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Biomedical subjects

Jun Matsui

Publications and source records attributed to Jun Matsui.

25 records · Page 2Linked to original sources
PubMed2004

Deficiency of BLNK hampers PLC-gamma2 phosphorylation and Ca2+ influx induced by the pre-B-cell receptor in human pre-B cells.

B-cell linker protein (BLNK) is a component of the B-cell receptor (BCR) as well as of the pre-BCR signalling pathway, and BLNK(-/-) mice have a block in B lymphopoiesis at the pro-B/pre-B cell stage. A recent report described the complete loss or drastic reduction of BLNK expression in approximately 50% of human childhood pre-B acute lymphoblastic leukaemias (ALL), therefore we investigated BLNK expression in human pre-B ALL cell lines. One of the four cell lines tested, HPB-NULL cells, was found to lack BLNK expression, and we used these human pre-B ALL cell lines that express and do not express BLNK to investigate the intracellular signalling events following pre-BCR cross-linking. When pre-BCR was cross-linked with anti-micro heavy-chain antibodies, significant phosphorylation of intracellular molecules, including Syk, Shc, ERK MAP kinase, and AKT, and an activation of Ras were observed without regard to deficiency of BLNK expression, suggesting that BLNK is not required for pre-BCR-mediated activation of MAP kinase and phosphatidyl-inositol 3 (PI3) kinase signalling. By contrast, phospholipase C-gamma2 (PLC-gamma2) phosphorylation and an increase in intracellular Ca(2+) level mediated by pre-BCR cross-linking were observed only in the BLNK-expressing cells, indicating that BLNK is essential for PLC-gamma2-induced Ca(2+) influx. Human pre-B cell lines expressing and not expressing BLNK should provide an in vitro model for investigation of the role of BLNK in the pre-BCR-mediated signalling mechanism.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Effects of fluvastatin in type 2 diabetic patients with hyperlipidemia: reduction in cholesterol oxidation products and VCAM-1.

The purpose of this study was to investigate the lipid-lowering and anti-oxidative effects of fluvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, in type 2 diabetic patients. Six patients (3 men and 3 women, mean age = 56.2) took 20 mg of fluvastatin once daily (at night) for 12 weeks. Several markers of oxidative stress were then measured in these patients including plasma cholesterol oxidation products, i.e. oxysterols, and the levels of circulating adhesion molecules. Plasma total cholesterol levels were reduced by 12.3% in these individuals after 4 weeks of treatment, with levels remaining below 220 mg/dl for the entire treatment period. LDL levels were significantly reduced at 4 (18.1%) and 12 weeks (16.1%), and triglyceride levels were significantly reduced after 8 (22.5%) and 12 (37.7%) weeks of treatment. HDL-C levels increased from 50.7 +/- 15.4 prior to treatment to 63.8 +/- 24.3 mg/dl after 12 weeks of treatment, though this increase was not statistically significant. Lipid hydroperoxide, thiobarbituric acid-reactive substance (TBARS), and oxysterol levels were also reduced, suggesting that fluvastatin also had anti-oxidative effects. Finally, VCAM-1 levels were similarly reduced by fluvastatin treatment. We conclude that fluvastatin safely improves the plasma lipid profile in type 2 diabetic patients with hyperlipidemia. We speculate that this drug might be doubly effective in reducing atherosclerosis and cardiac events in these patients as a result of its demonstrated anti-oxidative effects and its ability to reduce VCAM-1 levels.

Antioxidants↗
PubMed2003

Clofibrate, a peroxisome-proliferator, enhances reverse cholesterol transport through cytochrome P450 activation and oxysterol generation.

Fibrates are widely used hypolipidemic agents that activate the peroxisome proliferator-activated receptor a (PPARalpha) and regulate the expression of many genes involved in lipid metabolism. We studied the mechanism of the effect of clofibrate on cholesterol homeostasis. Rats were fed with chow containing clofibrate, cytochrome P-450 inhibitor ketoconazole, or clofibrate plus ketoconazole. Control rats were fed only with normal chow. The levels of six oxysterols in liver microsome were determined. The levels of mRNAs for liver X receptor alpha (LXRalpha), ATP-binding cassette A1 (ABCA1), PPARalpha and cholesterol 7alpha-hydroxylase (CYP7A) in the liver were analyzed by northern blotting. Clofibrate administration decreased plasma levels of total cholesterol and triglyceride and increased high-density lipoprotein-cholesterol (HDL-C). Clofibrate increased the levels of liver microsomal oxysterols including 25- and 27-hydroxycholesterol, which are potent activators of LXRalpha. Clofibrate also enhanced the expression of mRNAs for PPARalpha, LXRalpha, and ABCA1. Simultaneous administration of ketoconazole suppressed the effects of clofibrate on plasma lipids, hepatic oxysterol levels, and the expression of the genes. Clofibrate increases cytochrome P450 content and the resulting oxysterol generation may partly mediate the clofibrate-induced up-regulattion of LXRa and ABCA1, which are related to reverse cholesterol transport.

ATP Binding Cassette Transporter 1↗
PubMed2003

Quantitative analysis of apolipoprotein E secretion by human monocyte-derived macrophages in culture.

Apolipoprotein E (apo E) has an impact on lipid metabolism and its production by macrophages is considered to play a protective role against atherosclerosis. Apo A-I stimulates secretion of apo E from macrophages. We developed a new method to evaluate the ability of human monocyte-derived macrophages to secrete apo E, and the effects of factors such as apo A-I were examined. Monocytes separated from peripheral venous blood were cultured. The levels of apo E in macrophage-conditioned medium were quantified by immunoblotting with an anti-human apo E antiserum conjugated with alkaline phosphatase. The basal levels of apo E secretion and the response to exogenous apo A-I in macrophages from 10 healthy volunteers were measured. Sufficient accuracy and sensitivity were confirmed and coefficient of variation of the method was 18 +/- 11% (n = 10). It was confirmed that macrophage secreted apo E in a concentration-dependent manner in response to M-CSF and apo A-I. The average apo E concentration in the conditioned medium of macrophages from 10 healthy subjects was 30.9 +/- 14.7 ng/mg cell protein. After the addition of apo A-I, the average apo E concentration increased, by about 60%, to 49.4 +/- 29.7 ng/mg cell protein (p < 0.05). There was a positive correlation between the apo A-I-induced increase and plasma LDL cholesterol levels (r = +0.54, p < 0.05).

Apolipoprotein A-I↗
PubMed2002

Spectroscopic detection of short-lived anthracene derivative cation radicals using an electron transfer stopped-flow method with the tris(2,4-dibromophenyl)amine cation radical.

Dynamic transformation profiles of short-lived cation radicals of anthracene derivatives, including 1-methyl, 2-methyl and unsubstituted anthracenes, could be observed using an electron transfer stopped-flow method by adopting the tris(2,4-dibromophenyl)amine cation radical as a reaction initiator.

Journal Article↗
PubMed2002

Rum1, an inhibitor of cyclin-dependent kinase in fission yeast, is negatively regulated by mitogen-activated protein kinase-mediated phosphorylation at Ser and Thr residues.

The p25(rum1) is an inhibitor of Cdc2 kinase expressed in fission yeast and plays an important role in cell-cycle control. As its amino-acid sequence suggests that p25(rum1) has putative phosphorylation sites for mitogen-activated protein kinase (MAPK), we investigated the ability of MAPK to phosphorylate p25(rum1). Direct in vitro kinase assay using GST-fusion proteins of wild-type as well as various mutants of p25(rum1) demonstrated that MAPK phosphorylates the N-terminal portion of p25(rum1) and residues Thr13 and Ser19 are major phosphorylation sites for MAPK. In addition, phosphorylation of p25(rum1) by MAPK revealed markedly reduced Cdc2 kinase inhibitor ability of the protein. Together with the fact that replacement of both Thr13 and Ser19 with Glu, which mimics the phosphorylated state of these residues, also significantly reduces the activity of p25(rum1) as a Cdc2 inhibitor, it was suggested that the phosphorylation of Thr13 and Ser19 negatively regulates the function of p25(rum1). Further evidence indicates that phosphorylation of Thr13 and Ser19 may retain a negative effect on the function of p25(rum1) even in vivo. Therefore, MAPK may regulate the function of p25(rum1) via phosphorylation of its Thr and Ser residues and thus participate in cell cycle control in fission yeast.

Amino Acid Substitution↗