{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T20:46:25Z","timestamp":1790628385026,"version":"4.1.0"},"reference-count":109,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T00:00:00Z","timestamp":1757635200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002701","name":"Ministry of Education","doi-asserted-by":"publisher","award":["NRF-2020R1I1A2066868"],"award-info":[{"award-number":["NRF-2020R1I1A2066868"]}],"id":[{"id":"10.13039\/501100002701","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002701","name":"Ministry of Education","doi-asserted-by":"publisher","award":["2020R1A5A2019413"],"award-info":[{"award-number":["2020R1A5A2019413"]}],"id":[{"id":"10.13039\/501100002701","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002701","name":"Ministry of Education","doi-asserted-by":"publisher","award":["RS-2024-00350362"],"award-info":[{"award-number":["RS-2024-00350362"]}],"id":[{"id":"10.13039\/501100002701","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    The combined use of\n                    <jats:italic>\n                      <jats:italic>Zingiber officinale<\/jats:italic>\n                    <\/jats:italic>\n                    (ginger) and\n                    <jats:italic>\n                      <jats:italic>Citrus limon<\/jats:italic>\n                    <\/jats:italic>\n                    (lemon) has been traditionally recognized for its therapeutic potential, particularly in promoting cardiovascular health. However, the synergistic effects of these botanicals on hyperlipidemia and oxidative stress, two major contributors to cardiovascular disease, remain insufficiently characterized. This study employed an integrative approach involving\n                    <jats:italic>\n                      <jats:italic>in vivo<\/jats:italic>\n                    <\/jats:italic>\n                    ,\n                    <jats:italic>\n                      <jats:italic>in vitro<\/jats:italic>\n                    <\/jats:italic>\n                    , and\n                    <jats:italic>\n                      <jats:italic>in silico<\/jats:italic>\n                    <\/jats:italic>\n                    methodologies to assess the hypolipidemic and antioxidant properties of ginger and lemon juices.\n                    <jats:italic>\n                      <jats:italic>In vivo<\/jats:italic>\n                    <\/jats:italic>\n                    experiments were conducted using a murine model of Triton WR-1339-induced hyperlipidemia. Antioxidant activity was evaluated through DPPH and ABTS assays, while molecular docking simulations were performed to assess interactions with HMG-CoA reductase, a key enzyme in cholesterol metabolism. Phytochemical profiling revealed high levels of bioactive compounds, with ginger juice containing 6-gingerol (15.54% peak area), and lemon juice rich in hesperidin (13.85%) and rutin (5.57%). These constituents likely contributed to the observed pharmacological effects. The combined formulation led to marked improvements in lipid parameters, including reductions in total cholesterol (\u221254.3%), triglycerides (\u221249.8%), and LDL-C (\u221258.1%), alongside an increase in HDL-C (+47.6%) compared to hyperlipidemic controls (p\u2009&lt;\u20090.05). Antioxidant assays further demonstrated strong free radical scavenging activity, with IC\u2085\u2080 values of 30.92\u2009\u00b1\u20092.00 \u00b5g\/mL (ABTS) and 44.94\u2009\u00b1\u20091.02 \u00b5g\/mL (DPPH) for the combined formulation. Molecular docking confirmed high binding affinities of key compounds, with hesperidin and 6-gingerol displaying binding energies of \u221210.4 and \u22129.6 kcal\/mol, respectively, against HMG-CoA reductase. In summary, the combination of\n                    <jats:italic>\n                      <jats:italic>Zingiber officinale<\/jats:italic>\n                    <\/jats:italic>\n                    and\n                    <jats:italic>\n                      <jats:italic>Citrus limon<\/jats:italic>\n                    <\/jats:italic>\n                    juices exhibited potent lipid-lowering and antioxidant activities, outperforming the effects observed with individual extracts. These findings underscore their potential as natural therapeutic agents for the management of hyperlipidemia and oxidative stress. Further clinical investigations are warranted to validate these preclinical results and to explore their future application in the development of nutraceuticals or functional foods.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0319721","type":"journal-article","created":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T17:45:01Z","timestamp":1757699101000},"page":"e0319721","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Combinatorial effects of Zingiber officinale and Citrus limon juices: Hypolipidemic and antioxidant insights from in vivo, in vitro, and in silico investigations"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9484-2345","authenticated-orcid":true,"given":"Oussama","family":"Bekkouch","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayoub","family":"Bekkouch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamza","family":"Elbouny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilham","family":"Touiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soufiane El","family":"Assri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Choukri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Bourhia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiryang","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4479-8724","authenticated-orcid":true,"given":"Sojin","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinwon","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyo Jeong","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi-Hoon","family":"Ahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moon Nyeo","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8678-156X","authenticated-orcid":true,"given":"Bonglee","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Souliman","family":"Amrani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,9,12]]},"reference":[{"issue":"5","key":"pone.0319721.ref001","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1042\/EBC20200067","article-title":"Mammalian lipids: structure, synthesis and function","volume":"65","author":"S Cockcroft","year":"2021","journal-title":"Essays Biochem"},{"issue":"9","key":"pone.0319721.ref002","doi-asserted-by":"crossref","first-page":"14680","DOI":"10.1002\/jcp.28221","article-title":"Hypolipidemic effects of Rosmarinus officinalis L","volume":"234","author":"T Farkhondeh","year":"2019","journal-title":"J Cell Physiol"},{"issue":"6","key":"pone.0319721.ref003","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1055\/a-1388-5415","article-title":"Thymoquinone with Metformin Decreases Fasting, Post Prandial Glucose, and HbA1c in Type 2 Diabetic Patients","volume":"71","author":"SM Ali","year":"2021","journal-title":"Drug Res (Stuttg)"},{"issue":"1","key":"pone.0319721.ref004","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1177\/2047487314550804","article-title":"Muscle- and skeletal-related side-effects of statins: tip of the iceberg?","volume":"23","author":"J Auer","year":"2016","journal-title":"Eur J Prev Cardiol"},{"issue":"7","key":"pone.0319721.ref005","article-title":"Chinese herbal medicines for hypercholesterolemia","author":"ZL Liu","year":"2011","journal-title":"Cochrane Database Syst Rev"},{"issue":"3","key":"pone.0319721.ref006","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1590\/S0102-695X2012005000023","article-title":"Anti-hyperlipidemic activity of oryzanol, isolated from crude rice bran oil, on Triton WR-1339-induced acute hyperlipidemia in rats","volume":"22","author":"SB Ghatak","year":"2012","journal-title":"Rev bras farmacogn"},{"issue":"1","key":"pone.0319721.ref007","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1186\/s12906-024-04381-w","article-title":"Green-synthesized silver nanoparticles from Zingiber officinale extract: antioxidant potential, biocompatibility, anti-LOX properties, and in silico analysis","volume":"24","author":"T Ongtanasup","year":"2024","journal-title":"BMC Complement Med 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Ali","year":"2008","journal-title":"Food and Chemical Toxicology"},{"key":"pone.0319721.ref011","first-page":"516870","article-title":"Preventive and Protective Properties of Zingiber officinale (Ginger) in Diabetes Mellitus, Diabetic Complications, and Associated Lipid and Other Metabolic Disorders: A Brief Review","volume":"2012","author":"Y Li","year":"2012","journal-title":"Evid Based Complement Alternat Med"},{"key":"pone.0319721.ref012","author":"Kehal","year":"2013"},{"key":"pone.0319721.ref013","first-page":"252","article-title":"Essentielle de Citrus limon (vari\u00e9t\u00e9 Lisbon) extraite par hydrodistillation","volume":"1","author":"L Himed","year":"2016","journal-title":"Algerian J Natural Products"},{"issue":"3","key":"pone.0319721.ref014","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1002\/ptr.5256","article-title":"Antioxidant and anti-inflammatory properties of the citrus flavonoids hesperidin and hesperetin: an updated review of their molecular mechanisms 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Ethnopharmacol"},{"issue":"4","key":"pone.0319721.ref024","doi-asserted-by":"crossref","first-page":"371","DOI":"10.3923\/jpt.2011.371.380","article-title":"Anti-inflammatory and In vitro Antioxidant Property of Trigonella foenum graecum Seeds","volume":"6","author":"N Subhashini","year":"2011","journal-title":"J of Pharmacology and Toxicology"},{"key":"pone.0319721.ref025","doi-asserted-by":"crossref","unstructured":"Manzocco L, Anese M, Nicoli MC. Antioxidant properties of tea extracts as affected by processing. 1998.","DOI":"10.1006\/fstl.1998.0491"},{"key":"pone.0319721.ref026","doi-asserted-by":"crossref","first-page":"9734390","DOI":"10.1155\/2019\/9734390","article-title":"In Vitro Antioxidant and In Vivo Lipid-Lowering Properties of Zingiber officinale Crude Aqueous Extract and Methanolic Fraction: A Follow-Up Study","volume":"2019","author":"O Bekkouch","year":"2019","journal-title":"Evid Based Complement Alternat Med"},{"key":"pone.0319721.ref027"},{"key":"pone.0319721.ref028","first-page":"5317","article-title":"Mitochondrial lipid transport at a glance","volume":"126","author":"M Scharwey","year":"2013","journal-title":"J Cell Sci"},{"issue":"1","key":"pone.0319721.ref029","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1007\/BF02531272","article-title":"Triton-induced hyperlipidemia in rats as an animal model for screening hypolipidemic drugs","volume":"7","author":"PE Schurr","year":"1972","journal-title":"Lipids"},{"key":"pone.0319721.ref030","volume-title":"Guidance Document on Acute Oral Toxicity Testing. Guidance document on acute oral toxicity testing","author":"OECD Guideline","year":"2001"},{"key":"pone.0319721.ref031","article-title":"Crystal structure of the catalytic portion of human HMG-CoA reductase: insights into regulation of activity and catalysis","author":"ES Istvan","year":"2000","journal-title":"EMBO J"},{"key":"pone.0319721.ref032","unstructured":"AutoDock Vina. Available from: https:\/\/vina.scripps.edu\/. 2010."},{"issue":"2","key":"pone.0319721.ref033","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"O Trott","year":"2010","journal-title":"J Comput Chem"},{"issue":"1","key":"pone.0319721.ref034","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1002\/jcb.25608","article-title":"Natural Inhibitors of HMG-CoA Reductase-An Insilico Approach Through Molecular Docking and Simulation Studies","volume":"118","author":"S Suganya","year":"2017","journal-title":"J Cell Biochem"},{"key":"pone.0319721.ref035","article-title":"Hesperidin interaction with HMG-CoA-reductase enzyme in hypercholesterolemia: a study in silico","author":"A Rizqi","year":"2021","journal-title":"Berkala Kedokteran"},{"key":"pone.0319721.ref036","first-page":"190","article-title":"In-vitro and in-silico determinations of HMG-CoA reductase inhibition potential of caffeic acid for therapeutics of hypercholesterolemia","volume":"12","author":"R Heera","year":"2022","journal-title":"J App Pharm Sci"},{"key":"pone.0319721.ref037","doi-asserted-by":"crossref","first-page":"110301","DOI":"10.1016\/j.biopha.2020.110301","article-title":"Isorhamnetin: A review of pharmacological effects","volume":"128","author":"G Gong","year":"2020","journal-title":"Biomed Pharmacother"},{"issue":"9491","key":"pone.0319721.ref038","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1016\/S0140-6736(05)67402-8","article-title":"The metabolic syndrome--a new worldwide definition","volume":"366","author":"IDF Epidemiology Task Force Consensus Group","year":"2005","journal-title":"Lancet"},{"issue":"1","key":"pone.0319721.ref039","doi-asserted-by":"crossref","DOI":"10.1186\/s41936-018-0065-z","article-title":"Triton WR-1339-induced hyperlipidemia, DNA fragmentation, neurotransmitters inhibition, oxidative damage, histopathological and morphometric changes: the protective role of soybean oil","volume":"79","author":"HM Abdou","year":"2018","journal-title":"JoBAZ"},{"issue":"1","key":"pone.0319721.ref040","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1084\/jem.97.1.117","article-title":"The mechanism responsible for the hypercholesteremia induced by triton WR-1339","volume":"97","author":"M Friedman","year":"1953","journal-title":"J Exp Med"},{"key":"pone.0319721.ref041","doi-asserted-by":"crossref","first-page":"112961","DOI":"10.1016\/j.jep.2020.112961","article-title":"Effect of Phoenix dactylifera seeds (dates) extract in triton WR-1339 and high fat diet induced hyperlipidaemia in rats: A comparison with simvastatin","volume":"259","author":"EDT Bouhlali","year":"2020","journal-title":"J Ethnopharmacol"},{"issue":"1","key":"pone.0319721.ref042","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.fshw.2017.02.002","article-title":"Phenolic extract from Ocimum basilicum restores lipid metabolism in Triton WR-1339-induced hyperlipidemic mice and prevents lipoprotein-rich plasma oxidation","volume":"6","author":"I Touiss","year":"2017","journal-title":"Food Science and Human Wellness"},{"key":"pone.0319721.ref043","first-page":"106","article-title":"Study on antioxidant and hypolipidemic effects of polyphenol-rich extracts from Thymus vulgaris and Lavendula multifida","volume":"1","author":"M Ramchoun","year":"2009","journal-title":"Pharmacognosy Res"},{"issue":"6","key":"pone.0319721.ref044","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1080\/22311866.2022.2162580","article-title":"Hypolipidemic Effect ofThymus munbyanussubsp.ciliatusGreuter & Burdet.: Guinea Pig 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Luo","year":"2015","journal-title":"PLoS One"},{"issue":"2","key":"pone.0319721.ref083","doi-asserted-by":"crossref","first-page":"51","DOI":"10.26444\/jpccr\/136231","article-title":"Hypolipidemic action of Rutin on Triton WR-1339 induced hyperlipidemia in rats","volume":"15","author":"L NR","year":"2021","journal-title":"J Pre Clin Clin Res"},{"issue":"15","key":"pone.0319721.ref084","doi-asserted-by":"crossref","first-page":"12235","DOI":"10.1039\/C5RA16493A","article-title":"Synergistic effect of quercetin and 6-gingerol treatment in streptozotocin induced type 2 diabetic rats and poloxamer P-407 induced hyperlipidemia","volume":"6","author":"Y Shao","year":"2016","journal-title":"RSC Adv"},{"key":"pone.0319721.ref085","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.mce.2015.10.007","article-title":"Ameliorative potential of gingerol: Promising modulation of inflammatory factors and lipid marker enzymes expressions in HFD induced obesity in 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Ezeh","year":"2021","journal-title":"Cureus"},{"issue":"3","key":"pone.0319721.ref089","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0264646","article-title":"Ameliorations in dyslipidemia and atherosclerotic plaque by the inhibition of HMG-CoA reductase and antioxidant potential of phytoconstituents of an aqueous seed extract of Acacia senegal (L.) Willd in rabbits","volume":"17","author":"J Charan","year":"2022","journal-title":"PLoS One"},{"key":"pone.0319721.ref090","unstructured":"Istvan ES, Deisenhofer J. The structure of the catalytic portion of human HMG-CoA reductase. 1997. Available from: www.elsevier.com\/locate\/bba"},{"issue":"9","key":"pone.0319721.ref091","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1161\/CIRCRESAHA.120.316994","article-title":"How Far We Have Come, How Far We Have Yet to Go in Atherosclerosis Research","volume":"126","author":"P Libby","year":"2020","journal-title":"Circ Res"},{"issue":"10","key":"pone.0319721.ref092","doi-asserted-by":"crossref","first-page":"2696","DOI":"10.3390\/biomedicines11102696","article-title":"Peroxisome Proliferator-Activated Receptor \u03b1 in Lipoprotein Metabolism and Atherosclerotic Cardiovascular Disease","volume":"11","author":"EV Fuior","year":"2023","journal-title":"Biomedicines"},{"issue":"1","key":"pone.0319721.ref093","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.biocel.2008.06.010","article-title":"Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases","volume":"41","author":"BB Aggarwal","year":"2009","journal-title":"Int J Biochem Cell Biol"},{"issue":"3","key":"pone.0319721.ref094","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0264646","article-title":"Ameliorations in dyslipidemia and atherosclerotic plaque by the inhibition of HMG-CoA reductase and antioxidant potential of phytoconstituents of an aqueous seed extract of Acacia senegal (L.) Willd in rabbits","volume":"17","author":"J Charan","year":"2022","journal-title":"PLoS One"},{"issue":"8","key":"pone.0319721.ref095","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1158\/1055-9965.EPI-07-2934","article-title":"Pharmacokinetics of 6-gingerol, 8-gingerol, 10-gingerol, and 6-shogaol and conjugate metabolites in healthy human subjects","volume":"17","author":"SM Zick","year":"2008","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"issue":"6","key":"pone.0319721.ref096","doi-asserted-by":"crossref","first-page":"1652","DOI":"10.1039\/D4FB00135D","article-title":"Gingerol: extraction methods, health implications, bioavailability and signaling pathways","volume":"2","author":"MK Samota","year":"2024","journal-title":"Sustainable Food Technol"},{"key":"pone.0319721.ref097","doi-asserted-by":"crossref","unstructured":"Manach C, Williamson G, Morand C, Scalbert A, R\u00e9m\u00e9sy C. Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies 1-3. 2005.","DOI":"10.1093\/ajcn\/81.1.230S"},{"issue":"12","key":"pone.0319721.ref098","doi-asserted-by":"crossref","first-page":"2481","DOI":"10.3390\/nu14122481","article-title":"Hesperidin Bioavailability Is Increased by the Presence of 2S-Diastereoisomer and Micronization-A Randomized, Crossover and Double-Blind Clinical Trial","volume":"14","author":"A Crescenti","year":"2022","journal-title":"Nutrients"},{"issue":"4","key":"pone.0319721.ref099","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1016\/j.bmcl.2004.12.046","article-title":"Molecular docking of the highly hypolipidemic agent alpha-asarone with the catalytic portion of HMG-CoA reductase","volume":"15","author":"JL Medina-Franco","year":"2005","journal-title":"Bioorg Med Chem Lett"},{"key":"pone.0319721.ref100","first-page":"3313","article-title":"Exploration of natural product ingredients as inhibitors of human HMG-CoA reductase through structure-based virtual screening","volume":"9","author":"S-H Lin","year":"2015","journal-title":"Drug Des Devel Ther"},{"issue":"5519","key":"pone.0319721.ref101","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1126\/science.1061020","article-title":"The foot-and-mouth epidemic in Great Britain: pattern of spread and impact of interventions","volume":"292","author":"NM Ferguson","year":"2001","journal-title":"Science"},{"key":"pone.0319721.ref102","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.sajb.2023.02.001","article-title":"Evaluation of anti-HMG-CoA reductase potential and simultaneous determination of phenolic compounds in hydroalcoholic extract of Ficus cunia fruits by RP-HPLC","volume":"155","author":"SK Chaudhary","year":"2023","journal-title":"South African J Botany"},{"key":"pone.0319721.ref103","article-title":"Statins and cardiovascular diseases: from cholesterol lowering to pleiotropy","author":"Q Zhou","year":"2009","journal-title":"Curr Pharm Des"},{"key":"pone.0319721.ref104","unstructured":"Dhivya Jensi V, Ananda Gopu P. Comparative analysis of quercetin and leucocynidin against HMG-CoA reductase and their evaluation of hypolipidemic activity. 2018. https:\/\/doi.org\/10.2174\/1573401314666181228121042"},{"key":"pone.0319721.ref105","doi-asserted-by":"crossref","unstructured":"Liao JK. 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