficacy and safety of statin therapy","volume":"388","author":"Collins","year":"2016","journal-title":"Lancet"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/s41392-022-01125-5","article-title":"Regulation of cholesterol homeostasis in health and diseases: From mechanisms to targeted therapeutics","volume":"7","author":"Duan","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Pinto, S., Gaspar, M.M., Ascens\u00e3o, L., Fa\u00edsca, P., Reis, C.P., and Pacheco, R. (2022). Nanoformulation of Seaweed Eisenia bicyclis in Albumin Nanoparticles Targeting Cardiovascular Diseases: In Vitro and In Vivo Evaluation. Mar. Drugs, 20.","DOI":"10.3390\/md20100608"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1080\/13813455.2018.1441315","article-title":"Natural products for controlling hyperlipidemia: Review","volume":"125","author":"Temraz","year":"2019","journal-title":"Arch. Physiol. Biochem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1038\/nrendo.2016.210","article-title":"Functional foods and dietary supplements for the management of dyslipidaemia","volume":"13","author":"Hunter","year":"2017","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6565396","DOI":"10.1155\/2020\/6565396","article-title":"Natural Products and Their Bioactive Compounds: Neuroprotective Potentials against Neurodegenerative Diseases","volume":"2020","author":"Sirajudeen","year":"2020","journal-title":"Evid. Based Complement Alternat. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1111\/bph.13636","article-title":"Nutraceuticals in hypercholesterolaemia: An overview","volume":"174","author":"Santini","year":"2017","journal-title":"Br. J. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Rigogliuso, S., Campora, S., Notarbartolo, M., and Ghersi, G. (2023). Recovery of Bioactive Compounds from Marine Organisms: Focus on the Future Perspectives for Pharmacological, Biomedical and Regenerative Medicine Applications of Marine Collagen. Molecules, 28.","DOI":"10.3390\/molecules28031152"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Coelho, M., Duarte, A.P., Pinto, S., Botelho, H.M., Reis, C.P., Serralheiro, M.L., and Pacheco, R. (2023). Edible Seaweeds Extracts: Characterization and Functional Properties for Health Conditions. Antioxidants, 12.","DOI":"10.3390\/antiox12030684"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"G\u00f3mez-Guzm\u00e1n, M., Rodr\u00edguez-Nogales, A., Algieri, F., and G\u00e1lvez, J. (2018). Potential Role of Seaweed Polyphenols in Cardiovascular-Associated Disorders. Mar. Drugs, 16.","DOI":"10.3390\/md16080250"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"100026","DOI":"10.1016\/j.phyplu.2021.100026","article-title":"Prevention of cardiovascular disease through modulation of endothelial cell function by dietary seaweed intake","volume":"1","author":"Yamagata","year":"2021","journal-title":"Phytomed. Plus"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Meinita, M.D., Harwanto, D., and Choi, J.-S. (2022). Seaweed Exhibits Therapeutic Properties against Chronic Diseases: An Overview. Appl. Sci., 12.","DOI":"10.3390\/app12052638"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Collins, K.G., Fitzgerald, G.F., Stanton, C., and Ross, R.P. (2016). Looking Beyond the Terrestrial: The Potential of Seaweed Derived Bioactives to Treat Non-Communicable Diseases. Mar. Drugs, 14.","DOI":"10.3390\/md14030060"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Leandro, A., Pacheco, D., Cotas, J., Marques, J.C., Pereira, L., and Gon\u00e7alves, A.M.M. (2020). Seaweed\u2019s Bioactive Candidate Compounds to Food Industry and Global Food Security. Life, 10.","DOI":"10.3390\/life10080140"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.3389\/fmars.2021.740054","article-title":"Edible Seaweeds: A Potential Novel Source of Bioactive Metabolites and Nutraceuticals With Human Health Benefits","volume":"8","author":"Choudhary","year":"2021","journal-title":"Front. Mar. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Mahadevan, K. (2015). Seaweeds: A Sustainable Food Source, Academic Press.","DOI":"10.1016\/B978-0-12-418697-2.00013-1"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Pe\u00f1alver, R., Lorenzo, J.M., Ros, G., Amarowicz, R., Pateiro, M., and Nieto, G. (2020). Seaweeds as a Functional Ingredient for a Healthy Diet. Mar. Drugs, 18.","DOI":"10.3390\/md18060301"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1007\/s12272-017-0904-3","article-title":"Evaluation of the inhibitory effects of eckol and dieckol isolated from edible brown alga Eisenia bicyclis on human monoamine oxidases A and B","volume":"40","author":"Jung","year":"2017","journal-title":"Arch. Pharm. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/s12088-017-0693-x","article-title":"In Vitro Antibacterial Activity of Phlorotannins from Edible Brown Algae, Eisenia bicyclis Against Streptomycin-Resistant Listeria monocytogenes","volume":"58","author":"Kim","year":"2018","journal-title":"Indian J. Microbiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1007\/s10126-012-9459-y","article-title":"Edible seaweed, Eisenia bicyclis, protects retinal ganglion cells death caused by oxidative stress","volume":"14","author":"Kim","year":"2012","journal-title":"Mar. Biotechnol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1007\/s11130-018-0707-9","article-title":"Health Benefits and Pharmacological Effects of Porphyra Species","volume":"74","author":"Venkatraman","year":"2019","journal-title":"Plant Foods Hum. Nutr."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/S0304-3835(99)00106-8","article-title":"Inhibition of liver glutathione S-transferase placental form-positive foci development in the rat hepatocarcinogenesis by Porphyra tenera (Asakusa-nori)","volume":"141","author":"Ichihara","year":"1999","journal-title":"Cancer Lett."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1016\/j.bjp.2016.05.008","article-title":"Inhibition of HMG-CoA redutase activity and cholesterol permeation through Caco-2 cells by caffeoylquinic acids from Vernonia condensata leaves","volume":"26","author":"Arantes","year":"2016","journal-title":"Rev. Bras. Farmacogn."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.aca.2011.09.042","article-title":"Liquid chromatography-mass spectrometry based global metabolite profiling: A review","volume":"711","author":"Theodoridis","year":"2012","journal-title":"Anal Chim. Acta"},{"key":"ref_41","first-page":"92","article-title":"Multivariate Analysis in Metabolomics","volume":"1","author":"Worley","year":"2013","journal-title":"Curr. Metab."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"687585","DOI":"10.3389\/fcvm.2021.687585","article-title":"Hydrophilic or Lipophilic Statins?","volume":"8","author":"Climent","year":"2021","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Zhao, J., Cao, Q., Xing, M., Xiao, H., Cheng, Z., Song, S., and Ji, A. (2020). Advances in the Study of Marine Products with Lipid-Lowering Properties. Mar. Drugs, 18.","DOI":"10.3390\/md18080390"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1007\/s12272-001-2152-8","article-title":"Anti-hyperlipidemic effect of an edible brown algae, Ecklonia stolonifera, and its constituents on poloxamer 407-induced hyperlipidemic and cholesterol-fed rats","volume":"31","author":"Yoon","year":"2008","journal-title":"Arch. Pharm. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/1476-511X-9-40","article-title":"Curcumin inhibits cholesterol uptake in Caco-2 cells by down-regulation of NPC1L1 expression","volume":"9","author":"Feng","year":"2010","journal-title":"Lipids Health Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1208\/s12248-013-9456-8","article-title":"Drug discovery and regulatory considerations for improving in silico and in vitro predictions that use Caco-2 as a surrogate for human intestinal permeability measurements","volume":"15","author":"Larregieu","year":"2013","journal-title":"Aaps J."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Andr\u00e9, R., Pacheco, R., Alves, A.C., Santos, H.M., Bourbon, M., and Serralheiro, M. (2023). The hypocholesterolemic potential of the edible algae Fucus vesiculosus: Proteomic and quantitative PCR analysis, under revision.","DOI":"10.20944\/preprints202305.2272.v1"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1016\/j.cmet.2008.04.001","article-title":"The cholesterol absorption inhibitor ezetimibe acts by blocking the sterol-induced internalization of NPC1L1","volume":"7","author":"Ge","year":"2008","journal-title":"Cell Metab."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1080\/15287394.2019.1634378","article-title":"Cytotoxic activity of the seaweed compound fucosterol, alone and in combination with 5-fluorouracil, in colon cells using 2D and 3D culturing","volume":"82","author":"Ramos","year":"2019","journal-title":"J. Toxicol. Environ. Health A"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"153280","DOI":"10.1016\/j.phymed.2020.153280","article-title":"The carotenoid fucoxanthin can sensitize multidrug resistant cancer cells to doxorubicin via induction of apoptosis, inhibition of multidrug resistance proteins and metabolic enzymes","volume":"77","author":"Eid","year":"2020","journal-title":"Phytomedicine"},{"key":"ref_51","first-page":"1934578X211070415","article-title":"Evaluation on intestinal permeability of phlorotannins using Caco-2 cell monolayers","volume":"17","author":"Murata","year":"2022","journal-title":"Nat. Prod. Commun."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1017\/S0007114516000210","article-title":"Gastrointestinal modifications and bioavailability of brown seaweed phlorotannins and effects on inflammatory markers","volume":"115","author":"Corona","year":"2016","journal-title":"Br. J. Nutr."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/1742-4682-5-8","article-title":"A mathematical model of glutathione metabolism","volume":"5","author":"Reed","year":"2008","journal-title":"Theor. Biol. Med. Model."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"308","DOI":"10.5144\/0256-4947.2014.308","article-title":"Plasma level of hypoxanthine\/xanthine as markers of oxidative stress with different stages of obstructive sleep apnea syndrome","volume":"34","author":"Hira","year":"2014","journal-title":"Ann. Saudi Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2524s","DOI":"10.1093\/jn\/nxaa243","article-title":"Sulfur-Containing Amino Acids and Lipid Metabolism","volume":"150","author":"Blachier","year":"2020","journal-title":"J. Nutr."},{"key":"ref_56","unstructured":"KEGG (2022, July 16). Glutathione. Available online: https:\/\/www.genome.jp\/pathway\/map00480."},{"key":"ref_57","unstructured":"KEGG (2022, July 16). Alanine, Aspartate and Glutamate Metabolism. Available online: https:\/\/www.genome.jp\/pathway\/map00250."},{"key":"ref_58","unstructured":"KEGG (2022, July 16). Taurine and Hypotaurine Metabolism. Available online: https:\/\/www.genome.jp\/pathway\/map00430."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s10545-009-9006-9","article-title":"Dealing with methionine\/homocysteine sulfur: Cysteine metabolism to taurine and inorganic sulfur","volume":"34","author":"Stipanuk","year":"2011","journal-title":"J. Inherit Metab Dis."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e9197","DOI":"10.1002\/rcm.9197","article-title":"Untargeted metabolomic study of HepG2 cells under the effect of Fucus vesiculosus aqueous extract","volume":"35","author":"Guedes","year":"2021","journal-title":"Rapid Commun. Mass Spectrom."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"4696","DOI":"10.1002\/fsn3.1818","article-title":"Cysteine and homocysteine as biomarker of various diseases","volume":"8","author":"Rehman","year":"2020","journal-title":"Food Sci. Nutr."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.cmet.2006.03.007","article-title":"The ratio of phosphatidylcholine to phosphatidylethanolamine influences membrane integrity and steatohepatitis","volume":"3","author":"Li","year":"2006","journal-title":"Cell Metab."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Deschamps, C.L., Connors, K.E., Klein, M.S., Johnsen, V.L., Shearer, J., Vogel, H.J., Devaney, J.M., Gordish-Dressman, H., Many, G.M., and Barfield, W. (2015). The ACTN3 R577X Polymorphism Is Associated with Cardiometabolic Fitness in Healthy Young Adults. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0130644"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"310","DOI":"10.3892\/etm.2022.11239","article-title":"Exogenous spermine inhibits high glucose\/oxidized LDL-induced oxidative stress and macrophage pyroptosis by activating the Nrf2 pathway","volume":"23","author":"Qiu","year":"2022","journal-title":"Exp. Ther. Med."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Yu, Z., Jiao, Y., Zhang, J., Xu, Q., Xu, J., Li, R., Yuan, W., Guo, H., Sun, Z., and Zheng, L. (2022). Effect of Serum Spermidine on the Prognosis in Patients with Acute Myocardial Infarction: A Cohort Study. Nutrients, 14.","DOI":"10.3390\/nu14071394"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1186\/s13048-022-01022-z","article-title":"Targeting purine metabolism in ovarian cancer","volume":"15","author":"Liu","year":"2022","journal-title":"J. Ovarian Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/S0005-2736(02)00606-5","article-title":"Cellular and molecular aspects of thiamin uptake by human liver cells: Studies with cultured HepG2 cells","volume":"1567","author":"Said","year":"2002","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Biomembr."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"703783","DOI":"10.3389\/fnins.2021.703783","article-title":"Inosine as a Tool to Understand and Treat Central Nervous System Disorders: A Neglected Actor?","volume":"15","author":"Nascimento","year":"2021","journal-title":"Front. Neurosci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1016\/j.numecd.2018.06.013","article-title":"Thiamine deficiency and cardiovascular disorders","volume":"28","author":"Eshak","year":"2018","journal-title":"Nutr. Metab Cardiovasc. Dis."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1104\/pp.109.140046","article-title":"Thiamin confers enhanced tolerance to oxidative stress in Arabidopsis","volume":"151","author":"Miller","year":"2009","journal-title":"Plant Physiol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1021\/acs.chemrestox.6b00256","article-title":"Formation and Biological Targets of Quinones: Cytotoxic versus Cytoprotective Effects","volume":"30","author":"Bolton","year":"2017","journal-title":"Chem. Res. Toxicol."}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/13\/6\/1325\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:48:34Z","timestamp":1760125714000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/13\/6\/1325"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,5]]},"references-count":71,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["life13061325"],"URL":"https:\/\/doi.org\/10.3390\/life13061325","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,5]]}}}