{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:24:40Z","timestamp":1760145880811,"version":"build-2065373602"},"reference-count":25,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2024,9,3]],"date-time":"2024-09-03T00:00:00Z","timestamp":1725321600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science Kakenhi","doi-asserted-by":"publisher","award":["17KK0122","15K06589","A18-58"],"award-info":[{"award-number":["17KK0122","15K06589","A18-58"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Japan Agency for Medical Research and Development (AMED) for the translational","award":["17KK0122","15K06589","A18-58"],"award-info":[{"award-number":["17KK0122","15K06589","A18-58"]}]},{"name":"clinical research core institutes under the Tsukuba Clinical Research &amp; Development Organization","award":["17KK0122","15K06589","A18-58"],"award-info":[{"award-number":["17KK0122","15K06589","A18-58"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nanomaterials"],"abstract":"<jats:p>Hemozoin (Hz) is a heme crystal produced during malaria infection that stimulates immune cells, leading to the production of cytokines and chemokines. The immunostimulatory action of Hz has previously been applied in the development of alternative adjuvants. Crystallization of hemin is a chemical approach for producing Hz. Here, we focused on an enzymatic production method for Hz using the heme detoxification protein (HDP), which catalyzes heme dimer formation from hemin in Plasmodium. We examined the immunostimulatory effects of an enzymatically synthesized analog of Hz (esHz) produced by recombinant Plasmodium falciparum HDP. Enzymatically synthesized Hz stimulates a macrophage cell line and human peripheral mononuclear cells, leading to the production of interleukin (IL)-6 and IL-12p40. In mice, subcutaneous administration of esHz together with an antigen, ovalbumin (OVA), increased the OVA-specific immunoglobulin (Ig) G2c isotype level in the serum, whereas OVA-specific IgG1 was not induced. Our findings suggest that esHz is a useful Th-1 cell adjuvant.<\/jats:p>","DOI":"10.3390\/nano14171440","type":"journal-article","created":{"date-parts":[[2024,9,3]],"date-time":"2024-09-03T08:38:47Z","timestamp":1725352727000},"page":"1440","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Potential of Enzymatically Synthesized Hemozoin Analog as Th1 Cell Adjuvant"],"prefix":"10.3390","volume":"14","author":[{"given":"Kazuaki","family":"Hoshi","sequence":"first","affiliation":[{"name":"Research Center for Macromolecules and Biomaterials, National Institute for Materials Science (NIMS), Tsukuba 305-0047, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anh Thi Tram","family":"Tu","sequence":"additional","affiliation":[{"name":"Research Center for Macromolecules and Biomaterials, National Institute for Materials Science (NIMS), Tsukuba 305-0047, Japan"},{"name":"Department of Magnetic and Biomedical Materials, Faculty of Materials Science and Technology, University of Science, Ho Chi Minh City 70000, Vietnam"},{"name":"Ho Chi Minh City Campus, Vietnam National University, Ho Chi Minh City 70000, Vietnam"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miwako","family":"Shobo","sequence":"additional","affiliation":[{"name":"Research Center for Macromolecules and Biomaterials, National Institute for Materials Science (NIMS), Tsukuba 305-0047, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karin","family":"Kettisen","sequence":"additional","affiliation":[{"name":"Division of Pure and Applied Biochemistry, Department of Chemistry, Lund University, 22100 Lund, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3646-4072","authenticated-orcid":false,"given":"Lei","family":"Ye","sequence":"additional","affiliation":[{"name":"Division of Pure and Applied Biochemistry, Department of Chemistry, Lund University, 22100 Lund, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4966-8610","authenticated-orcid":false,"given":"Leif","family":"B\u00fclow","sequence":"additional","affiliation":[{"name":"Division of Pure and Applied Biochemistry, Department of Chemistry, Lund University, 22100 Lund, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0138-6692","authenticated-orcid":false,"given":"Yoji","family":"Hakamata","sequence":"additional","affiliation":[{"name":"School of Veterinary Nursing and Technology, Nippon Veterinary and Life Science University, Musashino 180-8602, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3979-7072","authenticated-orcid":false,"given":"Tetsuya","family":"Furuya","sequence":"additional","affiliation":[{"name":"Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu 183-8509, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6795-8377","authenticated-orcid":false,"given":"Ryutaro","family":"Asano","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Life science, Graduate School of Engineering, Tokyo University of Agriculture and Technology, Koganei 184-8588, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6299-5267","authenticated-orcid":false,"given":"Wakako","family":"Tsugawa","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Life science, Graduate School of Engineering, Tokyo University of Agriculture and Technology, Koganei 184-8588, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2838-0562","authenticated-orcid":false,"given":"Kazunori","family":"Ikebukuro","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Life science, Graduate School of Engineering, Tokyo University of Agriculture and Technology, Koganei 184-8588, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9833-2091","authenticated-orcid":false,"given":"Koji","family":"Sode","sequence":"additional","affiliation":[{"name":"Joint Department of Biomedical Engineering, The University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, NC 27599, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2136-8042","authenticated-orcid":false,"given":"Tomohiko","family":"Yamazaki","sequence":"additional","affiliation":[{"name":"Research Center for Macromolecules and Biomaterials, National Institute for Materials Science (NIMS), Tsukuba 305-0047, Japan"},{"name":"Graduate School of Life Science, Hokkaido University, Sapporo 060-0808, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"H1394","DOI":"10.1152\/ajpheart.00584.2011","article-title":"Hemin causes mitochondrial dysfunction in endothelial cells through promoting lipid peroxidation: The protective role of autophagy","volume":"302","author":"Higdon","year":"2012","journal-title":"Am. 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Int."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5208","DOI":"10.4049\/jimmunol.0713552","article-title":"Pure Hemozoin is inflammatory in vivo and activates the NALP3 inflammasome via release of uric acid","volume":"183","author":"Griffith","year":"2009","journal-title":"J. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"10107","DOI":"10.1021\/bi101397u","article-title":"The neutral lipid composition present in the digestive vacuole of Plasmodium falciparum concentrates heme and mediates \u03b2-hematin formation with an unusually low activation energy","volume":"49","author":"Hoang","year":"2010","journal-title":"Biochemistry"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"475","DOI":"10.4049\/jimmunol.174.1.475","article-title":"Hemozoin induces macrophage chemokine expression through oxidative stress-dependent and -independent mechanisms","volume":"174","author":"Jaramillo","year":"2005","journal-title":"J. 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