Biomedical subjects

H Sumichika

Publications and source records attributed to H Sumichika.

12 recordsLinked to original sources

PubMed2000

A novel anti-rheumatic drug suppresses tumor necrosis factor-alpha and augments interleukin-10 in adjuvant arthritic rats.

Tumor necrosis factor-alpha (TNF-alpha) plays an important role in the pathology of rheumatoid arthritis. When N-[1-(4-¿[4-(pyrimidin-2-yl)piperazin-1-yl]methyl¿phenyl)cycloprop yl] acetamide (Y-39041) (3-30 mg/kg) was orally administered to rats with established arthritis from day 15 to day 20, hindpaw volume was significantly reduced. This inhibitory activity of Y-39041 was kept up after administration was stopped. On day 17 Y-39041 suppressed lipopolysaccharide-induced TNF-alpha and interleukin-6 production in serum at doses of 3-30 mg/kg, and augmented interleukin-10 production at doses of 10 and 30 mg/kg. The finding that Y-39041 suppresses TNF-alpha and interleukin-6 production and augments interleukin-10 production could be beneficial in the therapy of chronic inflammatory diseases.

Acetamides↗

PubMed2000

Novel phenylpiperazine derivatives as dual cytokine regulators with TNF-alpha suppressing and IL-10 augmenting activity.

Phenylpiperazine derivatives were synthesized as dual cytokine regulators with TNF-alpha suppressing and IL-10 augmenting activity. Lead optimization led to compound 5k having the potent regulatory activity and demonstrating remarkable protective effects against the lethal challenge of LPS in mice. suggesting that 5k would be a promising drug candidate for the treatment of TNF-alpha associated diseases including septic shock.

Animals↗

PubMed2000

Novel DMARDs on the basis of a new concept of dual cytokine regulation, TNF-alpha suppression and IL-10 augmentation.

A series of arylpiperazine derivatives was synthesized to obtain agents showing apparent therapeutic effects in a chronic inflammatory animal model, starting from a lead possessing potent dual cytokine regulatory activity in vivo. We found a pyrimidylpiperazine derivative 17c showing the dual regulatory activity and an excellent therapeutic effect in an adjuvant-induced arthritis model.

Animals↗

PubMed2000

A novel dual regulator of tumor necrosis factor-alpha and interleukin-10 protects mice from endotoxin-induced shock.

A pyrimidylpiperazine derivative, N-[1-(4-¿[4-(pyrimidin-2-yl)piperazin-1-yl]methyl¿phenyl)cycloprop yl] acetamide (Y-39041), is a dual cytokine regulator of tumor necrosis factor (TNF)-alpha and interleukin-10 production. Lipopolysaccharide-induced TNF-alpha release in BALB/c mice was inhibited by the oral treatment with the compound at 10-100 mg/kg (about 80% suppression) while interleukin-10 release was augmented (about 10-fold increase at 30 mg/kg). In addition, Y-39041 (30 mg/kg, p.o.) completely protected mice from lipopolysaccharide-induced death by the treatment before and after lipopolysaccharide injection. The finding that Y-39041 suppresses TNF-alpha production and stimulates interleukin-10 production at the same time provides new insights for the treatment of septic shock, rheumatoid arthritis and Crohn's diseases.

Acetamides↗

PubMed1999

Reactive oxygen species are involved in the apoptosis induced by nonsteroidal anti-inflammatory drugs in cultured gastric cells.

We previously reported the induction of apoptotic DNA fragmentation by nonsteroidal anti-inflammatory drugs (NSAIDs) in cultured rat gastric cells, and indicated that prostaglandin-synthesis is only marginally involved in the apoptotic process. In the present study, we examined whether the generation of reactive oxygen species is critically involved in NSAID-induced apoptosis. Indomethacin, sodium diclofenac, flurbiprofen, zaltoprofen, etodolac, but not mofezolac, enhanced apoptotic DNA fragmentation and mRNA expression for cyclooxygenase-2 in AGS cells, a cell line derived from human gastric epithelium. The apoptotic effect of indomethacin was then confirmed by fluorescent staining of the cells with annexin V. Apoptotic DNA fragmentation induced by indomethacin and flurbiprofen was suppressed by incubation of the cells with the anti-oxidants pyrrolidine dithiocarbamate, diphenyleneiodonium chloride, and N-acetyl-L-cysteine. These two NSAIDs also enhanced release from the cells of 8-isoprostane, a nonenzymatic product by free-radical-mediated peroxidation of arachidonic acid. Further, lucigenin chemiluminescence showed that the intracellular production of reactive oxygen species increased in cells treated with indomethacin. The present data thus indicate a crucial association between the generation of reactive oxygen species and NSAID-induced apoptosis in gastric epithelial cells.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1996

An increase of B cells in the tumor-bearing state has the potential to induce anti-tumor immunity.

We investigated the role of an increased amount of B cells in the tumor-bearing state. The proportion of B cells increased concomitantly with tumor development in the regional lymph nodes (LN) of BALB/c mice bearing Meth A fibrosarcoma (Meth A). Tumor development was accompanied by an increased level of IgG antibodies against Meth A. CD4+ T cells of the regional LN in the early tumor-bearing stage produced significant levels of interferon-gamma and interleukin-4 in response to in vitro stimulation with coated anti-CD3 monoclonal antibody, whereas such capacities decreased in the late tumor-bearing stage. In a tumor-neutralizing assay, the growth of Meth A was significantly suppressed by a co-inoculation with splenic B cells from BALB/c mice in the late tumor-bearing state. This suppression of Meth A growth was tumor-specific and was abolished by the in vivo depletion of either CD4+ or CD8+ T cells. These findings thus suggest that tumor development was accompanied by an increase of B cells and tumor-specific IgG production, but such kinetic changes were not the result of a preferential activation of Th2 type CD4+ T cells. Furthermore, our results indicate that the increase of B cells in the tumor-bearing state has the potential to induce anti-tumor-specific T cell immunity.

Animals↗

PubMed1996

IL-3 derived from CD4+ T cells is essential for the in vitro expansion of mast cells from the normal adult mouse spleen.

A null cell line (SCM1) was established by a culture of spleen cells (SC) from normal adult C57B1/6 mice with complete medium alone for 10 days and followed by weekly cultures with a 25% WEHI-3 cell culture supernatant. Phenotype analysis showed that the SCM1 cells were negative for CD3, Thy1.2, B220, Mac-1, Gr-1, NK1.1 and MHC class II, but were positive for MHC class I, Fc gamma RII/ III, Fc epsilon RI, c-kit and the receptor against wheat germ agglutinin. These findings suggested that the SCM1 cells were mast cells. In an in vitro proliferation assay. SCM1 cells proliferated in the presence of either IL-3 or stem cell factor (SCF), but not in the presence of IL-4, whereas IL-4 showed an augmenting effect on their proliferation in the presence of either IL-3 or SCF. In analysing the mechanism by which such mast cells could be expanded from normal adult mouse SC, the addition of anti-IL-3 MoAb, but not anti-SCF MoAb, into the initial culture inhibited the subsequent expansion of either IL-3-or SCF-responding cells. The prior depletion of CD4+ T cells abrogated the capacity of the SC to enhance the expansion of SCF-responding cells, and this inability was restored by the addition of IL-3. Moreover, the culture supernatant of normal adult SC alone contained considerable levels of IL-3. Taken together, our findings suggest that, in an in vitro culture, CD4+ T cell-derived IL-3 therefore enhances the expansion of mast cells from the normal adult mouse spleen.

Aging↗

PubMed1996

Functional difference between Thy-1-positive and Thy-1-negative gamma delta T cells induced by Escherichia coli infection in mice.

There is an increase in number of gamma delta T cells in the peritoneal cavity after intraperitoneal (i.p.) inoculation with Escherichia coli. The E. coli-induced gamma delta T cells in C3H/He mice contain a large amount of Thy-1-negative population in addition to the Thy-1-positive population. We investigated the difference between the Thy-1-positive and the Thy-1-negative gamma delta T cells. Although it was found that only up to 4% of the gamma delta T cells on day 5 after infection were in cycling phase, and that the gamma delta T cells did not proliferate by immobilized anti-T-cell receptor (TCR) gamma delta monoclonal antibody stimulation, the gamma delta T cells proliferated in the presence of interleukin-2 (IL-2) and IL-7. The Thy-1-negative gamma delta T cells showed higher proliferative response compared with the Thy-1-positive gamma delta T cells. Furthermore, the Thy-1-negative gamma delta T cells showed lower IFN-gamma mRNA expression than the Thy-1-positive gamma delta T cells. On the other hand, both the Thy-1-positive and Thy-1-negative gamma delta T cells predominantly expressed V gamma 1, V gamma 4, V gamma 5, V gamma 6 and V delta 1, and no difference of V region usage was detected between them. These results suggest that functions of Thy-1-positive gamma delta T cells differ from Thy-1-negative gamma delta T cells although Thy-1-positive and Thy-1-negative gamma delta T cells may have similar V region repertoire and, possibly, similar antigen specificity.

Animals↗

PubMed1995

Differential requirements of CD45 for lymphocyte development and function.

CD45 exon 6-deficient mice show a profound block of thymocyte development at a transitional differentiation step from immature CD4+ CD8+ to mature single-positive cells. Only a few T lymphocytes are observed in the periphery of such animals, but B cell development is not affected. We investigated whether mature B lymphocytes in CD45 exon 6-deficient mice have normal functions in the absence of CD45 expression and show here that CD45-defective B lymphocytes from CD45 exon 6-deficient mice have intact B lymphocyte functions, including T-dependent and T-independent antigen-specific antibody production and class switching in vivo if normal CD4+ T lymphocytes were adoptively transferred into the mutant mice. From these results, we conclude that CD45 expression on B lymphocytes is not essential for B cell responses following antigen stimulation in vivo. However, CD4+ T helper function was severely diminished in CD45 exon 6-deficient mice, suggesting that the requirements of CD45 molecules in antigen-specific response and development are different between T and B lymphocytes.

Animals↗

PubMed1995

Induction of apoptosis of T cells by infecting mice with murine cytomegalovirus.

Cytomegalovirus (CMV) is associated with several lymphocyte dysfunctions, but the precise mechanisms of the dysfunctions are still unclear. To elucidate the mechanisms, a cell cycle-DNA content analysis was performed on splenic T cells of murine CMV (MCMV)-infected BALB/c mice. T cells from mice infected with 3 x 10(3) PFU of MCMV contained a higher percentage of hypodiploid nuclei after 12 or 24 h of culture than those from naive mice. T cells from infected mice also contained a larger amount of fragmented DNA. Taken together, these results suggested that infection with MCMV induced the apoptotic cell death of T cells. This induction of apoptosis accounted for the dysfunction of lymphocytes, at least partially. Flow cytometric analysis showed that T cells as well as B cells from MCMV-infected mice expressed an augmented level of Fas antigen, an apoptosis-associated cell surface molecule, which might be the cause of the apoptosis of cells. T cells from MCMV-infected C57BL/6-lpr/lpr mice with mutations at the lpr/fas locus, however, also showed a substantial level of apoptosis, which was reproducibly lower than that seen in C57BL/6 mice. Therefore, it was suggested that the Fas-mediated pathway contributed to but was not sufficient for the induction of apoptosis and that mechanisms other than the Fas-associated pathway were also involved in the induction of apoptosis.

Animals↗

PubMed1994

Th1 type CD4+ T cells may be a potent effector against poorly immunogenic syngeneic tumors.

We examined the possibility that Th1 type CD4+ T cells may be an effector against three kinds of syngeneic tumors such as highly immunogenic B16 melanoma (B16) and two poorly immunogenic lines of MCA fibrosarcoma (MCA) and 3LL carcinoma (3LL). In a proliferation assay, the Th1 type CD4+ T cell clone (MH2) recognized the purified protein derivatives (PPD) derived from Mycobacterium tuberculosis. In a tumor-neutralizing assay, MH2 showed anti-tumor activity against both B16 and MCA. In a model of pulmonary metastasis, MH2 also showed anti-tumor activity against both B16 and 3LL. In an assay of cytolysis, MH2 showed a moderate level of tumor necrosis factor-dependent cytolytic activity only against MCA. In a cytostasis assay, MH2 showed a high level of interferon gamma-dependent cytostatic activity against the three tumors in the presence of macrophages. The anti-tumor activity of MH2 against B16 and 3LL was suggested to be, at least in part, attributable to the augmented natural killer activity. Taken together, these findings suggest that we may potentially be able to utilize Th1 type CD4+ T cells as an effector for immunotherapy against poorly immunogenic tumors.

Animals↗

PubMed1994

Streptomyces ATP nucleotide 3'-pyrophosphokinase-gene cloning and sequence analysis.

Streptomyces ATP nucleotide 3'-pyrophosphokinase is an extracellular enzyme that transfers 5'-beta, gamma-pyrophosphoryl groups of ATP to a variety of nucleotides at the 3'-OH site. The enzyme gene was cloned from partially Sau3AI-digested chromosomal DNA of S. morookaensis in S. lividans TK24/pIJ699 and then in E. coli JM83/pUC12. Some transformants produced the active enzyme. The gene was sequenced by the dideoxynucleotide termination procedure. Its GC content was 72%. Its putative promoter regions, showing little homology to that of the Streptomyces consensus type, were pointed out. No sequence homology was found between the pyrophosphokinase and any other known genes including those of the most mechanistically similar bacterial stringent factor and related proteins. Northern hybridization analysis showed that the gene is constitutionally polycistronic and expressed under transcriptional control. Nuclease S1 mapping indicated that the gene transcription starts from its translation initiation site.

Amino Acid Sequence↗