C3123A polymorphism of the angiotensin II type 2 receptor gene and salt sensitivity in healthy Japanese men.
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Adult↗
Biomedical subjects
A Hara
Publications and source records attributed to A Hara.
Blockade of VEGF accelerates proteinuria, via decrease in nephrin expression in rat crescentic glomerulonephritis.
Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that maintains the glomerular and peritubular capillary (PTC) network in the kidney. The soluble form of the VEGF receptor-1 (soluble fms-like tyrosine kinase 1 (sFlt-1)) is known to regulate VEGF activity by binding VEGF in the circulation. We hypothesized that VEGF may be beneficial for maintaining glomerular filtration barrier and vascular network in rats with progressive glomerulonephritis (GN). For blockade of VEGF activity in vivo, rats were transfected twice with plasmid DNA encoding the murine sFlt-1 gene into femoral muscle 3 days before and 2 weeks after the induction of antiglomerular basement membrane antibody-induced GN. Inhibition of VEGF with sFlt-1 resulted in massive urinary protein excretion, concomitantly with downregulated expression of nephrin in nephritic rats. Further, blockade of VEGF induced mild proteinuria in normal rats. Administration of sFlt-1 affected neither the infiltration of macrophages nor crescentic formation. In contrast, treatment of sFlt-1 accelerated the progression of glomerulosclerosis and interstitial fibrosis accompanied with renal dysfunction and PTC loss at day 56. VEGF may play a role in maintaining the podocyte function as well as renal vasculature, thereby protecting glomeruli and interstitium from progressive renal insults.
Animals↗
Deduced primary structure of two forms of vitellogenin in Japanese common goby (Acanthogobius flavimanus).
Complete nucleotide sequences of two forms of vitellogenin (Vg) cDNA in Japanese common goby were determined from a liver cDNA library of E(2)-treated male fish. These two Vg cDNAs contained complete open reading frames encoding 1664 and 1238 amino acid residues including signal peptides, respectively. From comparison of the deduced amino acid sequences of both Vgs and the partial amino acid sequences of the yolk proteins, the longer sequence was concluded to be cDNA of the Vg-530 and the shorter one was that of the Vg-320 of the Japanese common goby which were reported in our previous paper. The deduced sequence of Vg-530 without signal peptide was arranged by lipovitellin heavy-chain (LvH), phosvitin (Pv), lipovitellin light-chain (LvL), and beta'-component beta'-c) domains from the N-terminus, and showed a range of 40-45% sequence identity to those of other fish. Furthermore, the deduced sequence of Vg-320 showed no obvious Pv domain, has a shortened C-terminal coding region after the LvH domain, and showed a close similarity to the phosvitin-less Vg of zebrafish. Moreover, biochemical analysis of the yolk proteins verified that Vg-530 cleaves into the Lv-Pv complex (molecular mass: 470 kDa) and beta'-c (33 kDa), while Vg-320 showed no change when incorporated into oocytes. The present study demonstrated the existence of the two different forms of Vgs at both the cDNA and protein level, and showed molecular alteration of the two Vgs during vitellogenesis. Two Vg sequence data will aid in designing nucleotide probes for detecting Vg gene expressions as a biomarker of environmental estrogens.
Amino Acid Sequence↗
Marked asymmetry of putaminal pathology in an MSA-P patient with Pisa syndrome.
We report on an autopsy case of a 62-year-old Japanese woman with a 2.5-year history of axial dystonia. She presented with a form of axial dystonia reminiscent of Pisa syndrome. The pathophysiological mechanism underlying forms of axial dystonia remains to be elucidated. We report here the histopathological findings of a multiple system atrophy of parkinsonian predominance (MSA-P) patient with Pisa syndrome.
Atrophy↗
Protein levels of genes encoded on chromosome 21 in fetal Down syndrome brain: Challenging the gene dosage effect hypothesis (Part IV).
Down syndrome (DS) is the most frequent genetic disorder with mental retardation and caused by trisomy 21. Although the molecular mechanisms of the various phenotypes of DS could be due to overexpression of gene(s) on chromosome 21, several groups have challenged this gene dosage effect hypothesis. The near completion of the sequencing of human chromosome 21 provides unprecedented opportunities to understand the molecular pathology of DS, however, functional information on gene products is limited so far. We therefore evaluated the levels of six proteins whose genes are encoded on chromosome 21 (trefoil factor 1, trefoil factor 2, trefoil factor 3, coxsackie virus and adenovirus receptor, carbonyl reductase 1 and interferon- alpha receptor) in fetal cerebral cortex from DS and controls at the early second trimester using Western blot analysis. None of the investigated proteins showed overexpression in DS compared to controls suggesting that these proteins are not involved in abnormal development of fetal DS brain and that DS phenotype can not be simply explained by the gene dosage effect hypothesis. We are systematically quantifying all proteins whose genes are encoded on chromosome 21 and these studies may provide a better understanding of genotype-phenotype correlation in DS.
Brain↗
Development of an RIA for salmon 41 kDa IGF-binding protein.
Salmon plasma contains at least three IGF-binding proteins (IGFBPs) with molecular masses of 41, 28 and 22 kDa. The 41 kDa IGFBP is similar to mammalian IGFBP-3 in size, type of glycosylation and physiological responses. In this study, we developed an RIA for the 41 kDa IGFBP. The 41 kDa IGFBP purified from serum was used for antibody production and as an assay standard. Binding of three different preparations of tracer were examined: (125)I-41 kDa IGFBP, (125)I-41 kDa IGFBP cross-linked with IGF-I and 41 kDa IGFBP cross-linked with (125)I-IGF-I (41 kDa IGFBP/(125)I-IGF-I). Only binding of 41 kDa IGFBP/(125)I-IGF-I was not affected by added IGFs, and therefore it was chosen for the tracer in the RIA. Plasma 41 kDa IGFBP levels measured by RIA were increased by GH treatment (178.9+/-4.9 ng/ml) and decreased after fasting (95.0+/-7.0 ng/ml). The molarities of plasma 41 kDa IGFBP and total IGF-I were comparable, and they were positively correlated, suggesting that salmon 41 kDa IGFBP is a main carrier of circulating IGF-I in salmon, as is mammalian IGFBP-3 in mammals. During the parr-smolt transformation (smoltification) of coho salmon, plasma 41 kDa IGFBP levels showed a transient peak (182.5+/-10.3 ng/ml) in March and stayed relatively constant thereafter, whereas IGF-I showed peak levels in March and April. Differences in the molar ratio between 41 kDa IGFBP and IGF-I possibly influence availability of IGF-I in the circulation during smoltification.
Animals↗
Chemoprevention of large bowel carcinogenesis; the role of control of cell proliferation and significance of beta-catenin-accumulated crypts as a new biomarker.
Control of cell proliferation is important for cancer prevention since cell proliferation has essential roles in carcinogenesis in the processes of both initiation and promotion. In large bowel carcinogenesis, carcinogens produce hyperproliferation of cells in the target sites and the cell proliferation persists even after the cessation of carcinogen exposure. Chemopreventive agents principally control the increased cell proliferation when given in the initiation as well as post-initiation phases. Aberrant crypt foci (ACF) which appear soon after carcinogen exposure in large bowel carcinogenesis in rodents have been used as a reliable biomarker for screening of potential chemopreventive agents. Recently, our group demonstrated the presence of probable premalignant lesions with frequent beta-catenin gene mutations and accumulation of the corresponding protein in the colonic epithelium of rats given a large bowel carcinogen. Such early-appearing lesions lack the morphological appearance of ACF. Expression of these beta-catenin-accumulated crypts (BCAC) is markedly suppressed by a chemopreventive cyclooxygenase-2 inhibitor, celecoxib. BCAC are suggested to be more reliable biomarkers than ACF for screening effective chemopreventive agents for colorectal cancer and for investigating the mode of action of the agents.
Animals↗
The loss of susceptibility to apoptosis in exudated tissue neutrophils is associated with their nuclear factor-kappa B activation.
Tissue neutrophils, human salivary neutrophils donated from healthy subjects and synovial fluid neutrophils collected from patients with rheumatoid arthritis were compared with circulating blood neutrophils. Concomitant treatment of circulating blood neutrophils with tumor necrosis factor-alpha (TNF-alpha) and cycloheximide induced neutrophil apoptosis, whereas the same treatment failed to induce significant apoptosis in salivary and synovial fluid neutrophils. Caspase-3 activation by TNF-alpha was observed in these tissue neutrophils, although its activity was significantly weaker than that in circulating blood neutrophils. In circulating blood neutrophils, TNF-alpha induced activation of nuclear factor-kappa B (NF-kappa B), whereas, in tissue neutrophils, NF-kappa B had been already activated without any stimulation, and no further activation was induced by the treatment with TNF-alpha. Furthermore, while pretreatment of neutrophils with an NF-kappa B inhibitor produced typical apoptotic changes in circulating blood neutrophils, this inhibitor did not produce any morphological apoptotic changes induced by TNF-alpha in tissue neutrophils. These results indicate that neutrophils undergo marked functional changes such as altered sensitivity to apoptosis-inducing stimuli in association with their exudation from blood into tissue, and that NF-kappa B activation is involved in the acquisition of resistance to TNF-alpha-induced apoptosis.
Apoptosis↗
An unusual vitamin E constituent (alpha-tocomonoenol) provides enhanced antioxidant protection in marine organisms adapted to cold-water environments.
A new vitamin E constituent having an unusual methylene unsaturation at the isoprenoid-chain terminus of alpha-tocopherol (alpha-Toc) was isolated from chum salmon eggs and was found to have identical antioxidant activity as does alpha-Toc in methanol or liposomal suspension at 37 degrees C. Here we report that this marine-derived tocopherol (MDT) is broadly distributed with alpha-Toc in the tissue of marine fish, and that the MDT composition of total vitamin E is greater in the flesh of cold-water salmon (12-20%) than in that of tropical fish (< or =2.5%). Vitamin E analysis of cultured masu salmon maintained on a MDT-deplete diet showed substantially less MDT content than native masu salmon, suggesting a trophic origin of MDT. This contention is supported by the finding of MDT in marine plankton from the cold waters of Hokkaido. We found that MDT inhibited peroxidation of cholesterol-containing phosphatidylcholine liposomes to a greater extent than did alpha-Toc at 0 degrees C. Furthermore, the ratios of the rate constants for MDT and alpha-Toc to scavenge peroxyl radicals increased with decreasing rates of radical flux in liposomes and fish oil at 0 degrees C, indicating that the enhanced activity of MDT at low temperature is attributed to its greater rate of diffusion in viscous lipids. These results suggest that MDT production, or its trophic accumulation, may reduce lipid peroxidation in marine organisms functionally adapted to cold-water environments.
Adaptation, Physiological↗
Roles of prostaglandin I(2) and thromboxane A(2) in cardiac ischemia-reperfusion injury: a study using mice lacking their respective receptors.
BACKGROUND: Prostaglandin (PG) I(2) and thromboxane (TX) A(2), the most common prostanoids in the cardiovascular system, are produced abundantly during cardiac ischemia/reperfusion (I/R); their roles in I/R injury, however, remain undetermined. We intended to clarify these roles of PGI(2) and TXA(2) using mice lacking the PGI(2) receptor, IP(-/-) mice, or the TXA(2) receptor, TP(-/-) mice. METHODS AND RESULTS: The left anterior descending coronary artery was occluded for 1 hour and then reperfused for 24 hours. The size of myocardial infarct in IP(-/-) mice was significantly larger than that in wild-type mice, although the size of the area at risk was similar between the 2 groups of mice. In contrast, there was no such difference between TP(-/-) and wild-type mice. To further determine whether PGI(2) and TXA(2) act directly on the cardiac tissue or indirectly through their action on blood constituents, we perfused excised heart according to the Langendorff technique. The isolated heart was then subjected to global ischemia followed by reperfusion. In IP(-/-) mice, developed tension and coronary flow rate during reperfusion were significantly lower and release of creatine kinase was significantly higher than those in wild-type mice. There were no such differences, however, between TP(-/-) and wild-type mice. CONCLUSIONS: PGI(2), which was produced endogenously during cardiac I/R, exerts a protective effect on cardiomyocytes independent of its effects on platelets and neutrophils. In contrast, TXA(2) has little role in the cardiac I/R injury.
Adenosine Triphosphate↗
Increased bleeding tendency and decreased susceptibility to thromboembolism in mice lacking the prostaglandin E receptor subtype EP(3).
BACKGROUND: Among the prostanoids, thromboxane (TX) A(2) is a potent stimulator of platelets, whereas prostaglandin (PG) I(2) inhibits their activation. The roles of PGE(2) in the regulation of platelet function have not been established, however, and the contribution of PGE(2) in hemostasis and thromboembolism is poorly understood. The present study was intended to clarify these roles of PGE(2) by using mice lacking the PGE(2) receptor subtype 3 (EP(3)(-/-) mice). METHODS AND RESULTS: Expression of mRNAs for EP(3) in murine platelets was confirmed by quantitative reverse transcription-polymerase chain reaction. PGE(2) and AE-248, a selective EP(3) agonist, showed concentration-dependent potentiation of platelet aggregation induced by U46619, a TXA(2) receptor agonist, although PGE(2) alone could not induce aggregation. PGE(2) and AE-248 increased cytosolic calcium ion concentration ([Ca(2+)](i)), and AE-248 inhibited the forskolin-induced increase in cytosolic cAMP concentration ([cAMP](i)), suggesting G(i) coupling of EP(3). The potentiating effects of PGE(2) and AE-248 on platelet aggregation along with their effects on [Ca(2+)](i) and [cAMP](i) were absent in EP(3)(-/-) mice. In vivo, the bleeding time was significantly prolonged in EP(3)(-/-) mice. Moreover, when mice were challenged intravenously with arachidonic acid, mortality and thrombus formation in the lung were significantly reduced in EP(3)(-/-) mice. CONCLUSIONS: - PGE(2) potentiated platelet aggregation induced by U46619 via EP(3) by increasing [Ca(2+)](i), decreasing [cAMP](i), or both. This potentiating action of PGE(2) via EP(3) is essential in mediating both physiological and pathological effects of PGE(2) in vivo.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
Protection of outer hair cells from reperfusion injury by an iron chelator and a nitric oxide synthase inhibitor in the guinea pig cochlea.
To examine whether an active process of the cochlea was injured by ischemia-reperfusion, time courses of distortion-product otoacoustic emissions (DPOAEs) were examined before, during and after 30 min cochlear ischemia using albino guinea pigs. DPOAEs decreased to the minimum level when the animals were subjected to ischemia. When the cochlea was recirculated, DPOAEs initially recovered with time until 20 min after the onset of reperfusion. However, thereafter the amplitude of DPOAEs gradually decreased toward the noise level. Administration of deferoxamine (an iron chelator) or N-nitro-L-arginine (a nitric oxide synthase inhibitor) ameliorated this decrease of DPOAEs during reperfusion and significantly increased the DPOAE amplitudes 60 min after the onset of reperfusion as compared with those in non-treated animals. These results suggest that cochlear reperfusion as well as ischemia injured the active process of the cochlea and that free radicals and nitric oxide play important roles in this injury.
Animals↗
Co-operative regulation of the transcription of human dihydrodiol dehydrogenase (DD)4/aldo-keto reductase (AKR)1C4 gene by hepatocyte nuclear factor (HNF)-4alpha/gamma and HNF-1alpha.
Human dihydrodiol dehydrogenase (DD) 4/aldo-keto reductase (AKR) 1C4 is a major isoform of hepatic DD that oxidizes trans-dihydrodiols of polycyclic aromatic hydrocarbons to reactive and redox-active o-quinones and that reduces several ketone-containing drugs. To investigate the mechanism of transcriptional regulation of the human DD4 gene, the 5'-flanking region of the gene was fused to the luciferase gene. The results of luciferase assays using HepG2 cells and of 1,10-phenanthroline-copper footprinting indicated that two positive regulatory regions were located in regions from -701 to -684 and from -682 to -666. The former region contained a putative hepatocyte nuclear factor (HNF)-4 binding motif, and the latter region contained an HNF-1 consensus binding sequence. DNA fragments of the HNF-4 or HNF-1 motif gave a shifted band in a gel-shift assay with nuclear extracts from HepG2 cells. The formation of the DNA-protein complex was inhibited by the HNF-4 or HNF-1 motif of the alpha(1)-antitrypsin gene. A supershift assay using antibodies to human HNF-4alpha, HNF-4gamma and HNF-1alpha showed that HNF-4alpha and HNF-4gamma bound to the HNF-4 motif, and that HNF-1alpha interacted with the HNF-1 motif. Introduction of mutations into the HNF-4 or HNF-1 motif lowered the luciferase activity to 10 or 8% respectively of that seen with the intact human DD4 gene. These results indicate that HNF-4alpha, HNF-4gamma and HNF-1alpha regulate co-operatively the transcription of the human DD4 gene in HepG2 cells.
Alcohol Oxidoreductases↗
Caspase activation as an apoptotic evidence in the gerbil hippocampal CA1 pyramidal cells following transient forebrain ischemia.
To determine whether apoptotic process is involved in the delayed neuronal death in hippocampal CA1 region following forebrain ischemia in gerbils, time dependent activation of caspase and DNA fragmentation were evaluated by immuno-staining and terminal dUTP nick-end-labeling staining, respectively. After transient forebrain ischemia in gerbils, activation of apoptosis related caspase, including caspase-3, was apparent, and it preceded DNA fragmentation in CA1 region. These observations suggest that apoptotic process is involved in hippocampal delayed neuronal death.
Animals↗
The inhibitory effects of mangiferin, a naturally occurring glucosylxanthone, in bowel carcinogenesis of male F344 rats.
Mangiferin, 1,3,6,7-tetrahydroxyxanthone-C2-beta-D-glucoside, is one of xanthone derivatives and C-glucosylxanthones, is widely distributed in higher plants and is one of constituents of folk medicines. Recent studies showed that mangiferin has a potential as an anti-oxidant and an anti-viral agent. In this study, we examined the effects of mangiferin in rat colon carcinogenesis induced by chemical carcinogen, azoxymethane (AOM). We performed two experiments: a short-term assay to investigate the effects of mangiferin on the development of preneoplastic lesions by AOM, aberrant crypt foci (ACF), and the following long-term assay for the influence of mangiferin on tumorigenesis induced by AOM. In the short-term assay, 0.1% mangiferin in a diet significantly inhibited the ACF development in rats treated with AOM compared to rats treated with AOM alone (64.6+/-22.0 vs. 108.3+/-43.0). In the long-term assay, the group treated with 0.1% mangiferin in initiation phase of the experimental protocol had significantly lower incidence and multiplicity of intestinal neoplasms induced by AOM (47.3 and 41.8% reductions of the group treated with AOM alone for incidence and multiplicity, respectively). In addition, the cell proliferation in colonic mucosa was reduced in rats treated with mangiferin (65-85% reductions of the group treated with AOM alone). These results suggest that mangiferin has potential as a naturally-occurring chemopreventive agent.
Animals↗
Functional annotation of a full-length mouse cDNA collection.
The RIKEN Mouse Gene Encyclopaedia Project, a systematic approach to determining the full coding potential of the mouse genome, involves collection and sequencing of full-length complementary DNAs and physical mapping of the corresponding genes to the mouse genome. We organized an international functional annotation meeting (FANTOM) to annotate the first 21,076 cDNAs to be analysed in this project. Here we describe the first RIKEN clone collection, which is one of the largest described for any organism. Analysis of these cDNAs extends known gene families and identifies new ones.
Animals↗
Identity of dimeric dihydrodiol dehydrogenase as NADP(+)-dependent D-xylose dehydrogenase in pig liver.
Dimeric dihydrodiol dehydrogenases (DDs, EC 1.3.1.20), which oxidize trans-dihydrodiols of aromatic hydrocarbons to the corresponding catechols, have been molecularly cloned from human intestine, monkey kidney, pig liver, dog liver, and rabbit lens. A comparison of the sequences with the DNA sequences in databases suggested that dimeric DDs constitute a novel protein family with 20 gene products. In addition, it was found that dimeric DD oxidizes several pentoses and hexoses, and the specificity resembles that of NADP(+)-dependent D-xylose dehydrogenase (EC 1.1.1.179) of pig liver. The inhibition of D-xylose dehydrogenase activity in the extracts of monkey kidney, dog liver and pig liver, its co-purification with dimeric DD activity from pig liver, and kinetic analysis of the D-xylose reduction by pig dimeric DD indicated that the two enzymes are the same protein.
Alcohol Oxidoreductases↗
Molecular cloning, expression and tissue distribution of hamster diacetyl reductase. Identity with L-xylulose reductase.
Using rapid amplification of cDNA ends PCR, a cDNA species for diacetyl reductase (EC 1.1.1.5) was isolated from hamster liver. The encoded protein consisted of 244 amino acids, and showed high sequence identity to mouse lung carbonyl reductase and hamster sperm P26h protein, which belong to the short-chain dehydrogenase/reductase family. The enzyme efficiently reduced L-xylulose as well as diacetyl, and slowly oxidized xylitol. The K(m) values for L-xylulose and xylitol were similar to those reported for L-xylulose reductase (EC 1.1.1.10) of guinea pig liver. The identity of diacetyl reductase with L-xylulose reductase was demonstrated by co-purification of the two enzyme activities from hamster liver and their proportional distribution in other tissues.
Acetoin Dehydrogenase↗