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Biomedical subjects

T Masaki

Publications and source records attributed to T Masaki.

At least 109 records · Page 6Linked to original sources
PubMed2000

Impaired response of UCP family to cold exposure in diabetic (db/db) mice.

Impaired activity of the uncoupling protein (UCP) family has been proposed to promote obesity development. The present study examined differences in UCP responses to cold exposure between leptin-resistance obese (db/db) mice and their lean (C57Ksj) littermates. Basal UCP1 and UCP3 mRNA expression in brown adipose tissue was lower in obese mice compared with lean mice, but UCP2 expression in white adipose tissue (WAT) was higher. Basal skeletal muscle UCP3 did not change remarkably. The UCP family mRNAs, which were upregulated 12 and 24 h after cold exposure (4 degrees C), were returned to prior levels 12 h after rewarming exposure (21 degrees C) in lean mice. The accelerating effects of cold exposure on the UCP family were impaired in db/db obese mice. Together with these changes, WAT lipoprotein lipase mRNA was downregulated, and the concentration of serum free fatty acid was increased in response to cold exposure in the lean mice but not in db/db obese littermates. The impaired function of the UCP family and diminished lipolysis in response to cold exposure indicate that the reduced lipolytic activity may contribute to the inactivation of the UCP family in db/db obese mice.

Adipose Tissue↗
PubMed2000

Identification of soluble forms of lectin-like oxidized LDL receptor-1.

Lectin-like oxidized LDL receptor-1 (LOX-1) is a type II membrane protein belonging to the C-type lectin family molecules, which can act as a cell-surface endocytosis receptor for atherogenic oxidized LDL. In this study, we show that soluble forms of LOX-1 are present in conditioned media of cultured bovine aortic endothelial cells (BAECs) and CHO-K1 cells stably transfected with LOX-1 cDNA. Immunoblot analysis of conditioned media from TNF-alpha-activated BAECs and CHO-K1 cells stably expressing LOX-1 revealed that soluble LOX-1 has an approximate molecular mass of 35 kDa. In TNF-alpha-activated BAECs, cell-surface expression of LOX-1 precedes soluble LOX-1 production. Cell-surface biotinylation followed by immunoprecipitation and immunoblotting showed that soluble LOX-1 in cell-conditioned media is derived from LOX-1 expressed on the cell surface. Production of soluble LOX-1 was inhibited by PMSF, suggesting that PMSF-sensitive proteases may be involved in this process. Purification of soluble LOX-1 by high-performance liquid chromatography and N-terminal amino acid sequencing of soluble LOX-1 identified the 2 cleavage sites between Arg(86)-Ser(87) and Lys(89)-Ser(90), which were located in the membrane proximal extracellular domain of LOX-1. The data demonstrate that cell-surface LOX-1 can be cleaved at 2 different sites and transformed into soluble forms. Further studies may explore therapeutic and diagnostic applications of soluble LOX-1 in atherosclerotic diseases.

Amino Acid Sequence↗
PubMed2000

Increased expression of lectin-like oxidized low density lipoprotein receptor-1 in initial atherosclerotic lesions of Watanabe heritable hyperlipidemic rabbits.

A novel lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) was recently identified in bovine aortic endothelial cells. It is strongly suggested to have a potential role in the initiation and development of atherosclerosis. In this study, we have isolated cDNA clones encoding the rabbit homologue of LOX-1 by screening a rabbit placenta cDNA library. In amino acid sequence and domain structure organization, the rabbit LOX-1 is highly conserved with the human counterpart. Transfection of rabbit LOX-1 cDNA to HEK-293 cells confers on them the activity to bind and internalize oxidized low density lipoprotein. Rabbit LOX-1 was identified as a 45-kDa protein by Western blot analysis with a specific monoclonal antibody. Notably, analyses by reverse transcription-polymerase chain reaction and Western blot revealed that LOX-1 was accumulated in 8-week-old Watanabe heritable hyperlipidemic rabbit aortas compared with normal rabbit aortas. Immunostaining confirmed that the augmented expression of LOX-1 was primarily localized within the intima at the earliest stages of atherogenesis. The most prominent staining was in the endothelial cells of lesions. Furthermore, the distinctive staining of LOX-1 was identified in the endothelium of non-lesion areas of Watanabe heritable hyperlipidemic rabbit aortas. Taken together, these findings support the possibility that LOX-1 might be involved in the initiation of atherosclerosis.

Amino Acid Sequence↗
PubMed2000

Synthesis of four stereoisomers of 1,4-thiazane-3-carboxylic acid 1-oxide via the asymmetric transformation (combined isomerization-preferential crystallization) of 1,4-thiazane-3-carboxylic acid.

In order to synthesize four stereoisomers of 1,4-thiazane-3-carboxylic acid 1-oxide (TCA SO), (S)-1,4thiazane-3-carboxylic acid [(S)-TCA], which is one of the precursors, was prepared by the asymmetric transformation (combined isomerization-preferential crystallization) of (RS)-TCA. This asymmetric transformation was used (2R, 3R)-tartaric acid [(R)-TA] as a resolving agent and salicylaldehyde as the epimerization catalyst in propanoic acid at 110 degrees C to afford a salt of (S)-TCA with (R)-TA in 100% de with a yield of over 90%. Optically pure (S)-TCA was obtained by treating the salt with triethylamine in methanol in a yield of over 80%, based on (RS)-TCA as the starting material. In addition, asymmetric transformation of (R)-TCA gave (S)-TCA in a yield of 60-70%. (S)-TCA was oxidized by hydrogen peroxide in dilute hydrochloric acid to selectively crystallize (1S, 3S)-TCA.SO. (1R, 3S)-TCA SO of 70% de from the filtrate was allowed to form a salt with (R)-TA after a treatment with triethylamine to give (1R, 3S)-TCA SO as a single diastereoisomer. (1R, 3R)- and (1S, 3R)-TCA.SO were also prepared by starting from (R)-TCA that had been synthesized from L-cysteine.

Crystallization↗
PubMed2000

1,25-dihydroxyvitamin D3 as well as its analogue OCT lower blood calcium through inhibition of bone resorption in hypercalcemic rats with continuous parathyroid hormone-related peptide infusion.

The effects of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and its analogue 22-oxa-1,25(OH)2D3 (22-oxacalcitriol) (OCT) on calcium and bone metabolism were examined in an animal model of hypercalcemia with continuous infusion of parathyroid hormone-related peptide (PTHrP), to determine whether active vitamin D could counteract the skeletal action of PTHrP in addition to its reported effect in suppressing the production of PTHrP in cancer cells. Parathyroid glands were removed from 8-week-old Sprague-Dawley rats to eliminate the confounding effects of endogenous PTH. Animals were then continuously infused with human PTHrP(1-34) at a constant rate via osmotic minipumps for 2 weeks, and at the same time treated orally or intravenously with OCT or 1,25(OH)2D3 four to nine times during the 2-week period. Under these conditions, OCT and, surprisingly, 1,25(OH)2D3 alleviated hypercalcemia in a dose-dependent manner. 1,25(OH)2D3 and OCT suppressed the urinary excretion of deoxypyridinoline, although they did not affect renal calcium handling, suggesting that the antihypercalcemic effect is attributable to the inhibition of bone resorption. These active vitamin D compounds also counteracted the effects of PTHrP at the proximal renal tubules, as reflected by a decrease in phosphate excretion. Histomorphometric analysis of bone revealed a dose-related decrease in parameters of bone resorption. These results suggest that 1,25(OH)2D3 as well as OCT has the potential to alleviate hypercalcemia, at least in part, through the inhibition of bone resorption in hypercalcemic rats with constant PTHrP levels. We propose that the main function of active vitamin D in high bone-turnover states is to inhibit bone resorption, and this may have important implications for the understanding of the role of active vitamin D in the treatment of metabolic bone diseases, such as osteoporosis.

Animals↗
PubMed2000

Alfacalcidol inhibits bone resorption and stimulates formation in an ovariectomized rat model of osteoporosis: distinct actions from estrogen.

Although alfacalcidol has been widely used for the treatment of osteoporosis in certain countries, its mechanism of action in bone, especially in the vitamin D-replete state, remains unclear. Here we provide histomorphometric as well as biochemical evidence that alfacalcidol suppresses osteoclastic bone resorption in an ovariectomized rat model of osteoporosis. Furthermore, when compared with 17beta-estradiol, a representative antiresorptive drug, it is evident that alfacalcidol causes a dose-dependent suppression of bone resorption, and yet maintains or even stimulates bone formation, as reflected in increases in serum osteocalcin levels and bone formation rate at both trabecular and cortical sites. 17beta-Estradiol, which suppresses bone resorption to the same extent as alfacalcidol, causes a parallel reduction in the biochemical and histomorphometric markers of bone formation. As a final outcome, treatment with alfacalcidol increases bone mineral density and improves mechanical strength more effectively than 17beta-estradiol, with a more pronounced difference in cortical bone. We conclude that estrogens depress bone turnover primarily by suppressing bone resorption and, as a consequence, bone formation as well, whereas alfacalcidol "supercouples" these processes, in that it suppresses bone resorption while maintaining or stimulating bone formation.

Animals↗
PubMed2000

Two cases of hypothyroidism complicated by renal dysfunction.

We report two patients in whom hypothyroidism was considered to cause renal dysfunction. Case 1 was a 65-year-old woman who stopped taking levothyroxine sodium for hypothyroidism. After 6 months, she developed proteinuria, edema, weight gain, and renal dysfunction. Renal biopsy revealed focal segmental proliferative glomerulonephritis. After re-administration of levothyroxine sodium, thyroid function and renal function both recovered. Case 2 was a 51-year-old man who presented with edema, difficulty in swallowing, muscular weakness, and fatigue. We diagnosed hypothyroidism, and focal segmental proliferative glomerulonephritis was revealed by renal biopsy. After administration of levothyroxine sodium, his symptoms resolved and his thyroid function and renal function both improved. Our experience suggests that hypothyroidism should be taken into consideration as one of the causes of renal dysfunction.

Aged↗
PubMed2000

Expression of macrophage migration inhibitory factor in patients with myeloperoxidase anti-neutrophil cytoplasmic antibody-associated glomerulonephritis.

AIM AND METHODS: To investigate the relationship between macrophage migration inhibitory factor and clinical or pathological findings in patients with myeloperoxidase anti-neutrophil cytoplasmic antibody MPO-ANCA-associated glomerulonephritis characterized by idiopathic necrotizing crescentic glomerulonephritis, renal biopsy specimens from 16 patients with MPO-ANCA-associated glomerulonephritis and 15 controls were stained using an enzyme antibody method to detect macrophage migration inhibitory factor and macrophages infiltrating the glomeruli. The relationship of this factor with various clinical parameters and with cellular crescents was determined. RESULTS: Macrophage migration inhibitory factor was detected in 11 out of 16 patients with MPO-ANCA-associated glomerulonephritis, but was not found in any of the controls. In the positive patients, the blood MPO-ANCA level was significantly higher than in the negative patients. Both cellular crescents and the number of macrophages infiltrating the glomeruli were significantly increased in the patients positive for macrophage migration inhibitory factor. CONCLUSION: Thus, macrophage migration inhibitory factor may be closely related to cellular crescent formation and disease activity in patients with MPO-ANCA-associated glomerulonephritis.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed2000

[Reduced signal intensity of T2 weighted MR imaging of thalamus and putamen in multiple sclerosis in Japan].

Although studies using magnetic resonance imaging (MRI) in multiple sclerosis (MS) patients have focused on findings in the white matter because of its demyelination pathogenesis, Drayer et al. have reported a high incidence of low signal intensity on T2 weighted MR imaging (MRI) in gray matter such as the thalamus and putamen. In Japan there has been no investigation of MRI findings of the basal ganglia in MS patients. Therefore, we attempted to examine the incidence and clinical significance of the imaging phenomenon in 34 Japanese patients with MS (12 male, 22 female, ages 18-54 years). As it is well known that the spinal cord and optic nerves are more frequently involved in MS than the brain in Japanese patients, we divided the patients into two subgroups based on their clinical features and the major sites of demyelination on MRI. One group included the 17 patients whose demyelinations occurred in the brain (brain-type), and the other group included the 17 patients whose abnormalities were found in the spinal cord with or without optic nerve involvement (non-brain type). As a control, MRI studies were also performed in age-matched patients with headache without any neurological signs. On T2 weighted MRI, decreased signal intensity in the thalamus was found in only four patients with MS, 11.8% of the total number examined, and in the putamen in three patients with MS, 8.8% of the total examined. All of the patients who showed abnormal decreased signal intensity in the thalamus and/or putamen belonged to the brain-type group, and these incidences were 23.5% in the thalamus and 17.6% in the putamen among the brain-type patients. No patient belonging to the non-brain type showed this imaging sign. This imaging sign was well correlated with the degree of white matter abnormalities in the brain estimated as a score according to modified Callanan et al.'s method. In addition, this sign was also correlated with the expanded disability status scales (EDSS) in the brain-type patients. These observations suggest that the axonal damages due to severe demyelination may induce the impaired transport of iron resulting in an accumulation of ferritin in the thalamus and putamen, and would cause decreased signal intensity on T2 weighted MRI. The relatively low incidence of decreased signal intensity in the thalamus and putamen in this study may be associated with differences in the clinical phenotype of MS between Japan and the USA. In brain-type patients the evaluation of basal ganglia on T2 weighted MRI may be a useful tool for estimating patients' disabilities.

Adolescent↗
PubMed2000

Lipid-lowering therapy and coagulation/fibrinolysis parameters in patients on peritoneal dialysis.

Patients on continuous ambulatory peritoneal dialysis (CAPD) often have abnormalities of lipid metabolism or coagulation and fibrinolysis, these patients may thus be more susceptible to atherosclerosis than those on hemodialysis. It has been reported that hypercoagulability and hyperfibrinolysis are correlated with abnormalities of lipid metabolism. Therefore, we investigated the effect of a decrease in lipids on the coagulation and fibrinolysis system in CAPD patients with hyperlipidemia who received lipid-lowering therapy. The patients included 5 men and 13 women, with a mean age of 52.5 years. Pravastatin sodium (10 mg/day) and ethyl icosapentate (1800 mg/day) were administered concomitantly for 8 weeks. Lipid levels and coagulation/fibrinolysis parameters were measured before and after therapy. The patients were divided into two groups depending on their response to therapy: responders showed a decrease in total cholesterol or triglycerides by at least 20% and non-responders showed less improvement. In the responders, the levels of protein C, tissue plasminogen activator/plasminogen activator inhibitor-I complex, factor XIII, alpha2-plasmin inhibitor, and D-dimer were significantly lower after therapy than before therapy. Protein C, factor XIII, and alpha2-plasmin inhibitor were also significantly decreased after therapy in non-responders, but the extent of the decrease was smaller. The plasminogen level was significantly increased after therapy in non-responders. These findings suggest that a decrease in lipid levels and/or some other action by lipid-lowering agents may correct abnormalities of coagulation and fibrinolysis in CAPD patients.

Adult↗
PubMed1999

Presenilin 1 suppresses the function of c-Jun homodimers via interaction with QM/Jif-1.

Presenilin 1 (PS1) is the causative gene for an autosomal dominant familial Alzheimer's disease (AD) mapped to chromosome 14. Here we show that QM/Jun-interacting factor (Jif)-1, a negative regulator of c-Jun, is a candidate to mediate the function of PS1 in the cell. We screened for proteins that bind to PS1 from a human embryonic brain cDNA library using the two-hybrid method and isolated one clone encoding the QM/Jif-1 gene. The binding of QM/Jif-1 to full-length PS1 was confirmed in vitro by pull-down assay, and in vivo by immunoprecipitation assays with human samples, including AD brains. Immunoelectronmicroscopic analysis showed that QM/Jif-1 and PS1 are colocalized at the endoplasmic reticulum, and the nuclear matrix in human brain neurons. Chloramphenicol acetyltransferase assays in F9 cells showed that PS1 suppresses transactivation by c-Jun/c-Jun but not by c-Jun/c-Fos heterodimers, consistent with the reported function of QM/Jif-1. By monitoring fluorescent recombinant protein and by gel mobility shift assays, PS1 was shown to accelerate the translocation of QM from the cytoplasm to the nucleus and to thereby suppress the binding of c-Jun homodimer to 12-O-tetradecanoylphorbol-13- acetate (TPA)-responsive element (TRE). PS1 suppressed c-jun-associated apoptosis by retinoic acid in F9 embryonic carcinoma cells, whereas this suppression of apoptosis is attenuated by mutation in PS1. Collectively, the novel function of PS1 via QM/Jif-1 influences c-jun-mediated transcription and apoptosis.

Adult↗
PubMed1999

Up-regulation of uterine UCP2 and UCP3 in pregnant rats.

Pregnancy produces profound changes in hormone dynamics, thermoregulation and energy metabolism. Uncoupling proteins (UCPs) have been identified in a variety of tissues and UCP1 is known to play important roles in energy homeostasis, while the regulation of UCP2 and UCP3 is still unclear. The present study aimed to investigate the effects of the changes during pregnancy on UCP gene expression in the uterus, as well as in brown adipose tissue (BAT), white adipose tissue (WAT), soleus muscle (Muscle), and liver, throughout the estrus and metestrus periods, at early, middle and late stages in pregnancy, and during post-gestational stages. The expression of uterine UCP2 and UCP3 were up-regulated by 3.2- and 1. 5-fold, respectively, during the late stage of pregnancy with an increase of WAT leptin mRNA expression and exogenous administration of leptin resulted in induction of the uterine UCP2 and UCP3 levels. Contrary to uterine UCPs, UCP1 mRNA expression in BAT was down-regulated by 0.5-fold and there were no remarkable changes in WAT or liver UCP2, or Muscle UCP3 expression throughout the periods. These results indicate that UCP gene expressions during pregnancy are regulated tissue-dependently, and up-regulation of uterine UCP2 and UCP3 mRNA may be due to increased leptin levels.

Adipose Tissue↗
PubMed1999

Neuron-specific expression of cationic amino acid transporter 3 in the adult rat brain.

CAT3 (cationic amino acid transporter 3) is a member of the murine CAT family which bears a system y(+) transport activity. On the Northern blot of adult rat tissues, the expression of CAT3 is restricted to the brain. In the present study, cellular localization of CAT3 mRNA and protein in the adult rat brain sections was examined by in situ hybridization with cRNA and immunostaining with a CAT3-specific antiserum, respectively. CAT3 mRNA was present both in the cerebral and cerebellar gray matter but most prominently in the nuclei located in the ventromedial part of the brain. These included preoptic nucleus, hypothalamic nucleus, reticular nucleus of thalamus, substantia nigra, central gray around the third ventricle and amygdala. CAT3 protein was also detected both in the cerebral and cerebellar gray matter and strong immunostaining was obtained in the olfactory cortex, hippocampus and cerebellar granular and Purkinje cell layers. Observations at higher magnifications revealed that both mRNA and protein were expressed by neurons but neither by glial nor endothelial cells. These results confirm the neuron-specificity of CAT3 in the adult rat brain and indicate that CAT3 is responsible for the neuronal system y(+) activity. The discrepancy between the distribution of mRNA and its translation product suggests a regional difference in the translation rate of the CAT3 transcript.

Amino Acid Sequence↗
PubMed1999

Targeted disruption of CRE-binding factor TREB5 gene leads to cellular necrosis in cardiac myocytes at the embryonic stage.

TREB5 (hXBP-1) is a basic region leucine zipper protein which binds to a CRE-like element in both human T-cell leukemia virus type 1 and MHC class II genes. To study the function(s) of TREB5 in normal development, we have generated TREB5 deficient mice by gene targeting. Heterozygous mutant mice have not exhibited any obvious abnormalities; however, homozygous mutant embryos die between embryonic days 10.5 and 14.5. The major defect responsible for lethality is cellular necrosis of cardiac myocytes located at the atrium and the truncus arteriosus with its following ventricle. Necrotic alteration was not observed in either the endocardial cushion or the conotruncal ridge. These results indicate that TREB5 plays an essential role in maintenance and/or growth of cardiac myocytes during cardiogenesis.

Animals↗
PubMed1999

Cytodifferentiation potentiates aFGF-induced p21(ras)/Erk signaling pathway in rat cultured astrocytes.

MBP kinase detection assay revealed that acidic FGF (aFGF) augmented MBP kinase activity in a dose-dependent manner in astrocytes (AC). The molar potency of this action of aFGF in dibutyryl cyclic AMP (DBcAMP)-treated AC was significantly higher than that in quiescent AC. Consistently, the molar potency of accumulation of p21(ras)-GTP by aFGF was significantly higher in DBcAMP-treated AC than in quiescent AC. However, binding study showed that B(max) and K(D) for [(125)I]aFGF in DBcAMP-treated AC were quite similar to those in quiescent AC. Furthermore, the expression levels of Grb2, SOS, and p21(ras) were not changed by treatment of AC with DBcAMP. These results suggest that cytodifferentiation potentiates the p21(ras)/Erk signaling pathway in AC in response to aFGF without changing the expression levels of signaling molecules mediating from the FGF receptor to p21(ras).

Animals↗
PubMed1999

Subcellular mechanisms of endothelin action in vascular system.

To elucidate the role of endothelin in the regulation of vascular function, the cellular and subcellular mechanisms for the synthesis of endothelin and the function of endothelin-receptors have been studied extensively. In this article, recent results regarding these problems are reviewed. (1) Oxidatively modified low-density-lipoprotein (LDL) reduces nitric oxide (NO) release via inhibition of the high-affinity arginine transporter of endothelial cells. (2) Endothelin-1-induced vasoconstriction is mediated by Ca2+ influx through a non-selective cation channel sensitive to 1-[beta-[3-(4-methoxyphenyl) propoxyl]-4-methoxyphenethyl]-1H-imidazole HCl (SK & F96365). (3) A distinct domain of the endothelin-receptor is required for the coupling of different G(alpha)-proteins. (4) Endothelin ET(A) receptor-mediated mitogenic activity is mediated by two pathways, one classical protein kinase C(PKC)-dependent, and the other phosphoinositide 3-kinase dependent. Both stimulate mitogen-activated protein kinase (MAPK). Endothelin ET(B) receptor-mediated mitogenic activity is also mediated by the PKC-dependent pathway. In contrast, endothelin ET(B) receptor-mediates differentiation and apoptosis via G(alpha)i coupling.

Animals↗
PubMed1999

Expression of lectinlike oxidized low-density lipoprotein receptor-1 in human atherosclerotic lesions.

BACKGROUND: Oxidized LDL (Ox-LDL) seems to play key roles in atherogenesis. Lectinlike Ox-LDL receptor-1 (LOX-1) is a recently identified cell-surface receptor for Ox-LDL. The relationship of this novel receptor for Ox-LDL to atherogenesis, however, has not yet been clarified. In this study, we explored the expression of LOX-1 in the atherosclerotic lesions of human carotid arteries. METHODS AND RESULTS: Using carotid endarterectomy specimens obtained from 21 patients and 2 samples of normal human aortas, we examined LOX-1 expression by reverse transcription-polymerase chain reaction and immunohistochemistry. In aortas without atherosclerosis, LOX-1 expression was undetectable by immunohistochemistry and negligible by reverse transcription-polymerase chain reaction. In carotid arteries, luminal endothelial cells covering early atherosclerotic lesions were more frequently positive for LOX-1 expression than those in advanced atherosclerotic lesions. Endothelial cells in the intimal neovasculature of advanced lesions also expressed LOX-1. In addition, macrophages and smooth muscle cells in the intima of advanced atherosclerotic plaques were positive for LOX-1 expression. CONCLUSIONS: LOX-1 may play important roles in Ox-LDL uptake and subsequent functional alteration in the luminal endothelium in early atherosclerotic lesions and in intimal neovascular endothelial cells in advanced plaques. Furthermore, LOX-1 may also be involved in Ox-LDL uptake and subsequent foam cell transformation in macrophages and smooth muscle cells in the atherosclerotic intima.

Aged↗