PubMed Health⌕ Search

Biomedical subjects

T Tatsumi

Publications and source records attributed to T Tatsumi.

At least 19 recordsLinked to original sources
PubMed2002

A single nucleotide polymorphism of the low molecular mass polypeptide 7 gene influences the interferon response in patients with chronic hepatitis C.

Transporter associated with antigen processing (TAP) and low molecular mass polypeptides (LMP) play crucial roles in the human leukocyte antigen (HLA) class I-restricted antigen presenting systems. This study was performed to elucidate whether these antigen-presenting gene polymorphisms could influence the response to interferon (IFN) treatment in patients with chronic hepatitis C. Polymorphisms of TAP and LMP genes in 175 hepatitis C virus (HCV) patients were determined by polymerase chain reaction-restriction fragment length polymorphism. The frequencies of these genes were compared between sustained-responders (n=49) and nonresponders (n=126), classified by biochemical and virological responses to IFN. The distributions of TAP1*, TAP2*, and LMP2 genes between sustained-responders and nonresponders did not differ. However, LMP7-K gene frequency in sustained-responders was higher than that in nonresponders [odds ratio 2.3 (95% confidence interval 1.1-4.6); 16%vs 7.9%]. Multivariate analysis revealed that LMP7-K and HCV-RNA quantity were independent factors influencing the outcome of IFN therapy [4.5 (1.4-14); P=0.011, 0.40 (0.24-0.65); P=0.0003, respectively]. Furthermore, among patients with a low viral load (< or = 2.0 Meq/mL), the LMP7-K positive patients had an even higher ratio of sustained response compared to those without LMP7-K [5.9 (1.6-22); 82%vs 44%; P=0.0062]. These findings suggest that a single nucleotide polymorphism of LMP7 gene is one of the important host factors which independently influence the response to IFN in patients with chronic hepatitis C.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Evidence of 29Si NMR paramagnetic shifts in rare-earth zeolite LSX.

Paramagnetic shifts have been observed for the first time in rare-earth zeolites; the 29Si MAS NMR spectra of rare-earth ion-exchanged low silica X show a large range of isotropic chemical shifts that can be attributed to Fermi contact interactions with the lanthanide electronic moments.

Journal Article↗
PubMed2001

Administration of interleukin-12 enhances the therapeutic efficacy of dendritic cell-based tumor vaccines in mouse hepatocellular carcinoma.

Dendritic cells (DCs) are potent antigen-presenting cells that are capable of priming systemic antitumor immune response. Here, we evaluated the combined effectiveness of tumor lysate-pulsed DC immunization and interleukin (IL)-12 administration on the induction of antitumor immunity in a mouse hepatocellular carcinoma (HCC) model. Mouse DCs were pulsed with lysate of BNL 1ME A.7R.1 (BNL), a BALB/c-derived HCC cell line, and then injected into syngeneic mice in combination with systemic administration of IL-12. Lymphocytes from mice treated with BNL lysate-pulsed DCs and IL-12 showed stronger cytolytic activity and produced higher amounts of IFN-gamma than those from mice treated with BNL lysate-pulsed DCs alone. Although immunization with BNL lysate-pulsed DCs alone did not lead to complete regression of established tumors, it significantly inhibited tumor growth compared with vehicle injection. Importantly, the combined therapy of BNL lysate-pulsed DCs and IL-12 resulted in tumor rejection or significant inhibition of tumor growth compared with mice treated with BNL lysate-pulsed DCs alone. In vivo lymphocyte depletion experiments demonstrated that this combination was dependent on both CD8+ and CD4+ T cells, but not natural killer cells. These results demonstrated that IL-12 administration enhanced the therapeutic effect of immunization of tumor lysate-pulsed DCs against HCC in mice. This combination of IL-12 and DCs may be useful for suppressing the growth of residual tumor after primary therapy of human HCC.

Animals↗
PubMed2001

Generation of hepatitis C virus-specific cytotoxic T lymphocytes from healthy individuals with peptide-pulsed dendritic cells.

BACKGROUND AND AIMS: In hepatitis C virus (HCV) infection, cytotoxic T lymphocytes (CTL) are involved in liver inflammation and contribute to the reduction of viral load. Antibodies for HCV-CTL precursor frequencies (CTLpf) are relatively low in chronic hepatitis C, and this may be related to the poor CTL response in vivo. The aim of this study was to assess the efficacy of dendritic cells (DC) as antigen-presenting cells in CTL generation from low CTLpf. METHODS: To confirm the rationale of using DC to prime naive T cells, five HCV-uninfected individuals were enrolled in the study. We obtained DC by maturation from peripheral progenitors under stimulation with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-4 and IL-1alpha. Autologous T cells were cultured with DC or concanavalin-A-induced blasts loaded with four HCV-derived peptides bearing human leukocyte antigen (HLA)-A*0201 or -A24 motifs for 28 days under IL-7 and IL-2 stimulation. The lytic activity against peptide-pulsed targets was assessed by using a [51Cr]-releasing assay. RESULTS: The DC strongly expressed HLA class I, II, B7-1 and B7-2, but not phenotypic markers of T-, B-, natural killer (NK)-cells or monocytes. The CD8-positive, HLA-class I-restricted and HCV peptide-specific CTL were generated with DC from HLA-A antigen-matched subjects, whereas no CTL activity was detected with concavalin (Con-A) blasts. We were thus able to generate HCV specific CTL from naive precursors with peptide-pulsed DC. CONCLUSIONS: This DC-based system can be used to generate CTL of desired antigen specificity, even from a source with low CTLpf.

Adult↗
PubMed2001

Important role of energy-dependent mitochondrial pathways in cultured rat cardiac myocyte apoptosis.

Recent studies have suggested that apoptosis and necrosis share common features in their signaling pathway and that apoptosis requires intracellular ATP for its mitochondrial/apoptotic protease-activating factor-1 suicide cascade. The present study was, therefore, designed to examine the role of intracellular energy levels in determining the form of cell death in cardiac myocytes. Neonatal rat cardiac myocytes were first incubated for 1 h in glucose-free medium containing oligomycin to achieve metabolic inhibition. The cells were then incubated for another 4 h in similar medium containing staurosporine and graded concentrations of glucose to manipulate intracellular ATP levels. Under ATP-depleting conditions, the cell death caused by staurosporine was primarily necrotic, as determined by creatine kinase release and nuclear staining with ethidium homodimer-1. However, under ATP-replenishing conditions, staurosporine increased the percentage of apoptotic cells, as determined by nuclear morphology and DNA fragmentation. Caspase-3 activation by staurosporine was also ATP dependent. However, loss of mitochondrial transmembrane potential (DeltaPsi(m)), Bax translocation, and cytochrome c release were observed in both apoptotic and necrotic cells. Moreover, cyclosporin A, an inhibitor of mitochondrial permeability transition, attenuated staurosporine-induced apoptosis and necrosis through the inhibition of DeltaPsi(m) reduction, cytochrome c release, and caspase-3 activation. Our data therefore suggest that staurosporine induces cell demise through a mitochondrial death signaling pathway and that the presence of intracellular ATP favors a shift from necrosis to apoptosis through caspase activation.

Adenosine Triphosphate↗
PubMed2001

A Kampo formulation: Byakko-ka-ninjin-to (Bai-Hu-Jia-Ren-Sheng-Tang) inhibits IgE-mediated triphasic skin reaction in mice: the role of its constituents in expression of the efficacy.

We have demonstrated that oral administration of a Kampo formulation, Byakko-ka-ninjin-to (Bai-Hu-Jia-Ren-Sheng-Tang), inhibited IgE-mediated triphasic skin reaction, including immediate phase response (IPR), late phase response (LPR) and very late phase response (vLPR), in passively sensitized mice with anti-DNP IgE antibody. Variant formulations of Byakko-ka-ninjin-to without Gypsum Fibrosum (Sekko), Glycyrrhizae Radix (Kanzo) or Oryzae Semen (Kobei) attenuated the inhibitory effect as compared with that of Byakko-ka-ninjin-to. The decreased effect of Byakko-ka-ninjin-to without Kanzo was restored by the addition of Kanzo to the variant formulations before oral administration, while the decreased effect of Byakko-ka-ninjin-to without Sekko could not be recovered by the addition of Sekko. Comparison of HPLC profiles of variant formulations without one crude drug with that of original Byakko-ka-ninjin-to revealed that some peaks could be detected only when five constituent crude drugs were simultaneously present during the preparation of Byakko-ka-ninjin-to formulation. Since elimination of Sekko from the Byakko-ka-ninjin-to constituents attenuated the efficacy although it did not show any activity per se, mutual interaction of Sekko with other constituents during the preparation may result in the production of new components. These findings suggest that the effect of Byakko-ka-ninjin-to formulation on cutaneous inflammatory disease can differ from the sum of the effect of the individual constituents.

2,4-Dinitrophenol↗
PubMed2001

Acute myocardial infarction due to a regressed giant coronary aneurysm as possible sequela of Kawasaki disease.

We report on a young patient admitted with an acute myocardial infarction due to a regressed coronary aneurysm who was treated with balloon angioplasty. The wall morphology of the coronary aneurysm using intravascular ultrasound imaging closely resembled that occurring after Kawasaki disease (KD), although our patient had no obvious past history of KD, suggesting so-called atypical KD.

Adult↗
PubMed2000

Cytokine-induced nitric oxide production inhibits mitochondrial energy production and impairs contractile function in rat cardiac myocytes.

OBJECTIVES: The present study examined whether nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) can directly inhibit aerobic energy metabolism and impair cell function in interleukin (IL)-1beta,-stimulated cardiac myocytes. BACKGROUND: Recent reports have indicated that excessive production of NO induced by cytokines can disrupt cellular energy balance through the inhibition of mitochondrial respiration in a variety of cells. However, it is still largely uncertain whether the NO-induced energy depletion affects myocardial contractility. METHODS: Primary cultures of rat neonatal cardiac myocytes were prepared, and NO2-/NO3- (NOx) in the culture media was measured using Griess reagent. RESULTS: Treatment with IL-1beta (10 ng/ml) increased myocyte production of NOx in a time-dependent manner. The myocytes showed a concomitant significant increase in glucose consumption, a marked increase in lactate production, and a significant decrease in cellular ATP (adenosine 5'-triphosphate). These metabolic changes were blocked by co-incubation with N(G)-monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthesis. Sodium nitroprusside (SNP), a NO donor, induced similar metabolic changes in a dose-dependent manner, but 8-bromo-cyclic guanosine 3',5'-monophosphate (8-bromo-cGMP), a cGMP donor, had no effect on these parameters. The activities of the mitochondrial iron-sulfur enzymes, NADH-CoQreductase and succinate-CoQreductase, but not oligomycin-sensitive ATPase, were significantly inhibited in the IL-1beta, or SNP-treated myocytes. Both IL-1beta and SNP significantly elevated maximum diastolic potential, reduced peak calcium current (I(Ca)), and lowered contractility in the myocytes. KT5823, an inhibitor of cGMP-dependent protein kinase, did not block the electrophysiological and contractility effects. CONCLUSIONS: These data suggest that IL-1beta-induced NO production in cardiac myocytes lowers energy production and myocardial contractility through a direct attack on the mitochondria, rather than through cGMP-mediated pathways.

Adenosine Triphosphate↗
PubMed2000

Tc-99m PMT whole-body scintigraphy for evaluated of therapeutic effect and for monitoring bone metastasis in a patient with hepatocellular carcinoma.

Detection of metastatic lesions by bone scintigraphy is highly sensitive but has a low rate of specificity. Often bone metastases from hepatocellular carcinoma are not detected by bone scintigraphy because of low uptake or a photopenic area in the tumor. In contrast, Tc-99m Sn-N-pyridoxy-5-methyltryptophan (Tc-99m PMT) whole-body scintigraphy reflects tumor viability, and the specificity of detection is so high that tumor structure can be shown well. Tc-99m PMT whole-body scintigraphy was helpful for evaluating the response to therapy and monitoring the course of the patient described here with bone metastasis from hepatocellular carcinoma.

Bone Neoplasms↗
PubMed1999

Impaired allostimulatory capacity of peripheral blood dendritic cells recovered from hepatitis C virus-infected individuals.

In hepatitis C virus (HCV) infection, Th responses are implicated in the pathogenesis of liver disease. The dendritic cell (DC) is the most potent activator of CD4 T cells for supporting Th1 differentiation. To clarify the roles of DC of HCV-infected individuals in the development of CD4 T cell responses, we generated peripheral DC with GM-CSF and IL-4 from 24 chronic hepatitis C patients and 14 healthy donors. We then compared their potentials for stimulating allogeneic CD4 T cells, autologous CD4 T cells against influenza A or HCV core Ags, and cytokine production. The DC from the patients (HCV-DC) expressed lower degrees of CD86 than DC from the donors (N-DC), whereas no difference was found in the HLA molecules and other costimulators. HCV-DC stimulated allogeneic T cells less than N-DC; however, influenza A- or core-pulsed HCV-DC retained the potentials for autologous T cell proliferation. In allogeneic DC/T cell cultures, the IFN-gamma levels with HCV-DC were lower than those with N-DC, which may be related to the low expressions of IL-12 p35 and p40 transcripts in HCV-DC. The stimulation with LPS disclosed that HCV-DC is less potent in IL-12 p70 production than N-DC. In the autologous cultures, the pulsing of the Ags to HCV-DC increased the IL-12 p40 and IFN-gamma production and up-regulated the transcription of both IL-12 subunits. Exogenous IL-2 or IL-12 restored the low allogeneic T cell proliferation with HCV-DC in a dose-dependent manner. Therefore, low expression of CD86 and/or IL-12 is crucially involved in the low allostimulatory capacity of HCV-DC. Low IL-12 and low IFN-gamma milieu with HCV-DC on encounters with alloantigens may impede Th1 polarization.

Adult↗
PubMed1999

Cardioprotective effect of angiotensin-converting enzyme inhibition against hypoxia/reoxygenation injury in cultured rat cardiac myocytes.

BACKGROUND: Although ACE inhibitors can protect myocardium against ischemia/reperfusion injury, the mechanisms of this effect have not yet been characterized at the cellular level. The present study was designed to examine whether an ACE inhibitor, cilazaprilat, directly protects cardiac myocytes against hypoxia/reoxygenation (H/R) injury. METHODS AND RESULTS: Neonatal rat cardiac myocytes in primary culture were exposed to hypoxia for 5.5 hours and subsequently reoxygenated for 1 hour. Myocyte injury was determined by the release of creatine kinase (CK). Both cilazaprilat and bradykinin significantly inhibited CK release after H/R in a dose-dependent fashion and preserved myocyte ATP content during H/R, whereas CV-11974, an angiotensin II receptor antagonist, and angiotensin II did not. The protective effect of cilazaprilat was significantly inhibited by Hoe 140 (a bradykinin B2 receptor antagonist), NG-monomethyl-L-arginine monoacetate (L-NMMA) (an NO synthase inhibitor), and methylene blue (a soluble guanylate cyclase inhibitor) but not by staurosporine (a protein kinase C inhibitor), aminoguanidine (an inhibitor of inducible NO synthase), or indomethacin (a cyclooxygenase inhibitor). Cilazaprilat significantly enhanced bradykinin production in the culture media of myocytes after 5.5 hours of hypoxia but not in that of nonmyocytes. In addition, cilazaprilat markedly enhanced the cGMP content in myocytes during hypoxia, and this augmentation in cGMP could be blunted by L-NMMA and methylene blue but not by aminoguanidine. CONCLUSIONS: The present study demonstrates that cilazaprilat can directly protect myocytes against H/R injury, primarily as a result of an accumulation of bradykinin and the attendant production of NO induced by constitutive NO synthase in hypoxic myocytes in an autocrine/paracrine fashion. NO modulates guanylate cyclase and cGMP synthesis in myocytes, which may contribute to the preservation of energy metabolism and cardioprotection against H/R injury.

Adrenergic beta-Antagonists↗
PubMed1999

Intracellular single-chain antibody against hepatitis B virus core protein inhibits the replication of hepatitis B virus in cultured cells.

Hepatitis B virus (HBV) is one of the major causes of chronic liver diseases and hepatocellular carcinoma. In this study, we used a single chain antibody (sFv), which is a man-made antibody with a strong affinity of immunoglobulin, to inhibit HBV replication. Because HBV replication can only take place in the viral nucleocapsid made of HBV core protein (HBc), we generated anti-HBc sFv and examined whether intracellular anti-HBc sFv could inhibit viral replication in the human hepatoblastoma-derived cell line that produces HBV (HB611). With respect to HBV replication intermediates, both single-stranded and partially double-stranded DNA intermediates were markedly suppressed in the cells expressing anti-HBc sFv, although HBV RNA intermediates were not affected. This suggested that intracellular anti-HBc sFv inhibited HBV DNA replication by inhibiting reverse transcription from HBV pregenome RNA to single-stranded DNA. Because the sFv-HBc complex was detected in the cells expressing anti-HBc sFv by immunoprecipitation analysis but the quantity of intracellular HBc was not affected, the anti-HBc sFv was suggested to inhibit HBV DNA replication by interfering with the function of HBc. These results indicate that intracellular sFv against HBc might be effective as a novel active molecule for gene therapy of hepatitis B.

Amino Acid Sequence↗
PubMed1999

B7-1 (CD80)-gene transfer combined with interleukin-12 administration elicits protective and therapeutic immunity against mouse hepatocellular carcinoma.

Human hepatocellular carcinoma (HCC) frequently recurs after primary therapy, resulting in poor prognosis. To try to find a way to prevent this, we examined the combined effectiveness of B7-1 (CD80)-gene transfer and interleukin-12 (IL-12) on the induction of protective antitumor immunity against poorly immunogenic BNL1ME A.7R. 1 (BNL) mouse HCC cells. We introduced mouse B7-1 gene into BNL1ME A. 7R.1 cells. Overexpression of B7-1 on BNL1ME A.7R.1 cells resulted in significant inhibititon of subcutaneous tumor development in syngeneic BALB/c mice, but not in complete rejection, suggesting that strong expression of B7-1 molecules may enhance the immunogenicity of BNL1ME A.7R.1 cells in immunocompetent mice. Lymphocyte study revealed that the cytolytic activity generated by immunization with B7-1 transfectants against BNL1ME A.7R.1 cells was mediated mainly by CD8(+) cytotoxic T lymphocytes (CTL). We examined the synergistic effect of IL-12 and immunization with B7-1 transfectants. The combination led to rejection of BNL1ME A.7R.1 cells in 6 of 10 tested mice and delayed tumor development in the remaining mice. Furthermore, the combined treatment against pre-established BNL1ME A.7R.1 tumors resulted in rejection in 3 of 8 tested mice or in significant inhibition of tumor growth in the remaining mice. In vivo lymphocyte subset depletion study indicated that the combined antitumor effect was dependent on the presence of both CD8(+) and CD4(+) T cells. In conclusion, the combination of immunization of B7-1-transfected HCC cells and IL-12 could induce protective and therapeutic immunity against parental HCC cells, and this combination may be therapeutically useful for suppressing recurrence of HCC.

Animals↗
PubMed1999

SD3212, a new antiarrhythmic drug, raises atrial fibrillation threshold in isolated rabbit hearts.

SD3212 is a new antiarrhythmic drug which has class I, III, and IV effects. The purpose of this study was to elucidate the electrophysiological effects of this compound on a rabbit atrial fibrillation model, and to test a hypothesis that atrial fibrillation threshold is a quantitative indicator of atrial vulnerability. Whole hearts were excised from rabbits, and the aortas cannulated to perfuse the coronary arteries. Atrial fibrillation was induced with a burst stimulation of 50 Hz for 1 s while 3 microM acetylcholine (ACh) was perfused. When the right atrial appendage was paced at 200-ms intervals, SD3212 prolonged interatrial conduction time: control 30 +/- 1.2 ms, ACh 33 +/- 1.4 ms, ACh + SD 1 microM 37 +/- 2.4 ms, ACh + SD 3 microM 52 +/- 8.1 ms. The drug also prolonged the effective refractory period: control 80 +/-3.0 ms, ACh 48 +/- 3.8 ms, ACh + SD 1 microM 65 +/- 4.7 ms, ACh + SD 3 microM 98 +/- 15 ms. The rate of induction of atrial fibrillation by rapid pacing was 26% in Tyrode's solution, 85% in the presence of ACh, and 38% in the presence of ACh + SD 1 microM. The atrial fibrillation threshold decreased from 8.6 +/- 0.8mA (control) to 2.5 +/- 0.7 mA in the presence of ACh. It increased again to 7.8 +/- 1.0 mA in the presence of SD3212 (1 microM). SD3212 prolonged both the conduction time and refractory period. A reversed use-dependency was not prominent. These features caused antifibrillatory effects. Thus, the atrial fibrillation threshold seems to be a good quantitative indicator of atrial vulnerability.

Analysis of Variance↗
PubMed1999

Involvement of transporter associated with antigen processing 2 (TAP2) gene polymorphisms in hepatitis C virus infection.

BACKGROUND & AIMS: Transporter associated with antigen processing (TAP) has essential roles in the antigen-presenting systems, translocating antigenic peptides from the cytosol into the endoplasmic reticulum. The aim of this study was to clarify whether TAP polymorphisms are involved in hepatitis C virus (HCV) infection. METHODS: The 145 HCV-infected Japanese patients examined in this study were categorized into two groups: 36 carriers with persistently normal alanine transaminase (ALT) values and 109 patients with chronic liver disease (CLD). TAP2 gene phenotypes were determined by means of polymerase chain reaction-restriction fragment length polymorphism, and their frequencies were compared between the two groups. RESULTS: Frequencies of TAP2*0101, *0102, and *0201 were not different between the two groups. However, TAP2*0103 frequency in carriers with normal ALT levels was significantly higher than that in patients with CLD (44% vs. 16%; P = 0.00064, Pc < 0.005). Although the TAP2*0103 allele was tightly linked with class II DRB1*1302-DQB1*0604 haplotype in this study, the TAP2*0103 frequency in the normal ALT group was also significantly higher than that in the CLD group even in DRB1*1302-DQB1*0604-negative patients (31% vs. 10%; P = 0.0076, Pc < 0.05). CONCLUSIONS: These findings suggest that TAP2*0103 may be closely associated with low serum ALT activity in HCV-infected Japanese patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗