Biomedical subjects

K Yoshimatsu

Publications and source records attributed to K Yoshimatsu.

At least 73 records · Page 4Linked to original sources

PubMed1997

Mechanism of action of E7010, an orally active sulfonamide antitumor agent: inhibition of mitosis by binding to the colchicine site of tubulin.

E7010 (N-[2-[(4-hydroxyphenyl)amino]-3-pyridinyl]-4-methoxybenzenesulfonami de), an orally active sulfonamide antitumor agent that is currently in a Phase I clinical trial, showed rather consistent growth-inhibitory activities against a panel of 26 human tumor cell lines (IC50 = 0.06-0.8 microg/ml), in contrast to vincristine (VCR; IC50 = 0.0002-0.04 microg/ml), 5-fluorouracil (IC50 = 0.2-30 microg/ml), Adriamycin (IC50 = 0.002-0.7 microg/ml), mitomycin C (IC50 = 0.007-3 microg/ml), 1-beta-D-arabinofuranoxylcytosine (IC50 = 0.005 to >30 microg/ml), camptothecin (IC50 = 0.002-0.4 microg/ml), and cisplatin (IC50 = 0.5-20 microg/ml). It caused a dose-dependent increase in the percentage of mitotic cells in parallel with a decrease in cell proliferation, like VCR. It also showed a dose-dependent inhibition of tubulin polymerization, which correlated well with the cell growth-inhibitory activity. 14C-labeled E7010 bound to purified tubulin, and this binding was inhibited by colchicine but not by VCR. However, its binding properties were different from those of colchicine, as well as those of VCR. E7010 was active against two kinds of VCR-resistant P388 cell lines, one of which showed multidrug resistance due to the overexpression of P-glycoprotein (resistant to Taxol), and the other did not show multidrug resistance (sensitive to Taxol). Furthermore, four E7010-resistant P388 cell lines showed no cross-resistance to VCR, a different pattern of resistance to podophyllotoxin, and collateral sensitivity to Taxol. Therefore, E7010 is a novel tubulin-binding agent that has a wider antitumor spectrum than VCR and has different properties from those of VCR or Taxol.

Aminophenols↗

PubMed1997

Protective effect of mucosal administration of recombinant human macrophage colony-stimulating factor (rhM-CSF) on mucosal infection of Sendai virus in mice.

We investigated the protection confered by the mucosal administration of recombinant human macrophage colony-stimulating factor (rhM-CSF) against mucosal infection of Sendai virus in mice. In an experimental infection model using Sendai virus, an intranasal (i.n.) administration of rhM-CSF (20 micrograms per mouse) 2 days before injection induced significant protection against a lethal infection of this virus. Also, its antiviral activity was dependent upon the dose of rhM-CSF. However, a subcutaneous (s.c.) administration of rhM-CSF with an effective dose (20 micrograms per mouse) i.n. did not confer protection. In a time course analysis of virus growth in the lungs, mice given rhM-CSF. i.n. significantly inhibited the early period of infection, compared with the untreated mice. Moreover, the level of interferon-gamma (IFN-gamma) in lung wash fluids from the rhM-CSF-treated mice was higher than that of the untreated mice. These results suggested that the mucosal (i.n.), but not the systemic (s.c.) administration of rhM-CSF augments host resistance against mucosal infection with Sendai virus, and that its prophylactic activity is related to growth inhibition of the virus and enhanced IFN-gamma secretion in the lungs.

Animals↗

PubMed1997

A case of tick-borne encephalitis in Japan and isolation of the the virus.

A case of tick-borne encephalitis (TBE) has not been reported for many years in Japan, although a serological survey of sera from domestic animals suggested the presence of TBE foci in Hokkaido, the northern island of Japan. Studies were conducted to prove the presence of an endemic focus of TBE virus in Japan by means of serology and virus isolation. In October 1993 in Hokkaido, a severe case of encephalitis in a dairy farmer's wife was diagnosed as TBE. Serological examination of paired serum specimens showed a rise in the neutralization antibody titer to Russian spring summer encephalitis virus. A seroepizootiological survey of dogs showed that the TBE-related virus was prevalent in the area. Three virus isolates were obtained from the blood of sentinel dogs, and antigenic analysis grouped the isolates into TBE-related viruses. Sequence analysis of the envelope protein gene identified one of the isolates as being of the same subtype as the Russian spring summer encephalitis (Far Eastern TBE) virus. The results provide evidence that TBE is endemic in a certain area of Japan.

Animals↗

PubMed1997

Hantavirus infection in SCID mice.

Severe combined immunodeficiency (SCID) mice were inoculated with Hantaan virus strain 76-118 (HTN) or Seoul virus strain SR-11 (SR) of hantaviruses. Susceptibility of SCID mice was compared with those of immunocompetent adult mice, newborn mice and nude mice. SCID mice inoculated with HTN or SR died 32 to 35 days after infection. Unlike newborn mice which also died of hantavirus infection, SCID mice survived longer than newborn mice and showed typical wasting symptoms rather than nervous symptoms. Immunohistochemical staining and virus isolation indicated that both HTN and SR inoculated SCID and SR inoculated nude mice showed systemic infection, but nude mice inoculated with SR survived for longer than 8 weeks after inoculation. Passive transfer of spleen cells from immunocompetent BALB/c mice conferred protection on SCID mice within 2 weeks of HTN infection. Immune mediated pathologic mechanism was examined by transferring the spleen cells to SCID mice inoculated with HTN virus 3 weeks before the cell transfer. The recipient SCID mice showed an increase of serum BUN level coinciding with the appearance of serum antibody to HTN virus, suggesting the immune mediated pathogenicity.

Adoptive Transfer↗

PubMed1997

[Anti tumor activity of farnesyl transferase inhibitor].

Posttranslational farnesylation by farnesyltransferase (FTase) is critical for the function of ras oncogene product and FTase has attracted attention as the new target of anticancer agents. B956 and B1352, obtained from the screening of CAAX analog inhibitors of FTase, induced flat reversion and inhibited the anchorage independent growth of ras transformant and ras mutated human tumor cell lines through the inhibition of posttranslational modification of ras p21. Inhibition of tumor growth in vivo was caused by inhibition of ras processing. Methyl ester prodrug of B956 and B1352 showed antitumor activity in ras mutated human tumor xenograft model. FTase inhibitor has the potential to be developed as therapy for ras mutated human tumors.

Alkyl and Aryl Transferases↗

PubMed1997

[Inhibitors of isoprenylation of ras p21].

Posttranslational modification and membrane localization are critical for the function of products of ras oncogenes which are frequently founded to be mutated in human tumors. Farnesylation by farnesyltransferase (FTase) is the first and obligatory step in the processing of ras p21, and FTase has attracted attention as a new target of anticancer agents. Many FTase inhibitors have been identified or synthesized in random screening, and studies on FPP analogs, CAAX analogs, and bisubstrate analogs. These inhibitors induced flat reversion and inhibited the anchorage-independent growth of ras transformant and ras-mutated human tumor cells through the inhibition of posttranslational modification of ras p21. B1086, L-739,749, L-744,832 and FTI-276, which are CAAX analogs, were reported to show inhibition of tumor growth in ras-mutated human tumor xenograft models and to induce regression of mammary and salivary carcinoma in ras transgenic mouse model. FTase inhibitors have the potential to be developed as therapy for ras-mutated human tumors. On the other hand, it has been reported that K-ras 4B p21 could be modified by geranylgeranyltransferase (GGTase). Therefore, GGTase inhibitors have also been evaluated in addition to FTase inhibitors.

Alkyl and Aryl Transferases↗

PubMed1996

Modes of Seoul virus infections: persistency in newborn rats and transiency in adult rats.

To understand the mode of persistent infection of Seoul virus in rodents, we examined the distribution of the virus genome and antibody production in infected rats. When 1-day-old rats were inoculated with the KI-83-262 strain, the S segment of viral genome was detected in sera, clots, lungs and kidneys from 3 to 184 days post inoculation (d.p.i.) by nested reverse transcriptase PCR. On the other hand, when 7-week-old rats were infected with this virus, viral genome was detected only in the lungs from 3 to 50 d.p.i. The neutralizing antibody titers of rats inoculated at 1-day of age were higher than those of rats inoculated at 7 weeks of age. In both age groups, however, the IgG avidity of antibody increased along with the course of infection. We found that urban rats (Rattus norvegicus) infected early in life harbored the virus for more than 6 months.

Animals↗

PubMed1996

Effect of MDP-Lys(L18) as a mucosal immunoadjuvant on protection of mucosal infections by Sendai virus and rotavirus.

To examine the effect of MDP-Lys(L18), a derivative of muramyl dipeptide (MDP), as a mucosal immunoadjuvant, we investigated its activity to augment host resistance against mucosal infections by Sendai virus and rotavirus in mice. In an experimental infection model using suckling mice (10-day-old) inoculated perorally (p.o.) with 1.5 x 10(6) p.f.u. mouse-1 of rotavirus strain SA11, intrarectal (i.r.) as well as p.o. administration of MDP-Lys(L18) (50 micrograms mouse-1) prior to virus infection markedly reduced rotavirus-induced diarrhea. Furthermore, when MDP-Lys(L18) was administered p.o. (1 mg mouse-1), i.r. (300 micrograms mouse-1) or intranasally (i.n., 100 micrograms mouse-1) various days before Sendai virus infection (2.6 x 10(4) HAD mouse-1), all the mucosal administration of MDP-Lys(L18) significantly protected a lethal infection of Sendai virus, showing a dose-dependent manner. However, the efficacy of MDP-Lys(L18) to induce the prophylactic activity against the viruses somewhat varied according to the administration route and timing. In time course analysis of virus isolation in vivo, the mice administered with MDP-Lys(L18) exhibited a significant reduction of both viruses in the lungs for Sendai virus and in the bowels for rotavirus. These results suggest that MDP-Lys(L18) is a potent mucosal immunoadjuvant to enhance nonspecific host resistance against two mucosal infectious viruses, Sendai virus and rotavirus.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1996

Characterization of the nucleocapsid protein of Hantaan virus strain 76-118 using monoclonal antibodies.

We characterized the antigenic sites on the nucleocapsid protein (NP) of Hantaan virus (HTN) using 10 monoclonal antibodies (MAbs). At least seven antigenic sites were revealed by a competitive binding assay and divided into three partially overlapping antigenic regions (I, II and III). Regions I [amino acids (aa) 1-103], II (aa 104-204) and III (aa 205-402) were mapped on NP by examining the reactivity of truncated gene products. Those that corresponded to region I reacted with immune mouse serum, indicating that the region contained major linear epitopes as reported with Four corners virus (FCV) and Puumala virus (PUU) NP. At least one MAb to each region inhibited viral growth when they were introduced into cells by scrape-loading. In addition, they conferred protection from a lethal HTN challenge to newborn mice. A PEPSCAN assay localized the epitope of MAb E5/G6 between aa 166-175. Since E5/G6, which had the highest inhibitory effect both in cells and in mice, showed no virus neutralization activity by ordinary neutralization test, this region is suggested to be important for the virus growth after entry into the cells.

Amino Acid Sequence↗

PubMed1996

Intellectual development of offspring of diabetic mothers.

We prospectively evaluated the intellectual development of 33 children who were born to 33 diabetic Japanese mothers and compared them to 34 children born to non-diabetic mothers (controls) during the same period at Kurume University Hospital between 1987 and 1989. Birthweight, maternal age and the infant's age at the time of intelligence testing did not differ significantly between the offspring of diabetic mothers (ODMs) and controls. Tanaka-Binet intelligence scores were significantly lower in the ODMs at 3 years of age than in controls (98.4 +/- 17.4 versus 113.4 +/- 15.3) (p = 0.0005). No correlation was found between IQ and maternal haemoglobin A1c levels during pregnancy. Maternal age and infant IQ were inversely correlated in ODMs (p = 0.0298, r = -0.3984), but no such correlation was demonstrated in the controls. The results indicated that the ODMs may show a poorer intellectual development than those of non-diabetic mothers.

Child Development↗

PubMed1996

Western blotting using recombinant Hantaan virus nucleocapsid protein expressed in silkworm as a serological confirmation of hantavirus infection in human sera.

Recombinant Hantaan virus nucleocapsid protein expressed in silkworm larvae was applied as a serological diagnostic antigen in Western blots (WB) of human sera. The sensitivity of this method was similar to that of the IFA test. Hemorrhagic fever with renal syndrome (HFRS) and nephropathia epidemica diagnosed by their cross-reactivity in WB. The specificity of this method was higher than that of IFA test because the background was low. Sera that exhibited high background staining in the IFA test were readily diagnosed with this method. We recommended WB using recombinant Hantaan virus nucleocapsid antigen as a confirmatory procedure for the serodiagnosis of hantavirus.

Animals↗

PubMed1995

Inhibition of human tumor xenograft growth by treatment with the farnesyl transferase inhibitor B956.

ras oncogenes are present in several types of cancers but are most frequently described in colon and pancreatic carcinomas. Consequently, ras is being targeted for drug development as a means to develop therapies for these types of cancer. The ras protein is posttranslationally modified by the addition of a farnesyl group, followed by cleavage of the COOH-terminal 3 amino acids and methylation of the prenylated cysteine. Because the posttranslational addition of farnesyl is obligatory not only for the remaining modifications to take place but also for ras control of cell growth, inhibitors of farnesylation are being developed as potential antitumor agents. In this report, a new peptidomimetic inhibitor of farnesyl transferase is described. This compound, B956, and its methyl ester B1086, inhibit the formation of colonies in soft agar of 14 human tumor cell lines expressing different ras oncogenes at concentrations between 0.2 and 60 microM. Higher concentrations of B956 (10-80 microM) were required to inhibit colony formation by 5 tumor cell lines without ras mutations. B956/B1086 at 100 mg/kg also inhibited tumor growth by EJ-1 human bladder carcinoma, HT1080 human fibrosarcoma, and to a lesser extent by HCT116 human colon carcinoma xenografts in nude mice. Furthermore, inhibition of tumor growth by B956 is shown to be correlated with inhibition of ras posttranslational processing in the tumor. Thus, peptidomimetic inhibitors of ras farnesylation have the potential to be developed as therapy for ras-dependent tumors.

Alkyl and Aryl Transferases↗

PubMed1995

Role of ADF/TRX and its inhibitor on the release of major basic protein from human eosinophils.

Adult T cell leukemia-derived factor (ADF)/Thioredoxin (TRX), originally defined as an IL-2 receptor alpha-chain/p55 inducer, has many cytokine-like activities. We reported that the release of major basic protein (MBP) from mature eosinophils stimulated with cytochalasin B and C5a were augmented after preincubation with recombinant ADF/TRX. The addition of a TRX specific inhibitor, BE40644, suppressed the augmentation of MBP release from mature eosinophils. It is suggested that BE40644 is applicable in allergic diseases associated with eosinophils.

Benzoquinones↗

PubMed1995

Rapid development of murine AIDS is dependent of signals provided by CD54 and CD11a.

Murine AIDS (MAIDS) is induced by infection with the replication-defective virus (BM5def) component in the LP-BM5 murine leukemia virus (MuLV) mixture. The disease is characterized by polyclonally activated CD4+ T cells and B cells. It is known that BM5def is expressed at highest levels in B lymphocytes and that B cells serve as viral antigen-presenting cells. Full and sustained activation of CD4+ T cells against a conventional Ag usually requires both TCR and costimulating signals. Among various molecules known to provide costimulatory function, the expression of CD54 (ICAM-1) and CD11a/CD18 (LFA-1) on MAIDS B cells was increased, whereas that of CD2, heat-stable Ag (CD24), CD80 (B7-1), and CD86 (B7-2) was unchanged from normal. C57BL/6 mice depleted of both CD54 and CD11a expression as a result of chronic administration of mAb had developed no MAIDS at 4 wk and 8 wk after LP-BM5 MuLV infection. In addition, the proliferative response of B cells to mitogen was well conserved, whereas MAIDS-associated increases in serum Ig levels were inhibited. Replication of BM5def was suppressed markedly in infected mice treated with the CD54 and CD11a mAbs. These results suggest that the CD54/CD11a signal transduction pathway is a critical determinant of MAIDS development, and the lack of an immune response against viral Ag is enough to suppress BM5def replication and to prevent MAIDS.

Animals↗

PubMed1995

Purification, primary structure, and evolution of cytochrome c-550 from the magnetic bacterium, Magnetospirillum magnetotacticum.

Cytochrome c-550 was purified from Magnetospirillum magnetotacticum to an electrophoretically homogeneous state, and some of its properties were determined. The cytochrome showed absorption peaks at 528 and 409 nm in the oxidized form, and at 550, 521, and 414 nm in the reduced form. Its midpoint redox potential at pH 7.0 was determined to be +289 mV. The primary structure of cytochrome c-550 was determined. Cytochrome c is composed of 97 amino acid residues, and its molecular weight was calculated to be 10,873, including heme c. Its primary structure is very similar to those of Rhodospirillum fulvum and Rhodospirillum molischianum cytochromes c2, suggesting that M. magnetotacticum is phylogenetically related to photosynthetic bacteria.

Amino Acid Sequence↗

PubMed1995

Effect of MDP-Lys(L18), a derivative of MDP, on enhancing host resistance against Hantaan virus infection in newborn mice.

We examined the effect of MDP-Lys(L18), a lipophilic derivative of muramyl dipeptide, on the enhancement of host resistance against virus infection in newborn mice. Newborn mice were inoculated with 4 LD50/mouse of Hantaan virus strain 76-118 (HTN) one day after birth. Mice given 100 micrograms/mouse of MDP-Lys(L18) before infection exhibited significantly higher survival rates than those of non-treated mice. The effect of MDP-Lys(L18) was also restorative when given to the mice 4 or 7 days after infection. The titers of virus isolated from the lungs and spleens 12 days after infection, were about 30-times lower in MDP-Lys(L18)-treated (lung: 1.0 x 10(3) FFU; spleen: 6.8 x 10(1) FFU/mouse), than those of non-treated mice (lung: 3.4 x 10(4) FFU; spleen: 1.9 x 10(3) FFU/mouse). Furthermore, the virus was undetectable in the brains of MDP-Lys(L18)-treated mice, whereas viruses were isolated from 3 of 6 non-treated mice. MDP-Lys(L18) augmented the number of peripheral leukocytes and splenocytes, as well as mitogenic responses of the cells from bone marrow and spleen of newborn mice. These results suggest that MDP-Lys(L18) enhanced the resistance of newborn mice against HTN virus in a systemic infection model, and that this mechanism is involved in the enhancement of hematopoiesis and responsiveness of immune-related cells to mitogens.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1995

Effects of muramyl dipeptide derivatives as adjuvants on the induction of antibody response to recombinant hepatitis B surface antigen.

The ability of two muramyl dipeptide (MDP) derivatives, B30-MDP and MDP-Lys(L18), to enhance the immunogenicity of recombinant hepatitis B surface antigen (rHBsAg) was examined. When mice were immunized intraperitoneally with rHBsAg together with each MDP derivative, the antibody titres were higher than those in mice immunized with alum-adsorbed rHBsAg, which is a commercially available hepatitis B vaccine. When mice were given a subcutaneous or intramuscular injection of rHBsAg and either MDP derivative, the antibody titres were the same as those in mice given alum-adsorbed rHBsAg. These results indicate the usefulness of MDP derivatives as immunoadjuvants for a new-generation vaccine.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1995

Characterization of the mode of Hantaan virus infection in adult mice using a nested reverse transcriptase polymerase chain reaction: transient virus replication in adult mice.

A polymerase chain reaction (PCR) for the detection of hantavirus genome was established and applied to analyze the mode of infection of Hantaan virus in adult ICR mice. The cDNA for the S genome segment of Hantaan virus was reverse-transcribed from the total RNA of organs of the infected mice. The sequence in the S genome segment of Hantaan virus was successfully amplified by reverse transcriptase (RT)-PCR followed by nested PCR. In 5-week-old ICR mice inoculated intraperitoneally with Hantaan virus, strain 76-118 (1.3 x 10(5) FFU/mouse), the virus was detected in clots and lungs from 3 to 10 days post-inoculation (p.i.) by nested PCR and virus-isolation techniques. No virus was detected in any specimens collected on 1 day and after 28 days p.i., and in spleens and brains through the observation period by both methods. The antibody which was measured by indirect immunofluorescence antibody assay (IFA) appeared at 7 days p.i. and the geometric mean titer was elevated to its maximum level of 1:203 at 10 days p.i., maintaining the same level until 35 days p.i. These results suggest that adult mice are transiently infected with Hantaan virus.

Animals↗