MDPI AGActa Medica Okayama2076-341715132025Protective Effects of the Ethyl Acetate Fraction of Distylium racemosum Against Metabolic Dysfunction-Associated Steatohepatitis7238ENYoung-HyeonLeeDepartment of Clinical Laboratory Science, Catholic University of PusanMin-HoYeoDepartment of Clinical Laboratory Science, Catholic University of PusanKyung-SooChangDepartment of Clinical Laboratory Science, Catholic University of PusanWeon-JongYoonClean Bio Business Division, Biodiversity Research Institute (JBRI), Jeju Technopark (JTP)Hye-SookKimDepartment of International Infectious Diseases Control, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityJongwanKimDepartment of Anatomy, College of Medicine, Dongguk UniversityHye-RanKimDepartment of Biomedical Laboratory Science, Dong-Eui Institute of TechnologyMetabolic dysfunction-associated steatohepatitis (MASH), previously referred to as non-alcoholic steatohepatitis (NASH), which is a progressive non-alcoholic fatty liver disease, is accompanied by hepatic steatosis, inflammation, and fibrosis. Despite its increasing prevalence, available treatment options for MASH are limited. Here, we investigated the protective effects of the Distylium racemosum ethyl acetate fraction (DRE) using MASH models and explored its key physiologically active components. Palmitic acid (PA)-induced AML12 hepatocytes and high-fat methionine- and choline-deficient-fed C57BL/6 mice were used as MASH models. Lipid accumulation was evaluated via triglyceride measurement, oil red O staining, and histological analysis. Lipid accumulation, inflammation, and fibrosis-associated gene expression were evaluated via real-time polymerase chain reaction. The physiologically active components of DRE were identified via high-performance liquid chromatography. Lipid accumulation and triglyceride levels were significantly reduced in PA-treated AML12 cells following DRE treatment. Additionally, DRE inhibited the expression of genes involved in lipogenesis (FAS and SREBP1c), inflammation (CD68, IL-6, and MCP-1), and fibrosis (COL1A1, COL1A2, and TIMP1). DRE reduced the liver weight, liver-to-body weight ratio, and hepatic steatosis in MASH model mice. It increased carnitine palmitoyltransferase-1 levels and decreased CD36 and transforming growth factor-β levels in the MASH mouse liver. High-performance liquid chromatography revealed that the extract contained rutin flavonoid family members. Overall, DRE was involved in lipid metabolism, inflammation, and fibrosis regulation, exerting potent hepatoprotective effects partly attributed to rutin and serving as a potential preventive candidate for MASH.No potential conflict of interest relevant to this article was reported.Elsevier BVActa Medica Okayama1383-57691062025The antimalarial activity of transdermal N-89 mediated by inhibiting ERC gene expression in P. Berghei-infected mice103026ENHiroakiMatsumoriDivision of International Infectious Diseases Control, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityThi QuyenDinhDivision of International Infectious Diseases Control, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityShin-ichiMiyoshiResearch Center for Intestinal Health Science, Okayama UniversityMasayukiMoritaDepartment of Anatomy, Kawasaki Medical SchoolHye-SookKimDivision of International Infectious Diseases Control, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityThrough studies of new antimalarial drugs, we identified 1,2,6,7-tetraoxaspiro[7.11]nonadecane (N-89) as a potential drug candidate. Here, we analyzed the antimalarial action of a transdermal formulation (td) of N-89, designed for easy use by children, using Plasmodium berghei-infected mice as a model for malaria patients. The td N-89 or artemisinin (ART) formulation was transdermally administered to P. berghei-infected mice with 0.2–0.4 % parasitemia, twice daily for four days, at an effective dose of 90 % for malaria. Parasitemia was decreased in td N-89 and td ART groups during the drug treatment; then, three of the eight mice in td N-89 group were completely cured without relapse. Additionally, abnormal trophozoites in td N-89 group were observed 8 h after administration and increased up to 24 h. To study the change in endoplasmic reticulum-resident calcium-binding protein (ERC) gene expression with td N-89, we investigated the gene expression of P. berghei ERC (PbERC) after td N-89 treatment. PbERC gene expression was increased time-dependently in control group, and was statistically decreased at 4 and 8 h and then increased similar to that of control group at 12 h in td ART group. In contrast, the expression in td N-89 group was almost steady starting from 0 h. We also studied parasite egress-related genes expression after td N-89 treatment, plasmepsin X, subtilisin-like protease 1 and merozoite surface protein 1, were suppressed at 12 h compared to control group. These results suggest that N-89 affects function of endoplasmic reticulum via regulating gene suppression and subsequently parasite growth is inhibited.No potential conflict of interest relevant to this article was reported.Korean Society for ParasitologyActa Medica Okayama2982-51646112023Antimalarial effect of synthetic endoperoxide on synchronized Plasmodium chabaudi infected mice3341ENNagwa S. M.AlyDivision of International Infectious Diseases Control, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityHiroakiMatsumoriDivision of International Infectious Diseases Control, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityThi QuyenDinhDivision of International Infectious Diseases Control, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityAkiraSatoDivision of International Infectious Diseases Control, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityShin-IchiMiyoshiDepartment of Sanitary Microbiology, Faculty of Pharmaceutical Sciences, Okayama UniversityKyung-SooChangDepartment of Clinical Laboratory Science, College of Health Sciences, Catholic University of PusanHak SunYuDepartment of Parasitology and Tropical Medicine, School of Medicine, Pusan National UniversityFumieKobayashiDepartment of Environmental Science, School of Life Environmental Science, Azabu UniversityHye-SookKimDivision of International Infectious Diseases Control, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama UniversityThe discovery of new antimalarial drugs can be developed using asynchronized Plasmodium berghei malaria parasites in vivo in mice. Studies on a particular stage are also required to assess the effectiveness and mode of action of drugs. In this report, we used endoperoxide 6-(1,2,6,7-tetraoxaspiro [7.11] nonadec-4-yl) hexan-1-ol (N-251) as a model antimalarial compound on P. chabaudi parasites. We examined the antimalarial effect of N-251 against ring-stage- and trophozoite-stage-rich P. chabaudi parasites and asynchronized P. berghei parasites using the 4-day suppressive test. The ED50 values were 27, 22, and 22 mg/kg, respectively, and the antimalarial activity of N-251 was verified in both rodent malaria parasites. To assess the stage-specific effect of N-251 in vivo, we evaluated the change of parasitemia and distribution of parasite stages using ring-stage- and trophozoite-stage-rich P. chabaudi parasites with one-day drug administration for one life cycle. We discovered that the parasitemias decreased after 13 and 9 hours post-treatment in the ring-stage- and trophozoite-stage-rich groups, respectively. Additionally, in the ring-stage-rich N-251 treated group, the ring-stage parasites hindered trophozoite parasite development. For the trophozoite-stage-rich N-251 treated group, the distribution of the trophozoite stage was maintained without a change in parasitemia until 9 hours. Because of these findings, it can be concluded that N-251 suppressed the trophozoite stage but not the ring stage. We report for the first time that N-251 specifically suppresses the trophozoite stage using P. chabaudi in mice. The results show that P. chabaudi is a reliable model for the characterization of stage-specific antimalarial effects.No potential conflict of interest relevant to this article was reported.PUBLIC LIBRARY SCIENCEActa Medica Okayama1932-6203882013New Preclinical Antimalarial Drugs Potently Inhibit Hepatitis C Virus Genotype 1b RNA Replicatione72519ENYoukiUedaMidoriTakedaKyokoMoriHiromichiDansakoTakajiWakitaHye-SookKimAkiraSatoYusukeWatayaMasanoriIkedaNobuyukiKatoBACKGROUND:
Persistent hepatitis C virus (HCV) infection causes chronic liver diseases and is a global health problem. Although new triple therapy (pegylated-interferon, ribavirin, and telaprevir/boceprevir) has recently been started and is expected to achieve a sustained virologic response of more than 70% in HCV genotype 1 patients, there are several problems to be resolved, including skin rash/ageusia and advanced anemia. Thus a new type of anti-HCV drug is still needed.
METHODOLOGY/PRINCIPAL FINDINGS:
Recently developed HCV drug assay systems using HCV-RNA-replicating cells (e.g., HuH-7-derived OR6 and Li23-derived ORL8) were used to evaluate the anti-HCV activity of drug candidates. During the course of the evaluation of anti-HCV candidates, we unexpectedly found that two preclinical antimalarial drugs (N-89 and its derivative N-251) showed potent anti-HCV activities at tens of nanomolar concentrations irrespective of the cell lines and HCV strains of genotype 1b. We confirmed that replication of authentic HCV-RNA was inhibited by these drugs. Interestingly, however, this anti-HCV activity did not work for JFH-1 strain of genotype 2a. We demonstrated that HCV-RNA-replicating cells were cured by treatment with only N-89. A comparative time course assay using N-89 and interferon-α demonstrated that N-89-treated ORL8 cells had more rapid anti-HCV kinetics than did interferon-α-treated cells. This anti-HCV activity was largely canceled by vitamin E. In combination with interferon-α and/or ribavirin, N-89 or N-251 exhibited a synergistic inhibitory effect.
CONCLUSIONS/SIGNIFICANCE:
We found that the preclinical antimalarial drugs N-89 and N-251 exhibited very fast and potent anti-HCV activities using cell-based HCV-RNA-replication assay systems. N-89 and N-251 may be useful as a new type of anti-HCV reagents when used singly or in combination with interferon and/or ribavirin.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812732015薬剤耐性マラリアに有望な新規抗マラリア薬開発の現況231235ENHye-SookKimAkaneKatamotoAkiraSatoYusukeWatayaHiroyukiDoiNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama1998ヌクレオシド構造を基本骨格とする新規抗マラリア剤の開発およびその作用機序に関する研究ENNo potential conflict of interest relevant to this article was reported.