Updated on 2022/09/30

写真a

 
HATABU Toshimitsu
 
Organization
Faculty of Environmental and Life Science Associate Professor
Position
Associate Professor
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Degree

  • 農学博士 ( 東京大学 )

  • 農学博士 ( 東京大学 )

  • 農学博士 ( 東京大学 )

Research Interests

  • 細胞生物学

  • 分子疫学

  • 免疫学

  • 寄生虫学

  • 動物生理学

Research Areas

  • Life Science / Animal physiological chemistry, physiology and behavioral biology

  • Life Science / Laboratory animal science

  • Life Science / Parasitology

  • Life Science / Animal life science  / 病態生理学

Education

  • The University of Tokyo   農学生命科学研究科   応用動物科学専攻

    - 1999

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    Country: Japan

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  • The University of Tokyo    

    - 1999

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  • Okayama University   農学部   総合農業科学

    - 1994

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    Country: Japan

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  • Okayama University    

    - 1994

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Research History

  • Okayama University   The Graduate School of Environmental and Life Science   Associate Professor

    2012.3

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  • Gunma University   School of Health Sciences Department of Laboratory Science, Faculty of Medicine   Assistant Professor

    2005.4 - 2012.3

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  • -: - 群馬大学医学部内講師

    2003

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  • -: - 群馬大学医学部助手

    2002.4 - 2005.3

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  • : 国立国際医療センター研究所 流動研究員

    1999 - 2002

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Professional Memberships

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Papers

  • Differential effects of orally administered Lactobacillus acidophilus L-55 on the gene expression of cytokines and master immune switches in the ileum and spleen of laying hen with an attenuated Newcastle disease virus vaccine

    Hung Hoang Son PHAM, Yusuke FUJII, Kensuke ARAKAWA, Toshimitsu HATABU

    Bioscience of Microbiota, Food and Health   41 ( 1 )   12 - 19   2022.1

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    Authorship:Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:BMFH Press  

    This study aimed to evaluate the benefits of oral administration of Lactobacillus acidophilus strain L-55 (LaL-55) to chickens inoculated with a Newcastle disease virus (NDV)-based live-attenuated vaccine by examining the mRNA expression of several genes related to viral infection in the spleen and ileum by quantitative reverse transcription polymerase chain reaction. In the spleen, interferon (IFN)-α was significantly higher in the low- and middle-dose LaL-55 groups at 6 weeks than at 4 weeks. IFN regulatory factor (IRF)-3 and IRF-7 expression was significantly higher in the low-dose LaL-55 group than in the middle- and high-dose LaL-55 groups. In the ileum, melanoma differentiation-associated gene 5 showed a dose-dependent increase at 4 weeks. IFN-γ and IRF-7 showed dose-dependent increases at 6 weeks. These results suggested that LaL-55 boosts the immune response to the NDV vaccine, albeit by different mechanisms in the spleen and ileum.

    DOI: 10.12938/bmfh.2021-026

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  • Reduction of macrophages by carrageenan decreases oocyst output and modifies local immune reaction in chick cecum with Eimeria tenella International journal

    Dung Thi Ho, Hung Hoang Son Pham, Wataru Aota, Makoto Matsubayashi, Naotoshi Tsuji, Toshimitsu Hatabu

    RESEARCH IN VETERINARY SCIENCE   139   59 - 66   2021.10

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:ELSEVIER SCI LTD  

    This study aimed to evaluate the disease severity and local immune responses in macrophage-depleted chicks with Eimeria tenella. Macrophages were reduced by intraperitoneal injection of a carrageenan solution at 12, 13, and 16 days old, whereas the control group received intraperitoneal phosphate-buffered saline. Both chick groups were orally inoculated with E. tenella sporulated oocysts at 14 days old. Feces were collected daily, which were then quantified for oocysts. The chicks were sacrificed on day 5, and the ceca were collected for histopathological observation. The gene expression levels were measured using real-time quantitative reverse transcription-polymerase chain reaction. Macrophage-depleted chicks have been observed to shed a significantly reduced number of fecal oocysts compared to the infected control group. The parasite burden score in cecum specimens of macrophage-depleted chicks was significantly lower than those of infected control on day 5 after infection. Furthermore, macrophage reduction yielded significantly lower cecum histopathological scores and CD4 expression than those of the infected control group. The expression of interleukin (IL)-18, IL-22, interferon-γ, and inducible nitric oxide synthase was also noted to be significantly upregulated in both infected control and macrophage-depleted chicks compared to uninfected chicks. IL-4, IL-13, IL-17, and perforin expressions were also higher with macrophage depletion than in both control groups. These results suggest that macrophages serve as an invasive gate or a transporting vehicle to the site of first merogony. Furthermore, mononuclear phagocytes may play an important role in local immune responses, thus contributing to parasite development during early E. tenella infection.

    DOI: 10.1016/j.rvsc.2021.07.003

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  • Relationship between Eimeria tenella associated-early clinical signs and molecular changes in the intestinal barrier function International journal

    Hung Hoang Son Pham, Makoto Matsubayashi, Naotoshi Tsuji, Toshimitsu Hatabu

    VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY   240   110321 - 110321   2021.10

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:ELSEVIER  

    The major clinical signs of coccidiosis in chickens due to Eimeria parasite are diarrhea and bloody feces. Previous studies showed that the impairment of the intestinal epithelial barrier and the elevation of the intestinal permeability are causes of clinical signs associated with coccidia challenges. Nevertheless, the information about molecular changes of the epithelial barrier at the early stage of the infection with a specific Eimeria species has not been mentioned. Hence, this study aims to elucidate the temporal relationships between epithelial barrier conditions and clinical signs in chickens infected with Eimeria tenella over the time from the earliest stages of infection. White Leghorn chickens were inoculated with 1 × 104 oocysts of E. tenella. Thereafter the chickens were monitored for their daily clinical signs through observation, and between 5 dpi to 10 dpi, feces were collected for oocysts counting. Chickens were then administrated with fluorescein isothiocyanate-dextran (FITC-d) for gastrointestinal permeability test and tissues were collected each day for histopathological observation and total RNA extraction. Finally, the mRNA expression levels of the tight and adherens junction genes and cytokine genes were evaluated using the quantitative real-time polymerase chain reaction (qRT-PCR). In this study, clinical signs such as diarrhea and bloody feces were observed concurrently from 3 to 8 dpi. Histopathology changes such as severe inflammation, hemorrhage, and epithelial desquamation were identified in the cecum specimens. The FITC-d level in the E. tenella-infected group was significantly higher than in the control group. In the infected group, the expression of claudin-2 gene was also upregulated, whereas the expressions of claudin-3 and E-cadherin genes were decreased as compared to the control group. These results implied that clinical signs of avian coccidiosis were associated with the intestinal barrier disruption via changes in expression levels of claudins and E-cadherin at the intestine.

    DOI: 10.1016/j.vetimm.2021.110321

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  • Involvement of cancer-derived EMT cells in the accumulation of F-18-fluorodeoxyglucose in the hypoxic cancer microenvironment International journal

    Sachi Sugita, Masanori Yamato, Toshimitsu Hatabu, Yosky Kataoka

    SCIENTIFIC REPORTS   11 ( 1 )   9668 - 9668   2021.5

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:NATURE RESEARCH  

    A high rate of glycolysis, one of the most common features of cancer, is used in positron emission tomography (PET) imaging to visualize tumor tissues using 18F-fluorodeoxyglucose (18F-FDG). Heterogeneous intratumoral distribution of 18F-FDG in tissues has been established in some types of cancer, and the maximum standardized uptake value (SUVmax) has been correlated with poor prognosis. However, the phenotype of cells that show high 18F-FDG accumulation in tumors remains unknown. Here, we combined quantitative micro-autoradiography with fluorescence immunohistochemistry to simultaneously visualize 18F-FDG distribution, the expression of multiple proteins, and hypoxic regions in the cancer microenvironment of a human A431 xenograft tumor in C.B-17/Icr-scid/scid mice. We found that the highest 18F-FDG accumulation was in cancer-derived cells undergoing epithelial-mesenchymal transition (EMT) in hypoxic regions, implicating these regions as a major contributor to increased glucose metabolism, as measured by 18F-FDG-PET.

    DOI: 10.1038/s41598-021-88414-1

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  • Alteration of chemokine production in bovine endometrial epithelial and stromal cells under heat stress conditions International journal

    Shunsuke Sakai, Toshimitsu Hatabu, Yuki Yamamoto, Koji Kimura

    PHYSIOLOGICAL REPORTS   8 ( 22 )   e14640   2020.11

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:WILEY  

    After parturition, cows frequently develop uterine bacterial infections, resulting in the onset of endometritis. To eliminate the bacteria, bovine endometrial cells secrete chemokines, such as IL-6 and MCP1, which attract macrophages (MΦs) to the subepithelial stroma. These attracted MΦs are not only involved in bacterial elimination but also the orchestration of inflammation and tissue repair. These immune responses aid in the recovery from endometritis; however, the recovery from endometritis takes longer in summer than in any other season. Based on these findings, we hypothesized that heat stress (HS) affects the chemokine production in endometrial cells. To confirm this hypothesis, we compared IL-6 and MCP1 production induced by lipopolysaccharide (LPS) in bovine endometrial epithelial and stromal cells under normal (38.5°C) and HS conditions (40.5°C). In the endometrial epithelial cells, IL-6 production stimulated by LPS was significantly (p < .05) suppressed under HS conditions. MCP1 production in endometrial epithelial cells was not detected under both the control and HS conditions regardless of the presence of LPS. Moreover, LPS significantly (p < .05) stimulated IL-6 and MCP1 production in endometrial stromal cells. Moreover, HS significantly (p < .05) enhanced their production compared to that under the control conditions. In addition, HS did not affect the migration ability of MΦs; however, the supernatant of the endometrial stromal cells cultured under the HS condition significantly (p < .05) attracted the MΦs when compared to the control condition. These results suggest that HS disrupts chemokine production in two types of endometrial cells and alters the distribution of MΦs in the endometrium during the summer.

    DOI: 10.14814/phy2.14640

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  • Morphological and molecular identification of Eimeria spp. in breeding chicken farms of Japan Reviewed

    Makoto Matsubayashi, Tomoyuki Shibahara, Tomohide Matsuo, Toshimitsu Hatabu, Junya Yamagishi, Kazumi Sasai, Takashi Isobe

    JOURNAL OF VETERINARY MEDICAL SCIENCE   82 ( 5 )   516 - 519   2020.5

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:JAPAN SOC VET SCI  

    There have been no reports of the prevalence of Eimeria spp. in poultry breeding farms in Japan unlike those of broiler farms. From 2017 to 2018, we examined the prevalence of Eimeria spp. on breeding farms in Japan by oocyst morphology and PCR analyses. A total of 143 samples was collected from 37 breeding farms in 21 prefectures of Japan. We detected oocysts of seven species at 34 of 37 breeding farms by PCR, and we identified E. brunetti at 51.5% of farms found to be positive for Eimeria. The differences in the identification of Eimeria spp. between the morphology and PCR assay methods of oocysts were pronounced for E. maxima and E. necatrix. We confirmed that molecular tools were more suitable for accurately estimating prevalence of Eimeria spp., and these findings suggest that E. brunetti could be widespread in Japan.

    DOI: 10.1292/jvms.19-0661

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  • Apoptosis inhibition mitigates aging effects in Drosophila melanogaster Reviewed International journal

    Hiroaki Kidera, Toshimitsu Hatabu, Kazuo H. Takahashi

    GENETICA   148 ( 2 )   69 - 76   2020.4

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    Aging is a natural biological process that results in progressive loss of cell, tissue, and organ function. One of the causing factors of the aging process is the decrease in muscle mass, which has not been fully verified in Drosophila. Apoptotic cell death may result in aberrant cell loss and can eventually diminish tissue function and muscle atrophy. If so, inhibition of apoptosis may prolong longevity and reduce motor function and muscle mass decline with age in Drosophila flies. Here, we used Drosophila melanogaster as study material, and induced the overexpression of Drosophila inhibitor of apoptosis protein 1 gene to inhibit apoptosis, and investigated the effect of apoptosis inhibition on the longevity and age-related declines in flight and climbing ability and muscle mass. As a result, the inhibition of apoptosis tended to mitigate the aging effects and prolonged longevity and reduced climbing ability decline with age. The current study suggests that apoptosis inhibition could mitigate the aging effects in D. melanogaster. Although such effects have already been known in mammals, the current results suggest that the apoptosis may play a similar role in insects as well.

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    Other Link: http://link.springer.com/article/10.1007/s10709-020-00088-1/fulltext.html

  • Daily Meal Supplemented with Astaxanthin-Enriched Yolk Has Mitigative Effects against Hypertension in Spontaneously Hypertensive Rats Reviewed

    Toshimitsu Hatabu, Takumi Harada, Yuri Takao, Dung Ho Thi, Akihiro Yamasato, Tatsuya Horiuchi, Atsuya Mochizuki, Yasuhiro Kondo

    BIOLOGICAL & PHARMACEUTICAL BULLETIN   43 ( 3 )   404 - 408   2020.3

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    The aim of this study was to investigate the effects of egg yolk powder enriched with astaxanthin (ASX-E) on blood pressure in spontaneously hypertensive rats (SHR) and to verify the benefits of ASX-E as a functional food. To investigate the antihypertensive effect, SHR were fed with an ASX-E mixed diet before hypertension development. Blood pressures were determined periodically during the study by the tail-cuff method. At the end of the study, animals were euthanized, and their thoracic aortas were collected to determine vascular conductance. The thoracic aorta tension was measured with a force displacement transducer. Concentration-dependent response relationships were determined by cumulative addition of 10-9-10-4 M Carbamoylcholine (Cch). Blood pressures of the SHR in the ASX-E mixed diet group were ASX-dose-dependently lower than that of those in the control group. In SHR fed with an ASX-E mixed diet, Cch induced vasorelaxation in the thoracic aorta with endothelium lining but not without endothelium. However, the antihypertensive effect of ASX-E was not observed on blood pressures in SHR that were fed with ASX-E only after the development of hypertension. Results suggest that ASX-E protects endothelial function and thereby prevents the development of hypertension. Hence, the results of our research indicate that daily consumption of ASX-E has a potential benefit on human health.

    DOI: 10.1248/bpb.b19-01013

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  • Oral administration of the probiotic bacterium Lactobacillus acidophilus strain L-55 modulates the immunological parameters of the laying hen inoculated with a Newcastle disease virus-based live attenuated vaccine Reviewed

    Dung Thi Ho, Toshimitsu Hatabu, Yosuke Sunada, Yasuhiro Kondo

    BIOSCIENCE OF MICROBIOTA FOOD AND HEALTH   39 ( 3 )   117 - 122   2020

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    Probiotic supplements containing living bacteria have attracted interest as a potential source of health benefits for humans and livestock. The aim of this study was to determine whether administration of Lactobacillus acidophilus strain L-55 (LaL-55) enhances the immune response among chicks exposed to a Newcastle disease virus (NDV)-based live attenuated vaccine. Oral administration of LaL-55 augmented the elevation in the total numbers of leukocytes and lymphocytes following inoculation with the NDV-based live attenuated vaccine. Monocyte counts increased after LaL-55 administration independent of inoculation with the NDV vaccine. Among chicks that were administered LaL-55, there was a dose-dependent increase in the NK cell activity measured by a 51Cr release assay at 2 weeks after the secondary NDV vaccine inoculation. Two weeks after the secondary inoculation with the NDV vaccine, interferon (IFN)-γ-mRNA expression was significantly elevated in mononuclear splenocytes from chicks that were administered LaL-55. Meanwhile, LaL-55 administration did not change the mRNA levels of IFN-α, IFN-β, and interleukin-1β. These results may suggest that coadministration of LaL-55 with an NDV vaccine augments the immune response against the virus. Therefore, LaL-55 may help protect against viral diseases in poultry.

    DOI: 10.12938/bmfh.2019-033

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  • Transitions in morphological forms and rapid development of the asexual schizonts of Eimeria tenella through serial passaging in chicks Reviewed International journal

    Makoto Matsubayashi, Hiroki Yamaguchi, Takeshi Hatta, Fumiya Kawahara, Toshimitsu Hatabu, Hiroshi Iseki, Junya Yamagishi, Takashi Isobe, Isao Teramoto, Akira Kaneko, Kiyoshi Kita, Naotoshi Tsuji, Kazumi Sasai

    INFECTION GENETICS AND EVOLUTION   75   103993 - 103993   2019.11

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    Attenuated strains of avian Eimeria parasites, generated by the selection of precocious lines through serial passaging in chicks, have been used widely as live vaccines. Detailed morphological transitions including their life cycle depending on the passages remain poorly understood. Here, we showed early development and acceleration of transitions in morphological forms of the asexual schizonts of E. tenella that had been attenuated for virulence by serial passaging. Our results may be helpful in understanding parasitism, facilitating further molecular analyses such as comparative genomic or transcriptomic tests.

    DOI: 10.1016/j.meegid.2019.103993

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  • Mulberry juice freeze-dried powder attenuates the disease severity by the maintaining of colon mucosa in mice with DSS-induced acute colitis Reviewed International journal

    Yang Wang, Toshimitsu Hatabu

    BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY   83 ( 5 )   914 - 922   2019.5

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:TAYLOR & FRANCIS LTD  

    This study aimed to evaluate the microbial compositions and gene expression related to inflammation in dextran sodium sulfate (DSS)-induced acute colitis and the effect of mulberry supplementation. Male BALB/c mice received a diet supplemented with mulberry juice freeze-dried powder (MFP) or not for 3 weeks. After 3 weeks, the mice received water containing 5% (w/v) DSS or not for 1 week. The disease activity index score in mice fed MFP was significantly decreased. A significant decrease in Bifidobacterium spp. and the Clostridium perfringens subgroup was observed in mice not fed MFP. The number of goblet cell and NLRP6 expression were observed in mice fed a diet supplemented with MFP compared with mice not fed MFP. These results may indicate that mulberry mitigates DSS-induced acute colitis by a changing the gut microbial flora and by improving mucosal conditions.

    DOI: 10.1080/09168451.2019.1580135

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  • 鶏コクシジウム症 アイメリア・テネラ感染メカニズムの解明に向けて Invited

    畑生 俊光

    岡山実験動物研究会報   34 ( 34 )   17 - 20   2018.4

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  • Antiplasmodial properties of kaempferol-3-O-rhamnoside isolated from the leaves of Schima wallichii against chloroquine-resistant Plasmodium falciparum. Reviewed International journal

    Melisa I Barliana, Eka W Suradji, Rizky Abdulah, Ajeng Diantini, Toshimitsu Hatabu, Junko Nakajima-Shimada, Anas Subarnas, Hiroshi Koyama

    Biomedical reports   2 ( 4 )   579 - 583   2014.7

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    Previous intervention studies have shown that the most effective agents used in the treatment of malaria were isolated from natural sources. Plants consumed by non-human primates serve as potential drug sources for human disease management due to the similarities in anatomy, physiology and disease characteristics. The present study investigated the antiplasmodial properties of the primate-consumed plant, Schima wallichii (S. wallichii) Korth. (family Theaceae), which has already been reported to have several biological activities. The ethanol extract of S. wallichii was fractionated based on polarity using n-hexane, ethyl acetate and water. The antiplasmodial activity was tested in vitro against chloroquine-resistant Plasmodium falciparum (P. falciparum) at 100 μg/ml for 72 h. The major compound of the most active ethyl acetate fraction was subsequently isolated using column chromatography and identified by nuclear magnetic resonance. The characterized compound was also tested against chloroquine-resistant P. falciparum in culture to evaluate its antiplasmodial activity. The ethanol extract of S. wallichii at 100 μg/ml exhibited a significant parasite shrinkage after 24 h of treatment. The ethyl acetate fraction at 100 μg/ml was the most active fraction against chloroquine-resistant P. falciparum. Based on the structural characterization, the major compound isolated from the ethyl acetate fraction was kaempferol-3-O-rhamnoside, which showed promising antiplasmodial activity against chloroquine-resistant P. falciparum with an IC50 of 106 μM after 24 h of treatment. The present study has provided a basis for the further investigation of kaempferol-3-O-rhamnoside as an active compound for potential antimalarial therapeutics.

    DOI: 10.3892/br.2014.271

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  • Changes in estrogen receptor expression in the chick thymus during late embryonic development Reviewed International journal

    Masafumi Katayama, Tomokazu Fukuda, Toshimitsu Hatabu, Kiyoaki Narabara, Asaki Abe, Yasuhiro Kondo

    ANIMAL SCIENCE JOURNAL   85 ( 3 )   277 - 285   2014.3

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    In chickens, although estrogen receptors (ER) are reported to be associated with the immunological processes, detailed information about the differences in ER expression in the tissues related to the development of lymphocytes is not fully known, especially during the developmental stage. To learn more about this immunological relationship, we used semi-quantitative polymerase chain reaction method to detect the ER expression levels in the thymus tissues of chicks during the developmental stage. Furthermore, ER-expressing cells were detected by immunohistochemistry. The results of this study show that the expression level of ER increased on embryonic day 16 and decreased on day 20. Furthermore, ER expression was significantly higher in male than in female chickens at day 16. The increased expression on day 16 and decreased level on day 20 were also reproduced in the incidence of immunoreactive cells, although there was a 1-day delay in the elevated incidence of the cells. This study revealed the changes in ER expression and the incidence of ER-positive cells in the thymus of chickens during the developmental stage.

    DOI: 10.1111/asj.12114

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  • Antiplasmodial prperties of kaempferol-3-O-rhamnoside isolated from leaves of Schima wallichii against chloroquine-resistant Plasmodium falciparum. Reviewed

    HATABU Toshimitsu

    2   579 - 583   2014

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  • Approach to epidemiological mechanism of infection or colonization of egg-laying chicken farms by Salmonella enterica Serovar enteritidis (SE) becoming the main source of contamination in food poisoning. Reviewed

    HATABU Toshimitsu

    5   376 - 392   2014

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  • Derivatives of Dictyostelium discoideum differentiation-inducing factor-3 suppress the activities of Trypanosoma cruzi in vitro and in vivo Reviewed International journal

    Junko Nakajima-Shimada, Toshimitsu Hatabu, Yukari Hosoi, Yoko Onizuka, Haruhisa Kikuchi, Yoshitern Oshima, Yuzuru Kubohara

    BIOCHEMICAL PHARMACOLOGY   85 ( 11 )   1603 - 1610   2013.6

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:PERGAMON-ELSEVIER SCIENCE LTD  

    Chagas disease (human American trypanosomiasis), which is caused by the protozoan parasite Trypanosoma cruzi, is responsible for numerous deaths each year; however, established treatments for the disease are limited. Differentiation-inducing factor-1 (DIF-1) and DIF-3 are chlorinated alkylphenones originally found in the cellular slime mold Dictyostelium discoideum that have been shown to possess pharmacological activities. Here, we investigated the effects of DIF-3 derivatives on the infection rate and growth of T. cruzi by using an in vitro assay system utilizing host human fibrosarcoma HT1080 cells. Certain DIF-3 derivatives, such as butoxy-DIF-3 (Bu-DIF-3), at micro-molar levels strongly suppressed both the infection rate and growth of T. cruzi in HT1080 cells and exhibited little toxicity for HT1080 cells. For example, the IC50 of DIF-3 and Bu-DIF-3 versus the growth of T. cruzi in HT1080 cells were 3.95 and 0.72μM, respectively, and the LD50 of the two compounds versus HT1080 cells were both greater than 100μM. We also examined the effects of DIF-3 and Bu-DIF-3 on T. cruzi activity in C57BL/6 mice. Intraperitoneally administered Bu-DIF-3 (50mg/kg) significantly suppressed the number of trypomastigotes in blood with no apparent adverse effects. These results strongly suggest that DIF-3 derivatives could be new lead compounds in the development of anti-trypanosomiasis drugs.

    DOI: 10.1016/j.bcp.2013.03.007

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  • Selenium-induced apoptosis-like cell death in Plasmodium falciparum Reviewed International journal

    Eka W. Suradji, Toshimitsu Hatabu, Kenji Kobayashi, Chiho Yamazaki, Rizky Abdulah, Minato Nakazawa, Junko Nakajima-Shimada, Hiroshi Koyama

    PARASITOLOGY   138 ( 14 )   1852 - 1862   2011.12

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:CAMBRIDGE UNIV PRESS  

    Plasmodium falciparum has for some time been developing resistance against known anti-malarial drugs, and therefore a new drug is urgently needed. Selenium (Se), an essential trace element, in the form of inorganic Se, selenite (SeO32-), has been reported to have an anti-plasmodial effect, but its mechanism is still unclear. In the present study, we evaluated the anti-plasmodial effect of several Se compounds against P. falciparum in vitro. The anti-plasmodial effect of several Se compounds was analysed and their apoptosis-inducing activity was evaluated by morphological observation, DNA fragmentation assay and mitochondrial function analysis. SeO32-, methylseleninic acid, selenomethionine and selenocystine have anti-plasmodial effects with 50% inhibition concentration at 9, 10, 45, and 65 μm, respectively, while selenate and methylselenocysteine up to 100 μm have no effect on parasite growth. The effective Se compounds caused the parasites to become shrunken and pyknotic and significantly increased mitochondrial damage against P. falciparum compared to the untreated control. In conclusion, SeO32-, methylseleninic acid, selenomethionine and selenocystine have anti-plasmodial activities that induce apoptosis-like cell death in P. falciparum, and the anti-plasmodial effects of Se seem to be based on its chemical forms. The apoptosis-like cell-death mechanism in P. falciparum can be beneficial to respond to the growing problem of drug resistance.

    DOI: 10.1017/S0031182011001399

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  • The Role of VAMP7/TI-VAMP in Cell Polarity and Lysosomal Exocytosis in vivo Reviewed International journal

    Mahito Sato, Shinichiro Yoshimura, Rika Hirai, Ayako Goto, Masataka Kunii, Nur Atik, Takashi Sato, Ken Sato, Reiko Harada, Junko Shimada, Toshimitsu Hatabu, Hiroshi Yorifuji, Akihiro Harada

    TRAFFIC   12 ( 10 )   1383 - 1393   2011.10

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    VAMP7 or tetanus neurotoxin-insensitive vesicle- associated membrane protein (TI-VAMP) has been proposed to regulate apical transport in polarized epithelial cells, axonal transport in neurons and lysosomal exocytosis. To investigate the function of VAMP7 in vivo, we generated VAMP7 knockout mice. Here, we show that VAMP7 knockout mice are indistinguishable from control mice and display a similar localization of apical proteins in the kidney and small intestine and a similar localization of axonal proteins in the nervous system. Neurite outgrowth of cultured mutant hippocampal neurons was reduced in mutant neurons. However, lysosomal exocytosis was not affected in mutant fibroblasts. Our results show that VAMP7 is required in neurons to extend axons to the full extent. However, VAMP7 does not seem to be required for epithelial cell polarity and lysosomal exocytosis.

    DOI: 10.1111/j.1600-0854.2011.01247.x

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  • EFFICACY OF MEFLOQUINE TREATMENT AND GENETIC PROFILES IN UNCOMPLICATED PLASMODIUM FALCIPARUM MALARIA IN SOUTHERN LAO PDR Reviewed International journal

    Hiromu Toma, Toshimitsu Hatabu, Viengxay Vanisaveth, M. Kaiissar Mannoor, Hisami Watanabe, Changchun Li, Jun Kobayashi, Samlane Phompida, Shigeyuki Kano, Yoshiya Sato

    SOUTHEAST ASIAN JOURNAL OF TROPICAL MEDICINE AND PUBLIC HEALTH   42 ( 4 )   759 - 763   2011.7

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    We conducted a 28-day follow-up of 17 Laotian patients diagnosed with uncomplicated Plasmodium falciparum malaria treated with mefloquine (Mephaquine, MQ) alone to determine the efficacy. All patients were completely cured with MQ, without reappearance of asexual stage parasitemia at follow-up. Of the 7 isolates tested for genotypic analysis, one isolate was a Y86 mutant type of the pfmdr1 gene, the others were N86 wild. These findings suggest no MQ resistance in the study area possibly because the drug is rarely used in southern Lao PDR.

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  • Association of molecular markers in Plasmodium falciparum crt and mdr1 with in vitro chloroquine resistance: A Philippine study International journal

    Toshimitsu Hatabu, Moritoshi Iwagami, Shin-ichiro Kawazu, Nao Taguchi, Aleyla D. Escueta, Elena A. Villacorte, Pilarita T. Rivera, Shigeyuki Kano

    PARASITOLOGY INTERNATIONAL   58 ( 2 )   166 - 170   2009.6

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    Specific mutations in the pfcrt and pfmdr1 genes have been reported to be associated with chloroquine-resistant falciparum malaria parasites worldwide. These genetic markers are considered to be useful tools for the elucidation of several aspects of the epidemiology of drug resistant malaria. In this study, Plasmodium falciparum isolates from three distinct areas of the Philippines were analyzed for drug-resistance-associated genetic mutations, and their association with the in vitro chloroquine (CQ) response. Two novel pfcrt 72-76 allelic types, CVMDT and SVMDT, were detected. The frequency of the pfcrt K76T mutation in the isolates that were successfully tested for in vitro CQ susceptibility was found to be 100% in Kalinga, 80% in Palawan, and 87% in Mindanao. The frequency of the pfmdr1 N86Y mutation was 39% in Kalinga, 35% in Palawan, and 93% in Mindanao isolates. No mutations were found at positions 1042 and 1246 of pfmdr1. However, there were no significant associations found between polymorphisms in these genes and in vitro CQ susceptibility. The results of this study indicate that mutations in pfcrt and pfmdr1 are not predictive of in vitro CQ resistance in Philippine isolates and may therefore not be suitable as molecular markers for surveillance.

    DOI: 10.1016/j.parint.2009.01.010

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  • Genetic diversity and population structure of Plasmodium falciparum in the Philippines. International journal

    Moritoshi Iwagami, Pilarita T Rivera, Elena A Villacorte, Aleyla D Escueta, Toshimitsu Hatabu, Shin-ichiro Kawazu, Toshiyuki Hayakawa, Kazuyuki Tanabe, Shigeyuki Kano

    Malaria journal   8   96 - 96   2009.5

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    BACKGROUND: In the Philippines, malaria morbidity and mortality have decreased since the 1990s by effective malaria control. Several epidemiological surveys have been performed in the country, but the characteristics of the Plasmodium falciparum populations are not yet fully understood. In this study, the genetic structure of P. falciparum populations in the Philippines was examined. METHODS: Population genetic analyses based on polymorphisms of 10 microsatellite loci of the parasite were conducted on 92 isolates from three provinces (Kalinga, Palawan, and Davao del Norte) with different malaria endemicity. RESULTS: The levels of genetic diversity and the effective population sizes of P. falciparum in the Philippines were similar to those reported in the mainland of Southeast Asia or South America. In the low malaria transmission area (Kalinga), there was a low level of genetic diversity and a strong linkage disequilibrium (LD) when the single-clone haplotype (SCH) was used in the multilocus LD analysis, while in the high malaria transmission areas (Palawan and Davao del Norte), there was a high level of genetic diversity and a weak LD when SCH was used in the multilocus LD analysis. On the other hand, when the unique haplotypes were used in the multilocus LD analysis, no significant LD was observed in the Kalinga and the Palawan populations. The Kalinga and the Palawan populations were, therefore, estimated to have an epidemic population structure. The three populations were moderately differentiated from each other. CONCLUSION: In each area, the level of genetic diversity correlates with the local malaria endemicity. These findings confirm that population genetic analyses using microsatellite loci are a useful tool for evaluating malaria endemicity.

    DOI: 10.1186/1475-2875-8-96

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  • マラリア原虫Plasmodium falciparumに対する無機セレン化合物の抗マラリア活性についての検討(Inorganic selenium parasiticidal effect on human malaria parasite Plasmodium falciparum in vitro) Reviewed

    スラジ・エカ, 畑生 俊光, 小林 健司, アブドゥラ・リズキー, 中澤 港, 嶋田 淳子, 小山 洋

    Biomedical Research on Trace Elements   19 ( 2 )   214 - 214   2008.6

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  • Phylogenetic relationship of Plasmodium falciparum populations in the Philippines. Reviewed International journal

    Moritoshi Iwagami, Toshimitsu Hatabu, Shin-Ichiro Kawazu, Aleyla S Escueta, Elena A Villacorte, Pilarita Tongol-Rivera, Shigeyuki Kano

    The Southeast Asian journal of tropical medicine and public health   39 ( 2 )   200 - 4   2008.3

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    Malaria is one of the major infectious diseases in the Philippines. It is being targeted for control through sustained early diagnosis, treatment and mosquito control. It is in this light that understanding the genetic background of the parasite population is important not only for basic biology of the organism but also for epidemiology and control of the disease. In the present study, molecular phylogenetic relationships of the 3 Plasmodium falciparum populations in the Philippines with the other populations in the world were inferred based on polymorphisms of 9 highly polymorphic microsatellite DNA loci in the parasite genome. A total of 92 P. falciparum isolates collected from 3 provinces (Kalinga, Palawan and Davao del Norte) in the Philippines, and 8 from other populations (3 African, 2 South American, 2 Papua New Guinean, and 1 Thai) that were previously reported, were used for the analysis. The phylogenetic tree showed that the 3 Philippine populations were genetically divergent from each other as compared to the other populations. The branching pattern of the tree suggests that the 3 Philippine populations were relatively close to the Thai population, rather than the Papua New Guinean populations, indicating that the ancestor of the 3 Philippines populations were introduced from Indochina peninsula, and not from countries located south of the Philippines such as Papua New Guinea or Indonesia.

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  • Plasmodium falciparum: the fungal metabolite gliotoxin inhibits proteasome proteolytic activity and exerts a plasmodicidal effect on P. falciparum. International journal

    Toshimitsu Hatabu, Masaki Hagiwara, Nao Taguchi, Masayuki Kiyozawa, Mamoru Suzuki, Shigeyuki Kano, Kumiko Sato

    Experimental parasitology   112 ( 3 )   179 - 83   2006.3

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    The in vitro antimalarial activity of the fungal metabolite gliotoxin (GTX) was evaluated, and its mechanism of action was studied. GTX showed plasmodicidal activity against both Plasmodium falciparum chloroquine-resistant strain K-1 and chloroquine-susceptible strain FCR-3. GTX cytotoxicity was significantly lower against a normal liver cell line (Chang Liver cells). The intracellular reduced glutathione level of parasitized and of normal red blood cells was not affected by GTX treatment. However, GTX decreased the chymotrypsin-like activity of parasite proteasomes in a time-dependent manner. The results of this study indicate that GTX possesses plasmodicidal activity and that this effect is due to inhibition of parasite proteasome activity, suggesting that GTX may constitute a useful antimalarial therapy.

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  • Pyrimethamine-sulfadoxine treatment of uncomplicated Plasmodium falciparum malaria in Lao PDR. International journal

    M Kaiissar Mannoor, Viengxay Vanisaveth, Boualy Keokhamphavanh, Hiromu Toma, Hisami Watanabe, Jun Kobayashi, Toshimitsu Hatabu, Nao Taguchi, Bousy Hongvangthong, Rattanaxay Phetsouvanh, Samlane Phompida, Shigeyuki Kano, Yoshiya Sato

    The Southeast Asian journal of tropical medicine and public health   36 ( 5 )   1092 - 5   2005.9

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    A 28-day in vivo treatment trial to evaluate the efficacy of pyrimethamine/sulfadoxine (Fansidar, PS) was conducted in 21 Lao patients with uncomplicated Plasmodium falciparum malaria. Sixteen patients (76%) were completely cured with PS without any reappearance of asexual stage parasitemia during the follow-up examination. On the other hand, 5 patients (24%) failed to respond to this trial medication, resulting in recrudescence of asexual stage P. falciparum malaria. PS resistance resulted in higher prevalence of post-treatment gametocytemia, 25% gametocyte carriers among PS sensitive cases versus 75% of the resistant cases. These findings suggest that although the level of PS resistance is still valid for treatment of malaria in the study area of Lao PDR, post-treatment induction of gametocytemia among resistant cases may result an increase in transmission rate of PS resistant falciparum malaria.

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  • Potent plasmodicidal activity of a heat-induced reformulation of deoxycholate-amphotericin B (Fungizone) against Plasmodium falciparum. International journal

    Toshimitsu Hatabu, Tsuyoshi Takada, Nao Taguchi, Mamoru Suzuki, Kumiko Sato, Shigeyuki Kano

    Antimicrobial agents and chemotherapy   49 ( 2 )   493 - 6   2005.2

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    The emergence and spread of drug-resistant Plasmodium falciparum continue to pose problems in malaria chemotherapy. Therefore, it is necessary to identify new antimalarial drugs and therapeutic strategies. In the present study, the activity of a heat-treated form of amphotericin B (HT-AMB) against P. falciparum was evaluated. The efficacy and toxicity of HT-AMB were also compared with those of the standard formulation (AMB). HT-AMB showed significant activity against a chloroquine-resistant strain (strain K-1) and a chloroquine-susceptible strain (strain FCR-3) in vitro. The 50% inhibitory concentrations of HT-AMB were 0.32 +/- 0.03 mug/ml for strain K-1 and 0.33 +/- 0.03 mug/ml for strain FCR-3. In the presence of 1.0 mug of HT-AMB per ml, only pyknotic parasites were observed after 24 h of incubation of early trophozoites (ring forms). However, when late trophozoites and schizonts were cultured with 1.0 mug of HT-AMB per ml, those forms multiplied to ring forms but the number of infected erythrocytes did not increase. These results indicate that HT-AMB possesses potent antiplasmodial activity and that the drug is more effective against the ring-form stage than against the late trophozoite and schizont stages. HT-AMB was observed to have little cytotoxic effect against a human liver cell line (Chang liver cells). In conclusion, the results suggest that HT-AMB has promising properties and merits further in vivo investigations as a treatment for falciparum malaria.

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  • A pilot field survey on the in vitro drug susceptibility of Plasmudium falciparum in Lao PDR. Tropical Medicine and Health. Reviewed

    Hatabu T, Vanisaveth V, Taguchi N, Kobayashi J, Mannor KM, Watanabe H, Toma H, Phompida S, Kano S

    Trop. Med. Health   33   103 - 104   2005

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  • In vitro susceptibility and genetic variations for chloroquine and mefloquine in Plasmodium falciparum isolates from Thai-Myanmar border. International journal

    Toshimitsu Hatabu, Shin-ichiro Kawazu, Somei Kojima, Kumiko Sato, Pratap Singhasivanon, Sornchai Looareesuwan, Shigeyuki Kano

    The Southeast Asian journal of tropical medicine and public health   36 Suppl 4   73 - 9   2005

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    In vitro drug susceptibility to chloroquine (CQ) and mefloquine (MF) were assessed in 39 P. falciparum isolates from the Thai-Myanmar border area. To further characterize CQ- and MF-resistance profiles in this area, we also analyzed pfcrt K76T mutation that is critical for CQ resistance, and pfmdr1 polymorphism that has an association with MF resistance. Eighteen isolates were successfully examined by in vitro tests for CQ, and 17 of them had resistance to the drug. Geometric mean concentration of CQ that inhibited the growth of parasites at 50% (IC50) was 371 +/- 227 nM (105-971 nM). Sixteen isolates were successfully examined by in vitro tests for MF, and 8 of them were resistant to the drug. Geometric mean of IC50 for MF was 41 +/- 31 nM (4-125 nM). Genotypes of drug resistance, such as pfcrt and pfmdr1 mutations, were also analyzed. All the 39 isolates had the same haplotype (CVIET) for PfCRT at its 72-76th amino acids. A pfmdr1 Y86 mutation was found in 95% of isolates. A pfmdr1 D1042 mutation was also present in 7 isolates, while no pfmdr1 Y1246 mutation was observed. These results indicated a correlation between CQ resistance and the pfcrt T76 and pfmdr1 Y86 mutations.

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  • Binding of Plasmodium falciparum-infected erythrocytes to the membrane-bound form of Fractalkine/CX3CL1. International journal

    Toshimitsu Hatabu, Shin-Ichiro Kawazu, Masamichi Aikawa, Shigeyuki Kano

    Proceedings of the National Academy of Sciences of the United States of America   100 ( 26 )   15942 - 6   2003.12

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    Plasmodium falciparum-infected erythrocytes (pRBCs) adhere to the endothelium via receptors expressed on the surface of vascular endothelial cells (EC) and sequester in the microvasculature of several organs and block the blood circulation. The sequestration, which involves receptors, may be related to the severity of malaria. Here, we report that pRBCs bind to the membrane-bound form of Fractalkine/CX3CL1 (FKN), which is expressed on the surface of vascular EC in various organs. pRBCs adhered to FKN on the surface of FKN cDNA-transfected Chinese hamster ovary cells (CHO-FKN cells). Both the recombinant human FKN-chemokine domain (FKN-CD) and anti-FKN-CD antibody efficiently blocked adherence of pRBCs to CHO-FKN cells. Similar to binding between FKN and FKN receptor on blood mononuclear cells, two amino acid residues, Lys-7 and Arg-47 within FKN-CD, were critical for FKN-pRBC binding. Immunohistological analysis revealed the expression of FKN on EC at the site of sequestration in the brain of a patient with cerebral malaria. These results suggest that the membrane-bound form of FKN acts as a receptor for pRBCs, and this may contribute to furthering our present understanding of cytoadherence in the pathology of falciparum malaria.

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  • In vitro susceptibility of Plasmodium falciparum isolates to chloroquine and mefloquine in southeastern Mindanao Island, the Philippines. International journal

    Toshimitsu Hatabu, Shin-ichiro Kawazu, Jun Suzuki, Reuben F Valenzuela, Elena A Villacorte, Mamoru Suzuki, Pilarita T Rivera, Shigeyuki Kano

    The Southeast Asian journal of tropical medicine and public health   34 ( 3 )   546 - 51   2003.9

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    Although the presence of multi-drug-resistant falciparum malaria has been reported in the Philippines, the distribution of drug-resistant malaria parasites has not yet been determined in Mindanao Island. In vitro susceptibility of P. falciparum to both chloroquine and mefloquine was assessed to forecast the spread of drug-resistant parasites in various foci in southeastern Mindanao Island. Of the 33 isolates of P. falciparum successfully tested, 10 (30%) were susceptible, 12 (36%) showed decreased susceptibility (80 nM < or = IC50 < 114 nM), and 11 (33%) were resistant (IC50 > or = 114 nM) to chloroquine. Ten (91%) of the resistant isolates and 9 (75%) of those with decreased susceptibility were from northern and northwestern Davao del Norte Province. Chloroquine-susceptible isolates were found among patients in the eastern parts of Davao del Norte and Davao Oriental provinces. Seven isolates from several foci in the study area were all mefloquine- susceptible (IC50 < 10 nM). This is the first report indicating the potential emergence of chloroquine-resistant P. falciparum on Mindanao Island, which is presently regarded as a drug-susceptible area.

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  • [An imported case of falciparum malaria successfully treated with Artemether-Lumefantrine in Japan].

    Azumi Ishizaki, Yoshiki Kikuchi, Toshimitsu Hatabu, Shigeyuki Kano, Akira Yasuoka, Shinichi Oka

    Kansenshogaku zasshi. The Journal of the Japanese Association for Infectious Diseases   77 ( 1 )   34 - 7   2003.1

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    Spread of multi-drug resistant malaria in the endemic areas has made malaria control more difficult. Thus, WHO recommends combination therapy for the treatment of malaria. The aim of combination therapy is to improve efficacy and to reduce the incidence of resistance development to the each component of the combination. Particularly, the combination with artemisinin derivatives shows good outcome in Thailand where high resistance for mefloquine has already been found. We report the first case of falciparum malaria, successfully treated with Artemether-Lumefantrine in Japan. Artemether-Lumefantrine is a newly developed artemisinin-based combination agent for the treatment of uncomplicated multi-drug resistant malaria. This drug has proved highly effective and well tolerated by some clinical trials abroad. This Japanese female case showed a good clinical course without any side effect.

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  • [Severe falciparum malaria with prolonged hemolytic anemia after successful treatment with intravenous artesunate].

    Ichiro Itoda, Takeshi Yasunami, Ken Kikuchi, Hisashi Yamaura, Kyoichi Totsuka, Kentaro Yoshinaga, Masanao Teramura, Hideaki Mizoguchi, Toshimitsu Hatabu, Shigeyuki Kano

    Kansenshogaku zasshi. The Journal of the Japanese Association for Infectious Diseases   76 ( 8 )   600 - 3   2002.8

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    We report a 68-year-old woman with severe falciparum malaria contracted in Tanzania. She presented high parasitemia and was treated successfully with intravenous artesunate, a qinghaosu derivative, and aggressive supportive therapy. She developed hemolytic anemia and jaundice on day 11 and blood transfusion was required. This case illustrates that intravenous artesunate has excellent antimalarial activity with rapid efficacy and that no severe adverse effect but conventional aggressive supportive therapy is still important in the treatment of severe falciparum malaria.

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  • The expression system of biologically active canine interleukin-8 in Leishmania promastigotes. International journal

    Toshimitsu Hatabu, Yasunobu Matsumoto, Shin-ichiro Kawazu, Yuko Nakamura, Tsugihiko Kamio, Hong Gang Lu, Kwang-Poo Chang, Yoshihisa Hashiguchi, Shigeyuki Kano, Takashi Onodera, Yoshitsugu Matsumoto

    Parasitology international   51 ( 1 )   63 - 71   2002.3

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    It has been reported that Leishmania promastigotes have ability to express foreign genes on drug selectable plasmids. To investigate further abilities of the recently described expression vector, P6.5, in the transfection of Leishmania organisms (Chen D-Q, Kolli BK, Yadava N et al. Episomal expression of specific sense and antisense mRNAs in Leishmania amazonensis: modulation of gp63 levels in promastigotes and their infection of macrophages in vitro. Infect Immun 2000;68:80--86), the constructed expression vector, which contains canine interleukin-8 (cIL-8) coding cDNA, was introduced by electroporation to promastigotes of four species of the genus Leishmania: Leishmania amazonensis, L. equatorensis, L. donovani and L. infantum. Extrachromosomal DNAs and total RNAs from the transfected promastigotes were subjected to polymerase chain reaction (PCR) and reverse transcriptase-PCR, respectively, using cIL-8 gene specific primers, and a predicted product of 330 bp was detected. Western blot analysis using a mouse monoclonal antibody raised against cIL-8 demonstrated the successful expression of cIL-8 in the transfectants and culture supernatants. Culture supernatants of the transfected L. amazonensis and L. equatorensis promastigotes showed a high chemotactic activity to both dog and mouse polymorphonuclear leukocytes. These results indicate that Leishmania promastigotes transfected with the expression vector P6.5 containing cIL-8 cDNA are capable of producing biologically active cIL-8. The Leishmania expression system using the P6.5 vector might be a useful alternative for the production of biologically active recombinant cytokines.

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  • PCR-amplification, sequencing, and comparison of the var/PfEMP-1 gene from the blood of patients with falciparum malaria in the Philippines. International journal

    Nozomu Ikenoue, Shin-ichiro Kawazu, Toshimitsu Hatabu, Elena A Villacorte, Pilarita T Rivera, Shigeyuki Kano

    The Southeast Asian journal of tropical medicine and public health   33 Suppl 3   8 - 13   2002

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    The adhesion of Plasmodium falciparum-infected erythrocytes to vascular endothelium and to uninfected red blood cells (RBCs) plays a key role in the pathology of severe malaria. Adhesion is known to be mediated in part by the antigenically-variant erythrocyte membrane protein-1 (PfEMP-1), which is encoded by the var-gene family of P. falciparum. It has recently been reported that in vitro a single parasite simultaneously transcribes multiple var-genes but that, through a developmentally regulated process, the parasite selects only one PfEMP-1 that will to reach the surface of the host RBC. Were this to be true in vivo, one would expect a correlation between the type of var/PfEMP-1 that is expressed on the parasite-infected RBC and the severity of clinical disease. In order to test this assumption, we determined the sequence of the var-gene that was expressed by the parasites in patients' blood samples. Seven blood samples were collected from patients with or without severe clinical symptoms (cerebral malaria): two samples were from patients diagnosed as having imported falciparum malaria at the International Medical Center of Japan (IMCJ); the five others were from patients of the Davao Regional Hospital in Davao, the Philippines. The parasites (ring stage) in the blood samples were cultured for 24 hours; the matured trophozoites, in which the var-gene selection had taken place, served as material for mRNA isolation. The cDNA corresponding to the Duffy-binding-like (DBL)-1 domain of the var-gene was amplified by RT-PCR, using a region-specific primer set. The amplified cDNAs were cloned into the plasmid vector; the resultant clones (32) were sequenced on both strands. The results indicated that there was considerable diversity in the sequence of the DBL-1 domain among the clones, even among those from a single patient. In conclusion, it was difficult to demonstrate the correlation between the type of var-gene transcripts found in the RBCs of malaria patients and the severity of their symptoms.

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  • 子宮内膜における免疫系は暑熱ストレスにより変化する

    酒井 駿介, 畑生 俊光, 山本 ゆき, 木村 康二

    The Journal of Reproduction and Development   64 ( Suppl. )   j83 - j83   2018.9

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  • Eimeria tenella 弱毒株の作出と比較ゲノム解析による弱毒化分子機構の解明

    松林 誠, 川原 史也, 山岸 潤也, 八田 岳士, 畑生 俊光, 山口 浩貴, 寺本 勲, 金子 明, 磯部 尚, 北 潔, 辻 尚利, 笹井 和美

    日本獣医学会学術集会講演要旨集   161回   316 - 316   2018.8

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  • ニワトリコクシジウム症 アイメリア・テネラ感染メカニズムの解明に向けて

    畑生 俊光

    岡山実験動物研究会報   ( 34 )   80 - 80   2018.4

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  • Eimeria tenella弱毒株の作出および病理組織学的比較解析

    山口 浩貴, 松林 誠, 川原 史也, 八田 岳士, 畑生 俊光, 山岸 潤也, 磯部 尚, 寺本 勲, 金子 明, 北 潔, 辻 尚利, 笹井 和美

    日本獣医学会学術集会講演要旨集   160回   336 - 336   2017.8

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  • 南米型トリパノソーマ感染細胞におけるオートファゴソーム形成と関連タンパク質の解析

    高橋 千由紀, 畑生 俊光, 嶋田 淳子

    The Kitakanto Medical Journal   63 ( 3 )   327 - 327   2013.8

  • ネズミマラリア感染臓器におけるスカベンジャー受容体の発現解析

    宮下 大地, 畑生 俊光, 嶋田 淳子

    The Kitakanto Medical Journal   63 ( 3 )   327 - 327   2013.8

  • Plasmodium berghei感染マウス臓器におけるスカベンジャー受容体SRCLの発現解析

    宮下 大地, 畑生 俊光, 嶋田 淳子

    関東甲信地区医学検査学会講演集   48回   145 - 145   2011.10

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  • 南米型トリパノソーマ感染細胞におけるオートファジーとアポトーシスとの関連性の解析

    高橋 千由紀, 畑生 俊光, 嶋田 淳子

    関東甲信地区医学検査学会講演集   48回   144 - 144   2011.10

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  • 群馬県における肺吸虫の分布調査 群馬県内利根川水系産サワガニにおける肺吸虫類メタセルカリア寄生状況について

    富澤 将太, 畑生 俊光, 嶋田 淳子

    関東甲信地区医学検査学会講演集   48回   145 - 145   2011.10

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  • Trypanosoma cruzi infection induces nitric oxide production and S-nitrosylation of cellular FLIP in host cell

    Junko Nakajima-Shimada, Toshimitsu Hatabu

    Medimond S.r.l   2011

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  • 菌類代謝産物の抗マラリア活性(1)

    内山 奈穂子, 畑生 俊光, 嶋田 淳子, 川原 信夫, 板橋 武史, 河合 賢一

    日本生薬学会年会講演要旨集   56回   208 - 208   2009.9

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  • 高校生における麻疹予防接種歴調査、抗体価測定と予防教育

    豊島 幸子, 畑生 俊光, 嶋田 淳子, 大平 孝雄, 八木 秀明

    The Kitakanto Medical Journal   59 ( 3 )   325 - 325   2009.8

  • Association of molecular markers in Plasmodium falciparum crt and mdr1 with in vitro chloroquine resistance: a Philippine study. Reviewed International journal

    Toshimitsu Hatabu, Moritoshi Iwagami, Shin-ichiro Kawazu, Nao Taguchi, Aleyla D Escueta, Elena A Villacorte, Pilarita T Rivera, Shigeyuki Kano

    Parasitology international   58 ( 2 )   166 - 70   2009.6

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    Specific mutations in the pfcrt and pfmdr1 genes have been reported to be associated with chloroquine-resistant falciparum malaria parasites worldwide. These genetic markers are considered to be useful tools for the elucidation of several aspects of the epidemiology of drug resistant malaria. In this study, Plasmodium falciparum isolates from three distinct areas of the Philippines were analyzed for drug-resistance-associated genetic mutations, and their association with the in vitro chloroquine (CQ) response. Two novel pfcrt 72-76 allelic types, CVMDT and SVMDT, were detected. The frequency of the pfcrt K76T mutation in the isolates that were successfully tested for in vitro CQ susceptibility was found to be 100% in Kalinga, 80% in Palawan, and 87% in Mindanao. The frequency of the pfmdr1 N86Y mutation was 39% in Kalinga, 35% in Palawan, and 93% in Mindanao isolates. No mutations were found at positions 1042 and 1246 of pfmdr1. However, there were no significant associations found between polymorphisms in these genes and in vitro CQ susceptibility. The results of this study indicate that mutations in pfcrt and pfmdr1 are not predictive of in vitro CQ resistance in Philippine isolates and may therefore not be suitable as molecular markers for surveillance.

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  • Association of molecular markers in Plasmodium falciparum crt and mdr1 with in vitro chloroquine resistance: a Philippine study. Reviewed International journal

    Toshimitsu Hatabu, Moritoshi Iwagami, Shin-ichiro Kawazu, Nao Taguchi, Aleyla D Escueta, Elena A Villacorte, Pilarita T Rivera, Shigeyuki Kano

    Parasitology international   58 ( 2 )   166 - 70   2009.6

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    Specific mutations in the pfcrt and pfmdr1 genes have been reported to be associated with chloroquine-resistant falciparum malaria parasites worldwide. These genetic markers are considered to be useful tools for the elucidation of several aspects of the epidemiology of drug resistant malaria. In this study, Plasmodium falciparum isolates from three distinct areas of the Philippines were analyzed for drug-resistance-associated genetic mutations, and their association with the in vitro chloroquine (CQ) response. Two novel pfcrt 72-76 allelic types, CVMDT and SVMDT, were detected. The frequency of the pfcrt K76T mutation in the isolates that were successfully tested for in vitro CQ susceptibility was found to be 100% in Kalinga, 80% in Palawan, and 87% in Mindanao. The frequency of the pfmdr1 N86Y mutation was 39% in Kalinga, 35% in Palawan, and 93% in Mindanao isolates. No mutations were found at positions 1042 and 1246 of pfmdr1. However, there were no significant associations found between polymorphisms in these genes and in vitro CQ susceptibility. The results of this study indicate that mutations in pfcrt and pfmdr1 are not predictive of in vitro CQ resistance in Philippine isolates and may therefore not be suitable as molecular markers for surveillance.

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  • Genetic diversity and population structure of Plasmodium falciparum in the Philippines. Reviewed International journal

    Moritoshi Iwagami, Pilarita T Rivera, Elena A Villacorte, Aleyla D Escueta, Toshimitsu Hatabu, Shin-ichiro Kawazu, Toshiyuki Hayakawa, Kazuyuki Tanabe, Shigeyuki Kano

    Malaria journal   8   96 - 96   2009.5

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    BACKGROUND: In the Philippines, malaria morbidity and mortality have decreased since the 1990s by effective malaria control. Several epidemiological surveys have been performed in the country, but the characteristics of the Plasmodium falciparum populations are not yet fully understood. In this study, the genetic structure of P. falciparum populations in the Philippines was examined. METHODS: Population genetic analyses based on polymorphisms of 10 microsatellite loci of the parasite were conducted on 92 isolates from three provinces (Kalinga, Palawan, and Davao del Norte) with different malaria endemicity. RESULTS: The levels of genetic diversity and the effective population sizes of P. falciparum in the Philippines were similar to those reported in the mainland of Southeast Asia or South America. In the low malaria transmission area (Kalinga), there was a low level of genetic diversity and a strong linkage disequilibrium (LD) when the single-clone haplotype (SCH) was used in the multilocus LD analysis, while in the high malaria transmission areas (Palawan and Davao del Norte), there was a high level of genetic diversity and a weak LD when SCH was used in the multilocus LD analysis. On the other hand, when the unique haplotypes were used in the multilocus LD analysis, no significant LD was observed in the Kalinga and the Palawan populations. The Kalinga and the Palawan populations were, therefore, estimated to have an epidemic population structure. The three populations were moderately differentiated from each other. CONCLUSION: In each area, the level of genetic diversity correlates with the local malaria endemicity. These findings confirm that population genetic analyses using microsatellite loci are a useful tool for evaluating malaria endemicity.

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  • Genetic diversity and population structure of Plasmodium falciparum in the Philippines. Reviewed International journal

    Moritoshi Iwagami, Pilarita T Rivera, Elena A Villacorte, Aleyla D Escueta, Toshimitsu Hatabu, Shin-ichiro Kawazu, Toshiyuki Hayakawa, Kazuyuki Tanabe, Shigeyuki Kano

    Malaria journal   8   96 - 96   2009.5

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    BACKGROUND: In the Philippines, malaria morbidity and mortality have decreased since the 1990s by effective malaria control. Several epidemiological surveys have been performed in the country, but the characteristics of the Plasmodium falciparum populations are not yet fully understood. In this study, the genetic structure of P. falciparum populations in the Philippines was examined. METHODS: Population genetic analyses based on polymorphisms of 10 microsatellite loci of the parasite were conducted on 92 isolates from three provinces (Kalinga, Palawan, and Davao del Norte) with different malaria endemicity. RESULTS: The levels of genetic diversity and the effective population sizes of P. falciparum in the Philippines were similar to those reported in the mainland of Southeast Asia or South America. In the low malaria transmission area (Kalinga), there was a low level of genetic diversity and a strong linkage disequilibrium (LD) when the single-clone haplotype (SCH) was used in the multilocus LD analysis, while in the high malaria transmission areas (Palawan and Davao del Norte), there was a high level of genetic diversity and a weak LD when SCH was used in the multilocus LD analysis. On the other hand, when the unique haplotypes were used in the multilocus LD analysis, no significant LD was observed in the Kalinga and the Palawan populations. The Kalinga and the Palawan populations were, therefore, estimated to have an epidemic population structure. The three populations were moderately differentiated from each other. CONCLUSION: In each area, the level of genetic diversity correlates with the local malaria endemicity. These findings confirm that population genetic analyses using microsatellite loci are a useful tool for evaluating malaria endemicity.

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  • フィリピンの熱帯熱マラリア原虫集団の遺伝的構造と流行度

    石上盛敏, リベラ ピラリタ, ビラコルテ エレーナ, エスクエタ アレイラ, 畑生俊光, 河津信一郎, 早川敏之, 田邉和裄, 狩野繁之

    Trop Med Health   125   2008.10

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  • Phylogenetic relationship of Plasmodium falciparum populations in the Philippines

    Moritoshi Iwagami, Toshimitsu Hatabu, Shin-ichiro Kawazu, Aleyla S. Escueta, Elena A. Villacorte, Pilarita Tongol-Rivera, Shigeyuki Kano

    Southeast Asian Journal of Tropical Medicine and Public Health   39 ( 2 )   200 - 204   2008.3

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    Malaria is one of the major infectious diseases in the Philippines. It is being targeted for control through sustained early diagnosis, treatment and mosquito control. It is in this light that understanding the genetic background of the parasite population is important not only for basic biology of the organism but also for epidemiology and control of the disease. In the present study, molecular phylogenetic relationships of the 3 Plasmodium falciparum populations in the Philippines with the other populations in the world were inferred based on polymorphisms of 9 highly polymorphic microsatellite DNA loci in the parasite genome. A total of 92 P. falciparum isolates collected from 3 provinces (Kalinga, Palawan and Davao del Morte) in the Philippines, and 8 from other populations (3 African, 2 South American, 2 Papua New Guinean, and 1 Thai) that were previously reported, were used for the analysis. The phylogenetic tree showed that the 3 Philippine populations were genetically divergent from each other as compared to the other populations. The branching pattern of the tree suggests that the 3 Philippine populations were relatively close to the Thai population, rather than the Papua New Guinean populations, indicating that the ancestor of the 3 Philippines populations were introduced from Indochina peninsula, and not from countries located south of the Philippines such as Papua New Guinea or Indonesia.

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  • Phylogenetic relationship of Plasmodium falciparum populations in the Philippines International journal

    Moritoshi Iwagami, Toshimitsu Hatabu, Shin-ichiro Kawazu, Aleyla S. Escueta, Elena A. Villacorte, Pilarita Tongol-Rivera, Shigeyuki Kano

    Southeast Asian Journal of Tropical Medicine and Public Health   39 ( 2 )   200 - 204   2008.3

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    Malaria is one of the major infectious diseases in the Philippines. It is being targeted for control through sustained early diagnosis, treatment and mosquito control. It is in this light that understanding the genetic background of the parasite population is important not only for basic biology of the organism but also for epidemiology and control of the disease. In the present study, molecular phylogenetic relationships of the 3 Plasmodium falciparum populations in the Philippines with the other populations in the world were inferred based on polymorphisms of 9 highly polymorphic microsatellite DNA loci in the parasite genome. A total of 92 P. falciparum isolates collected from 3 provinces (Kalinga, Palawan and Davao del Morte) in the Philippines, and 8 from other populations (3 African, 2 South American, 2 Papua New Guinean, and 1 Thai) that were previously reported, were used for the analysis. The phylogenetic tree showed that the 3 Philippine populations were genetically divergent from each other as compared to the other populations. The branching pattern of the tree suggests that the 3 Philippine populations were relatively close to the Thai population, rather than the Papua New Guinean populations, indicating that the ancestor of the 3 Philippines populations were introduced from Indochina peninsula, and not from countries located south of the Philippines such as Papua New Guinea or Indonesia.

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  • 節足動物媒介感染症の効果的な防除等の対策研究 マラリア重症患者の管理および治療体制に関する研究

    狩野繁之, 水野泰孝, 石上盛敏, 竹内勤, 奥浩之, 畑生俊光, 谷畑健生, LOOAREESUWAN Sornchai, KRUDSOOD Srivicha

    節足動物媒介感染症の効果的な防除等の対策研究 平成19年度総括・分担研究報告書   2008

  • 熱帯熱マラリア原虫に対するアムホテリシンBの発育阻止機序の解析

    畑生俊光, 畑生俊光, 川合覚, 山口武士, 山田圭一, 奥浩之, 片貝良一, 嶋田淳子, 狩野繁之

    日本寄生虫学会大会プログラム・抄録集   76th   2007

  • Plasmodium falciparum: the fungal metabolite gliotoxin inhibits proteasome proteolytic activity and exerts a plasmodicidal effect on P. falciparum. Reviewed International journal

    Toshimitsu Hatabu, Masaki Hagiwara, Nao Taguchi, Masayuki Kiyozawa, Mamoru Suzuki, Shigeyuki Kano, Kumiko Sato

    Experimental parasitology   112 ( 3 )   179 - 83   2006.3

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    The in vitro antimalarial activity of the fungal metabolite gliotoxin (GTX) was evaluated, and its mechanism of action was studied. GTX showed plasmodicidal activity against both Plasmodium falciparum chloroquine-resistant strain K-1 and chloroquine-susceptible strain FCR-3. GTX cytotoxicity was significantly lower against a normal liver cell line (Chang Liver cells). The intracellular reduced glutathione level of parasitized and of normal red blood cells was not affected by GTX treatment. However, GTX decreased the chymotrypsin-like activity of parasite proteasomes in a time-dependent manner. The results of this study indicate that GTX possesses plasmodicidal activity and that this effect is due to inhibition of parasite proteasome activity, suggesting that GTX may constitute a useful antimalarial therapy.

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  • Plasmodium falciparum: the fungal metabolite gliotoxin inhibits proteasome proteolytic activity and exerts a plasmodicidal effect on P. falciparum. Reviewed International journal

    Toshimitsu Hatabu, Masaki Hagiwara, Nao Taguchi, Masayuki Kiyozawa, Mamoru Suzuki, Shigeyuki Kano, Kumiko Sato

    Experimental parasitology   112 ( 3 )   179 - 83   2006.3

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    The in vitro antimalarial activity of the fungal metabolite gliotoxin (GTX) was evaluated, and its mechanism of action was studied. GTX showed plasmodicidal activity against both Plasmodium falciparum chloroquine-resistant strain K-1 and chloroquine-susceptible strain FCR-3. GTX cytotoxicity was significantly lower against a normal liver cell line (Chang Liver cells). The intracellular reduced glutathione level of parasitized and of normal red blood cells was not affected by GTX treatment. However, GTX decreased the chymotrypsin-like activity of parasite proteasomes in a time-dependent manner. The results of this study indicate that GTX possesses plasmodicidal activity and that this effect is due to inhibition of parasite proteasome activity, suggesting that GTX may constitute a useful antimalarial therapy.

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  • Pyrimethamine-sulfadoxine treatment of uncomplicated Plasmodium falciparum malaria in Lao PDR. Reviewed International journal

    M Kaiissar Mannoor, Viengxay Vanisaveth, Boualy Keokhamphavanh, Hiromu Toma, Hisami Watanabe, Jun Kobayashi, Toshimitsu Hatabu, Nao Taguchi, Bousy Hongvangthong, Rattanaxay Phetsouvanh, Samlane Phompida, Shigeyuki Kano, Yoshiya Sato

    The Southeast Asian journal of tropical medicine and public health   36 ( 5 )   1092 - 5   2005.9

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    A 28-day in vivo treatment trial to evaluate the efficacy of pyrimethamine/sulfadoxine (Fansidar, PS) was conducted in 21 Lao patients with uncomplicated Plasmodium falciparum malaria. Sixteen patients (76%) were completely cured with PS without any reappearance of asexual stage parasitemia during the follow-up examination. On the other hand, 5 patients (24%) failed to respond to this trial medication, resulting in recrudescence of asexual stage P. falciparum malaria. PS resistance resulted in higher prevalence of post-treatment gametocytemia, 25% gametocyte carriers among PS sensitive cases versus 75% of the resistant cases. These findings suggest that although the level of PS resistance is still valid for treatment of malaria in the study area of Lao PDR, post-treatment induction of gametocytemia among resistant cases may result an increase in transmission rate of PS resistant falciparum malaria.

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  • Pyrimethamine-sulfadoxine treatment of uncomplicated Plasmodium falciparum malaria in Lao PDR. Reviewed International journal

    M Kaiissar Mannoor, Viengxay Vanisaveth, Boualy Keokhamphavanh, Hiromu Toma, Hisami Watanabe, Jun Kobayashi, Toshimitsu Hatabu, Nao Taguchi, Bousy Hongvangthong, Rattanaxay Phetsouvanh, Samlane Phompida, Shigeyuki Kano, Yoshiya Sato

    The Southeast Asian journal of tropical medicine and public health   36 ( 5 )   1092 - 5   2005.9

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    A 28-day in vivo treatment trial to evaluate the efficacy of pyrimethamine/sulfadoxine (Fansidar, PS) was conducted in 21 Lao patients with uncomplicated Plasmodium falciparum malaria. Sixteen patients (76%) were completely cured with PS without any reappearance of asexual stage parasitemia during the follow-up examination. On the other hand, 5 patients (24%) failed to respond to this trial medication, resulting in recrudescence of asexual stage P. falciparum malaria. PS resistance resulted in higher prevalence of post-treatment gametocytemia, 25% gametocyte carriers among PS sensitive cases versus 75% of the resistant cases. These findings suggest that although the level of PS resistance is still valid for treatment of malaria in the study area of Lao PDR, post-treatment induction of gametocytemia among resistant cases may result an increase in transmission rate of PS resistant falciparum malaria.

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  • Potent plasmodicidal activity of a heat-induced reformulation of deoxycholate-amphotericin B (Fungizone) against Plasmodium falciparum. Reviewed International journal

    Toshimitsu Hatabu, Tsuyoshi Takada, Nao Taguchi, Mamoru Suzuki, Kumiko Sato, Shigeyuki Kano

    Antimicrobial agents and chemotherapy   49 ( 2 )   493 - 6   2005.2

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    The emergence and spread of drug-resistant Plasmodium falciparum continue to pose problems in malaria chemotherapy. Therefore, it is necessary to identify new antimalarial drugs and therapeutic strategies. In the present study, the activity of a heat-treated form of amphotericin B (HT-AMB) against P. falciparum was evaluated. The efficacy and toxicity of HT-AMB were also compared with those of the standard formulation (AMB). HT-AMB showed significant activity against a chloroquine-resistant strain (strain K-1) and a chloroquine-susceptible strain (strain FCR-3) in vitro. The 50% inhibitory concentrations of HT-AMB were 0.32 +/- 0.03 mug/ml for strain K-1 and 0.33 +/- 0.03 mug/ml for strain FCR-3. In the presence of 1.0 mug of HT-AMB per ml, only pyknotic parasites were observed after 24 h of incubation of early trophozoites (ring forms). However, when late trophozoites and schizonts were cultured with 1.0 mug of HT-AMB per ml, those forms multiplied to ring forms but the number of infected erythrocytes did not increase. These results indicate that HT-AMB possesses potent antiplasmodial activity and that the drug is more effective against the ring-form stage than against the late trophozoite and schizont stages. HT-AMB was observed to have little cytotoxic effect against a human liver cell line (Chang liver cells). In conclusion, the results suggest that HT-AMB has promising properties and merits further in vivo investigations as a treatment for falciparum malaria.

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  • Potent plasmodicidal activity of a heat-induced reformulation of deoxycholate-amphotericin B (Fungizone) against Plasmodium falciparum. Reviewed International journal

    Toshimitsu Hatabu, Tsuyoshi Takada, Nao Taguchi, Mamoru Suzuki, Kumiko Sato, Shigeyuki Kano

    Antimicrobial agents and chemotherapy   49 ( 2 )   493 - 6   2005.2

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    The emergence and spread of drug-resistant Plasmodium falciparum continue to pose problems in malaria chemotherapy. Therefore, it is necessary to identify new antimalarial drugs and therapeutic strategies. In the present study, the activity of a heat-treated form of amphotericin B (HT-AMB) against P. falciparum was evaluated. The efficacy and toxicity of HT-AMB were also compared with those of the standard formulation (AMB). HT-AMB showed significant activity against a chloroquine-resistant strain (strain K-1) and a chloroquine-susceptible strain (strain FCR-3) in vitro. The 50% inhibitory concentrations of HT-AMB were 0.32 +/- 0.03 mug/ml for strain K-1 and 0.33 +/- 0.03 mug/ml for strain FCR-3. In the presence of 1.0 mug of HT-AMB per ml, only pyknotic parasites were observed after 24 h of incubation of early trophozoites (ring forms). However, when late trophozoites and schizonts were cultured with 1.0 mug of HT-AMB per ml, those forms multiplied to ring forms but the number of infected erythrocytes did not increase. These results indicate that HT-AMB possesses potent antiplasmodial activity and that the drug is more effective against the ring-form stage than against the late trophozoite and schizont stages. HT-AMB was observed to have little cytotoxic effect against a human liver cell line (Chang liver cells). In conclusion, the results suggest that HT-AMB has promising properties and merits further in vivo investigations as a treatment for falciparum malaria.

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  • 群馬県における成人のスギ花粉およびダニIgE抗体保有率 10年間における変化および自覚症状との関連について

    比田井裕子, 畑生 俊光, 荒木忠晴, 佐藤 久美子, 嶋田 淳子

    北関東医学雑誌   Vol.55 307 ( 3 )   307 - 307   2005

  • 群馬県におけるToxoplasma gondii抗体保有率の推移

    川島悟美, 畑生 俊光, 佐藤 久美子, 狩野繁之, 嶋田 淳子

    北関東医学会誌   Vol55 307 ( 3 )   307 - 307   2005

  • In vitro susceptibility and genetic variations for chloroquine and mefloquine in Plasmodium falciparum isolates from Thai-Myanmar border

    HATABU, TOSHIMITSU

    Southeast Asian J Trop Med Public Health   Vol 36 suppl 4: 73-78   2005

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  • A study of chloroquine resistance of Plasmodium falciparum using the in-vitro sensitivity test and polymerase chain reaction (PCR).

    HATABU, TOSHIMITSU

    Acta Medica Philippina   39(2): 7-10   2005

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  • A Pilot Field Survey on the in Vitro Drug Susceptibility of Plasmodium Falciparum in Lao PDR

    Toshimitsu Hatabu, Nao Taguchi, Shigeyuki Kano, Viengxay Vanisaveth, Samlane Phompida, Jun Kobayashi, M. Kaiissar Mannoor, Hiromu Toma, Hisami Watanabe

    Tropical Medicine and Health   33 ( 2 )   103 - 104   2005

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  • A Pilot Field Survey on the in Vitro Drug Susceptibility of Plasmodium Falciparum in Lao PDR

    Toshimitsu Hatabu, Nao Taguchi, Shigeyuki Kano, Viengxay Vanisaveth, Samlane Phompida, Jun Kobayashi, M. Kaiissar Mannoor, Hiromu Toma, Hisami Watanabe

    Tropical Medicine and Health   33 ( 2 )   103 - 104   2005

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  • In vitro susceptibility and genetic variations for chloroquine and mefloquine in Plasmodium falciparum isolates from Thai-Myanmar border. Reviewed International journal

    Toshimitsu Hatabu, Shin-ichiro Kawazu, Somei Kojima, Kumiko Sato, Pratap Singhasivanon, Sornchai Looareesuwan, Shigeyuki Kano

    The Southeast Asian journal of tropical medicine and public health   36 Suppl 4   73 - 9   2005

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    In vitro drug susceptibility to chloroquine (CQ) and mefloquine (MF) were assessed in 39 P. falciparum isolates from the Thai-Myanmar border area. To further characterize CQ- and MF-resistance profiles in this area, we also analyzed pfcrt K76T mutation that is critical for CQ resistance, and pfmdr1 polymorphism that has an association with MF resistance. Eighteen isolates were successfully examined by in vitro tests for CQ, and 17 of them had resistance to the drug. Geometric mean concentration of CQ that inhibited the growth of parasites at 50% (IC50) was 371 +/- 227 nM (105-971 nM). Sixteen isolates were successfully examined by in vitro tests for MF, and 8 of them were resistant to the drug. Geometric mean of IC50 for MF was 41 +/- 31 nM (4-125 nM). Genotypes of drug resistance, such as pfcrt and pfmdr1 mutations, were also analyzed. All the 39 isolates had the same haplotype (CVIET) for PfCRT at its 72-76th amino acids. A pfmdr1 Y86 mutation was found in 95% of isolates. A pfmdr1 D1042 mutation was also present in 7 isolates, while no pfmdr1 Y1246 mutation was observed. These results indicated a correlation between CQ resistance and the pfcrt T76 and pfmdr1 Y86 mutations.

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  • A study of chloroquine resistance of Plasmodium falciparum using the in-vitro sensitivity test and polymerase chain reaction (PCR).

    HATABU, TOSHIMITSU

    Acta Medica Philippina   39(2): 7-10   2005

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  • Plasmodium falciparum: selenium-induced cytotoxicity to P-falciparum

    N Taguchi, T Hatabu, H Yamaguchi, M Suzuki, K Sato, S Kano

    EXPERIMENTAL PARASITOLOGY   106 ( 1-2 )   50 - 55   2004.1

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    The in vitro antimalarial activity of sodium selenite (NaSe) was investigated and the mechanism of its action was studied. NaSe had antimalarial activity against both the chloroquine-susceptible strain FCR-3 and chloroquine-resistant strain K-I of Plasmodium falciparum. The shrunken cytoplasm of the parasite was observed in a smear 12h after treatment with NaSe. Co-treatment with copper sulfate (CuSO4) in culture did not affect the antimalarial activity of NaSe, but NaSe cytotoxicity against the mammalian cell line Alexander was decreased significantly. The intracellular reduced glutathione level of parasitized red blood cells was decreased significantly by treatment with NaSe, and the decrease was consistent with their mortality. Treatment with NaSe had a strong inhibitory effect on plasmodial development, and NaSe cytotoxicity to human cells was decreased by co-treatment with CuSO4. These results suggest that co-treatment with NaSe and CuSO4 may be useful as a new antimalarial therapy. (C) 2004 Elsevier Inc. All rights reserved.

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  • Plasmodium falciparum: selenium-induced cytotoxicity to P-falciparum

    N Taguchi, T Hatabu, H Yamaguchi, M Suzuki, K Sato, S Kano

    EXPERIMENTAL PARASITOLOGY   106 ( 1-2 )   50 - 55   2004.1

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    The in vitro antimalarial activity of sodium selenite (NaSe) was investigated and the mechanism of its action was studied. NaSe had antimalarial activity against both the chloroquine-susceptible strain FCR-3 and chloroquine-resistant strain K-I of Plasmodium falciparum. The shrunken cytoplasm of the parasite was observed in a smear 12h after treatment with NaSe. Co-treatment with copper sulfate (CuSO4) in culture did not affect the antimalarial activity of NaSe, but NaSe cytotoxicity against the mammalian cell line Alexander was decreased significantly. The intracellular reduced glutathione level of parasitized red blood cells was decreased significantly by treatment with NaSe, and the decrease was consistent with their mortality. Treatment with NaSe had a strong inhibitory effect on plasmodial development, and NaSe cytotoxicity to human cells was decreased by co-treatment with CuSO4. These results suggest that co-treatment with NaSe and CuSO4 may be useful as a new antimalarial therapy. (C) 2004 Elsevier Inc. All rights reserved.

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  • 野外調査地における熱帯熱マラリア in vitro 薬剤感受性試験の応用ーラオス人民民主共和国におけるマラリア疫学調査ー

    畑生 俊光

    熱帯   第37巻221-225 ( 221-292 )   221 - 225   2004

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  • A Pilot Field Trial of an in Vitro Drug Susceptibility Test Using the Anaeropack® Malaria Culture System on the Thai-Myanmar Border

    Toshimitsu Hatabu, Shin-Ichiro Kawazu, Somei Kojima, Pratap Singhasivanon, Srivicha Krudsood, Sornchai Looareesuwan, Shigeyuki Kano

    Tropical Medicine and Health   32 ( 4 )   335 - 337   2004

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    The AnaeroPack® malaria culture system with a portable thermostat incubator was evaluated in a field laboratory on the Thai-Myanmar border conducting in vitro drug susceptibility tests on blood samples from 5 Karen children infected with P. falciparum. Only one isolate was susceptible to chloroquine
    the others were highly resistant. The IC60 value of an isolate was only resistant to mefloquine, whereas the values of the 3 patients who presumably showed recrudescence were slightly elevated in the susceptible ranges. These results suggested that chloroquine should no longer be used for P. falciparum malaria in this geographic area, and that mefloquine should be carefully monitored for its in vivo effectiveness. In this study, the AnaeroPack® malaria culture system with portable thermostatic incubator is a powerful and useful mobile tool, which aids in providing detailed evidence-based distribution data concerning of drug resistant malaria in the field. © 2004, Japanese Society of Tropical Medicine. All rights reserved.

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  • A Pilot Field Trial of an in Vitro Drug Susceptibility Test Using the Anaeropack® Malaria Culture System on the Thai-Myanmar Border

    Toshimitsu Hatabu, Shin-Ichiro Kawazu, Somei Kojima, Pratap Singhasivanon, Srivicha Krudsood, Sornchai Looareesuwan, Shigeyuki Kano

    Tropical Medicine and Health   32 ( 4 )   335 - 337   2004

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    The AnaeroPack® malaria culture system with a portable thermostat incubator was evaluated in a field laboratory on the Thai-Myanmar border conducting in vitro drug susceptibility tests on blood samples from 5 Karen children infected with P. falciparum. Only one isolate was susceptible to chloroquine
    the others were highly resistant. The IC60 value of an isolate was only resistant to mefloquine, whereas the values of the 3 patients who presumably showed recrudescence were slightly elevated in the susceptible ranges. These results suggested that chloroquine should no longer be used for P. falciparum malaria in this geographic area, and that mefloquine should be carefully monitored for its in vivo effectiveness. In this study, the AnaeroPack® malaria culture system with portable thermostatic incubator is a powerful and useful mobile tool, which aids in providing detailed evidence-based distribution data concerning of drug resistant malaria in the field. © 2004, Japanese Society of Tropical Medicine. All rights reserved.

    DOI: 10.2149/tmh.32.335

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  • 生薬由来成分による抗マラリア効果の検討

    石原亜矢, 畑生俊光, 奥浩之, 鈴木守, 佐藤久美子

    日本寄生虫学会大会プログラム・抄録集   73rd   2004

  • Binding of Plasmodium falciparum-infected erythrocytes to the membrane-bound form of Fractalkine/CX3CL1. Reviewed International journal

    Toshimitsu Hatabu, Shin-Ichiro Kawazu, Masamichi Aikawa, Shigeyuki Kano

    Proceedings of the National Academy of Sciences of the United States of America   100 ( 26 )   15942 - 6   2003.12

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    Plasmodium falciparum-infected erythrocytes (pRBCs) adhere to the endothelium via receptors expressed on the surface of vascular endothelial cells (EC) and sequester in the microvasculature of several organs and block the blood circulation. The sequestration, which involves receptors, may be related to the severity of malaria. Here, we report that pRBCs bind to the membrane-bound form of Fractalkine/CX3CL1 (FKN), which is expressed on the surface of vascular EC in various organs. pRBCs adhered to FKN on the surface of FKN cDNA-transfected Chinese hamster ovary cells (CHO-FKN cells). Both the recombinant human FKN-chemokine domain (FKN-CD) and anti-FKN-CD antibody efficiently blocked adherence of pRBCs to CHO-FKN cells. Similar to binding between FKN and FKN receptor on blood mononuclear cells, two amino acid residues, Lys-7 and Arg-47 within FKN-CD, were critical for FKN-pRBC binding. Immunohistological analysis revealed the expression of FKN on EC at the site of sequestration in the brain of a patient with cerebral malaria. These results suggest that the membrane-bound form of FKN acts as a receptor for pRBCs, and this may contribute to furthering our present understanding of cytoadherence in the pathology of falciparum malaria.

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  • Binding of Plasmodium falciparum-infected erythrocytes to the membrane-bound form of fractalkine/CX(3)CL1

    T Hatabu, S Kawazu, M Aikawa, S Kano

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   100 ( 26 )   15942 - 15946   2003.12

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    Plasmodium falciparum-infected erythrocytes (pRBCs) adhere to the endothelium via receptors expressed on the surface of vascular endothelial cells (EC) and sequester in the microvasculature of several organs and block the blood circulation. The sequestration, which involves receptors, may be related to the severity of malaria. Here, we report that pRBCs bind to the membrane-bound form of Fractalkine/ CX(3)CL1 (FKN), which is expressed on the surface of vascular EC in various organs. pRBCs adhered to FKN on the surface of FKN cDNA-transfected Chinese hamster ovary cells (CHO-FKN cells). Both the recombinant human FKN-chemokine domain (FKN-CD) and anti-FKN-CD antibody efficiently blocked adherence of pRBCs to CHO-FKN cells. Similar to binding between FKN and FKN receptor on blood mononuclear cells, two amino acid residues, Lys-7 and Arg-47 within FKN-CD, were critical for FKN-pRBC binding. Immunohistological analysis revealed the expression of FKN on EC at the site of sequestration in the brain of a patient with cerebral malaria. These results suggest that the membrane-bound form of FKN acts as a receptor for pRBCs, and this may contribute to furthering our present understanding of cytoadherence in the pathology of falciparum malaria.

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  • In vitro susceptibility of Plasmodium falciparum isolates to chloroquine and mefloquine in southeastern Mindanao Island, the Philippines. Reviewed International journal

    Toshimitsu Hatabu, Shin-ichiro Kawazu, Jun Suzuki, Reuben F Valenzuela, Elena A Villacorte, Mamoru Suzuki, Pilarita T Rivera, Shigeyuki Kano

    The Southeast Asian journal of tropical medicine and public health   34 ( 3 )   546 - 51   2003.9

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    Although the presence of multi-drug-resistant falciparum malaria has been reported in the Philippines, the distribution of drug-resistant malaria parasites has not yet been determined in Mindanao Island. In vitro susceptibility of P. falciparum to both chloroquine and mefloquine was assessed to forecast the spread of drug-resistant parasites in various foci in southeastern Mindanao Island. Of the 33 isolates of P. falciparum successfully tested, 10 (30%) were susceptible, 12 (36%) showed decreased susceptibility (80 nM < or = IC50 < 114 nM), and 11 (33%) were resistant (IC50 > or = 114 nM) to chloroquine. Ten (91%) of the resistant isolates and 9 (75%) of those with decreased susceptibility were from northern and northwestern Davao del Norte Province. Chloroquine-susceptible isolates were found among patients in the eastern parts of Davao del Norte and Davao Oriental provinces. Seven isolates from several foci in the study area were all mefloquine- susceptible (IC50 < 10 nM). This is the first report indicating the potential emergence of chloroquine-resistant P. falciparum on Mindanao Island, which is presently regarded as a drug-susceptible area.

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  • In vitro susceptibility of Plasmodium falciparum isolates to chloroquine and mefloquine in southeastern Mindanao Island, the Philippines. Reviewed International journal

    Toshimitsu Hatabu, Shin-ichiro Kawazu, Jun Suzuki, Reuben F Valenzuela, Elena A Villacorte, Mamoru Suzuki, Pilarita T Rivera, Shigeyuki Kano

    The Southeast Asian journal of tropical medicine and public health   34 ( 3 )   546 - 51   2003.9

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    Although the presence of multi-drug-resistant falciparum malaria has been reported in the Philippines, the distribution of drug-resistant malaria parasites has not yet been determined in Mindanao Island. In vitro susceptibility of P. falciparum to both chloroquine and mefloquine was assessed to forecast the spread of drug-resistant parasites in various foci in southeastern Mindanao Island. Of the 33 isolates of P. falciparum successfully tested, 10 (30%) were susceptible, 12 (36%) showed decreased susceptibility (80 nM < or = IC50 < 114 nM), and 11 (33%) were resistant (IC50 > or = 114 nM) to chloroquine. Ten (91%) of the resistant isolates and 9 (75%) of those with decreased susceptibility were from northern and northwestern Davao del Norte Province. Chloroquine-susceptible isolates were found among patients in the eastern parts of Davao del Norte and Davao Oriental provinces. Seven isolates from several foci in the study area were all mefloquine- susceptible (IC50 < 10 nM). This is the first report indicating the potential emergence of chloroquine-resistant P. falciparum on Mindanao Island, which is presently regarded as a drug-susceptible area.

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  • 熱帯熱マラリア原虫フィリピン・ミンダナオ島分離株におけるpfcrtおよびpfmdr‐1遺伝子多型の解析

    畑生俊光, 河津信一郎, VILLACORTE E A, 佐藤久美子, RIVERA P T, 狩野繁之

    日本寄生虫学会大会プログラム・抄録集   72nd   120   2003.3

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  • タイ・ミャンマー国境地域におけるアネロパックマラリア培養システムを用いた薬剤感受性試験

    畑生 俊光, 狩野 繁之, 小島 荘明, シンハシバノン・プラタップ, ルーアリースワン・ソンチャイ

    Clinical Parasitology   13 ( 1 )   75 - 77   2003.2

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    著者等が開発したアネロパックマラリア原虫培養システムの更なる野外調査地での有用性を確認するため,in vivo多剤耐性熱帯熱マラリアの流行が報告されているタイ・ミャンマー国境地域において,in vitro薬剤感受性試験を試みた.なお,培養システムには改良型冷却機能つき小型恒温槽を使用した.ラジャナガリンドラ・トロピカル・ディジーズ・インターナショナル・センター(RTIC)を来院した5名の患者より分離した熱帯熱マラリア原虫を用いた薬剤感受性試験を行ったところ,80%がクロロキン耐性であった.メフロキンについては,80%の原虫が感受性であったが,再燃を疑わせる患者3名から分離した原虫については,メフロキンに対する感受性の低下が認められた.以上の事から,アネロパックマラリア培養システムと改良携帯型恒温槽を用いたin vitro薬剤感受性試験は,従来報告されているin vivoの結果からだされている薬剤耐性マラリアの流行分布に関する疫学的考察を強化する手法として有用であると考えられた

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  • [An imported case of falciparum malaria successfully treated with Artemether-Lumefantrine in Japan]. Reviewed

    Azumi Ishizaki, Yoshiki Kikuchi, Toshimitsu Hatabu, Shigeyuki Kano, Akira Yasuoka, Shinichi Oka

    Kansenshogaku zasshi. The Journal of the Japanese Association for Infectious Diseases   77 ( 1 )   34 - 7   2003.1

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    Spread of multi-drug resistant malaria in the endemic areas has made malaria control more difficult. Thus, WHO recommends combination therapy for the treatment of malaria. The aim of combination therapy is to improve efficacy and to reduce the incidence of resistance development to the each component of the combination. Particularly, the combination with artemisinin derivatives shows good outcome in Thailand where high resistance for mefloquine has already been found. We report the first case of falciparum malaria, successfully treated with Artemether-Lumefantrine in Japan. Artemether-Lumefantrine is a newly developed artemisinin-based combination agent for the treatment of uncomplicated multi-drug resistant malaria. This drug has proved highly effective and well tolerated by some clinical trials abroad. This Japanese female case showed a good clinical course without any side effect.

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  • An Imported Case of Falciparum Malaria Successfully Treated with Artemether-Lumefantrine in Japan

    ISHIZAKI Azumi, KIKUCHI Yoshiki, HATABU Toshimitsu, KANO Shigeyuki, YASUOKA Akira, OKA Shinichi

    Journal of the Japanese Association for Infectious Diseases   77(1):34-7 ( 1 )   34 - 37   2003

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    Spread of multi-drug resistant malaria in the endemic areas has made malaria control more difficult. Thus, WHO recommends combination therapy for the treatment of malaria. The aim of combination therapy is to improve efficacy and to reduce the incidence of resistance development to the each component of the combination. Particularly, the combination with artemisinin derivatives shows good outcome in Thailand where high resistance for mefloquine has already been found. We report the first case of falciparum malaria, successfully treated with Artemether-Lumefantrine in Japan. Artemether-Lumefantrine is a newly developed artemisinin-based combination agent for the treatment of uncomplicated multi-drug resistant malaria. This drug has proved highly effective and well tolerated by some clinical trials abroad. This Japanese female case showed a good clinical course without any side effect.

    DOI: 10.11150/kansenshogakuzasshi1970.77.34

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  • PCR-amplification, sequencing, and comparison of the var/PfEMP-1 gene from the blood of patients with falciparum malaria in the Philippines.

    HATABU, TOSHIMITSU

    Southeast Asian Journal of Tropical Medicine and Public Health   33 suppl(3):8-13   2003

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  • 群馬大学公開講座実施報告。科学する心を育てようーミクロの世界を覗いてみようー

    福田 利夫, 佐藤 久美子, 畑生 俊光, 小河原 はつ江, 佐竹 史明, 吉田 朋美

    群馬保健学紀要   24   117 - 122   2003

  • 薬剤耐性マラリアの分布に関する調査研究

    畑生 俊光

    北関東医学会誌   53巻3号 ( 3 )   327 - 328   2003

  • 亜セレン酸ナトリウムが及ぼすマラリア原虫培養系への影響

    田口 直, 畑生 俊光, 澁澤 美奈, 石原 亜矢, 佐藤 久美子

    関東甲信地区医学検査学会講演集   39回   121 - 121   2002.11

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  • Severe Falciparum Malaria with Prolonged Hemolytic Anemia after Successful Treatment with Intravenous Artesunate

    ITODA Ichiro, YASUNAMI Takeshi, KIKUCHI Ken, YAMAURA Hisashi, TOTSUKA Kyoichi, YOSHINAGA Kentaro, TERAMURA Masanao, MIZOGUCHI Hideaki, HATABU Toshimitsu, KANO Shigeyuki

    76 ( 8 )   600 - 603   2002.8

  • [Severe falciparum malaria with prolonged hemolytic anemia after successful treatment with intravenous artesunate]. Reviewed

    Ichiro Itoda, Takeshi Yasunami, Ken Kikuchi, Hisashi Yamaura, Kyoichi Totsuka, Kentaro Yoshinaga, Masanao Teramura, Hideaki Mizoguchi, Toshimitsu Hatabu, Shigeyuki Kano

    Kansenshogaku zasshi. The Journal of the Japanese Association for Infectious Diseases   76 ( 8 )   600 - 3   2002.8

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    We report a 68-year-old woman with severe falciparum malaria contracted in Tanzania. She presented high parasitemia and was treated successfully with intravenous artesunate, a qinghaosu derivative, and aggressive supportive therapy. She developed hemolytic anemia and jaundice on day 11 and blood transfusion was required. This case illustrates that intravenous artesunate has excellent antimalarial activity with rapid efficacy and that no severe adverse effect but conventional aggressive supportive therapy is still important in the treatment of severe falciparum malaria.

    DOI: 10.11150/kansenshogakuzasshi1970.76.600

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  • ネズミマラリア原虫(Plasmodium yoelii)ペルオキシレドキシンの媒介蚊体内発育ステージにおける発現

    河津信一郎, 野崎智義, 坪井敬文, 中野陽子, 畑生俊光, 鳥居本美, 狩野繁之

    日本獣医学会学術集会講演要旨集   133rd   72 - 72   2002.3

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  • ネズミマラリア原虫Plasmodium berghei強毒株(NK65),弱毒株(XAT)間におけるプロテオーム解析の試み

    石川浩之, 河津信一郎, 畑生俊光, 駒木加奈子, 中野陽子, 鈴木守, 狩野繁之

    日本寄生虫学会大会プログラム・抄録集   71st   114   2002.3

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  • フィリピン・ミンダナオ島における熱帯熱マラリア原虫クロロキン感受性の検討

    畑生俊光, 河津信一郎, 鈴木淳, VALENZUELA R F, VILLACORTE E A, RIVERA P T, 狩野繁之

    日本寄生虫学会大会プログラム・抄録集   71st   118   2002.3

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  • The expression system of biologically active canine interleukin-8 in Leishmania promastigotes

    T Hatabu, Y Matsumoto, S Kawazu, Y Nakamura, T Kamio, HG Lu, KP Chang, Y Hashiguchi, S Kano, T Onodera, Y Matsumoto

    PARASITOLOGY INTERNATIONAL   51 ( 1 )   63 - 71   2002.3

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    It has been reported that Leishmania promastigotes have ability to express foreign genes on drug selectable plasmids. To investigate further abilities of the recently described expression vector, P6.5, in the transfection of Leishmania organisms (Chen D-Q, Kolli BK, Yadava N et al. Episomal expression of specific sense and antisense mRNAs in Leishmania amazonensis: modulation of gp63 levels in promastigotes and their infection of macrophages in vitro. Infect Immun 2000;68:80-86). the constructed expression vector, which contains canine interleukin-8 (cIL-8) coding cDNA, was introduced by electroporation to promastigotes of four species of the genus Leishmania: Leishmania amazonensis, L. equatorensis, L. donovani and L. infantum. Extrachromosomal DNAs and total RNAs from the transfected promastigotes were subjected to polymerase chain reaction (PCR) and reverse transcriptase-PCR, respectively, using cIL-8 gene specific primers, and a predicted product of 330 bp was detected. Western blot analysis using a mouse monoclonal antibody raised against cIL-8 demonstrated the successful expression of cIL-8 in the transfectants and culture supernatants. Culture supernatants of the transfected L. amazonensis and L. equatorensis promastigotes showed a high chemotactic activity to both dog and mouse polymorphonuclear leukocytes. These results indicate that Leishmania promastigotes transfected with the expression vector P6.5 containing cIL-8 cDNA are capable of producing biologically active cIL-8. The Leishmania expression system using the P6.5 vector might be a useful alternative for the production of biologically active recombinant cytokines. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

    DOI: 10.1016/S1383-5769(01)00107-6

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  • The expression system of biologically active canine interleukin-8 in Leishmania promastigotes. Reviewed International journal

    Toshimitsu Hatabu, Yasunobu Matsumoto, Shin-ichiro Kawazu, Yuko Nakamura, Tsugihiko Kamio, Hong Gang Lu, Kwang-Poo Chang, Yoshihisa Hashiguchi, Shigeyuki Kano, Takashi Onodera, Yoshitsugu Matsumoto

    Parasitology international   51 ( 1 )   63 - 71   2002.3

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    It has been reported that Leishmania promastigotes have ability to express foreign genes on drug selectable plasmids. To investigate further abilities of the recently described expression vector, P6.5, in the transfection of Leishmania organisms (Chen D-Q, Kolli BK, Yadava N et al. Episomal expression of specific sense and antisense mRNAs in Leishmania amazonensis: modulation of gp63 levels in promastigotes and their infection of macrophages in vitro. Infect Immun 2000;68:80--86), the constructed expression vector, which contains canine interleukin-8 (cIL-8) coding cDNA, was introduced by electroporation to promastigotes of four species of the genus Leishmania: Leishmania amazonensis, L. equatorensis, L. donovani and L. infantum. Extrachromosomal DNAs and total RNAs from the transfected promastigotes were subjected to polymerase chain reaction (PCR) and reverse transcriptase-PCR, respectively, using cIL-8 gene specific primers, and a predicted product of 330 bp was detected. Western blot analysis using a mouse monoclonal antibody raised against cIL-8 demonstrated the successful expression of cIL-8 in the transfectants and culture supernatants. Culture supernatants of the transfected L. amazonensis and L. equatorensis promastigotes showed a high chemotactic activity to both dog and mouse polymorphonuclear leukocytes. These results indicate that Leishmania promastigotes transfected with the expression vector P6.5 containing cIL-8 cDNA are capable of producing biologically active cIL-8. The Leishmania expression system using the P6.5 vector might be a useful alternative for the production of biologically active recombinant cytokines.

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  • PCR-amplification, sequencing, and comparison of the var/PfEMP-1 gene from the blood of patients with falciparum malaria in the Philippines. Reviewed International journal

    Nozomu Ikenoue, Shin-ichiro Kawazu, Toshimitsu Hatabu, Elena A Villacorte, Pilarita T Rivera, Shigeyuki Kano

    The Southeast Asian journal of tropical medicine and public health   33 Suppl 3   8 - 13   2002

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    The adhesion of Plasmodium falciparum-infected erythrocytes to vascular endothelium and to uninfected red blood cells (RBCs) plays a key role in the pathology of severe malaria. Adhesion is known to be mediated in part by the antigenically-variant erythrocyte membrane protein-1 (PfEMP-1), which is encoded by the var-gene family of P. falciparum. It has recently been reported that in vitro a single parasite simultaneously transcribes multiple var-genes but that, through a developmentally regulated process, the parasite selects only one PfEMP-1 that will to reach the surface of the host RBC. Were this to be true in vivo, one would expect a correlation between the type of var/PfEMP-1 that is expressed on the parasite-infected RBC and the severity of clinical disease. In order to test this assumption, we determined the sequence of the var-gene that was expressed by the parasites in patients' blood samples. Seven blood samples were collected from patients with or without severe clinical symptoms (cerebral malaria): two samples were from patients diagnosed as having imported falciparum malaria at the International Medical Center of Japan (IMCJ); the five others were from patients of the Davao Regional Hospital in Davao, the Philippines. The parasites (ring stage) in the blood samples were cultured for 24 hours; the matured trophozoites, in which the var-gene selection had taken place, served as material for mRNA isolation. The cDNA corresponding to the Duffy-binding-like (DBL)-1 domain of the var-gene was amplified by RT-PCR, using a region-specific primer set. The amplified cDNAs were cloned into the plasmid vector; the resultant clones (32) were sequenced on both strands. The results indicated that there was considerable diversity in the sequence of the DBL-1 domain among the clones, even among those from a single patient. In conclusion, it was difficult to demonstrate the correlation between the type of var-gene transcripts found in the RBCs of malaria patients and the severity of their symptoms.

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  • フィリピン・ミンダナオ島における熱帯熱マラリア原虫の薬剤感受性 酸素吸収・炭酸ガス発生剤(アネロパック)を用いた薬剤感受性試験

    畑生俊光, 鈴木淳, VALENZUELA R F, VILLACORTE E A, RIVERA R T, 河津信一郎, 狩野繁之

    日本熱帯医学会雑誌   29 ( 増刊 )   160 - 160   2001.8

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  • Molecular characterization of a 2-Cys peroxiredoxin from the human malaria parasite Plasmodium falciparum

    S Kawazu, K Komaki, N Tsuji, S Kawai, N Ikenoue, T Hatabu, H Ishikawa, Y Matsumoto, K Himeno, S Kano

    MOLECULAR AND BIOCHEMICAL PARASITOLOGY   116 ( 1 )   73 - 79   2001.8

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    We have identified the 2-Cys peroxiredoxin (PfPrx-1) from the human malaria parasite Plasmodium falciparum. The PfPrx-1 showed the highest identity at amino acid level to the type Il Prx among the currently known six subfamilies of mammalian Prx. The sequence identity between the PfPrx-1 and the previously reported I-Cys Prx. of P. falciparum (PfPrx-2), which corresponded to mammalian type VI Prx, was 25%. This suggests that the parasite possesses two Prx subfamilies. The PfPrx-1 showed significant sequence similarities with those of 2-Cys peroxiredoxins of plants in the BLASTX search. This may reflect the consequences of a genetic transfer from an algal endosymbiont to the parasite nucleus during evolution. The recombinant PfPrx-1 protein (rPfPrx-1) was expressed as a histidine fusion protein in Escherichia coli and purified with Ni chromatography. The rPfPrx-1 existed as dimers under non-reducing conditions and dissociated into monomers in the presence of dithiothreitol. The PfPrx-1 protein also exists as a dimer in the parasites themselves. The reduction of the oxidized enzyme by the donation of electrons from E. coli thioredoxin (Trx)/Trx reductase system was demonstrated in its reaction with H2O2, using the rPfPrx-1 protein. These results suggested that the PfPrx-1 can act as a terminal peroxidase of the parasite Trx system. An elevated expression of the PfPrx-1 protein seen in the trophozoite, the stage with active metabolism, suggests an association of the parasite Trx. system with its intracellular redox control. (C) 2001 Elsevier Science B.V. All rights reserved.

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  • Molecular characterization of a 2-Cys peroxiredoxin from the human malaria parasite Plasmodium falciparum

    S Kawazu, K Komaki, N Tsuji, S Kawai, N Ikenoue, T Hatabu, H Ishikawa, Y Matsumoto, K Himeno, S Kano

    MOLECULAR AND BIOCHEMICAL PARASITOLOGY   116 ( 1 )   73 - 79   2001.8

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    We have identified the 2-Cys peroxiredoxin (PfPrx-1) from the human malaria parasite Plasmodium falciparum. The PfPrx-1 showed the highest identity at amino acid level to the type Il Prx among the currently known six subfamilies of mammalian Prx. The sequence identity between the PfPrx-1 and the previously reported I-Cys Prx. of P. falciparum (PfPrx-2), which corresponded to mammalian type VI Prx, was 25%. This suggests that the parasite possesses two Prx subfamilies. The PfPrx-1 showed significant sequence similarities with those of 2-Cys peroxiredoxins of plants in the BLASTX search. This may reflect the consequences of a genetic transfer from an algal endosymbiont to the parasite nucleus during evolution. The recombinant PfPrx-1 protein (rPfPrx-1) was expressed as a histidine fusion protein in Escherichia coli and purified with Ni chromatography. The rPfPrx-1 existed as dimers under non-reducing conditions and dissociated into monomers in the presence of dithiothreitol. The PfPrx-1 protein also exists as a dimer in the parasites themselves. The reduction of the oxidized enzyme by the donation of electrons from E. coli thioredoxin (Trx)/Trx reductase system was demonstrated in its reaction with H2O2, using the rPfPrx-1 protein. These results suggested that the PfPrx-1 can act as a terminal peroxidase of the parasite Trx system. An elevated expression of the PfPrx-1 protein seen in the trophozoite, the stage with active metabolism, suggests an association of the parasite Trx. system with its intracellular redox control. (C) 2001 Elsevier Science B.V. All rights reserved.

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  • 熱帯熱マラリア原虫(Plasmodium falciparum)2‐Cys型ペルオキシレドキシンの性状解析

    河津信一郎, 駒木加奈子, 辻尚利, 川合覚, 池ノ上望, 石川浩之, 畑生俊光, 松本芳嗣, 狩野繁之

    日本獣医学会学術集会講演要旨集   131st   65 - 65   2001.3

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  • P181 Immunohistochemical analysis of liver and spleen in beige mutant mice infected with P. berghei XAT

    HATABU Toshimitsu, ISHIKAWA Hiroyuki, KOMAKI Kanako, MIZUNO Yasutaka, FUKUDA Toshio, SUZUKI Mamoru, KAWAZU Shinichiro, KANO Shigeyuki

    Med. Entomol. Zool.   52 ( 0 )   123 - 123   2001

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    DOI: 10.7601/mez.52.123_1

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  • A case of falciparum malaria successfully treated with intravenus artesunete.

    HATABU, TOSHIMITSU

    感染症学雑誌   75(9): 822-5   2001

  • A case of falciparum malaria successfully treated with intravenus artesunete.

    HATABU, TOSHIMITSU

    感染症学雑誌   75(9): 822-5   2001

  • フィリピンミンダナオ島のマラリア流行調査ー携帯型連続培養システムを用いたマラリア原虫薬剤感受性試験ー

    畑生 俊光

    熱帯   第34巻187-196   2001

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  • P165 Molecular cloning of 2-Cys peroxiredoxin from the human malaria parasite Plasmodium falciparum

    KAWAZU Shinichiro, KOMAKI Kanako, TSUJI Naotoshi, KAWAI Satoru, ISHIKAWA Hiroyuki, HATABU Toshimitsu, MATSUMOTO Yoshitsugu, KANO Shigeyuki

    Med. Entomol. Zool.   52 ( 0 )   119 - 119   2001

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    DOI: 10.7601/mez.52.119_1

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  • P164 Study on vitamin A uptake of Plasmodium falciparum in vitro

    MIZUNO Yasutaka, KAWAZU Shin-ichiro, HATABU Toshimitsu, KOMAKI Kanako, ISHIKAWA Hiroyuki, KANO Shigeyuki, OHTOMO Hiroshi

    Med. Entomol. Zool.   52 ( 0 )   118 - 118   2001

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    DOI: 10.7601/mez.52.118_4

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  • P166 Production of transgenic Plasmodium falciparum overexpressing an anti-oxidant enzyme, peroxiredoxin

    KOMAKI Kanako, KAWAZU Shinichiro, HATABU Toshimitsu, ISHIKAWA Hiroyuki, KANO Shigeyuki

    Med. Entomol. Zool.   52 ( 0 )   119 - 119   2001

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    DOI: 10.7601/mez.52.119_2

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  • P94W4-4 Growth inhibition of Plasmodium falciparum by treatment with anti-recombinant Pf-enolase IgG

    ISHIKAWA Hiroyuki, KAWAZU Shin ichiro, HATABU Toshimitsu, KOMAKI Kanako, IKENOUE Nozomu, SUZUKI Mamoru, KANO Shigeyuki

    Med. Entomol. Zool.   52 ( 0 )   101 - 101   2001

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    DOI: 10.7601/mez.52.101_2

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  • CD4(+) cells are indispensable for ulcer development in murine cutaneous leishmaniasis

    M Terabe, T Kuramochi, M Ito, T Hatabu, C Sanjoba, KP Chang, T Onodera, Y Matsumoto

    INFECTION AND IMMUNITY   68 ( 8 )   4574 - 4577   2000.8

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    One of the most characteristic clinical features in cutaneous leishmaniasis is the development of nodules followed by ulcerations at the site of infection. Leishmania amazonensis-infected mice show similar ulcerative lesions. Leishmania-infected severe combined immunodeficiency (SCID) mice, however, have been shown to develop nonulcerative nodules. In the present study, the roles of T cells in ulceration were examined using SCID mice in cell reconstitution experiments. After development of nonulcerative nodules, SCID mice were inoculated with splenocytes from either Leishmania-infected or naive immunocompetent mice, resulting in ulceration in all mice. When naive splenocytes were depleted of CD4(+), CD8(+), or B220(+) cell populations and the remaining cells were injected into Leishmania-infected SCID mice after the development of nodules, only SCID mice inoculated with splenocytes depleted of CD4(+) cells did not show ulceration. The evidence obtained in this study clearly shows that the CD4(+) cell population is indispensable for ulceration in leishmaniasis lesions of SCID mice.

    DOI: 10.1128/IAI.68.8.4574-4577.2000

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  • CD4(+) cells are indispensable for ulcer development in murine cutaneous leishmaniasis

    M Terabe, T Kuramochi, M Ito, T Hatabu, C Sanjoba, KP Chang, T Onodera, Y Matsumoto

    INFECTION AND IMMUNITY   68 ( 8 )   4574 - 4577   2000.8

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    One of the most characteristic clinical features in cutaneous leishmaniasis is the development of nodules followed by ulcerations at the site of infection. Leishmania amazonensis-infected mice show similar ulcerative lesions. Leishmania-infected severe combined immunodeficiency (SCID) mice, however, have been shown to develop nonulcerative nodules. In the present study, the roles of T cells in ulceration were examined using SCID mice in cell reconstitution experiments. After development of nonulcerative nodules, SCID mice were inoculated with splenocytes from either Leishmania-infected or naive immunocompetent mice, resulting in ulceration in all mice. When naive splenocytes were depleted of CD4(+), CD8(+), or B220(+) cell populations and the remaining cells were injected into Leishmania-infected SCID mice after the development of nodules, only SCID mice inoculated with splenocytes depleted of CD4(+) cells did not show ulceration. The evidence obtained in this study clearly shows that the CD4(+) cell population is indispensable for ulceration in leishmaniasis lesions of SCID mice.

    DOI: 10.1128/IAI.68.8.4574-4577.2000

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  • Molecular cloning and characterization of a peroxiredoxin from the human malaria parasite Plasmodium falciparum

    S Kawazu, N Tsuji, T Hatabu, S Kawai, Y Matsumoto, S Kano

    MOLECULAR AND BIOCHEMICAL PARASITOLOGY   109 ( 2 )   165 - 169   2000.7

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    Language:English   Publisher:ELSEVIER SCIENCE BV  

    DOI: 10.1016/S0166-6851(00)00243-7

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  • Molecular cloning and characterization of a peroxiredoxin from the human malaria parasite Plasmodium falciparum

    S Kawazu, N Tsuji, T Hatabu, S Kawai, Y Matsumoto, S Kano

    MOLECULAR AND BIOCHEMICAL PARASITOLOGY   109 ( 2 )   165 - 169   2000.7

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    DOI: 10.1016/S0166-6851(00)00243-7

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  • Cultivation of Plasmodium falciparum Isolates Under the Anaeropack Gas Condition in a Portable Thermostatic Incubator.

    MIZUNO YASUTAKA, HATABU TOSHIMITSU, KAWAZU SHIN-ICHIRO, MASUDA GOHTA, OHTOMO HIROSHI, SUZUKI MAMORU, KANO SHIGEYUKI

    Tropical Medicine and Health   23: 393-399 ( 4 )   383 - 385   2000

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    DOI: 10.2149/tmh1973.28.383

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  • Cultivation of Plasmodium falciparum isolates under the AnaeroPack gas condition in a portable thermostatic incubator.

    HATABU, TOSHIMITSU

    Japanese Journal of Tropical Medicine and Hygine   23: 393-399 ( 4 )   383 - 385   2000

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    DOI: 10.2149/tmh1973.28.383

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  • 改良型ポータブル恒温槽及び酸素吸収・炭酸ガス発生剤(アネロパックTM)を用いた熱帯熱マラリア原虫の培養

    畑生 俊光, 水野 泰孝, 河津 信一郎, 鈴木 守, 狩野 繁之

    日本獣医学会学術集会講演要旨集   128回   161 - 161   1999.9

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  • Leishmania amazonensis infection in nude mice

    M Terabe, T Hatabu, H Takahashi, M Ito, T Onodera, Y Matsumoto

    EXPERIMENTAL ANIMALS   48 ( 2 )   119 - 123   1999.4

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    Leishmania amazonensis is an intracellular protozoan parasite of macrophages. Cutaneous leishmaniasis in an immunocompetent host begins as papules or nodules followed by ulceration at the site of promastigote inoculation. In this study, the pathological changes of cutaneous leishmaniasis lesions in T cell deficient nude mice were examined. When infected with L. amazonensis promastigotes, nude mice developed non-ulcerative cutaneous nodules, By histological examination of cutaneous lesions, massive accumulation of vacuolated histiocytes containing amastigotes was observed in all the nude mice. Although infiltration of mononuclear and polymorphonuclear cells was seen in the lesions of immunocompetent mice, few such cells were observed in the lesions of nude mice. These results indicate the importance of T cells on the ulcer formation in cutaneous leishmaniasis.

    DOI: 10.1538/expanim.48.119

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  • Leishmania amazonensis infection in nude mice

    M Terabe, T Hatabu, H Takahashi, M Ito, T Onodera, Y Matsumoto

    EXPERIMENTAL ANIMALS   48 ( 2 )   119 - 123   1999.4

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    Leishmania amazonensis is an intracellular protozoan parasite of macrophages. Cutaneous leishmaniasis in an immunocompetent host begins as papules or nodules followed by ulceration at the site of promastigote inoculation. In this study, the pathological changes of cutaneous leishmaniasis lesions in T cell deficient nude mice were examined. When infected with L. amazonensis promastigotes, nude mice developed non-ulcerative cutaneous nodules, By histological examination of cutaneous lesions, massive accumulation of vacuolated histiocytes containing amastigotes was observed in all the nude mice. Although infiltration of mononuclear and polymorphonuclear cells was seen in the lesions of immunocompetent mice, few such cells were observed in the lesions of nude mice. These results indicate the importance of T cells on the ulcer formation in cutaneous leishmaniasis.

    DOI: 10.1538/expanim.48.119

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  • LEISHMANIASIS IN CENTRAL EURASIA

    MATSUMOTO YOSHITSUGU, HATABU TOSHIMITSU, SANJOBA CHIZU, MATSUMOTO YASUNOBU, SASAKI TETSUHIKO, KAWAZU SHIN-ICHIRO, NAKAI YUTAKA, KATAKURA KEN, ITO MAMORU, NAGAKURA KOICHI, AIKAWA MASAMICHI

    Japanese journal of tropical medicine and hygiene   27 ( 1 )   59 - 62   1999.3

  • Non-ulcerative cutaneous lesion in immunodeficient mice with Leishmania amazonensis infection

    Takashi Kuramochi, Toshimitsu Hatabu, Mamoru Ito, Yoshihito Ueyama, Shin-Ichiro Kawazu, Takashi Onodera, Yoshitsugu Matsumoto

    Parasitology International   48 ( 1 )   47 - 53   1999.3

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    Cutaneous leishmaniasis begins as papules or nodules at the site of promastigote inoculation. The next key pathogenic event in this disease is the formation of an ulcer at this site. Leishmania infection in immunodeficient mice, however, showed non-ulcerative cutaneous lesions suggesting the involvement of the immune system in ulcer formation. Severe combined immunodeficient (SCID), recombination-activating gene 2 knockout (RAG-2(-/-)), and immunocompetent mice were inoculated subcutaneously with cultured L. amazonensis promastigotes. Macroscopic nodules appeared at the inoculation site within 2 weeks of infection in all the mice and gradually extended to the surrounding skin tissue. Although nodules of immunocompetent mice ulcerated within 6 weeks, immunodeficient mice did not form ulcers even after 25 weeks of inoculation. These results strongly suggest the importance of functional T and B cells in ulcer formation of cutaneous leishmaniasis and are consistent with clinical features of non-ulcerative cutaneous leishmaniasis in some AIDS patients. The present study also indicates that the L. amazonensis-infected immunodeficient mouse model might be suitable for studying the mechanisms of ulcer formation in cutaneous leishmaniasis.

    DOI: 10.1016/S1383-5769(98)00040-3

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  • Non-ulcerative cutaneous lesion in immunodeficient mice with Leishmania amazonensis infection

    Takashi Kuramochi, Toshimitsu Hatabu, Mamoru Ito, Yoshihito Ueyama, Shin-Ichiro Kawazu, Takashi Onodera, Yoshitsugu Matsumoto

    Parasitology International   48 ( 1 )   47 - 53   1999.3

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    Cutaneous leishmaniasis begins as papules or nodules at the site of promastigote inoculation. The next key pathogenic event in this disease is the formation of an ulcer at this site. Leishmania infection in immunodeficient mice, however, showed non-ulcerative cutaneous lesions suggesting the involvement of the immune system in ulcer formation. Severe combined immunodeficient (SCID), recombination-activating gene 2 knockout (RAG-2(-/-)), and immunocompetent mice were inoculated subcutaneously with cultured L. amazonensis promastigotes. Macroscopic nodules appeared at the inoculation site within 2 weeks of infection in all the mice and gradually extended to the surrounding skin tissue. Although nodules of immunocompetent mice ulcerated within 6 weeks, immunodeficient mice did not form ulcers even after 25 weeks of inoculation. These results strongly suggest the importance of functional T and B cells in ulcer formation of cutaneous leishmaniasis and are consistent with clinical features of non-ulcerative cutaneous leishmaniasis in some AIDS patients. The present study also indicates that the L. amazonensis-infected immunodeficient mouse model might be suitable for studying the mechanisms of ulcer formation in cutaneous leishmaniasis.

    DOI: 10.1016/S1383-5769(98)00040-3

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  • リーシュマニア原虫を用いた哺乳動物遺伝子発現系の検討

    中村 優子, 畑生 俊光, 松本 安喜, 河津 信一郎, Chang K.-P, 佐伯 圭一, 小野寺 節, 松本 芳嗣

    日本獣医学会学術集会講演要旨集   127回   93 - 93   1999.3

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  • Leishmania spp.とζ-crystallin/NADPH oxidoreductase homologue(P36)遺伝子の比較

    河津 信一郎, 片倉 賢, 永倉 貢一, 畑生 俊光, 伊藤 守, 中井 裕, 相川 正道, Chang K.-P, 神尾 次彦, 狩野 繁之, 松本 芳嗣

    日本獣医学会学術集会講演要旨集   127回   93 - 93   1999.3

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  • Leishmania mini-exon genes for molecular epidemiology of leishmaniasis in China and Ecuador

    Ken Katakura, Shin-Ichiro Kawazu, Chizu Sanjyoba, Toshimitsu Naya, Yoshitsugu Matsumoto, Mamoru Ito, Koichi Nagakura, Masamichi Aikawa, Yoshihisa Hashiguchi

    Tokai Journal of Experimental and Clinical Medicine   23 ( 6 )   393 - 399   1998.12

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    The mini-exon gene is unique and is tandemly repeated in the Leishmania genome. The transcribed region is highly conserved, but the non-transcribed spacer region is distinct in length and in sequence among different Leishmania species. The usefulness of PCR amplification of the Leishmania mini-exon gene was examined for molecular epidemiology of visceral and cutaneous leishmaniasis. We previously described a PCR method for amplification of the mini-exon gene and obtained positive amplification in bone marrow aspirates of patients with visceral leishmaniasis in China. In this study, we have cloned and sequenced two PCR products from the patients. The sequences of two products revealed 100% identity and showed more similarity to the mini-exon gene of L. donovani Indian strain than those of L. donovani complex in Africa and South America. We also applied this PCR method to the diagnosis of cutaneous leishmaniasis. We obtained positive PCR amplification in skin biopsy materials taken from patients with cutaneous leishmaniasis in Ecuador. Since this PCR amplification is simple and requires only a pair of primers to detect all Leishmania species distributed in Ecuador, the method may be a useful tool for the detection of parasites, not only from patients, but also from sandflies and reservoir animals in this area of endemicity.

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  • Leishmania mini-exon genes for molecular epidemiology of leishmaniasis in China and Ecuador

    Ken Katakura, Shin-Ichiro Kawazu, Chizu Sanjyoba, Toshimitsu Naya, Yoshitsugu Matsumoto, Mamoru Ito, Koichi Nagakura, Masamichi Aikawa, Yoshihisa Hashiguchi

    Tokai Journal of Experimental and Clinical Medicine   23 ( 6 )   393 - 399   1998.12

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    The mini-exon gene is unique and is tandemly repeated in the Leishmania genome. The transcribed region is highly conserved, but the non-transcribed spacer region is distinct in length and in sequence among different Leishmania species. The usefulness of PCR amplification of the Leishmania mini-exon gene was examined for molecular epidemiology of visceral and cutaneous leishmaniasis. We previously described a PCR method for amplification of the mini-exon gene and obtained positive amplification in bone marrow aspirates of patients with visceral leishmaniasis in China. In this study, we have cloned and sequenced two PCR products from the patients. The sequences of two products revealed 100% identity and showed more similarity to the mini-exon gene of L. donovani Indian strain than those of L. donovani complex in Africa and South America. We also applied this PCR method to the diagnosis of cutaneous leishmaniasis. We obtained positive PCR amplification in skin biopsy materials taken from patients with cutaneous leishmaniasis in Ecuador. Since this PCR amplification is simple and requires only a pair of primers to detect all Leishmania species distributed in Ecuador, the method may be a useful tool for the detection of parasites, not only from patients, but also from sandflies and reservoir animals in this area of endemicity.

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  • Diagnosis of kala-azar by nested PCR based on amplification of the Leishmania mini-exon gene

    K Katakura, S Kawazu, T Naya, K Nagakura, M Ito, M Aikawa, JQ Qu, LR Guan, XP Zuo, JJ Chai, KP Chang, Y Matsumoto

    JOURNAL OF CLINICAL MICROBIOLOGY   36 ( 8 )   2173 - 2177   1998.8

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    To diagnose visceral leishmaniasis (kala-azar), we have developed a nested PCR method based on amplification of the mini-exon gene, which is unique and tandomly repeated in the Leishmania genome. Nested PCR was sufficiently sensitive for the detection of DNA in an amount equivalent to a single Leishmania parasite or less. We examined the usefulness of this PCR method using bone marrow aspirates and buffy coat cells collected from kala-azar patients who had or had not received chemotherapy in northwest China. We obtained PCR positivity for all of the parasitologically positive bone marrow samples from the patients. Some ambiguities with the primary PCR results were eliminated by the subsequent nested PCR. The buffy coat samples from 7 of 12 patients with splenomegaly were positive by the nested PCR, although only 2 of them were positive for parasites by culture. However, buffy coat samples from nine children, whose splenomegaly has been reduced and clinically cured by antimony treatment, were all negative. Thus; this nested PCR method represents a new tool for the diagnosis of kala-azar,vith patient blood samples instead of bone marrow or spleen aspirates obtained by more invasive procedures.

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  • Diagnosis of kala-azar by nested PCR based on amplification of the Leishmania mini-exon gene

    K Katakura, S Kawazu, T Naya, K Nagakura, M Ito, M Aikawa, JQ Qu, LR Guan, XP Zuo, JJ Chai, KP Chang, Y Matsumoto

    JOURNAL OF CLINICAL MICROBIOLOGY   36 ( 8 )   2173 - 2177   1998.8

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    Language:English   Publisher:AMER SOC MICROBIOLOGY  

    To diagnose visceral leishmaniasis (kala-azar), we have developed a nested PCR method based on amplification of the mini-exon gene, which is unique and tandomly repeated in the Leishmania genome. Nested PCR was sufficiently sensitive for the detection of DNA in an amount equivalent to a single Leishmania parasite or less. We examined the usefulness of this PCR method using bone marrow aspirates and buffy coat cells collected from kala-azar patients who had or had not received chemotherapy in northwest China. We obtained PCR positivity for all of the parasitologically positive bone marrow samples from the patients. Some ambiguities with the primary PCR results were eliminated by the subsequent nested PCR. The buffy coat samples from 7 of 12 patients with splenomegaly were positive by the nested PCR, although only 2 of them were positive for parasites by culture. However, buffy coat samples from nine children, whose splenomegaly has been reduced and clinically cured by antimony treatment, were all negative. Thus; this nested PCR method represents a new tool for the diagnosis of kala-azar,vith patient blood samples instead of bone marrow or spleen aspirates obtained by more invasive procedures.

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  • Membrane knobs of unfixed Babesia bovis-infected erythrocytes: New findings as revealed by atomic force microscopy and surface potential spectroscopy

    Masamichi Aikawa, Shin-Ichiro Kawazu, Tujihiko Kamio, Yoshitsugu Matsumoto, Toshimitsu Naya, Motomi Torii, Yoshihiro Ito, Bernard Tandler, Yamaji Nakano, Tsutomu Takeuchi, Soshi Shiraishi, Kiyoshi Kanamura

    Parasitology International   46 ( 4 )   241 - 246   1997

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    Atomic force microscopy (AFM) and surface potential microscopy (SPS) were used to examine the structure of the knobs of unfixed Babesia bovis-infected erythrocytes, AFM revealed each knob was found to consist of two subunits, components that have not been observed in chemically fixed knobs by transmission electron microscopy. In addition, SPS revealed the knob surface has a positive electrical charge and that the remainder of the erythrocyte surface has a negative charge. These factors might be central to the phenomenon of cytoadherence in cerebral babesiosis. © 1997 Elsevier Science Ireland Ltd.

    DOI: 10.1016/S1383-5769(97)00031-7

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Presentations

  • Scavenger receptor-Aは分子内cysteine-rich領域で熱帯熱マラリア原虫感染赤血球と接着する

    感染症沖縄フォーラム  2010 

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  • 熱帯熱マラリア原虫感染赤血球に対する新規接着因子としてのスカベンジャー受容体MARCOの同定

    日本寄生虫学会  2010 

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  • スカベンジャーレセプターMARCOは分子内領域SRCR domainを用いて熱帯熱マラリア感染赤血球と接着する

    感染症沖縄フォーラム  2010 

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  • CXCL16/SR-PSOX, membrane-bound form chemokine/a member of scavenger receptor, acts as a receptor of both the cytoadherence and erythrophagocytosis in severe malaria.

    2009 

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  • Class A scavenger receptor mediates the cytoadherence of Plasmodium falciparum-infected erythrocytes.

    The 9th Awaji International Forum on Infection and Immunity  2009 

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  • Class A scavenger receptor mediates the cytoadherence of Plasmodium falciparum-infected erythrocytes.

    The 9th Awaji International Forum on Infection and Immunity  2009 

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  • CXCL16/SR-PSOX, membrane-bound form chemokine/a member of scavenger receptor, acts as a receptor of both the cytoadherence and erythrophagocytosis in severe malaria.

    2009 

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  • 新規細胞接着因子としてのScavenger Receptor with C type Lectin (SRCL) の同定

    日本寄生虫学会  2009 

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  • Scavenger receptor-Aは分子内cystein-rich領域で熱帯熱マラリア原虫感染赤血球を認識する。

    分子寄生虫マラリアフォーラム  2009 

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  • 重症マラリア病態形成に関るスカベンジャーレセプターの役割

    第6回感染症沖縄フォーラム  2008 

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  • SR-PSOX/CXCL16, scavenger receptor/membrane bound form chemokine, is a cytoadherence-related molecule to Plasmodium falciparum-infected erythrocytes

    XVIIth International Congress of Tropical Medicine and Malaria  2008 

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  • 新規細胞接着因子としてのスカベンジャーレセプターAの解析

    2008 

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  • SR-PSOX/CXCL16, scavenger receptor/membrane bound form chemokine, is a cytoadherence-related molecule to Plasmodium falciparum-infected erythrocytes

    XVIIth International Congress of Tropical Medicine and Malaria  2008 

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  • Scavenger receptor/membrane-bound form chemokine, SR-PSOX/CXCL16, mediates the phagocytosis of Plasmodium falciparum-infected erythrocytes by mononuclear phagocytes and the cytoadherence to the endothelial cells.

    The 1st International Conference on Malaria Vaccines for the World  2007 

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  • 重症マラリア病態形成因子としてのスカベンジャーレセプターの解析

    分子寄生虫学ワークショップ  2007 

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  • 熱帯熱マラリア原虫に対するアムホテリシンBの発育阻止機序の解析

    第76回日本寄生虫学会  2007 

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  • 貪食細胞はマラリア原虫感染によりどのように変化するか?

    第15回分子寄生虫学ワークショップ  2007 

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  • Scavenger receptor/membrane-bound form chemokine, SR-PSOX/CXCL16, mediates the phagocytosis of Plasmodium falciparum-infected erythrocytes by mononuclear phagocytes and the cytoadherence to the endothelial cells.

    The 1st International Conference on Malaria Vaccines for the World  2007 

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  • マラリア原虫感染赤血球に対する接着・貪食因子としての膜結合型ケモカインCXCL16の同定

    第五回分子寄生虫マラリア研究フォーラム  2006 

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  • 熱帯熱マラリア原虫感染赤血球に対する新規細胞接着因子としての膜結合型ケモカインCXCL16の同定

    第75回日本寄生虫学会  2006 

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  • Trypanosoma cruzi infection inhibits Fas-mediated host-cell apoptosis and induces c-FLIP expression.

    The 20th IUBMB Congress and 11th FAOBMB Congress  2006 

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  • Molecular Epidemiology of Plasmodium falciparum in the Philippines

    Joint International Tropical Medicine Meeting 2006 and 6th Asia-Pacific Travel Health Conference  2006 

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  • 真菌由来化合物ヒポクレリンAの抗マラリア効果の検討

    第75回日本寄生虫学会  2006 

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  • Trypanosoma cruzi感染細胞におけるc-FLIPのユビキチン化機構の解析

    第75回日本寄生虫学会  2006 

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  • 真菌由来化合物ヒポクレリンAの抗マラリア効果の検討

    日本寄生虫学会  2006 

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  • Trypanosoma cruzi infection inhibits Fas-mediated host-cell apoptosis and induces c-FLIP expression.

    The 20th IUBMB Congress and 11th FAOBMB Congress  2006 

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  • Trypanosoma cruzi感染細胞におけるc-FLIPのユビキチン化機構の解析

    第75回日本寄生虫学会  2006 

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  • 熱帯熱マラリア原虫感染赤血球に対する新規細胞接着因子としての膜結合型ケモカインCXCL16の同定

    日本寄生虫学会  2006 

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  • Molecular Epidemiology of Plasmodium falciparum in the Philippines

    Joint International Tropical Medicine Meeting 2006 and 6th Asia-Pacific Travel Health Conference  2006 

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  • Inhibition of Fas-mediated host-cell apoptosis by Trypanosoma cruzi infection:Up-regulation of anti-apoptotic host proteins.

    The 5th Awaji International Forum on Infection and Immunity  2005 

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  • 群馬県内成人のトキソプラズマ抗体保有状況 -ここ10年間でどう変化したか-

    第74回日本寄生虫学会  2005 

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  • フィリピンで分離した熱帯熱マラリア原虫株のクロロキン耐性関連遺伝子pfcrt変異とin vitro CQ感受性の相関について

    第65回日本寄生虫学会東日本支部会  2005 

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  • Malaria vaccine candidate using enolase antigen of Plasmodium falciparum. Medicine and Health in the Topics

    XVth Internatiopnal Congress for Tropical Medicine and Malaria  2005 

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  • 群馬県における成人のスギ花粉およびダニIgE抗体保有率 10年間における変化および自覚症状との関連について

    北関東医学会  2005 

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  • 群馬県におけるToxoplasma gondii抗体保有率の推移

    北関東医学会  2005 

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  • 熱処理アムホテリシンBによる抗マラリア効果の検討

    第74回日本寄生虫学会  2005 

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  • Inhibition of Fas-mediated host-cell apoptosis by Trypanosoma cruzi infection:Up-regulation of anti-apoptotic host proteins.

    The 5th Awaji International Forum on Infection and Immunity  2005 

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  • Malaria vaccine candidate using enolase antigen of Plasmodium falciparum. Medicine and Health in the Topics

    XVth Internatiopnal Congress for Tropical Medicine and Malaria  2005 

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  • 真菌由来抗生物質グリオトキシンによる抗マラリア原虫効果の検討

    第74回日本寄生虫学会  2005 

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  • アムホテリシンBの抗マラリア効果の検討

    第73回日本寄生虫学会  2004 

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  • in vitro drug susceptibility and genetic variation of Plasmodium falciparum isolates from Thai-Myanmer border

    Joint International Tropical Medicine Meeting 2004  2004 

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  • Plasmodium falciparum-infected erythrocytes bind to the membrane-bound form of Fractalkine/CX3CL1

    日独原虫病学会  2004 

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  • Plasmodium falciparum-infected erythrocytes bind to the membrane-bound form of Fractalkine/CX3CL1

    日独原虫病学会  2004 

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  • 生薬由来成分による抗マラリア効果の検討

    第73回日本寄生虫学会大会  2004 

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  • 生薬由来成分による抗マラリア効果の検討

    第73回日本寄生虫学会大会  2004 

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  • in vitro drug susceptibility and genetic variation of Plasmodium falciparum isolates from Thai-Myanmer border

    Joint International Tropical Medicine Meeting 2004  2004 

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  • 新規マラリア原虫感染赤血球接着分子としての膜結合型フラクタルカインの同定

    第73回日本寄生虫学会  2003 

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  • 群馬県における幼児および児童・生徒の蟯虫卵保有状況の年次推移

    第73回日本寄生虫学会  2003 

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  • 熱帯熱マラリア原虫フィリピンミンダナオ島分離株におけるpfcrtおよびpfmdr-1遺伝子多型の解析

    第72回日本寄生虫学会  2003 

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  • ネズミマラリア原虫ペルオキシレドキシンの蚊体内発育ステージにおける発現

    第71回日本寄生虫学会  2002 

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  • フィリピンミンダナオ島における熱帯熱マラリア原虫クロロキン感受性の検討

    第71回日本寄生虫学会  2002 

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  • ネズミマラリア原虫Plasmodium berghei強毒株、弱毒株間におけるプロテオーム解析の試み

    第71回日本寄生虫学会  2002 

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  • ネズミマラリア原虫ペルオキシレドキシンの蚊体内発育ステージにおける発現

    第133回日本獣医学会  2002 

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  • マラリア原虫感染赤血球を貪食したマクロファージの応答性についての解析

    第71回日本寄生虫学会  2002 

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  • 熱帯熱マラリア原虫2-Cys型ペルオキシレドキシンの性状解析

    第70回日本寄生虫学会  2001 

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  • Antibody reaction to the Plasmodium falciparum enolase, a glycolytic enzyme

    The 50th annual meeting of the American Society of Tropical Medicine and Hygine  2001 

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  • 熱帯熱マラリア原虫における抗酸化酵素ペルオキシレドキシンの過剰発現株の作製

    第70回日本寄生虫学会  2001 

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  • Role of ploymorphonuclear leukocytes in cutaneous leishmaniasis

    WORLDleish2  2001 

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  • Antibody reaction to the Plasmodium falciparum enolase, a glycolytic enzyme

    The 50th annual meeting of the American Society of Tropical Medicine and Hygine  2001 

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  • Differentiation of leishmaniasis species complexes based on PCR amplificasion of highly conserved gene(gp36)

    WORLDleish2  2001 

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  • PCR-based differentiation of the species complexes in Leishmania spp.

    WORLDleish2  2001 

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  • CD4+ cells are indespensable for ulcer development in murine cutaneous leishmaniasis

    WORLDleish2  2001 

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  • Differentiation of leishmaniasis species complexes based on PCR amplificasion of highly conserved gene(gp36)

    WORLDleish2  2001 

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  • フィリピンミンダナオ島における熱帯熱マラリア原虫の薬剤感受性ー酸素吸収炭酸ガス発生剤を用いた薬剤感受性試験ー

    第42回日本熱帯医学会  2001 

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  • P. berghei XAT感染Beigeマウスにおける肝臓および脾臓浸潤細胞の免疫組織学的検討

    第70回日本寄生虫学会  2001 

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  • Role of ploymorphonuclear leukocytes in cutaneous leishmaniasis

    WORLDleish2  2001 

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  • CD4+ cells are indespensable for ulcer development in murine cutaneous leishmaniasis

    WORLDleish2  2001 

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  • 熱帯熱マラリア原虫由来解糖系酵素エノラーゼをターゲットとした原虫増殖抑止能に関する基礎的研究

    第70回日本寄生虫学会  2001 

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  • 熱帯熱マラリア原虫におけるビタミンA代謝機構の解明

    第70回日本寄生虫学会  2001 

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  • 2-Cys型ペルオキシレドキシンの性状解析

    第131回日本獣医学会  2001 

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  • 野外調査地における簡易検査キットOptiMALによるマラリア診断の有効性の検討

    第12回日本臨床寄生虫学会  2001 

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  • PCR-based differentiation of the species complexes in Leishmania spp.

    WORLDleish2  2001 

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Industrial property rights

  • 脂肪蓄積抑制剤及びその製造方法並びに血糖値上昇抑制剤及び腸内細菌叢改善剤

    神崎 浩, 仁戸田 照彦, 畑生 俊光

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    Applicant:国立大学法人 岡山大学

    Application no:特願2020-004396  Date applied:2020.1.15

    Announcement no:特開2021-109865  Date announced:2021.8.2

    J-GLOBAL

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  • 抗マラリア薬有効成分としてのグリオトキシンの新規用途、及びグリオトキシンを有効成分とする抗マラリア薬。

    佐藤 久美子, 畑生 俊光, 萩原 昌樹, 清澤 正幸, 鈴木 守

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    Applicant:国立大学法人群馬大学

    Application no:特願2005-069560  Date applied:2005.3.11

    Announcement no:特開2006-249019  Date announced:2006.9.21

    J-GLOBAL

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  • 植物精油成分を含む殺菌剤と該殺菌剤を用いた感染症予防方法

    佐藤 久美子, 田村 遵一, 畑生 俊光, 小池 弘人, 佐藤 浩子

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    Applicant:佐藤 久美子

    Application no:特願2004-300925  Date applied:2004.10.15

    Announcement no:特開2006-111577  Date announced:2006.4.27

    J-GLOBAL

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  • 微細霧を用いた消臭、病原微生物処理及び香気散布に係る方法

    佐藤 久美子, 田村 遵一, 畑生 俊光, 小池 弘人

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    Applicant:佐藤 久美子

    Application no:特願2003-281534  Date applied:2003.7.29

    Announcement no:特開2005-046338  Date announced:2005.2.24

    J-GLOBAL

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Awards

  • 第14回奨励賞

    2005  

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    Country:Japan

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  • パイオニア・スピリット賞

    2001  

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    Country:Japan

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Research Projects

  • 5-ALA産生乳酸菌の作製とその家畜用ワクチンプラットホームとしての可能性

    Grant number:22H02498  2022.04 - 2026.03

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    畑生 俊光, 荒川 健佑

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    Grant amount:\17550000 ( Direct expense: \13500000 、 Indirect expense:\4050000 )

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  • Studies on host autophagy and apoptosis in Trypanosoma cruzi infected cells

    Grant number:24590502  2012.04 - 2016.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    Shimada Junko, HATABU Toshimitsu

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    Grant amount:\5460000 ( Direct expense: \4200000 、 Indirect expense:\1260000 )

    Autophagy has emerged as an essential component of the defense system against intracellular pathogens. We demonstrated that Trypanosoma cruzi, an intracellular protozoan parasite, was not eliminated by host autophagic machinery. Puncta of LC3, an autophagy marker, were significantly increased after the infection, indicating that T. cruzi infection activated the early step of host autophagy. However, the degradation of p62, with a known marker in autolysosome formation, and autolysosomes were not observed in the infected cells. These results indicated that T. cruzi infection inhibits host autophagy pathway before the autolysosome formation. Furthermore, autophagosome formation was inhibited at the step of conversion from LC3-Atg3 to LC3-Ⅱin T. cruzi infected cells.

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  • Analysis of the factors of host-parasite relationship in severe malaria pathology

    Grant number:23790457  2011 - 2012

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)  Grant-in-Aid for Young Scientists (B)

    HATABU Toshimitsu, SHIMADA Junko, AMEMIYA Kenji, MIYAMOTO Yuto, MIYASHITA Daichi

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    Grant amount:\4420000 ( Direct expense: \3400000 、 Indirect expense:\1020000 )

    1) To confirm the ligands to SRs, the candidate proteins were searched on the PlasmoDB. Four of the Plasmodiumproteins were identified and their recombinant proteins were successfully made by common methods using E. coli, and now confirming their biological functions. 2) The expression of SRs was observed in mice infected with P. b e r g h e i ANKA (PbANKA). The expression of class A SR, MARCO, was markedly enhanced by PbANKA infection in lung, liver, and spleen, but not class B SR, CD36. MARCO was histopathologically expressed on the macrophages in marginal zone macrophages and endothelial cells in liver sinusoid. The differentiation of gene expression in both lethal and recovered mice group from P. y o e l l i17XL (Py17XL) infection were measuredby DNA microarray. The expression of 5893 in 59304 genes was enhanced in recovered group compared with lethal it. The results suggested that different types of macrophages were induced in both lethal (M2a macrophage) and recovered mice (M2c-like macrophage).

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  • Regulation of oxidative stress and apoptosis in Trypanosoma cruzi infected cells

    Grant number:21590461  2009 - 2011

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    SHIMADA Junko, HATABU Toshimitsu

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    Grant amount:\4680000 ( Direct expense: \3600000 、 Indirect expense:\1080000 )

    In Trypanosoma cuzi infected cells, the production of reactive oxygen species including nitric oxide (NO) was increased and inducible nitric oxide synthase (iNOS) gene was up-regulated. The inhibition of apoptosis in infected cells was reduced by the addition of NOS inhibitors. Furthermore, cellular FLICE-like inhibitory protein (c-FLIP), an apoptosis inhibitory protein, was nitrosylated in T. cruzi infected cells.

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  • マラリア原虫による宿主免疫修飾機構の解析

    Grant number:21022009  2009 - 2010

    日本学術振興会  科学研究費助成事業 特定領域研究  特定領域研究

    畑生 俊光

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    Grant amount:\7600000 ( Direct expense: \7600000 )

    重症熱帯熱マラリアの病態形成機構は、マラリア原虫感染赤血球(pRBC)の宿主細胞への細胞接着が重要な現象と考えられ、未知因子の存在が推測されている。我々は、生体における老化赤血球などの排除機構に着目し、その排除に関わるスカベンジャーレセプター(SR)に着目した。SRsの重症マラリア病態形成機構への関与を検討する目的で、SRs強制発現細胞株を作製しpRBCとの接着を観察した。また、Plasmodium berghei ANKA(PbANKA)感染マウスモデルを用い、PbANKA感染前後の脳、肺、肝臓、脾臓、心臓における9種類のSRs(SR-A、NARCO、SRCL、CD36、CD68、SREC-I、SR-PSOX、FEEL-I、CD163)のmRNA発現について検討した。pRBCとSRsの接着を検討するために、SR-A、MARCO、SR-PSOX、CD68、SRCL、SREC-Iそれぞれについて強制発現細胞株を作製した。細胞接着試験の結果、SR-A、MARCO、SR-PSOX、SRCLおよびSREC-IについてはpRBCとの接着が観察されたが、CD68は観察されなかった。PbANKA感染マウスモデルの観察結果から、CD36、CD163、SR-PSOX、SREC-1、について感染前後の発現臓器毎の違いは認められなかったが、MARCOは、感染7日後に肝臓、脾臓、肺でmRNA発現増強が観察された。SR-Aは、感染前の肝臓で強く発現が観察されたが、感染7日後には全臓器で発現が増強した。FEEL-Iは感染前の発現は認められなかったが、感染3日後より全臓器での発現が観察された。本研究の結果から、貪食細胞表面に発現が報告されているSR-AおよびMARCOは、これらの臓器においてマラリア原虫感染により発現誘導されるpRBCの接着・貪食因子である可能性が推測された。一方、CD36やSR-PSOXは、血管内皮細胞やマクロファージに発現することが報告されているが、pRBC感染前後で発現臓器等に差が認められなかったことから、血管内皮細胞ではpRBC接着因子として、貪食細胞ではpRBC貪食因子として機能し、発現部位で機能が異なる可能性が推測された。

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  • Research of host molecules associated with the pathogenesis of severe malarial anemia

    Grant number:20790322  2008 - 2009

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)  Grant-in-Aid for Young Scientists (B)

    HATABU Toshimitsu

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    Grant amount:\4420000 ( Direct expense: \3400000 、 Indirect expense:\1020000 )

    Severe falciparum malaria such as cerebral malaria and severe anemia is leading cause of morbidity and mortality. Plasmodium falciparum-infected red blood cells (pRBCs) adhere to the endothelial cells via receptors expressed on the surface of the endothelial cells, sequester in the microvasculature of several organs. Severe anemia which may be due to a number of factors including rupture of the pRBCs and phagocytosis of pRBCs is another cause of death. However, the molecular mechanism underlying both the cytoadherence and erythrophagocytosis related with severe malaria is not completely understood. Here, we report that the pRBCs bind to the class A scavenger receptors, SR-A and MARCO, which is expressed on the surface of the activated phagocytes.
    To identify the cytoadherence of pRBCs to SR-A and MARCO, human SR-A or MARCO cDNA was transfected to CHO cells (CHO-SR-A or CHO-MARCO cells). Furthermore, several mutants of both molecules were made to identify the sites related with pRBC adherence. pRBCs adhered to the both CHO- SR-A and CHO-MARCO cells, but not to the CHO-mock cells. The pRBC did not observed adherence to the deletion mutants of SRCR domain in both scavenger receptors.
    These results may suggest that both SR-A and MARCO acts as a host factor related with cytoadherence of the pRBCs, and contribute to our present understanding the pathology of severe falciparum malaria.

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  • Genetic epidemiological research on drug resistant malaria which has originated and been spreading in Asian countries.

    Grant number:19406013  2007 - 2009

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

    KANO Shigeyuki, MITAMURA Toshihide, HATABU Toshimitsu, IWAGAMI Moritoshi, TANABE Kazuyuki, KAWAZU Shin-Ichiro, NAKAZAWA Shusuke, TONGOL-RIVERA Pilarita, LOOAREESUWAN Sornchai, KRUDSOOD Srivicha, KHO Weon-Gyu, SOCHEAT Duong

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    Grant amount:\17030000 ( Direct expense: \13100000 、 Indirect expense:\3930000 )

    In the malaria endemic Philippines, the level of genetic diversity of Plasmodium falciparum correlates with the local malaria endemicity. The Thai P.f.populations had been under strong chloroquine selective pressure but the Vietnamese population had not, and that the origin of chloroquine resistance in Vietnam might be different from Thailand. The genealogical origin of P. vivax populations in South Korea was from the two different populations in southern China. These findings confirm that population genetic analyses are a useful tool for epidemiology of malaria.

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  • Molecular mechanisms of Trypanosoma cruzi survival using host apoptosis inhibitor

    Grant number:18590398  2006 - 2007

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    SHIMADA Junko, HATABU Toshimitsu

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    Grant amount:\3990000 ( Direct expense: \3600000 、 Indirect expense:\390000 )

    Trypanosoma cruzi is a protozoan parasite that causes Chagas' disease in South America. We demonstrated that the parasite infection inhibits death receptor-mediated apoptosis in host cells. This inhibition is thought to be a defense strategy for the parasite to escape from host immune responses. We clarified that the parasite dramatically up-regulates cellular FLICE-like inhibitory protein (c-FLIP), the only known mammalian inhibitor specific for death receptor signaling. We also found that c-FLIP knock-down with a small interfering RNA significantly restores Fas-mediated apoptosis in infected cells. To elucidate the mechanisms of c-FLIP up-regulation, we examined posttranscriptional regulation of c-FLIP expression in T. cruzi infected cells. It has been reported that c-FLIP is a key target for S-nitrosylation by nitric oxide (NO) in cancer cells. HT1080 or THP-1 cells were infected with T. cruzi or treated with NO donors, and further cultured for 1-3 days. Cell lysates were immunoprecipitated and analyzed by Western blot using anti-S-nitrosocysteine antibody in control and infected cells. By the addition of the NO donors, sodium nitroprusside, the nitrosylated level of FLIP was strongly increased. In infected cells nitrosylated c-FLIP was clearly detected in supernatant. These findings suggest that endogenously produced NO synthesized by NO synthase is a mediator of T. cruzi infection. S-nitrosylation of FLIP is an important mechanism utilized by NO rendering FLIP resistant to ubiquitination and proteasomal degradation by FasL.

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  • マラリア重症化における膜結合型ケモカインの機能的役割に関する研究

    Grant number:18790290  2006 - 2007

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    畑生 俊光

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    Grant amount:\3400000 ( Direct expense: \3400000 )

    (1)研究計画より、次年度以降に検討するスカベンジャーレセプター(SR)をピックアップした。具体的には9 classに分類されるSRのうちclass Aに類されるもの3種類およびclass Fに類されるもの1種類をターゲットとする。これら4種類のうち研究計画を前倒ししてSR-AIについて発現細胞を作成し、マラリア原虫感染赤血球との接着を検討した。その結果、SR-AI発現細胞に対してマラリア原虫感染赤血球の接着が確認され、この接着は抗SR-AI抗体によって阻害されることが判明した。一方でアネキシンVでは阻害されなかった。その他については、現在蛋白発現細胞を作成している。
    (2)ヤウスモデルを使用した感染実験を計画していた。遺伝子一過性発現マウスの作成は行わなかった。一方、感染モデルでは感染経過と赤血球表面への感染経過に伴うホスファチジルセリン発現動態の検討を行った。その結果、原虫寄生率の上昇に平行してホスファチジルセリン陽性赤血球率も上昇した。しかしながら、ホスファチジルセリン陽性赤血球率は最高値約20%(寄生率最高値約40%)であった。その後寄生率の減少及び感染の終息に伴いホスファチジルセリン陽性赤血球率も漸減した。すなわち感染の推移とホスファチジルセリン陽性赤血球率の動態はほぼ一致した。
    SR-PSOXについては遺伝子破壊マウスの国内作成が確認されたことから、当該マウスの導入と感染実験を今後予定している。

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  • A genomic epidemiological research on a drug resistant malaria spreading in Asian countries.

    Grant number:16406012  2004 - 2006

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

    KANO Shigeyuki, KAWAZU Shin-ichiro, HATABU Toshimitsu

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    Grant amount:\13300000 ( Direct expense: \13300000 )

    A mutation from Lys to Thr in the codon 76 of Plasmodium falciparum chloroquine resistant transporter protein (PfCRT) is associated with CQ resistance, and the genotype is used as a molecular marker to monitor the distribution and frequency of the CQ resistant malaria. In the present study, selection of the resistant strain in mixed cultures of a drug resistant strain (K1 which shows K76T) and a susceptible strain (FCR-3 which shows 76K) under a low chloroquine pressure (<80nM) was nicely observed in vivo using real-time PCR analysis.
    Then, we analyzed the frequency of the mutation in codon 72-76 of the pfcrt gene and 3 microsatellite (MS) DNA markers flanking the pfcrt, using P. falciparum isolates from the Philippines, Thailand, and southern part of Vietnam. Thirty-nine isolates from Thailand showed identical K76T but 6 out of 13 isolates from the Philippines showed mixed type. Twenty-seven of 39 isolates from Vietnam showed CQ susceptible genotype coding CVMNK, while other 10 did CQ resistance type (CVIET, CVIDT, CVMDT). The other 2 isolates were proved to be mixed with CQ susceptible/resistant.
    In the further analysis of the Vietnam isolates, the MS DNA markers of the CQ susceptible isolates were revealed to be highly polymorphic, while those of CQ resistant isolates were less polymorphic. One of the CQ resistant isolates (CVIET) had a different MS DNA pattern from K1 (CQ resistant strain; CVIET) from Thailand. The other CQ resistant isolate types (CVIDT, CVMDT) shared the same MS DNA patterns and these patterns were different from those of the CQ susceptible isolates nor K1. These results showed that the origin of the CQ resistant isolates in Vietnam might not be due to an introduction of the isolates from Thailand. Instead, it is suggested that the CQ resistant mutations possibly occurred within Vietnam.

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  • マラリア重症化に係わる新規病原因子の探求

    Grant number:16790242  2004 - 2005

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    畑生 俊光

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    Grant amount:\3600000 ( Direct expense: \3600000 )

    本研究年度は、膜結合型ケモカインの一つフラクタルカイン(FKN)に対して熱帯熱マラリア原虫感染赤血球が接着する際に利用する、新規熱帯熱マラリア原虫感染赤血球表面発現蛋白質の同定を試みた。研究方法は、(1)FKN接着熱帯熱マラリア原虫株を確立し、当該原虫株よりcDNAライブラリーを作製し、浮遊細胞株Jurkat株へ遺伝子導入する。その後、作製したcDNA導入細胞株と培養プレート表面にコーティングした組み換えFKN蛋白質(rFKN)との直接接着を観察することで、目的蛋白質をクローニングする。(2)yeast two-hybrid(Y2H)法を利用した蛋白質スクリーニングを行う、の2通りで行った。(1)について、FKN接着株を確立した後、当該原虫株よりcDNAライブラリーを作製した。作製したcDNAライブラリーを2種類の哺乳動物細胞発現ベクターに組み込んだマラリア原虫cDNAライブラリー強制発現ベクターを確立した。これらベクターをFKN受容体の発現がないことを確認した浮遊細胞株Jurkatにリポフェクション法およびエレクトロポレーション法にて遺伝子導入した。当該発現ベクターにはC末端側にGFP遺伝子を組み込んでおり、導入遺伝子産物はGFPとの融合蛋白質として発現される。そこで、導入遺伝子産物の発現はFACScanにて確認した。薬剤選抜後、rFKNとの接着を確認したが、当該細胞株とrFKNとの接着は確認できなかった。現在もスクリーニング継続中である。(2)について、Y2Hにてマラリア原虫cDNAライブラリー産物およびFKNとの相互作用を検討した結果、5個の候補蛋白質が同定された。これらの内、2個の蛋白質は接着関連蛋白質のホモローグであり、3個は未知の蛋白質であることがデータベースとの照合の結果明らかとなった。

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  • 細胞内寄生性原虫の病態形成・重症化機構の解析

    1999

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    Grant type:Competitive

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  • 細胞内寄生性原虫の病態形成・重症化機構の解析

    1999

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    Grant type:Competitive

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