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Biomedical subjects

Y Aikawa

Publications and source records attributed to Y Aikawa.

At least 19 recordsLinked to original sources
PubMed2003

Inhibitory effects of an anti-rheumatic agent T-614 on immunoglobulin production by cultured B cells and rheumatoid synovial tissues engrafted into SCID mice.

OBJECTIVE: To clarify the pharmacological action of an anti-rheumatic agent T-614, we investigated its effects on immunoglobulin (Ig) production by cultured B cells and Ig secretion from synovial tissues of patients with rheumatoid arthritis (RA) using SCID mice engrafted with human RA tissue (SCID-HuRAg). METHODS: Murine B cells were prepared from mouse spleen by a T-cell depletion method. The cells were cultured with lipopolysaccharide (LPS) and/or interleukin 4 (IL-4) in the absence or presence of T-614. Human B cells were isolated from peripheral blood of healthy donors and the Ig production was induced by co-culture with autologous T cells and anti-CD3 antibody. SCID-HuRAg was prepared according to our previous method. T-614 was orally administered to the mice once daily for 4 weeks starting on the fourth week after the implantation. Then, peripheral blood was obtained and the implanted tissues were removed. Igs in the culture media or the sera were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: In murine B-cell cultures, T-614 significantly decreased not only the IgM production stimulated with LPS but IgG1 production induced by LPS and IL-4. Regarding human B cells stimulated with T cells, it also inhibited IgM and IgG production. In SCID-HuRAg mice, high concentrations of polyclonal human IgG were detectable in the sera of all mice. A significant decrease in the IgG level was observed in the T-614-treated group compared with the control group. CONCLUSIONS: We showed that T-614 inhibited Ig production by the cultured B cells and also decreased the high level of human IgG observed in SCID-HuRAg mice. These results may support its effect on plasma Ig in RA patients and provide insights into the mechanisms of its anti-rheumatic effect.

Animals↗
PubMed2002

An anti-rheumatic agent T-614 inhibits NF-kappaB activation in LPS- and TNF-alpha-stimulated THP-1 cells without interfering with IkappaBalpha degradation.

OBJECTIVE: Compound T-614, a member of the methanesulfoanilide class of anti-inflammatory agents, shows potent anti-arthritic activity in animal models of rheumatoid arthritis. The aim of the present investigation was to characterize the anti-arthritic activity of T-614 in terms of regulation of the nuclear transcription factor NF-kappaB, which is associated with expression of many immune and inflammatory genes. MATERIALS AND METHODS: THP-1 cells (human monocytic leukemia cell line) were used throughout this in vitro study, and lipopolysaccharide (LPS) and tumor necrosis factor (TNF)-alpha were employed for activation of the cells. Cytokine production was assayed by enzyme-linked immunosorbent assay (ELISA). The mRNA levels were determined by a semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) assay. Assessment of the NF-kappaB DNA binding activity was performed by an electrophoretic mobility shift assay (EMSA) using a digoxigenin (DIG)-labeled double-stranded oligonucleotide containing kappaB-binding site. Degradation kinetics of the cytosolic NF-kappaB inhibitor a (IkappaBalpha) were studied by Western blot analysis. RESULTS: T-614 inhibited LPS-stimulated production of TNF-alpha, interleukin (IL)-6, and IL-8 in a concentration-dependent manner with decreasing mRNA levels (IL-6 and IL-8). EMSA study showed that T-614 prevented TNF-alpha as well as LPS-stimulated activation of NF-kappaB, and Western blot analysis proved that T-614 did not affect degradation of IkappaBalpha protein. CONCLUSIONS: These results suggest that the inhibitory effect of T-614 on the production of TNF-alpha, IL-6 and IL-8 in LPS-stimulated THP-1 cells may involve transcriptional regulation through suppression of NF-kappaB activation without interfering with IkappaBalpha degradation.

Antirheumatic Agents↗
PubMed2001

Activation of AML1-mediated transcription by MOZ and inhibition by the MOZ-CBP fusion protein.

The AML1-CBF beta transcription factor complex is the most frequent target of specific chromosome translocations in human leukemia. The MOZ gene, which encodes a histone acetyltransferase (HAT), is also involved in some leukemia-associated translocations. We report here that MOZ is part of the AML1 complex and strongly stimulates AML1-mediated transcription. The stimulation of AML1-mediated transcription is independent of the inherent HAT activity of MOZ. Rather, a potent transactivation domain within MOZ appears to be essential for stimulation of AML1-mediated transcription. MOZ, as well as CBP and MOZ-CBP, can acetylate AML1 in vitro. The amount of AML1-MOZ complex increases during the differentiation of M1 myeloid cells into monocytes/macrophages, suggesting that the AML1-MOZ complex might play a role in cell differentiation. On the other hand, the MOZ-CBP fusion protein, which is created by the t(8;16) translocation associated with acute monocytic leukemia, inhibits AML1-mediated transcription and differentiation of M1 cells. These results suggest that MOZ-CBP might induce leukemia by antagonizing the function of the AML1 complex.

Acetyltransferases↗
PubMed2001

Fusion of MOZ and p300 histone acetyltransferases in acute monocytic leukemia with a t(8;22)(p11;q13) chromosome translocation.

Histone acetyltransferase p300 functions as a transcriptional co-activator which interacts with a number of transcription factors. Monocytic leukemia zinc finger protein (MOZ) has histone acetyltransferase activity. We report the fusion of the MOZ gene to the p300 gene in acute myeloid leukemia with translocation t(8;22)(p11;q13). FISH and Southern blot analyses showed the rearrangement of the MOZ and p300 genes. We determined the genomic structure of the p300 and the MOZ genes and the breakpoints of the translocation. Analysis of fusion transcripts indicated that the zinc finger and acetyltransferase domains of MOZ are fused to a largely intact p300. These results suggest that MOZ-p300, which has two acetyltransferase domains, could be involved in leukemogenesis through aberrant regulation of histone acetylation.

Acetyltransferases↗
PubMed2001

Regional wall stress predicts ventricular remodeling after anteroseptal myocardial infarction in the Healing and Early Afterload Reducing Trial (HEART): an echocardiography-based structural analysis.

BACKGROUND: Increased left ventricular (LV) wall stress after myocardial infarction (MI) has been implicated in LV remodeling. However, the relationship between LV wall stress and LV remodeling is incompletely defined. METHOD: We prospectively studied the relationship between regional wall stress and LV remodeling by application of the finite element method to end-systolic LV models from patients enrolled in the Healing and Early Afterload Reducing Therapy (HEART) Trial. Individual LV models were constructed from orthogonal apical echocardiographic views obtained at day 14 after anteroseptal MI in 64 patients. Of these, 31 patients received low-dose (0.625 mg) ramipril and 33 patients received full-dose (10 mg) ramipril. LV wall stress was calculated by the finite element method and correlated with change in LV volume from day 14 to day 90 after MI. RESULTS: Among all patients, increases in apical regional wall stress were associated with LV volume changes (P -trend =.015). The relationship between apical regional wall stress and change in LV volume was strongest in the low-dose ramipril group (r = 0.53, P =.002) and remained significant after adjustment for end-diastolic volume, infarct size, ejection fraction, and systolic blood pressure yet was attenuated in the full-dose ramipril group. CONCLUSIONS: Apical regional wall stress is an independent predictor of subsequent LV remodeling after MI. The relationship between increased apical wall stress and LV dilatation appears to be attenuated by full-dose angiotensin-converting enzyme inhibition.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

Inhibitory effect of T-614 on tumor necrosis factor-alpha induced cytokine production and nuclear factor-kappaB activation in cultured human synovial cells.

OBJECTIVE: To investigate the mechanism of the immunosuppressive effect of T-614 [N-(3-formylamino-4-oxo-6-phenoxy-4H-chromen-7-yl)methanesulfonamide], a new antirheumatic drug whose clinical efficacy has been determined for the treatment of patients with rheumatoid arthritis (RA). METHODS: RA synovial fibroblast-like cells were cultured with tumor necrosis factor-alpha (TNF-alpha, 10 ng/ml) in the presence or absence of T-614. After incubation, cytokine production was measured by ELISA. Expression of interleukin 6 (IL-6) and IL-8 mRNA was examined by real-time quantitative reverse transcriptase-polymerase chain reaction analysis and TNF-alpha induced nuclear factor-kappaB (NF-kappaB) activation was observed using immunostaining with an antibody against NF-kappaB p65. RESULTS: T-614 suppressed TNF-alpha induced production of IL-6, IL-8, and monocyte chemoattractant protein 1, and also reduced the accumulation of IL-6 and IL-8 mRNA in a concentration dependent manner. T-614 interfered with the TNF-alpha induced translocation of NF-kappaB to the nucleus from the cytoplasm. CONCLUSION: Inhibition of NF-kappaB activation and transcription of proinflammatory cytokines by T-614 contributes to its clinical antirheumatic effect.

Antirheumatic Agents↗
PubMed2000

Effect of acupuncture-like stimulation on cortical cerebral blood flow in anesthetized rats.

The effect of acupuncture-like stimulation of various areas (cheek, forepaw, upper arm, chest, back, lower leg, hindpaw, perineum) on cortical cerebral blood flow (CBF) was examined in anesthetized rats. An acupuncture needle (diameter, 340 microm) was inserted into the skin and underlying muscles at a depth of about 5 mm and twisted to the right and left once a second for 1 min. CBF of the cortex was measured using a laser Doppler flowmeter. Stimulation of the cheek, forepaw, upper arm and hindpaw produced significant increases in CBF, but stimulation of the chest, back, lower leg and perineum did not produce significant responses. Stimulation of the cheek, forepaw, and hindpaw produced an increase in mean arterial pressure (MAP), while stimulation of the back produced a decrease in MAP. Stimulation of the upper arm, chest, lower leg and perineum did not produce a significant MAP response. After spinal transection at the 1st to 2nd thoracic level, the blood pressure response to stimulation of the cheek and forepaw was suppressed, whereas an increase in CBF still took place. The increase in CBF induced by forepaw stimulation was abolished by severance of the somatic nerves at the brachial plexus. Forepaw stimulation enhanced the activity of the radial, ulnar and median nerves. Furthermore, in the present study, passing of an electric current through acupuncture needles showed that excitation of group III (Adelta) and group IV (C) afferent fibers in the somatic nerve was capable of producing an increase in CBF, whereas excitation of group I (Aalpha) and group II (Abeta) fibers was ineffective. The increase in CBF induced by forepaw stimulation was almost abolished by intravenous administration of muscarinic and nicotinic cholinergic blocking agents (atropine 5 mg/kg and mecamylamine 20 mg/kg), and by bilateral lesions in the nucleus basalis of Meynert. Acupuncture-like stimulation of a forepaw increased acetylcholine release in the cerebral cortex. We concluded that the increase in CBF, independent of systemic blood pressure, elicited by acupuncture stimulation is a reflex response in which the afferent nerve pathway is composed of somatic group III and IV afferent nerves, and efferent nerve pathway includes intrinsic cholinergic vasodilators originating in the nucleus basalis of Meynert.

Acetylcholine↗
PubMed1999

A 2-Mb sequence-ready contig map and a novel immunoglobulin superfamily gene IGSF4 in the LOH region of chromosome 11q23.2.

Human chromosome 11q23.2 has been proposed to contain a tumor suppressor gene(s) whose deletion has been associated with cancer of the lung and breast and with neuroblastoma. To analyze the genomic structure and to isolate a candidate tumor suppressor gene from this region, we constructed a 2-Mb sequence-ready contig map using bacteriophage P1 (P1), bacterial artificial chromosome (BAC), and P1-derived artificial chromosome (PAC). The map comprises a contig of 24 overlapping P1, BAC, and PAC clones. To isolate gene fragments from the region, we performed direct cDNA library screening, exon trapping, EST mapping, and genomic sequencing using the P1, BAC, and PAC clones. Sequence analysis of 5 clones, which spans 23% (458,738 bp) of the region, and extensive gene scanning along the entire region revealed that the region is extraordinarily scarce in genes, but we identified one ubiquitously expressed novel gene and one testis-specific gene fragment. The novel gene, which we call IGSF4 (immunoglobulin superfamily 4), is transcribed into a 1.6- or 4.4-kb RNA encoding a 442-amino-acid protein. It shares strong homology with mouse IGSF-B12 and cell adhesion molecules NCAM1 and NCAM2 within their Ig-like C2-type domains. The IGSF4 gene, a novel gene that is shown to be located in the common loss of heterozygosity region, possesses a number of interesting features and may be good candidate for a tumor suppressor gene.

Amino Acid Sequence↗
PubMed1999

Involvement of PITPnm, a mammalian homologue of Drosophila rdgB, in phosphoinositide synthesis on Golgi membranes.

Phosphatidylinositol transfer protein (PITP) is involved in phospholipase C-mediated signaling and membrane trafficking. We previously reported cloning and characterization of a gene encoding for membrane-bound PITP, named PITPnm, that is a mammalian homologue of the Drosophila retinal degeneration B (rdgB) gene (Aikawa, Y., Hara, H., and Watanabe, T. (1997) Biochem. Biophys. Res. Commun. 236, 559-564). Here we report the subcellular localization of PITPnm protein and provide evidence for its involvement in phosphatidylinositol 4-phosphate (PtdIns 4-P) synthesis. PITPnm is an integral membrane protein that largely localized in close association with membranes of Golgi vacuoles and the endoplasmic reticulum (ER). The amino terminus region of PITPnm was exposed to cytoplasmic side. Interaction with various phosphoinositides was observed in the amino terminus region spanning from 196 amino acids to 257 amino acids of PITPnm. At the amino terminus regions of 1-372 amino acids, PITPnm formed a complex with type III PtdIns 4-kinase. The transmembrane and carboxyl-terminal portions (residues 418-1242) functioned to retain the PITPnm in the Golgi vacuole. These results suggest that PITPnm plays a role in phosphoinositide synthesis on the Golgi vacuoles and possibly in the PtdIns signaling pathway in mammalian cells.

1-Phosphatidylinositol 4-Kinase↗
PubMed1999

Occurrence of free D-amino acids and aspartate racemases in hyperthermophilic archaea.

The occurrence of free D-amino acids and aspartate racemases in several hyperthermophilic archaea was investigated. Aspartic acid in all the hyperthermophilic archaea was highly racemized. The ratio of D-aspartic acid to total aspartic acid was in the range of 43.0 to 49.1%. The crude extracts of the hyperthermophiles exhibited aspartate racemase activity at 70 degrees C, and aspartate racemase homologous genes in them were identified by PCR. D-Enantiomers of other amino acids (alanine, leucine, phenylalanine, and lysine) in Thermococcus strains were also detected. Some of them might be by-products of aspartate racemase. It is proven that D-amino acids are produced in some hyperthermophilic archaea, although their function is unknown.

Amino Acid Isomerases↗
PubMed1998

A new anti-rheumatic drug, T-614, effectively suppresses the development of autoimmune encephalomyelitis.

In the present study, we examined the therapeutic effects of T-614 (3-formylamino-7-methylsulfonylaminoxy-4H-1-benzopyran-4-one), a new anti-rheumatic drug, on a T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis (EAE). T-614 dose-dependently suppressed the development of active EAE induced in Lewis rats by immunization with myelin basic protein (MBP) when administered for 2 weeks starting on the day of immunization (day 0 to 14). Amelioration of clinical signs was also obtained by the treatment at the effector phase (day 7 to 14) of the disease. Furthermore, T-614 treatment of recipient rats that had received MBP-sensitized lymphoid cells resulted in suppression of the clinical severity of EAE. Immunohistological examination revealed that the number of TCR alpha beta-expressing T cells and the extent of MHC class II expression in the spinal cord of rats treated with T-614 was markedly reduced. In vitro study using MBP-specific T cells showed that the addition of T-614 inhibited the proliferative responses of T cells and the production of pro-inflammatory cytokines such as IFN-gamma, IL-6 and TNF produced by T and accessory cells. Taken together, these findings imply that T-614 suppresses the development of EAE by inhibiting the proliferation of autoreactive T cells and pro-inflammatory cytokine production not only by T cells but also by macrophages/microglia. This may be attributable to the result that T-614 is more effective at the effector phase rather than the induction phase. Thus, this drug has a potential value for the treatment of various T cell-mediated autoimmune diseases including multiple sclerosis (MS) as well as rheumatoid arthritis.

Animals↗
PubMed1998

Interaction between apoptotic cells and reactive brain cells in the central nervous system of rats with autoimmune encephalomyelitis.

To elucidate the role of brain cells in the immune regulation in the central nervous system (CNS), acute and chronic relapsing experimental autoimmune encephalomyelitis (EAE) was induced in Lewis rats and the location of apoptotic inflammatory cells and their interaction with astrocytes and microglia was investigated at various stages of the disease. Apoptotic cells detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) were few in number at day 10-12 post-immunization (PI), increased and peaked at day 13 PI. Then, these cells decreased gradually by day 21 PI. The most characteristic finding was that apoptotic cells were mainly distributed in the CNS parenchyma with only a few cells present in perivascular cuffs. Double staining by the TUNEL method and immunocytochemistry for astrocytes and microglia revealed that astrocytes were more closely associated with apoptotic cells than microglia. Apoptotic cell death may be one mechanism by which T cells are eliminated from the CNS. Furthermore, the present study suggests that astrocytes, rather than microglia, induce programmed cell death of infiltrating inflammatory cells.

Animals↗
PubMed1998

Role of natural killer cells and TCR gamma delta T cells in acute autoimmune encephalomyelitis.

To elucidate the role of NK cells and TCR gamma delta+ T cells in acute experimental autoimmune encephalomyelitis (EAE) induced in Lewis rats, the distribution, number and function of these cells were studied using several methods. Immunohistochemical and flow cytometric analysis revealed that a certain number of NK cells (17 of the total inflammatory cells) infiltrated the central nervous system (CNS) at the peak stage of EAE and were mainly located in the perivascular region. On the other hand, virtually no TCR gamma delta+ T cells were found in the CNS. NK-T (NKR-P1+TCR alpha beta+) cells were few and did not increase in number in the CNS and lymphoid organs. In the cytotoxic assay using YAC-1 cells, effector cells isolated from the spleen of rats at the peak of EAE showed essentially the same cytotoxicity as those isolated from normal controls although the total number of NK cells decreased to one fifth of that of normal rats. Furthermore, in vivo administration of anti-NK cell (3.2.3 and anti-asialo GM1), but not of anti-TCR gamma delta (V65), antibodies exacerbated the clinical features of EAE and induced fatal EAE in some rats. These findings suggest that NK cells play a suppressive role in acute EAE whereas TCR gamma delta+ T cells are not involved in the development of or recovery from the disease.

Acute Disease↗
PubMed1998

A quadricuspid aortic valve diagnosed by transesophageal echocardiography: report of a case.

A quadricuspid aortic valve is a very rare anomaly which may cause aortic regurgitation in adulthood. We describe herein the case of a 54-year-old man with aortic regurgitation in whom a quadricuspid aortic valve was diagnosed, not through transthoracic investigation, but by transesophageal echocardiography (TEE). TEE also indicated that the right coronary ostium was located in a lower position. Subsequent aortic valve replacement was successfully performed, at which time the diagnosis was confirmed. Thus, TEE played an important role in identifying the anatomy of the aortic valve and the location of the coronary ostium.

Aortic Valve↗
PubMed1998

Assessment of regional left ventricular wall stress after myocardial infarction by echocardiography-based structural analysis.

OBJECTIVES: The objective of this study was to determine the distribution of regional left ventricular (LV) wall stress after myocardial infarction (MI). BACKGROUND: After a large MI, structural changes occur in the heart that ultimately may lead to alterations in LV size and shape, a process generally referred to as ventricular remodeling. Regional variation in myocardial wall stress may be responsible for initiation of physiologic and cellular changes that result in myocardial hypertrophy, dilatation, and remodeling after MI. Simplified geometric analytic methods of estimating global LV wall stress cannot determine regional variation such as that occurring after MI. METHODS AND RESULTS: To assess regional LV wall stress after MI, we applied the finite element method to patient-specific end-systolic LV models generated from echocardiographic imaging. After validation by comparison with analytic solutions of LV wall stress in idealized ventricles, LV models were constructed from rotated orthogonal apical images from 13 normal volunteers, 16 patients with recent (<4 days) anterior MI, and 7 patients with recent infero-posterior MI. The mean Von Mises stress was calculated for the entire LV and for 5 separate regions of the LV. Von Mises LV wall stress was increased globally in patients with anterior MI (211 +/- 46 kdyne/cm2; P < .002) or infero-posterior MI (175 +/- 23 kdyne/cm2; P = .04) compared with normal patients (144 +/- 57 kdyne/cm2). Global wall stress correlated directly with ejection fraction (P < .0001) and inversely with wall motion index (P < .004) in patients with anterior MI. Wall stress in the apical regions was increased by a factor of 2.3 in patients with anterior MI (P < .0001), whereas other regions did not differ from normal patients. There were no individual regions that were significantly different from normal in patients with infero-posterior MI. CONCLUSIONS: Anterior MI is associated with an increase in apical end-systolic wall stress compared with normal and infero-posterior MI. This may be an important stimulus for LV remodeling after anterior MI.

Female↗
PubMed1997

Myosin-induced autoimmune polymyositis in the rat.

Experimental autoimmune myositis (EAM) was induced in Lewis rats by immunization with partially purified and purified skeletal myosin. Although clinical signs such as muscle weakness were very mild, multiple inflammatory lesions in the skeletal muscle, but not in the heart, were found by histological examination. Immunohistochemical staining revealed that muscle fiber-infiltrating cells were CD8+ and CD11b+ cells and that CD4+, TCR alphabeta+, B and NK cells were mainly located in the endomysium and interfiber connective tissue. These findings were in contrast to those obtained in experimental autoimmune encephalomyelitis lesions in which CD4+ cells predominate over CD8+ cells. T cells and sera isolated from myosin-immunized animals responded vigorously to myosin. However, neither sensitized lymphoid cells mainly comprising CD4+ cells nor purified anti-myosin immunoglobulin G mediated the disease into naive rats, suggesting that T cells other than CD4+ cells such as CD8+ cells may be the final effector. Taken together, EAM induced in Lewis rats is similar to human polymyositis (PM). EAM can serve as a good model for human PM and give insight into the pathogenesis of the disease.

Adoptive Transfer↗
PubMed1997

Molecular cloning and characterization of mammalian homologues of the Drosophila retinal degeneration B gene.

Null mutations in the retinal degeneration B gene (rdgB) in flies result in an activity-dependent retinal degeneration. Here we report the isolation of the mouse and human homologues of rdgB gene that are strongly expressed in brain and moderately expressed in other tissues. The deduced amino acid sequences encoding a 1244 a.a protein bear a 96% similarity between mouse and human and resemble the Drosophila rdgB, particularly in the phosphatidylinositol transfer domain at the N-terminus and in six putative transmembrane domains at the C-terminus. Immunoblots with antiserum raised against a bacterially expressed fragment of the mouse rdgB showed the band with a molecular weight of about 170 kDa. Interestingly, a burst of mouse rdgB expression occurs on 17th day of gestation, suggesting a crucial role of the gene product in brain development at this particular stage. A gene, mpt-1, encoding for mouse rdgB was mapped to the proximal end of chromosome 19, which is the same location as Mvb-1, a gene locus encoding the modifier of mouse vibrator mutation (mv).

Amino Acid Sequence↗