{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T14:04:27Z","timestamp":1787666667993,"version":"build-2736575974"},"reference-count":48,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,11,13]],"date-time":"2024-11-13T00:00:00Z","timestamp":1731456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Korea Institute of Marine Science &amp; Technology Promotion (KIMST)","award":["RS-2023-00254674"],"award-info":[{"award-number":["RS-2023-00254674"]}]},{"name":"Ministry of Oceans and Fisheries","award":["RS-2023-00254674"],"award-info":[{"award-number":["RS-2023-00254674"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>Haematococcus pluvialis contains valuable bioactive compounds, including astaxanthin, proteins, and fatty acids. Astaxanthin is known for its various health benefits, such as preserving the redox balance and reducing inflammation. However, its low stability and poor water solubility present challenges for various applications. Hot-melt extrusion (HME) technology enhances the aqueous solubility of H. pluvialis extracts, increasing the usable astaxanthin content through nanoencapsulation (HME-DDS-applied extracts, ASX-60F and ASX-100F). This study compared the effects of HME-DDS-derived extracts (ASX-60F and ASX-100F) and the non-applied extract (ASX-C) under inflammatory and oxidative stress conditions. In animal models of sepsis, 60F and 100F treatment exhibited higher survival rates and a lower expression of pro-inflammatory biomarkers compared to those treated with C. In lipopolysaccharide-stimulated RAW 264.7 macrophages, nitric oxide (NO) production and the expression of pro-inflammatory mediators such as cyclooxygenase-2 and inducible NO synthase were reduced by 60F or 100F treatments via ERK\/p-38 mitogen-activated protein kinase (MAPK) signaling. Moreover, 60F or 100F inhibited reactive oxygen species production regulated by nuclear factor erythroid 2-related factor 2 (Nrf2)\/heme oxygenase-1 (HO-1) signaling. Collectively, these findings suggest that HME-DDS-derived H. pluvialis extracts exert anti-inflammatory and antioxidant effects by inhibiting MAPK phosphorylation and activating Nrf2\/HO-1 expression.<\/jats:p>","DOI":"10.3390\/md22110512","type":"journal-article","created":{"date-parts":[[2024,11,13]],"date-time":"2024-11-13T06:10:48Z","timestamp":1731478248000},"page":"512","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Hot-Melt Extrusion Drug Delivery System-Formulated Haematococcus pluvialis Extracts Regulate Inflammation and Oxidative Stress in Lipopolysaccharide-Stimulated Macrophages"],"prefix":"10.3390","volume":"22","author":[{"given":"Tae-Young","family":"Gil","sequence":"first","affiliation":[{"name":"Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ha-Yeon","family":"Sim","sequence":"additional","affiliation":[{"name":"Department of Integrated Drug Development and Natural Products, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ha-Yeon","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Bio-Health Convergence, Kangwon National University, Chuncheon 24341, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suji","family":"Ryu","sequence":"additional","affiliation":[{"name":"Department of Bio-Health Convergence, Kangwon National University, Chuncheon 24341, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0535-345X","authenticated-orcid":false,"given":"Jong-Suep","family":"Baek","sequence":"additional","affiliation":[{"name":"Department of Bio-Health Convergence, Kangwon National University, Chuncheon 24341, Republic of Korea"},{"name":"BeNatureBioLab, Chuncheon 24206, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dae Geun","family":"Kim","sequence":"additional","affiliation":[{"name":"LED Agri-bio Fusion Technology Research Center (LAFTRC), Jeonbuk National University, Jeonbuk 54596, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaehoon","family":"Sim","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2937-874X","authenticated-orcid":false,"given":"Hyo-Jin","family":"An","sequence":"additional","affiliation":[{"name":"Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e661","DOI":"10.1016\/S2214-109X(22)00043-2","article-title":"Neonatal sepsis and mortality in low-income and middle-income countries from a facility-based birth cohort: An international multisite prospective observational study","volume":"10","author":"Milton","year":"2022","journal-title":"Lancet Glob. Health"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Kumar, S., Saxena, J., Srivastava, V.K., Kaushik, S., Singh, H., Abo-El-Sooud, K., Abdel-Daim, M.M., Jyoti, A., and Saluja, R. (2022). The Interplay of Oxidative Stress and ROS Scavenging: Antioxidants as a Therapeutic Potential in Sepsis. Vaccines, 10.","DOI":"10.3390\/vaccines10101575"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1038\/454427a","article-title":"Inflammation","volume":"454","author":"Weiss","year":"2008","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1128\/CMR.00046-08","article-title":"Pathogen recognition and inflammatory signaling in innate immune defenses","volume":"22","author":"Mogensen","year":"2009","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.lfs.2007.04.035","article-title":"Regulation of LPS stimulated ROS production in peritoneal macrophages from alloxan-induced diabetic rats: Involvement of high glucose and PPARgamma","volume":"81","author":"Barreto","year":"2007","journal-title":"Life Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7432797","DOI":"10.1155\/2016\/7432797","article-title":"Oxidative Stress and Inflammation: What Polyphenols Can Do for Us?","volume":"2016","author":"Hussain","year":"2016","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1159\/000485089","article-title":"Antioxidants Maintain Cellular Redox Homeostasis by Elimination of Reactive Oxygen Species","volume":"44","author":"He","year":"2017","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1146\/annurev-pharmtox-011112-140320","article-title":"Role of nrf2 in oxidative stress and toxicity","volume":"53","author":"Ma","year":"2013","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1056\/NEJMoa1114287","article-title":"Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis","volume":"367","author":"Gold","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Fiorelli, S., Porro, B., Cosentino, N., Di Minno, A., Manega, C.M., Fabbiocchi, F., Niccoli, G., Fracassi, F., Barbieri, S., and Marenzi, G. (2019). Activation of Nrf2\/HO-1 Pathway and Human Atherosclerotic Plaque Vulnerability:an In Vitro and In Vivo Study. Cells, 8.","DOI":"10.3390\/cells8040356"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Hirayama, D., Iida, T., and Nakase, H. (2017). The Phagocytic Function of Macrophage-Enforcing Innate Immunity and Tissue Homeostasis. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19010092"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Oslan, S.N.H., Tan, J.S., Oslan, S.N., Matanjun, P., Mokhtar, R.A.M., Shapawi, R., and Huda, N. (2021). Haematococcus pluvialis as a Potential Source of Astaxanthin with Diverse Applications in Industrial Sectors: Current Research and Future Directions. Molecules, 26.","DOI":"10.3390\/molecules26216470"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3849692","DOI":"10.1155\/2019\/3849692","article-title":"Astaxanthin: A Potential Mitochondrial-Targeted Antioxidant Treatment in Diseases and with Aging","volume":"2019","author":"Sztretye","year":"2019","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Kohandel, Z., Farkhondeh, T., Aschner, M., Pourbagher-Shahri, A.M., and Samarghandian, S. (2022). Anti-inflammatory action of astaxanthin and its use in the treatment of various diseases. Biomed. Pharmacother., 145.","DOI":"10.1016\/j.biopha.2021.112179"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2156582","DOI":"10.1155\/2020\/2156582","article-title":"Structures of Astaxanthin and Their Consequences for Therapeutic Application","volume":"2020","author":"Brotosudarmo","year":"2020","journal-title":"Int. J. Food Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.brainres.2008.11.076","article-title":"Astaxanthin inhibits reactive oxygen species-mediated cellular toxicity in dopaminergic SH-SY5Y cells via mitochondria-targeted protective mechanism","volume":"1254","author":"Liu","year":"2009","journal-title":"Brain Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4110","DOI":"10.1021\/acs.biomac.4c00214","article-title":"Solubilization of Hydrophobic Astaxanthin in Water by Physical Association with Phytoglycogen Nanoparticles","volume":"25","author":"Whiting","year":"2024","journal-title":"Biomacromolecules"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Li, Y., Hu, K., Huang, C., Hu, Y., Ji, H., Liu, S., and Gao, J. (2022). Improvement of solubility, stability and antioxidant activity of carotenoids using deep eutectic solvent-based microemulsions. Colloids Surf. B Biointerfaces, 217.","DOI":"10.1016\/j.colsurfb.2022.112591"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1208\/s12249-024-02749-2","article-title":"Hot-Melt Extrusion: From Theory to Application in Pharmaceutical Formulation-Where Are We Now?","volume":"25","author":"Patil","year":"2024","journal-title":"AAPS PharmSciTech"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Zheng, Y., and Pokorski, J.K. (2021). Hot melt extrusion: An emerging manufacturing method for slow and sustained protein delivery. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnology, 13.","DOI":"10.1002\/wnan.1712"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Lee, J., Kim, M.H., and Kim, H. (2022). Anti-Oxidant and Anti-Inflammatory Effects of Astaxanthin on Gastrointestinal Diseases. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232415471"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Go, E.J., Ryu, B.R., Ryu, S.J., Kim, H.B., Lee, H.T., Kwon, J.W., Baek, J.S., and Lim, J.D. (2021). An Enhanced Water Solubility and Stability of Anthocyanins in Mulberry Processed with Hot Melt Extrusion. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222212377"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.ijpharm.2017.10.056","article-title":"Melt extrusion with poorly soluble drugs\u2014An integrated review","volume":"535","author":"Repka","year":"2018","journal-title":"Int. J. Pharm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6281892","DOI":"10.1155\/2022\/6281892","article-title":"Magnoliae flos Downregulated Lipopolysaccharide-Induced Inflammatory Responses via NF-kappaB\/ERK-JNK MAPK\/STAT3 Pathways","volume":"2022","author":"Gil","year":"2022","journal-title":"Mediat. Inflamm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.mcna.2020.02.011","article-title":"Sepsis and Septic Shock\u2014Basics of diagnosis, pathophysiology and clinical decision making","volume":"104","author":"Font","year":"2020","journal-title":"Med. Clin. N. Am."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"976","DOI":"10.7150\/thno.63751","article-title":"Mitochondrial STAT3 exacerbates LPS-induced sepsis by driving CPT1a-mediated fatty acid oxidation","volume":"12","author":"Li","year":"2022","journal-title":"Theranostics"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Hung, Y.L., Fang, S.H., Wang, S.C., Cheng, W.C., Liu, P.L., Su, C.C., Chen, C.S., Huang, M.Y., Hua, K.F., and Shen, K.H. (2017). Corylin protects LPS-induced sepsis and attenuates LPS-induced inflammatory response. Sci. Rep., 7.","DOI":"10.1038\/srep46299"},{"key":"ref_28","first-page":"1884","article-title":"Astaxanthin prevents against lipopolysaccharide-induced acute lung injury and sepsis via inhibiting activation of MAPK\/NF-kappaB","volume":"11","author":"Cai","year":"2019","journal-title":"Am. J. Transl. Res."},{"key":"ref_29","first-page":"3338","article-title":"Astaxanthin suppresses lipopolysaccharide-induced myocardial injury by regulating MAPK and PI3K\/AKT\/mTOR\/GSK3beta signaling","volume":"22","author":"Xie","year":"2020","journal-title":"Mol. Med. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"498","DOI":"10.3109\/08830185.2014.889129","article-title":"The role of the liver in sepsis","volume":"33","author":"Yan","year":"2014","journal-title":"Int. Rev. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"765","DOI":"10.2147\/IJN.S394802","article-title":"An Overview of Drug Delivery Nanosystems for Sepsis-Related Liver Injury Treatment","volume":"18","author":"Lu","year":"2023","journal-title":"Int. J. Nanomed."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.cherd.2020.01.035","article-title":"Influence of compression at elevated temperature on the compactibility of thermo-mechanically processed polymers","volume":"156","author":"Partheniadis","year":"2020","journal-title":"Chem. Eng. Res. Des."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"110159","DOI":"10.1016\/j.intimp.2023.110159","article-title":"Astaxanthin suppresses oxidative stress and calcification in vertebral cartilage endplate via activating Nrf-2\/HO-1 signaling pathway","volume":"119","author":"Yang","year":"2023","journal-title":"Int. Immunopharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.freeradbiomed.2014.03.035","article-title":"Natural forms of vitamin E: Metabolism, antioxidant, and anti-inflammatory activities and their role in disease prevention and therapy","volume":"72","author":"Jiang","year":"2014","journal-title":"Free Radic. Biol. Med."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Li, B., Nasser, M.I., Masood, M., Adlat, S., Huang, Y., Yang, B., Luo, C., and Jiang, N. (2020). Efficiency of Traditional Chinese medicine targeting the Nrf2\/HO-1 signaling pathway. Biomed. Pharmacother., 126.","DOI":"10.1016\/j.biopha.2020.110074"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/j.fct.2012.12.027","article-title":"Induction of HO-1 through p38 MAPK\/Nrf2 signaling pathway by ethanol extract of Inula helenium L. reduces inflammation in LPS-activated RAW 264.7 cells and CLP-induced septic mice","volume":"55","author":"Park","year":"2013","journal-title":"Food Chem. Toxicol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Rostami, S., Alyasin, A., Saedi, M., Nekoonam, S., Khodarahmian, M., Moeini, A., and Amidi, F. (2023). Astaxanthin ameliorates inflammation, oxidative stress, and reproductive outcomes in endometriosis patients undergoing assisted reproduction: A randomized, triple-blind placebo-controlled clinical trial. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1144323"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Chang, M.X., and Xiong, F. (2020). Astaxanthin and its Effects in Inflammatory Responses and Inflammation-Associated Diseases: Recent Advances and Future Directions. Molecules, 25.","DOI":"10.3390\/molecules25225342"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"105479","DOI":"10.1016\/j.phrs.2021.105479","article-title":"Therapeutic uses of natural astaxanthin: An evidence-based review focused on human clinical trials","volume":"166","author":"Donoso","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Yin, Y., Xu, N., Shi, Y., Zhou, B., Sun, D., Ma, B., Xu, Z., Yang, J., and Li, C. (2021). Astaxanthin Protects Dendritic Cells from Lipopolysaccharide-Induced Immune Dysfunction. Mar. Drugs, 19.","DOI":"10.3390\/md19060346"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/j.jss.2015.02.026","article-title":"Protective effect of astaxanthin against multiple organ injury in a rat model of sepsis","volume":"195","author":"Zhou","year":"2015","journal-title":"J. Surg. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2795090","DOI":"10.1155\/2016\/2795090","article-title":"The Reactive Oxygen Species in Macrophage Polarization: Reflecting Its Dual Role in Progression and Treatment of Human Diseases","volume":"2016","author":"Tan","year":"2016","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Jalmi, S.K., and Sinha, A.K. (2015). ROS mediated MAPK signaling in abiotic and biotic stress- striking similarities and differences. Front. Plant Sci., 6.","DOI":"10.3389\/fpls.2015.00769"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2375","DOI":"10.1016\/j.ijbiomac.2022.10.024","article-title":"Lentinan inhibits oxidative stress and alleviates LPS-induced inflammation and apoptosis of BMECs by activating the Nrf2 signaling pathway","volume":"222","author":"Meng","year":"2022","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Kim, J., Lee, H.J., Park, S.K., Park, J.H., Jeong, H.R., Lee, S., Lee, H., Seol, E., and Hoe, H.S. (2021). Donepezil Regulates LPS and Abeta-Stimulated Neuroinflammation through MAPK\/NLRP3 Inflammasome\/STAT3 Signaling. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910637"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.7150\/ijbs.34211","article-title":"Caffeine Inhibits NLRP3 Inflammasome Activation by Suppressing MAPK\/NF-kappaB and A2aR Signaling in LPS-Induced THP-1 Macrophages","volume":"15","author":"Zhao","year":"2019","journal-title":"Int. J. Biol. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Wu, M.F., Huang, Y.H., Chiu, L.Y., Cherng, S.H., Sheu, G.T., and Yang, T.Y. (2022). Curcumin Induces Apoptosis of Chemoresistant Lung Cancer Cells via ROS-Regulated p38 MAPK Phosphorylation. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23158248"},{"key":"ref_48","first-page":"8","article-title":"Two-stage LEDs illuminated plastic bag photobioreactor for production of astaxanthin from Haematococcus pluvialis and manipulated egg yolk pigment by astaxanthin","volume":"6","author":"Hoa","year":"2023","journal-title":"T\u1ea1p Ch\u00ed Khoa H\u1ecdc V\u00e0 C\u00f4ng Ngh\u1ec7"}],"container-title":["Marine Drugs"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-3397\/22\/11\/512\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:31:12Z","timestamp":1760113872000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-3397\/22\/11\/512"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,13]]},"references-count":48,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["md22110512"],"URL":"https:\/\/doi.org\/10.3390\/md22110512","relation":{},"ISSN":["1660-3397"],"issn-type":[{"value":"1660-3397","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,13]]}}}