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Biomedical subjects

Yasushi Saito

Publications and source records attributed to Yasushi Saito.

At least 19 recordsLinked to original sources
PubMed2007

Effect of rosuvastatin 5-20mg on triglycerides and other lipid parameters in Japanese patients with hypertriglyceridemia.

To evaluate the potential dose effect of rosuvastatin on triglyceride (TG) levels in Japanese hypertriglyceridemic patients, we randomized 154 patients with TG levels of >or=200 and <800 mg/dL to 8 weeks of treatment with rosuvastatin 5, 10 or 20mg once daily; bezafibrate 200mg twice daily; or placebo. Compared with placebo, TG was reduced by 30.1% with rosuvastatin 5mg, 30.1% with 10mg and 32.3% with 20mg (all p<or=0.0001), with no evidence of a dose effect. Changes in TG were evident after 2 weeks of treatment and maintained thereafter. In a benchmark comparison, rosuvastatin across its dose range reduced TG by 29.1-31.1% from baseline versus 45.4% for bezafibrate. Compared with bezafibrate, rosuvastatin was superior with respect to changes in non-high-density lipoprotein cholesterol (non-HDL-C, -36.8 to -44.3% for rosuvastatin versus -2.0% for bezafibrate), low-density lipoprotein cholesterol (-31.9 to -41.0% versus +29.3%), total cholesterol (-27.1 to -33.3% versus +2.1%), although smaller improvements in HDL-C (12.4-16.7% versus 19.6%) were observed. Rosuvastatin also produced superior dose-related decreases in median high-sensitivity C-reactive protein (22.9-38.5%). Treatment was well tolerated in both rosuvastatin and bezafibrate patients, with clinically important increases in alanine aminotransferase being rare, no adverse effect on renal function being observed and no cases of myopathy or rhabdomyolysis being reported. The current study does not suggest a dose-related effect of rosuvastatin in lowering TG in hypertriglyceridemic Japanese patients, although dose-related improvements in other elements of the atherogenic lipid profile were observed.

Apolipoproteins↗
PubMed2006

Advanced glycation end products attenuate cellular insulin sensitivity by increasing the generation of intracellular reactive oxygen species in adipocytes.

Advanced glycation end products (AGE) have been observed in various pathological conditions especially in diabetes mellitus. However, it is unclear as to whether AGE are involved in insulin resistance in adipose tissues. In this study, we examined the effects of AGE on insulin sensitivity in adipocytes by examining the effects of AGE and its mechanisms on the glucose uptake in adipocytes and adipocyte differentiation. Glucose-, glyceraldehyde-, or glycolaldehyde-derived AGE inhibited the differentiation of 3T3-L1 cells. These AGE also inhibited the glucose uptake in the absence or presence of insulin, which were completely prevented by antibody against AGE or receptor for AGE (RAGE). The AGE increased the intracellular reactive oxygen species (ROS) generation in 3T3-L1 adipocytes, and the effects of AGE on glucose uptake were completely reversed by the treatment with an anti-oxidant, N-acetylcysteine. The AGE also induced the expression of monocyte chemoattractant protein-1, which has been implicated in the development of obesity-associated glucose intolerance, in 3T3-L1 adipocytes. Our present study suggests that AGE-RAGE interaction inhibits the glucose uptake through the overgeneration of intracellular ROS, thus indicating that it is involved in the development of obesity-related insulin resistance.

3T3-L1 Cells↗
PubMed2006

A retrospective search for predictors of clinical response to selective granulocyte and monocyte apheresis in patients with ulcerative colitis.

Recently, selective granulocytapheresis (Adacolumn) has appeared as a new treatment for patients with inflammatory bowel disease. This study sought to determine predictors of response to this new nonpharmacologic mode of therapy by retrospectively evaluating 28 patients who received granulocytapheresis after experiencing active ulcerative colitis (UC). Between April 2000 and March 2004, 28 consecutive patients received granulocytapheresis for active UC with the Adacolumn, which is filled with cellulose acetate beads as the column leukocytapheresis carriers; the carriers adsorb granulocytes, monocytes/macrophages, and a small fraction of lymphocytes (FcgammaR and complement receptors bearing leukocytes). Each patient could receive up to 10 Adacolumn sessions, at 2 sessions per week. In 2004, clinical response was retrospectively evaluated. Seven days after the last Adacolumn session, 20 of 28 patients had remission (colitis activity index [CAI] < or =4) including all 8 patients who had their first UC episode. The mean duration of UC in the 8 first episode cases was 3.4 months compared with 40.2 months for all 28 patients and 65.4 months for the 8 nonresponders. The response to Adacolumn was independent of basal CAI. The 8 nonresponders were given conventional medication (CM) or cyclosporine (CsA) if the former failed. Two responded to CM, 3 to CsA, and 3 underwent colectomy. First UC episode and short disease duration appear good predictors of response to granulocytapheresis. Selective granulocytapheresis might be an effective first-line treatment.

Adolescent↗
PubMed2006

Molecular cloning and characterization of rat brain endothelial cell derived gene-1 (tumor suppressor candidate 5) expressing abundantly in adipose tissues.

We report the cloning and expressional analysis of rat brain endothelial cell derived gene-1 (BEC-1), detected as a gene dominantly expressed in rat brain endothelial cells by the use of suppression subtractive hybridization technique. The complementary deoxyribonucleic acid sequence of BEC-1 messenger ribonucleic acid was completely determined with a full length of 3410 bp. The open reading frame within the sequence consisted of 522 bp, and the predicted protein sequence was 173 amino acid residues. BEC-1 gene was thought to be rat tumor suppressor candidate 5 (TUSC5), since BEC-1 had considerable homology with both mouse TUSC5 and human located at 17-p-13 point three 1 (LOST1) categorized as human TUSC5 (identities of 97% and 85%, respectively), which were recently identified as a novel tumor suppressor gene candidate. Expressional analyses for BEC-1 mRNA with real-time PCR and of BEC-1 protein by Western blotting demonstrated that both were dominantly expressed in the adipose tissues of Sprague-Dawley (SD) rats. We analyzed and compared the differential expressions of BEC-1 (TUSC5) mRNA and protein in fat tissues between obese homozygous (fa/fa) and lean wild-type (+/+) Zucker rats. Both expressions in the epididymal white adipose tissue (WAT) were highest, followed by those in the interscapular brown adipose tissue (BAT), subcutaneous, and mesenteric WATs, respectively. Interestingly, both expressions in epididymal WAT of obese Zucker rats were significantly lower than those in lean rats. Although cold exposure at 4 degrees C for 6 h significantly stimulated uncoupling protein-1 (UCP-1) mRNA expression, it significantly inhibited BEC-1 (TUSC5) mRNA expression in the interscapular BAT. These data indicated that rat BEC-1 (TUSC5) was abundantly expressed in adipose tissues, and that it might be involved in their regulation independently of UCP-1.

Adipose Tissue, Brown↗
PubMed2006

Increased matrix metalloproteinase-3 mRNA expression in visceral fat in mice implanted with cultured preadipocytes.

Using preadipocyte implantation methods, we recently demonstrated that adipocytes in the visceral area change their function, as the expression of tumor necrosis factor-alpha (TNF-alpha) increases, thereby causing insulin resistance. In order to clarify the mechanism for changes in the function of adipocytes in visceral area, we examined the mRNA expression profiles in visceral fat tissue specimens. Four weeks after cell implantation, we performed a microarray analysis using the RNA of fat tissue specimens implanted either with 3T3-L1 cells or PBS alone. Sixty-three genes were thus isolated and the expression of matrix metalloproteinase-3 (MMP-3) mRNA was found to dramatically increase in the fat tissue specimens. The neutralization of MMP-3 protein inhibited adipogenesis and the free fatty acid-induced TNF-alpha secretion in 3T3-L1 adipocytes. These results suggest a potential role of MMP-3, which promotes the TNF-alpha secretion, thus contributing to the disturbance of the functions in the adipocytes which accumulate in the visceral area.

3T3-L1 Cells↗
PubMed2006

Geranylgeranyl-pyrophosphate (GGPP) synthase is down-regulated during differentiation of osteoblastic cell line MC3T3-E1.

Isoprenylation of geranylgeranyl-pyrophosphate (GGPP) is critical for activation of small GTPases. We examined the roles of GGPP synthase (GGPPS) during the differentiation induced by the cell-to-cell contact in osteoblastic cell line MC3T3-E1 cells. We found that (1) both mRNA and protein expression of GGPPS was reduced with decrement of its activity during the differentiation, (2) GGOH, which is converted to GGPP in the cells, inhibited differentiation. These results suggest that the decrement of GGPP is critical for the cell-to-cell contact-induced differentiation, in which the down-regulation of GGPPS might be involved.

Animals↗
PubMed2006

Activation of diacylglycerol O-acyltransferase 1 gene results in increased tumor necrosis factor-alpha gene expression in 3T3-L1 adipocytes.

The tumor necrosis factor-alpha (TNF-alpha) expression has been reported to be largely dependent on the size of adipocytes. We herein investigated the gene regulation of diacylglycerol O-acyltransferase (DGAT) in order to clarify the mechanism of TNF-alpha expression induced in large adipocytes. 3T3-L1 cells were cultured in the presence of 5 mM or 25 mM glucose to generate adipocytes from which the triglyceride content differs. The expression of TNF-alpha, DGAT1, and DGAT2 were upregulated in adipocytes cultured with 25 mM glucose. Furthermore, knockdown of DGAT1 gene significantly inhibited the TNF-alpha expression. Finally, the DGAT1 expression levels were closely related to the TNF-alpha level in 3T3-L1 adipocytes.

3T3-L1 Cells↗
PubMed2006

Pitavastatin attenuates the PDGF-induced LR11/uPA receptor-mediated migration of smooth muscle cells.

Statins, inhibitors of HMG-CoA reductase, elicit various actions on vascular cells including the modulation of proliferation and migration of smooth muscle cells (SMCs). Here, we have elucidated the mechanism by which statins, in particular pitavastatin, attenuate the migration activity of SMCs. The expression of LR11, a member of the LDL receptor family and an enhancer of cell surface localization of urokinase-type plasminogen activator receptor (uPAR), is increased in cultured SMCs by treatment with PDGF-BB. Pitavastatin attenuates the PDGF-BB -induced surface expression of LR11 and uPAR. The increased migration of SMCs observed both upon overexpression of LR11 and via stimulation of secretion of soluble LR11 is not reversed by pitavastatin. In vivo studies showed that the SMCs expressing LR11 in plaques are almost congruent with intimal cells expressing nonmuscle myosin heavy chain (SMemb). Pitavastatin reduced the expression of LR11 and SMemb, and the levels of LR11, uPAR, and SMemb in cultured intimal SMCs were reduced to those seen in medial SMCs. We propose that this statin reduces PDGF-induced migration through the attenuation of the LR11/uPAR system in SMCs. Modulation of the LR11/uPAR system with statins suggests a novel treatment strategy for atherogenesis based on suppression of intimal SMC migration.

Animals↗
PubMed2006

A patient with Werner syndrome and adiponectin gene mutation.

Werner syndrome is a premature aging disease characterized by genomic instability and increased cancer risk. Here, we report a 45-year-old diabetic man as the first Werner syndrome patient found to have an adiponectin gene mutation. Showing graying and loss of hair, skin atrophy, and juvenile cataract, he was diagnosed with Werner syndrome type 4 by molecular analysis. His serum adiponectin concentration was low. In the globular domain of the adiponectin gene, I164T in exon 3 was detected. When we examined effects of pioglitazone (15 mg/day) on serum adiponectin multimer and monomer concentrations using selective assays, the patient's relative percentage increased in adiponectin concentration was almost same as that in the 18 diabetic patients without an adiponectin mutation, but the absolute adiponectin concentration was half of those seen in diabetic patients treated with the same pioglitazone dose who had no adiponectin mutation. The response suggested that pioglitazone treatment might help to prevent future Werner syndrome-related acceleration of atherosclerosis. Present and further clinical relevant to atherosclerosis in this patient should be imformative concerning the pathogenesis and treatment of atherosclerosis in the presence of hypoadiponectinemia and insulin resistance.

Adiponectin↗
PubMed2006

IL-25 enhances allergic airway inflammation by amplifying a TH2 cell-dependent pathway in mice.

BACKGROUND: A novel IL-17 family cytokine, IL-25, has been reported to induce IL-4, IL-5, and IL-13 production from undefined non-T/non-B cells and then induce T(H)2-type immune responses. However, the roles of IL-25 in inducing allergic airway inflammation remain unknown. OBJECTIVE: We sought to determine whether IL-25 is involved in causing allergic airway inflammation. METHODS: We examined the expression of IL-25 mRNA in the lungs of sensitized mice on antigen inhalation. We also examined the effect of IL-25 neutralization by soluble IL-25 receptor on antigen-induced airway inflammation. We then generated IL-25 transgenic mice that express IL-25 specifically in the lung under the control of the Clara cells-10-kd protein promoter and investigated the effect of enforced IL-25 expression on antigen-induced airway inflammation. RESULTS: IL-25 mRNA was expressed in the lungs of sensitized mice on antigen inhalation, and the neutralization of IL-25 by soluble IL-25 receptor decreased antigen-induced eosinophil and CD4(+) T-cell recruitment into the airways. The enforced expression of IL-25 in the lung itself failed to induce allergic airway inflammation, whereas the expression of IL-25 significantly enhanced antigen-induced T(H)2 cytokine production, eosinophil and CD4(+) T cell recruitment, and goblet cell hyperplasia in the airways. Moreover, IL-25-induced enhancement of allergic airway inflammation was inhibited by the depletion of CD4(+) T cells or by the absence of signal transducer and activator of transcription 6. CONCLUSION: IL-25 enhances antigen-induced allergic airway inflammation by amplifying a T(H)2 cell-dependent pathway. CLINICAL IMPLICATIONS: IL-25 might be involved in the enhancement, prolongation, or both of T(H)2 cell-mediated allergic diseases, such as asthma.

Adjuvants, Immunologic↗
PubMed2006

Risk of coronary events in Japanese patients with both hypercholesterolemia and type 2 diabetes mellitus on low-dose simvastatin therapy: implication from Japan Lipid Intervention Trial (J-LIT).

Hypercholesterolemic patients with type 2 diabetes mellitus are at increased risk of coronary heart disease (CHD); however, direct evidence is very limited in Japanese patients. The J-LIT is the first nationwide study conducted to assess the relationship between serum lipid levels and development of coronary events in Japanese hypercholesterolemic patients. We analyzed the coronary events in the J-LIT study subjects by having type 2 diabetes or not. Of the total 41,801 subjects without prior CHD who received open-label simvastatin, 5mg/day, 6554 (male 40.2%, age 57.8+/-7.8) subjects had type 2 diabetes, while 35,247 (male 30.0%, age 57.8+/-7.9) did not. In this analysis, relative coronary event risks based on a 0.26 mmol/l (10mg/dl) increase in low density lipoprotein-cholesterol (LDL-C), were similar between hypercholesterolemic subjects with and without type 2 diabetes (17.3% versus 19.4%). Although all subjects were treated with simvastatin, the subjects with type 2 diabetes have significantly more coronary events compared to the subjects without type 2 diabetes (1.80/1000 and 0.76/1000 patient-years, respectively). Given the results above, to reduce the risk of coronary events in Japanese patients with both hypercholesterolemia and type 2 diabetes, careful and strict cholesterol management is needed in addition to the control of blood glucose.

Adult↗
PubMed2006

Mammalian Polycomb complexes are required for Peyer's patch development by regulating lymphoid cell proliferation.

The vertebrate Polycomb Group (PcG) genes encode proteins that form large multimeric and chromatin-associated complexes implicated in the stable repression of developmentally essential genes. Rnf110 and Phc2 are shown to be components of mammalian PcG multimeric complexes in HeLa cells. Here we report defects in Peyer's patch (PP) development in Rnf110 mutant mice, which is synergically exaggerated by Phc2 mutation. PP development involves a series of inductive interactions and subsequent differentiation and proliferation between lymphoid and mesenchymal cells in late gestational stage. Rnf110 and Phc2 mutations impair development of PP anlagen by affecting proliferation of lymphoid lineage cells populated in PP anlagen in gene-dosage dependent manner. We suggest that PcG complexes may act to mediate certain inductive signals maybe through IL-7Ralpha to allow sufficient proliferation of lymphoid inducer cells during PP organogenesis.

Animals↗
PubMed2006

Modulation of smooth muscle cell migration by members of the low-density lipoprotein receptor family.

Low-density lipoprotein receptor family members (LRs) play a key role in the catabolism of many membrane-associated proteins, such as complexes between proteinases and their receptors, in addition to being involved in lipoprotein metabolism as suspected by the hitherto well-established functions of low-density lipoprotein receptor, in a variety of tissues. Recent studies using receptor-deficient or -overexpressing animals and cells have suggested that certain LRs are important regulators of the migration (and proliferation) of vascular smooth muscle cells (SMCs). LR expression is markedly induced in intimal or medial SMCs during the formation of atherosclerotic lesions. Because LRs can modulate the activity of the urokinase-type plasminogen activator (uPA) receptor and possibly of the platelet-derived growth factor (PDGF) receptor, LRs may influence the migration of SMCs through functional modulation of these membrane receptors. Therefore, SMC migration may be regulated by time-restricted expression of LRs. In agreement with the concept of functional interaction between LRs and membrane signaling receptors, a negative regulator of uPA receptor protein catabolism, LR11, has been identified. Statins modulate the PDGF-induced migration of intimal SMCs via the LR11/uPA receptor cascade. Selective modification of the LRs/uPA receptor/PDGF receptor systems in SMCs may be important for suppression of atherosclerotic plaque formation as well as for preventing intimal thickening after angioplasty.

Animals↗
PubMed2006

Critical roles of muscle-secreted angiogenic factors in therapeutic neovascularization.

The discovery of bone marrow-derived endothelial progenitors in the peripheral blood has promoted intensive studies on the potential of cell therapy for various human diseases. Accumulating evidence has suggested that implantation of bone marrow mononuclear cells effectively promotes neovascularization in ischemic tissues. It has also been reported that the implanted cells are incorporated not only into the newly formed vessels but also secrete angiogenic factors. However, the mechanism by which cell therapy improves tissue ischemia remains obscure. We enrolled 29 "no-option" patients with critical limb ischemia and treated ischemic limbs by implantation of peripheral mononuclear cells. Cell therapy using peripheral mononuclear cells was very effective for the treatment of limb ischemia, and its efficacy was associated with increases in the plasma levels of angiogenic factors, in particular interleukin-1beta (IL-1beta). We then examined an experimental model of limb ischemia using IL-1beta-deficient mice. Implantation of IL-1beta-deficient mononuclear cells improved tissue ischemia as efficiently as that of wild-type cells. Both wild-type and IL-1beta-deficient mononuclear cells increased expression of IL-1beta and thus induced angiogenic factors in muscle cells of ischemic limbs to a similar extent. In contrast, inability of muscle cells to secrete IL-1beta markedly reduces induction of angiogenic factors and impairs neovascularization by cell implantation. Implanted cells do not secret angiogenic factors sufficient for neovascularization but, instead, stimulate muscle cells to produce angiogenic factors, thereby promoting neovascularization in ischemic tissues. Further studies will allow us to develop more effective treatments for ischemic vascular disease.

Aged↗
PubMed2006

Involvement of TNF receptor-associated factor 6 in IL-25 receptor signaling.

IL-25 (IL-17E) induces IL-4, IL-5, and IL-13 production from an unidentified non-T/non-B cell population and subsequently induces Th2-type immune responses such as IgE production and eosinophilic airway inflammation. IL-25R is a single transmembrane protein with homology to IL-17R, but the IL-25R signaling pathways have not been fully understood. In this study, we investigated the signaling pathway under IL-25R, especially the possible involvement of TNFR-associated factor (TRAF)6 in this pathway. We found that IL-25R cross-linking induced NF-kappaB activation as well as ERK, JNK, and p38 activation. We also found that IL-25R-mediated NF-kappaB activation was inhibited by the expression of dominant negative TRAF6 but not of dominant negative TRAF2. Furthermore, IL-25R-mediated NF-kappaB activation, but not MAPK activation, was diminished in TRAF6-deficient murine embryonic fibroblast. In addition, coimmunoprecipitation assay revealed that TRAF6, but not TRAF2, associated with IL-25R even in the absence of ligand binding. Finally, we found that IL-25R-mediated gene expression of IL-6, TGF-beta, G-CSF, and thymus and activation-regulated chemokine was diminished in TRAF6-deficient murine embryonic fibroblast. Taken together, these results indicate that TRAF6 plays a critical role in IL-25R-mediated NF-kappaB activation and gene expression.

Animals↗
PubMed2006

The role of Smad3-dependent TGF-beta signal in vascular response to injury.

Transforming growth factor (TGF)-beta is a multifunctional cytokine involved in the regulation of proliferation, differentiation, migration, and survival of many different cell types. The role of TGF-beta in atherosclerosis has been intensively studied, but the precise function of the downstream signals in this disease entity remains unclear. We recently discovered that mice lacking Smad3, a major downstream mediator of TGF-beta, show enhanced neointimal hyperplasia with decreased matrix deposition in response to vascular injury. This review summarizes the current view on involvement of TGF-beta in atherosclerotic vascular disease and discusses the role of Smad3-dependent TGF-beta signal in vascular response to injury.

Animals↗