{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T17:58:41Z","timestamp":1787680721510,"version":"build-2784847793"},"reference-count":60,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T00:00:00Z","timestamp":1634083200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health","award":["R01CA208396"],"award-info":[{"award-number":["R01CA208396"]}]},{"name":"VA Merit Award","award":["I01 BX004065-1"],"award-info":[{"award-number":["I01 BX004065-1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Dietary change leads to a precipitous increase in non-alcoholic fatty liver disease (NAFLD) from simple steatosis to the advanced form of non-alcoholic steatohepatitis (NASH), affecting approximately 25% of the global population. Although significant efforts greatly advance progress in clarifying the pathogenesis of NAFLD and identifying therapeutic targets, no therapeutic agent has been approved. Astaxanthin (ASTN), a natural antioxidant product, exerts an anti-inflammation and anti-fibrotic effect in mice induced with carbon tetrachloride (CCl4) and bile duct ligation (BDL); thus, we proposed to further investigate the potential effect of ASTN on a diet-induced mouse NASH and liver fibrosis, as well as the underlying cellular and molecular mechanisms. By treating pre-development of NASH in mice induced with a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD), we have demonstrated that oral administration ASTN preventively ameliorated NASH development and liver fibrosis by modulating the hepatic immune response, liver inflammation, and oxidative stress. Specifically, ASTN treatment led to the reduction in liver infiltration of monocyte-derived macrophages, hepatic stellate cell (HSC) activation, oxidative stress response, and hepatocyte death, accompanied by the decreased hepatic gene expression of proinflammatory cytokines such as TNF-\u03b1, TGF-\u03b21, and IL-1\u03b2. In vitro studies also demonstrated that ASTN significantly inhibited the expression of proinflammatory cytokines and chemokine CCL2 in macrophages in response to lipopolysaccharide (LPS) stimulation. Overall, in vivo and in vitro studies suggest that ASTN functions as a promising therapeutic agent to suppress NASH and liver fibrosis via modulating intrahepatic immunity.<\/jats:p>","DOI":"10.3390\/ijms222011037","type":"journal-article","created":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T21:36:15Z","timestamp":1634160975000},"page":"11037","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Astaxanthin Prevents Diet-Induced NASH Progression by Shaping Intrahepatic Immunity"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4895-5864","authenticated-orcid":false,"given":"Ming","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Surgery, University of Missouri, Columbia, MO 65212, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric T.","family":"Kimchi","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Missouri, Columbia, MO 65212, USA"},{"name":"Harry S. Truman Memorial VA Hospital, Columbia, MO 65201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin F.","family":"Staveley-O\u2019Carroll","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Missouri, Columbia, MO 65212, USA"},{"name":"Harry S. Truman Memorial VA Hospital, Columbia, MO 65201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangfu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Missouri, Columbia, MO 65212, USA"},{"name":"Harry S. Truman Memorial VA Hospital, Columbia, MO 65201, USA"},{"name":"Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO 65212, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/j.jhep.2018.10.033","article-title":"Non-alcoholic fatty liver disease\u2014A global public health perspective","volume":"70","author":"Younossi","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.cld.2015.10.011","article-title":"Histology of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis in Adults and Children","volume":"20","author":"Kleiner","year":"2016","journal-title":"Clin. Liver Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/hep.28431","article-title":"Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes","volume":"64","author":"Younossi","year":"2016","journal-title":"Hepatology"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Akahane, T., Akahane, M., Namisaki, T., Kaji, K., Moriya, K., Kawaratani, H., Takaya, H., Sawada, Y., Shimozato, N., and Fujinaga, Y. (2020). Association between Non-Alcoholic Fatty Liver Disease and Chronic Kidney Disease: A Cross-Sectional Study. J. Clin. Med., 9.","DOI":"10.3390\/jcm9061635"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e24557","DOI":"10.1097\/MD.0000000000024557","article-title":"Association of non-alcoholic fatty liver disease and all-cause mortality in hospitalized cardiovascular disease patients: A systematic review and meta-analysis","volume":"100","author":"Saokaew","year":"2021","journal-title":"Medicine (Baltimore)"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Simon, T.G., Roelstraete, B., Hartjes, K., Shah, U., Khalili, H., Arnell, H., and Ludvigsson, J.F. (2021). Non-alcoholic fatty liver disease in children and young adults is associated with increased long-term mortality. J. Hepatol.","DOI":"10.1016\/j.jhep.2021.06.034"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Zhang, C., and Yang, M. (2021). The Emerging Factors and Treatment Options for NAFLD-Related Hepatocellular Carcinoma. Cancers, 13.","DOI":"10.3390\/cancers13153740"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Zhang, C., and Yang, M. (2021). Current Options and Future Directions for NAFLD and NASH Treatment. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22147571"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Arroyave-Ospina, J.C., Wu, Z., Geng, Y., and Moshage, H. (2021). Role of Oxidative Stress in the Pathogenesis of Non-Alcoholic Fatty Liver Disease: Implications for Prevention and Therapy. Antioxidants, 10.","DOI":"10.3390\/antiox10020174"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1093\/oxfordjournals.pcp.a078171","article-title":"Astaxanthin Accumulation in the Green Alga Haematococcus pluvialis1","volume":"32","author":"Boussiba","year":"1991","journal-title":"Plant Cell Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3487","DOI":"10.3390\/md12063487","article-title":"Chlorella zofingiensis as an alternative microalgal producer of astaxanthin: Biology and industrial potential","volume":"12","author":"Liu","year":"2014","journal-title":"Mar. Drugs"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Barredo, J.L., Garc\u00eda-Estrada, C., Kosalkova, K., and Barreiro, C. (2017). Biosynthesis of Astaxanthin as a Main Carotenoid in the Heterobasidiomycetous Yeast Xanthophyllomyces dendrorhous. J. Fungi, 3.","DOI":"10.3390\/jof3030044"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Brasil, F.B., de Almeida, F.J.S., Luckachaki, M.D., Dall\u2019Oglio, E.L., and de Oliveira, M.R. (2021). Astaxanthin prevents mitochondrial impairment in the dopaminergic SH-SY5Y cell line exposed to glutamate-mediated excitotoxicity: Role for the Nrf2\/HO-1\/CO-BR axis. Eur. J. Pharmacol., 908.","DOI":"10.1016\/j.ejphar.2021.174336"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1507\/endocrj.EJ17-0500","article-title":"Protective effects of astaxanthin on a combination of D-galactose and jet lag-induced aging model in mice","volume":"65","author":"Ni","year":"2018","journal-title":"Endocr. J."},{"key":"ref_15","unstructured":"Badak, B., Aykanat, N.E.B., Kacar, S., Sahinturk, V., Arik, D., and Canaz, F. (2021). Effects of astaxanthin on metastasis suppressors in ductal carcinoma. A preliminary study. Ann. Ital. Chir., 10."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Davinelli, S., Nielsen, M.E., and Scapagnini, G. (2018). Astaxanthin in Skin Health, Repair, and Disease: A Comprehensive Review. Nutrients, 10.","DOI":"10.3390\/nu10040522"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.4103\/1673-5374.300460","article-title":"Astaxanthin alleviates pathological brain aging through the upregulation of hippocampal synaptic proteins","volume":"16","author":"Liu","year":"2021","journal-title":"Neural Regen. Res."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Li, Y., Wang, Q., Chu, C., and Liu, S. (2020). Astaxanthin protects retinal ganglion cells from acute glaucoma via the Nrf2\/HO-1 pathway. J. Chem. Neuroanat., 110.","DOI":"10.1016\/j.jchemneu.2020.101876"},{"key":"ref_19","first-page":"4099","article-title":"The cardioprotective effect of astaxanthin against isoprenaline-induced myocardial injury in rats: Involvement of TLR4\/NF-\u03baB signaling pathway","volume":"25","author":"Zaafan","year":"2021","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_20","first-page":"1884","article-title":"Astaxanthin prevents against lipopolysaccharide-induced acute lung injury and sepsis via inhibiting activation of MAPK\/NF-\u03baB","volume":"11","author":"Cai","year":"2019","journal-title":"Am. J. Transl. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6679","DOI":"10.1038\/s41598-021-86146-w","article-title":"Astaxanthin protects against early acute kidney injury in severely burned rats by inactivating the TLR4\/MyD88\/NF-\u03baB axis and upregulating heme oxygenase-1","volume":"11","author":"Guo","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.intimp.2018.01.011","article-title":"Astaxanthin ameliorates cerulein-induced acute pancreatitis in mice","volume":"56","author":"Zhang","year":"2018","journal-title":"Int. Immunopharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Shen, M., Chen, K., Lu, J., Cheng, P., Xu, L., Dai, W., Wang, F., He, L., Zhang, Y., and Chengfen, W. (2014). Protective effect of astaxanthin on liver fibrosis through modulation of TGF-\u03b21 expression and autophagy. Mediat. Inflamm., 2014.","DOI":"10.1155\/2014\/954502"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1002\/jcsm.12530","article-title":"Astaxanthin stimulates mitochondrial biogenesis in insulin resistant muscle via activation of AMPK pathway","volume":"11","author":"Nishida","year":"2020","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"21833","DOI":"10.3390\/ijms141121833","article-title":"Rodent models of nonalcoholic fatty liver disease\/nonalcoholic steatohepatitis","volume":"14","author":"Imajo","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1111\/iep.12008","article-title":"An improved mouse model that rapidly develops fibrosis in non-alcoholic steatohepatitis","volume":"94","author":"Matsumoto","year":"2013","journal-title":"Int. J. Exp. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1111\/iep.12240","article-title":"Hepatocellular carcinoma in a mouse model fed a choline-deficient, L-amino acid-defined, high-fat diet","volume":"98","author":"Matsuo","year":"2017","journal-title":"Int. J. Exp. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1159\/000501851","article-title":"Rodent Models of Nonalcoholic Fatty Liver Disease","volume":"101","author":"Zhong","year":"2020","journal-title":"Digestion"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1038\/s41591-018-0104-9","article-title":"Mechanisms of NAFLD development and therapeutic strategies","volume":"24","author":"Friedman","year":"2018","journal-title":"Nat. Med."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Mederacke, I., Hsu, C.C., Troeger, J.S., Huebener, P., Mu, X., Dapito, D.H., Pradere, J.P., and Schwabe, R.F. (2013). Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat. Commun., 4.","DOI":"10.1038\/ncomms3823"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"9448","DOI":"10.1073\/pnas.1201840109","article-title":"Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis","volume":"109","author":"Kisseleva","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/s41575-019-0210-2","article-title":"Adaptive immunity: An emerging player in the progression of NAFLD","volume":"17","author":"Sutti","year":"2020","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Ore, A., and Akinloye, O.A. (2019). Oxidative Stress and Antioxidant Biomarkers in Clinical and Experimental Models of Non-Alcoholic Fatty Liver Disease. Medicina (Kaunas), 55.","DOI":"10.3390\/medicina55020026"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/s41575-019-0145-7","article-title":"From NASH to HCC: Current concepts and future challenges","volume":"16","author":"Anstee","year":"2019","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1016\/j.lfs.2006.09.041","article-title":"Astaxanthin ameliorates features of metabolic syndrome in SHR\/NDmcr-cp","volume":"80","author":"Hussein","year":"2007","journal-title":"Life Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1507\/endocrj.EJ20-0699","article-title":"Anti-diabetic effects of astaxanthin on an STZ-induced diabetic model in rats","volume":"68","author":"Zhuge","year":"2021","journal-title":"Endocr. J."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Ni, Y., Nagashimada, M., Zhuge, F., Zhan, L., Nagata, N., Tsutsui, A., Nakanuma, Y., Kaneko, S., and Ota, T. (2015). Astaxanthin prevents and reverses diet-induced insulin resistance and steatohepatitis in mice: A comparison with vitamin E. Sci. Rep., 5.","DOI":"10.1038\/srep17192"},{"key":"ref_38","first-page":"341","article-title":"Astaxanthin improves glucose metabolism and reduces blood pressure in patients with type 2 diabetes mellitus","volume":"27","author":"Mashhadi","year":"2018","journal-title":"Asia Pac. J. Clin. Nutr."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"9252","DOI":"10.1039\/D0FO01223H","article-title":"Inflammation response after the cessation of chronic arsenic exposure and post-treatment of natural astaxanthin in liver: Potential role of cytokine-mediated cell-cell interactions","volume":"11","author":"Zhang","year":"2020","journal-title":"Food Funct."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/S1016-8478(23)13772-1","article-title":"Astaxanthin inhibits nitric oxide production and inflammatory gene expression by suppressing I(kappa)B kinase-dependent NF-kappaB activation","volume":"16","author":"Lee","year":"2003","journal-title":"Mol. Cells"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1136\/gutjnl-2011-300304","article-title":"Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury","volume":"61","author":"Baeck","year":"2012","journal-title":"Gut"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Li, J., Xia, Y., Liu, T., Wang, J., Dai, W., Wang, F., Zheng, Y., Chen, K., Li, S., and Abudumijiti, H. (2015). Protective effects of astaxanthin on ConA-induced autoimmune hepatitis by the JNK\/p-JNK pathway-mediated inhibition of autophagy and apoptosis. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0120440"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3760","DOI":"10.1111\/bph.15099","article-title":"Astaxanthin attenuates hepatic damage and mitochondrial dysfunction in non-alcoholic fatty liver disease by up-regulating the FGF21\/PGC-1\u03b1 pathway","volume":"177","author":"Wu","year":"2020","journal-title":"Br. J. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Daemen, S., Chan, M.M., and Schilling, J.D. (2021). Comprehensive analysis of liver macrophage composition by flow cytometry and immunofluorescence in murine NASH. STAR Protoc., 2.","DOI":"10.1016\/j.xpro.2021.100511"},{"key":"ref_45","first-page":"106","article-title":"Differential Sensitivity of Kupffer Cells and Hepatic Monocyte-Derived Macrophages to Bacterial Lipopolysaccharide","volume":"1","author":"Roth","year":"2019","journal-title":"Clin. Exp. Gastroenterol. Hepatol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/978-981-15-7360-6_21","article-title":"Prevention of NAFLD\/NASH by Astaxanthin and \u03b2-Cryptoxanthin","volume":"1261","author":"Ota","year":"2021","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1038\/s41586-021-03233-8","article-title":"Auto-aggressive CXCR6(+) CD8 T cells cause liver immune pathology in NASH","volume":"592","author":"Dudek","year":"2021","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/s41586-021-03362-0","article-title":"NASH limits anti-tumour surveillance in immunotherapy-treated HCC","volume":"592","author":"Pfister","year":"2021","journal-title":"Nature"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1002\/hep.31755","article-title":"Microbiota-Driven Activation of Intrahepatic B Cells Aggravates NASH through Innate and Adaptive Signaling","volume":"74","author":"Barrow","year":"2021","journal-title":"Hepatology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2277","DOI":"10.1002\/hep.31889","article-title":"The Emerging Role of B Cells in the Pathogenesis of NAFLD","volume":"74","author":"Barrow","year":"2021","journal-title":"Hepatology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1016\/S0002-9440(10)63522-5","article-title":"Role of fibroblast growth factor type 1 and 2 in carbon tetrachloride-induced hepatic injury and fibrogenesis","volume":"163","author":"Yu","year":"2003","journal-title":"Am. J. Pathol."},{"key":"ref_52","first-page":"166","article-title":"Expression of basic fibroblast growth factor in rat liver fibrosis and hepatic stellate cells","volume":"25","author":"Peng","year":"2005","journal-title":"J. Huazhong Univ. Sci. Technol. Med. Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/BF01213308","article-title":"Plasma level of basic fibroblast growth factor increases with progression of chronic liver disease","volume":"32","author":"Tanimizu","year":"1997","journal-title":"J. Gastroenterol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1002\/ijc.26003","article-title":"Fibroblast growth factor-2 enhances NK sensitivity of hepatocellular carcinoma cells","volume":"130","author":"Tsunematsu","year":"2012","journal-title":"Int. J. Cancer"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"104247","DOI":"10.18632\/oncotarget.22200","article-title":"Metformin reverses bFGF-induced epithelial-mesenchymal transition in HCC cells","volume":"8","author":"Chengye","year":"2017","journal-title":"Oncotarget"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Dewidar, B., Meyer, C., Dooley, S., and Meindl-Beinker, A.N. (2019). TGF-\u03b2 in Hepatic Stellate Cell Activation and Liver Fibrogenesis-Updated 2019. Cells, 8.","DOI":"10.3390\/cells8111419"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Gao, Y., Yang, L., Chin, Y., Liu, F., Li, R.W., Yuan, S., Xue, C., Xu, J., and Tang, Q. (2020). Astaxanthin n-Octanoic Acid Diester Ameliorates Insulin Resistance and Modulates Gut Microbiota in High-Fat and High-Sucrose Diet-Fed Mice. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21062149"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Zhu, Y., Gu, Z., Liao, Y., Li, S., Xue, Y., Adu Firempong, M., Xu, Y., Yu, J., Smyth, H.D.C., and Xu, X. (2021). Improved intestinal absorption and oral bioavailability of astaxanthin via poly (ethylene glycol)-graft-chitosan nanoparticle: Preparation, in vitro evaluation and pharmacokinetics in rats. J. Sci. Food Agric.","DOI":"10.1002\/jsfa.11435"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Ponto, T., Latter, G., Luna, G., Leite-Silva, V.R., Wright, A., and Benson, H.A.E. (2021). Novel Self-Nano-Emulsifying Drug Delivery Systems Containing Astaxanthin for Topical Skin Delivery. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13050649"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e001038","DOI":"10.1136\/jitc-2020-001038","article-title":"Synergizing sunitinib and radiofrequency ablation to treat hepatocellular cancer by triggering the antitumor immune response","volume":"8","author":"Qi","year":"2020","journal-title":"J. Immunother. Cancer"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/20\/11037\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:12:35Z","timestamp":1760166755000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/20\/11037"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,13]]},"references-count":60,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["ijms222011037"],"URL":"https:\/\/doi.org\/10.3390\/ijms222011037","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,13]]}}}