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Biomedical subjects

T Kamitani

Publications and source records attributed to T Kamitani.

At least 73 records · Page 4Linked to original sources
PubMed1997

Preferential modification of nuclear proteins by a novel ubiquitin-like molecule.

Sentrin is a novel ubiquitin-like protein that protects cells against both anti-Fas and tumor necrosis factor-induced cell death. Antiserum recognizing the N terminus of sentrin revealed the presence of a 18-kDa sentrin monomer, a 90-kDa band (p90), and multiple high molecular mass bands. Because sentrin possesses the conserved Gly-Gly residues near the C terminus, it is likely that these additional bands represent conjugation of sentrin to other proteins in a manner that is similar to the ubiquitination pathway. Transient expression of hemagglutinin epitope-tagged sentrin mutants in COS cells demonstrated that the sentrin C terminus is cleaved, which allows it to be conjugated to other proteins via the conserved C-terminal Gly residue. Immunocytochemical staining and cell fractionation analysis demonstrated that sentrin monomer is localized predominantly to the cytosol. However, p90 and the majority of sentrinized proteins appeared to be localized to the nucleus. When the conserved Gly-Gly residues of sentrin were changed to Gly-Ala, only sentrin monomer and p90 but not the high molecular mass bands were observed. Thus, p90 generation appears to be required for the formation of high molecular mass bands in the nucleus. Taken together, sentrinization represents a novel pathway for nuclear protein modification, which is distinct from ubiquitination.

Amino Acid Sequence↗
PubMed1997

Effects of TMK688, a novel anti-allergic drug, on allergic nasal obstruction and exudative responses in sensitized guinea pigs.

TMK688 (1-[[5'-(3"-methoxy-4"-ethoxycarbonyloxyphenyl)-2',4'-pentadien oyl] aminoethyl]-4-diphenylmethoxypiperidine) is being developed as an orally effective antiallergic drug having both 5-lipoxygenase inhibitory activity and anti-histamine activity (Shizawa et al. 1996; Tohda et al. 1997). The efficacy of TMK688 against allergic rhinitis was examined in passively sensitized guinea pigs. TMK688 inhibited the increase in intranasal resistance following antigen challenge at doses of 1 and 3.2 mg/kg p.o. The allergic nasal obstruction was also suppressed by 10 mg/kg i.v. of FPL-55712, a peptide leukotriene receptor antagonist, but not by 3.2 mg/kg i.v. pyrilamine, a histamine H1 receptor antagonist, or by 10 mg/kg p.o. of ketotifen, an anti-allergic drug having anti-histamine activity, suggesting that the nasal obstruction was caused by leukotrienes. Following antigen challenge, the intranasal release of leukotrienes B4 and C4, and histamine increased in passively sensitized guinea pigs. TMK688 tended to suppress the increase in immunoreactive leukotrienes B4 and C4 in the nasal lavage fluid at a dose of 1 mg/kg p.o., and significantly inhibited the increase at 3.2 mg/kg. The brilliant blue dye leakage following antigen challenge from the blood stream into the nasal cavities was significantly inhibited by not only TMK688 and FPL-55712 but also pyrilamine, suggesting that the allergic dye leakage was caused cooperatively by leukotrienes and histamine. However, ketotifen showed no significant suppression of the dye leakage even at 10 mg/kg p.o., although this drug inhibited the histamine-induced dye leakage at far lower doses (0.1 mg/kg p.o. or higher) in unsensitized guinea pigs. Therefore, histamine is not necessarily the major mediator of allergic dye leakage in our experiment. These findings demonstrate that TMK688 may be superior to antihistamines as a therapeutic agent for allergic rhinitis.

Animals↗
PubMed1997

Acute necrotizing eosinophilic myocarditis with giant cell infiltration after remission of idiopathic thrombocytopenic purpura.

Acute necrotizing eosinophilic myocarditis is characterized by acute onset, fulminant congestive heart failure, and extensive necrosis of myocytes with striking eosinophilic infiltration. However, multinucleated giant cells sometimes appear in the fulminant phase of severe myocarditis. This is the first case of a patient with a 1 year previous history of idiopathic thrombocytopenic purpura, who presented with acute necrotizing eosinophilic myocarditis with giant cell infiltration.

Acute Disease↗
PubMed1997

[Clinical evaluation of 123I-BMIPP myocardial SPECT in patients with hypertensive heart disease and hypertrophic cardiomyopathy: comparison with the findings of 201Tl SPECT and Gd enhanced magnetic resonance imaging].

123I-BMIPP SPECT (123I-BMIPP), 201Tl SPECT (201Tl), and Gd-DTPA enhanced magnetic resonance myocardial imaging (MR) were performed in patient groups with hypertensive heart disease (HHD), apical hypertrophic cardiomyopathy (APH), and hypertrophic cardiomyopathy without APH(HCM). SPECT was divided into 20 segments and each segment was scored as one of 4 grades (0 = normal; 1 = mildly decreased; 2 = severely decreased; and 3 = defect) according to the RI uptake. Gd enhancement in MR was interpreted visually. A decreased in the uptake of 123I-BMIPP showed in 54 of 141 hypertrophic (> 13 mm, measured by ultrasonic cardiography) segments in HHD, in 32 of 66 in APH and in 103 of 207 in HCM respectively. Whereas 201Tl SPECT showed decreased uptake in 18 of 141 hypertrophic segments, in 18 of 66 in APH, and in 27 of 207 in HCM, respectively. 123I-BMIPP showed a higher incidence of these scintigraphic abnormalities than did 201Tl in the hypertrophic segments. And also in the hypertrophic segments, decreased in the uptake of 123I-BMIPP occurred more frequently in HCM than in HHD. In HCM, decreased 123I-BMIPP uptake appeared more frequently in segments 1, 2, 9, and 10 (antero-septal junction) than in other segments, but in APH, such decreases occurred more often in segments 17, 18, 19, and 20 (apex). Enhanced signal intensity with Gd-DTPA appeared in more segments in the HCM group than in the APH or HHD groups. We concluded that HCM had the most extensive and severe structural changes--including metabolic and ischemic changes--among three groups, and that the combination of these three examinations was useful for evaluating the characteristics of hypertrophic myocardium.

Aged↗
PubMed1997

The inhibitory effect of TMK688, a novel anti-allergic drug having both 5-lipoxygenase inhibitory activity and anti-histamine activity, against bronchoconstriction, leukotriene production and inflammatory cell infiltration in sensitized guinea pigs.

BACKGROUND: TMK688 is being developed as an anti-allergic drug having both 5-lipoxygenase inhibitory activity and anti-histamine activity. METHOD: We compared the inhibition of the late asthmatic responses by TMK688 with that by other anti-allergic agents in actively sensitized guinea pigs, and examined the relationship between 5-lipoxygenase inhibition and the late asthmatic responses. RESULTS: At 1-3.2 mg/kg, TMK688 inhibited the increases in respiratory resistance, leukotriene (LT) B4 and C4 production in the lungs and eosinophil infiltration into the alveoli during the late asthmatic response, whereas the effects tended to lessen at the dose of 10 mg/kg. These effects are thought to be caused by the 5-lipoxygenase inhibitory activity of TMK688 because Azelastine, an anti-allergic drug having potent antihistamine activity, exhibited no effect. ONO-1078, a peptide LT antagonist, inhibited the late-phase bronchoconstriction at a dose of 100 mg/kg p.o., but not the increase in the infiltration of inflammatory cells into the alveoli, suggesting that the late-phase bronchoconstriction is induced, in part, by peptide LTs, i.e. LT C4, D4 and E4 and that the inflammatory cell infiltration may be caused by LTB4. TMK688 inhibited the immediate bronchoconstriction dose-dependently, and the effect was significant at a dose of 10 mg/kg orally. Since Azelastine, Ketotifen and Oxatomide suppressed the bronchoconstriction at far lower doses than did TMK688, the inhibitory effect was mainly caused by its antihistamine activity. CONCLUSIONS: TMK688 appears to be a novel anti-allergic drug having inhibitory effects on both the bronchoconstriction and the infiltration of inflammatory cells during late asthmatic responses.

Animals↗
PubMed1996

Protection against Fas/APO-1- and tumor necrosis factor-mediated cell death by a novel protein, sentrin.

Fas/APO-1 and TNF receptor 1 share a common signaling motif in their cytoplasmic tail called the "death domain." Using the death domain as bait in the yeast two-hybrid system, several death domain-containing proteins that participate in cell death signaling have been identified. Here we report the isolation of a novel protein, sentrin, which interacts with Fas/APO-1 and TNF receptor 1 but not with FADD/MORT1 or CD40. Two-hybrid interaction assays reveal that sentrin associates only with the signal-competent forms of Fas/APO-1 or TNF receptor 1 death domains. Sentrin is a novel protein of 101 amino acids with homology to ubiquitin, Nedd8, and a Saccharomyces cerevisiae protein, Smt3. When overexpressed, sentrin provides protection against both anti-Fas/APO-1 and TNF-induced cell death.

Adaptor Proteins, Signal Transducing↗
PubMed1996

5-Lipoxygenase inhibitory and antihistamine activities of linetastine.

The ability of linetastine (TMK688, 1-[¿5'-(3"-methoxy-4"-ethoxycarbonyloxyphenyl)-2',4'-pentadieno yl¿ aminoethyl]-4-diphenylmethoxypiperidine, CAS 110501-66-1) to inhibit leukotriene production and to antagonize the effect of histamine was examined in comparison with the ability of azelastine, an antiallergic drug having an antihistamine activity. Linetastine and its active metabolite TMK777 (1-[¿5'-(3"-methoxy-4"-hydroxyphenyl)-2',4'-pentadienoyl¿ aminoethyl]-4-diphenylmethoxypiperidine, CAS 101619-11-8) inhibited the release of leukotrienes B4 and C4 from calcium ionophore-stimulated human leukocytes. The respective IC50 values of leukotriene B4 were 1.2 x 10(-7) mol/l and 8.6 x 10(-8) mol/l, and those of leukotriene C4 were 1.5 x 10(-7) mol/l and 7.1 x 10(-8) mol/l. Azelastine also inhibited the release of leukotriene B4 and C4, but its IC50 values were higher than 1 x 10(-5) mol/l. Linetastine at 1-10 mg/kg p.o. inhibited the increase in leukotriene B4 and C4 production in the lungs during late asthmatic responses in actively sensitized guinea-pigs. The effect of 3.2 mg/kg lasted for more than 16 b. Since repeated oral administration of linetastine, 1 mg/kg once a day for 7 successive days, showed the same inhibitory effect on the increase in respiratory resistance and the leukotriene production as single oral administration, the effect of linetastine was neither tachyphylactic nor cumulative. Azelastine at 10 mg/kg had no effect on the leukotriene production. Linetastine TMK777 and azelastine dose-dependently inhibited the histamine-induced contraction of isolated guinea-pig trachea in a noncompetitive manner, the respective pD2 values were 7.28, 7.98 and 8.07. Linetastine inhibited histamine-induced bronchoconstriction dose-dependently at 1-10 mg/kg (p.o.) in guinea-pigs, and the effect lasted for more than 24 h. Repeated oral administration of linetastine, 0.32 to 3.2 mg/kg once a day for 7 successive days inhibited the histamine-induced bronchoconstriction, the same as single oral dosing. Azelastine at 0.32 mg/kg p.o. also showed antihistamine activity. In conclusion, linetastine inhibits both the production of leukotrienes and the effect of histamine at almost the same dose and the effects were long lasting.

Animals↗
PubMed1995

Clinical usefulness of 123I-metaiodobenzylguanidine myocardial scintigraphy in diabetic patients with cardiac sympathetic nerve dysfunction.

To assess the clinical utility of 123I-metaiodobenzylguanidine (MIBG) scintigraphy in evaluating cardiac sympathetic nerve disturbance in diabetic patients, we performed MIBG scintigraphy in 18 diabetic patients and 11 normal controls. Diabetic patients with symptomatic neuropathy (DM2) had a significantly lower heart to mediastinum uptake ratio than did those without neuropathy or normal controls in initial and delayed images (initial image, 1.90 +/- 0.27 vs 2.32 +/- 0.38, 2.41 +/- 0.40, p< 0.01; delayed image, 1.80 +/- 0.31 vs 2.48 +/- 0.35 2.56 +/- 0.28, p < 001, respectively). Defect score, assessed visually, were higher in DM2 patients than in patients in the other two groups (initial image, 7 +/- 2.6 vs 1.5 +/- 1.9, 0.7 +/- 0.9; delayed image 10.6 +/- 3.3 vs 4.0 +/- 2.5, 1.7 +/- 1.6 p < 0.01, respectively). The maximum washout rate in DM2 patients was also higher than those in patients in the other two groups. The findings of these indices obtained from MIBG scintigraphy coincided with the % low-frequency power extracted from heart rate fluctuations using a power spectral analysis and the results of the Schellong test, which were used to evaluate sympathetic function. These results suggest that MIBG scintigraphy may be useful for evaluating cardiac sympathetic nerve disturbance in patients with diabetes.

3-Iodobenzylguanidine↗
PubMed1995

Effect and safety of liposome-encapsulated hemoglobin neo red cells (NRCs) as a perfusate for total cardiopulmonary bypass.

We developed a liposome encapsulated hemoglobin named Neo Red Cells (NRC), NRC (1) readily circulates, (2) shows a high oxygen transport efficiency, and (3) has a strong capsule membrane. In this study, we evaluated the effect of NRC as a priming solution for total cardiopulmonary bypass (TCPB) using a dog. The TCPB was started after removal of 57.1-73.3% of autologous blood and continued for 7 hours. During TCPB using NRC, the vascular resistance (VR) decreased to 1/4 of VR when red blood cells (RBC) were used. This change suggests that NRC, the viscosity of which is lower than that of RBC, reduced the load on the circulation system. The oxygen volume delivered by NRC was higher than that delivered by RBC, resulting in a greater oxygen consumption with NRC. During TCPB using NRC, the serum LDH level was lower than that using RBC. So we concluded that NRC compensated for the reduction in the oxygen transport ability, which is a disadvantage of dilution TCPB, and further increased the circulation improving effect and anti-hemolytic effect, which are advantages of the procedure. It, thus, enhanced both the safety and effectiveness of dilution TCPB.

Animals↗
PubMed1994

Glycosyl-phosphatidylinositol anchor synthesis in paroxysmal nocturnal hemoglobinuria: partial or complete defect in an early step.

The defect in the biosynthesis of the glycosyl-phosphatidyl inositol (GPI) anchor in paroxysmal nocturnal hemoglobinuria (PNH) appears to be in the initial steps. In biosynthetic studies using [3H]mannose, abnormal granulocytes of eight patients, and B lymphocytes transformed by Epstein-Barr virus of six different patients synthesized dolichyl phosphoryl mannose, but little or no later mannosylated intermediates. When fused with murine cell lines known to be deficient at different biosynthetic steps of the GPI anchor, the GPI-anchor-deficient granulocytes of 21/21 patients and lymphocytes from 6/6 patients complemented all murine cell lines except those of class A; cells of this class are not able to add N-acetylglucosamine to phosphatidylinositol. These studies indicate that the defect in GPI-anchor synthesis in PNH is early in the pathway, and is the same as that of class A mutants, but may be partial in some patients, resulting in the production of small amounts of mannosylated intermediates.

Antigens, CD↗
PubMed1994

Biosynthesis and processing of the glycosylphosphatidylinositol anchor in mammalian cells.

Many T cell surface proteins are attached to the cell membrane by glycosylphosphatidylinositol (GPI) anchors, which may be involved in cell signaling, protein targeting or protein release. Proteins destined to be GPI-anchored have both N- and C-terminal signal peptides, which permit the nascent polypeptides to transverse the endoplasmic reticulum and to be transferred to preformed GPI anchors in a transamidase reaction. The biosynthetic pathway of the GPI anchor in mammalian cells has been elucidated using a panel of T cell mutants that cannot express GPI-anchored proteins on their cell surfaces. The first step in anchor biosynthesis is the transfer of N-acetylglucosamine (GlcNAc) to a phosphoinositol (PI) acceptor to form GlcNAc-PI, which is then deacetylated to form GlcN-PI. Subsequently, a fatty acid is added to the inositol ring and three mannose residues are transferred to the elongating GPI core. Finally, ethanolamine phosphates are transferred to the mannose residues. Three human cDNAs encoding for GPI synthases (Classes A, F and H) have been identified using expression cloning technique. Mutation in the X-linked class A gene was shown to be the cause of paroxysmal nocturnal hemoglobinuria, an acquired disease affecting hematopoietic stem cells in which the abnormal cells are deficient in GlcNAc-PI formation. The potential involvement of GPI-anchored proteins or GPIs in T cell activation is also discussed.

Acylation↗
PubMed1994

Effect of neo red cells on hemodynamics and blood gas transport in canine hemorrhagic shock and its safety for vital organs.

The purpose of this study was to evaluate the effects of liposome encapsulated hemoglobin named "Neo Red Cells (NRC)" on canine hemorrhagic shock model and its safety for the vital organs in a whole blood exchange model. HEMORRHAGIC SHOCK: Nine adult mongrel dogs were used. Under mechanical ventilation inhaling room air, blood was withdrawn via an artery at a rate of 40 ml/min in order to induce hemorrhagic shock (systolic pressure below 60 mm Hg) and then NRC was transfused. For each animal, three to five cycles of bloodletting and NRC transfusion were performed. After blood exchange, total peripheral resistance index (TPRI) decreased and cardiac index (CI) increased. These changes were more marked in the high exchange group (exchange rate over 88%; five animals) than in the low exchange group (less than 88%; four animals), indicating that the low viscosity NRC reduced the load on the circulatory system. The A-V difference in oxygen content per lg hemoglobin was greater after blood exchange, indicating that oxygen binding capacity of NRC is higher than that of red blood cells. WHOLE BLOOD EXCHANGE: Five beagles were used for the blood exchange. The blood was withdrawn from an artery at a rate of 15 ml/min and NRC was infused at the same time. A dog whose blood was exchanged with hydroxyethylstarch instead of NRC died within 15 hours after blood exchange. Three dogs whose blood was exchanged with NRC (exchange rate was from 82 to 90%) have been living over a year without any side effects. A dog sacrificed on the 15th postoperative day for autopsy, microscopically showed no side effects in vital organs. We conclude that NRC is more suitable than natural blood for treatment of hemorrhagic shock and safe for vital organs.

Animals↗
PubMed1994

Characteristics of neo red cells, their function and safety: in vivo studies.

A new type of artificial oxygen carriers, the Neo Red Cells (NRCs) have been developed and investigated for oxygen transporting efficiency and safety in experimental animals. Stroma free hemoglobin from outdated human red blood cells together with inositol hexaphosphate as an allosteric effector under sterile, pyrogen free condition were encapsulated in liposomes and then were coated with polyethylene glycol bond to hydrogenated soy phosphatidylethanolamine as a surface modifier to prevent aggregation of NRCs in plasma. The efficiency of the NRCs in tissue oxygenation was studied in rabbits which were made severely anemic by drawing 85% of their blood and immediately replacing it with NRC solution. The animals, all recovered to pre-anemic conditions within 6-8 hr and lived normally until being sacrificed, 6 months after the exchange transfusion. The circulation half-life and tissue distribution of NRCs were studied using radiolabeled NRCs. Within the circulation, the half-life of NRCs was 21 hr and extravascularly, they were distributed mainly in and metabolized by the reticuloendothelial system within 7 days. Our observations suggest that the NRCs prepared and investigated in this study are efficient oxygen carriers without causing serious adverse reactions and can be prepared free from pathogenic micro-organisms by special filtration technique before encapsulation of Hb. Currently, experiments are ongoing to control auto-oxidation of oxyHb to metHb which is higher in NRCs than in native red cells at physiological conditions.

Animals↗
PubMed1993

Correction of the class H defect in glycosylphosphatidylinositol anchor biosynthesis in Ltk- cells by a human cDNA clone.

Previous attempts to express glycosylphosphatidylinositol-anchored proteins in Ltk- cells have not been successful because Ltk- cells cannot synthesize N-acetylglucosamine-phosphatidylinositol, the first intermediate in anchor biosynthesis. Using complementation cloning, we have identified a human cDNA that corrects the defect in anchor biosynthesis and allows the expression of glycosylphosphatidylinositol-anchored proteins in Ltk- cells. The nucleotide sequence predicts a novel cytosolic protein of 188 amino acids.

Amino Acid Sequence↗
PubMed1993

[Cranial MRI in hepatic disease--relationship between MR imaging and clinical symptoms and laboratory analysis of liver function].

Magnetic resonance imaging studies on 12 cases with hepatic disease were performed. In 11 adult patients with chronic hepatic failure, T1-weighted images demonstrated increased signal in the globus pallidus in 7 patients (63.6%) and in some parts of the cerebral peduncles in 6 patients (54.5%), in the substantia innominata in 4 patients (36.3%). There might be some correlation between the abnormality of MR imaging and clinical symptoms of hepatic encephalopathy. There was a significant correlation between the intensity of the signal and Fischer's ratio of amino acid analysis. In one patient with Wilson's disease, who developed symptoms of central nervous system, T1-weighted images demonstrated increased signal in the globus pallidus. After treatment of D-penicillamine, the signal of the globus pallidus decreased.

Adult↗
PubMed1993

Oxygen transport capacity and hemodynamic effect of newly developed artificial blood "Neo Red Cells (NRC)".

The purpose of this study was to evaluate liposome-encapsulated hemoglobin, named Neo Red Cells (NRC), on hemodynamics and oxygen-transport capacity in a blood exchange experiment. The experiment was carried out in nine mongrel dogs. Depending on the percentage of blood exchange with NRC, the animals were divided into two groups; Group I (4 animals with an exchange rate less than 88%), and Group II (5 animals with an exchange rate over 88%). After blood exchange, total peripheral vascular resistance index (TPRI) decreased and cardiac index (CI) increased. These changes were more marked in Group II than in Group I, thus showing that NRC relieved the burden on the heart, probably due to the fact that the viscosity of NRC is 2 cp which is less than 1/3 that of whole blood. The oxygen binding capacity per 1g hemoglobin in NRC was 2-4 times as much as red blood cells. Thus, NRC was superior to natural red blood cells in terms of oxygen transport capacity and its effects on the circulatory system.

Animals↗
PubMed1992

Complexity of ethanolamine phosphate addition in the biosynthesis of glycosylphosphatidylinositol anchors in mammalian cells.

Biosynthetic intermediates for the mammalian glycosylphosphatidylinositol (GPI) anchor have been described. The earliest GPI anchor precursor is N-acetylglucosaminylphosphatidylinositol, which is deacetylated to give glucosaminylphosphatidylinositol. This is followed by fatty acylation of the inositol ring, sequential addition of mannose residues donated by dolichyl mannosyl phosphate, and finally addition of ethanolamine phosphate. Here, we show that the final steps of GPI anchor biosynthesis are more complex than we have previously reported. Six distinct GPI anchor precursors were found to contain at least 1 ethanolamine phosphate residue. The headgroups of these glycolipids were purified and analyzed by a combination of Bio-Gel P4 chromatography and high resolution thin-layer chromatography. The sizes of neutral glycans were determined following HF dephosphorylation. The position of the ethanolamine phosphate residue was inferred from results of alpha-mannosidase treatment. Finally, the number of negative charges on the headgroups were determined by Mono Q chromatography. Our results show that the addition of ethanolamine phosphate is controlled by at least two different genes. Thus, the class F mutant, though unable to add ethanolamine phosphate to the third mannose residue, does incorporate ethanolamine phosphate into the first and second mannose residues. Only the wild type cells are capable of incorporating ethanolamine phosphate into the third mannose residue. Furthermore, the GPI core contains up to 3 ethanolamine phosphate residues. These results should facilitate the elucidation of the biochemical defects in paroxysmal nocturnal hemoglobinuria.

Animals↗