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Biomedical subjects

Yuji Matsuzawa

Publications and source records attributed to Yuji Matsuzawa.

At least 91 records · Page 5Linked to original sources
PubMed2003

Imatinib inhibits various types of activating mutant kit found in gastrointestinal stromal tumors.

Mutations of proto-oncogene c-KIT in gastrointestinal stromal tumors (GISTs) are considered to cause a constitutive activation of KIT responsible for their oncogenesis. Imatinib has therapeutic potential for GISTs because of its inhibitory effect on KIT kinase activity. To investigate the effect of Imatinib on various c-KIT mutations found in GISTs, we examined kinase activity of KIT, cell proliferation and tumorigenicity of transfectants with various c-KIT mutations. Murine lymphoid Ba/F3 cells transfected with one of the three types of mutants (KIT(del559-560), KIT(642Glu), and KIT(820Tyr)) or wild-type KIT were used for the experiments. Phosphorylation of KIT, mitogen-activated protein (MAP) and Akt was studied by immunoblotting with or without immunoprecipitation. In vitro studies on cell proliferation using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylcetrazolium bromide colorimetric assay and in vivo tumorigenicity assay using nude mice were also carried out. Imatinib could inhibit the KIT, MAP and Akt phosphorylation of all the transfectants but had a weaker effect on KIT(820Tyr). Imatinib potently inhibited the proliferation of cells transfected with KIT(820Tyr) at the concentration of 10 microM whereas it inhibited the other 3 types at 1 microM. Moreover, Imatinib could inhibit the tumor formation in nude mice transplanted with transfectants. In various types of activating mutant KIT, Imatinib could inhibit the constitutive activation of KIT signal transduction and cell proliferation both in vitro and in vivo although the effect of Imatinib on KIT(820Tyr) was weaker than that on KIT(del559-560) or KIT(642Glu).

Animals↗
PubMed2003

Measurement of fasting serum apoB-48 levels in normolipidemic and hyperlipidemic subjects by ELISA.

The present study was designed to evaluate the metabolism of chylomicron and chylomicron remnants by measuring serum apolipoprotein B-48 (apoB-48) levels in 335 normolipidemic and 253 hyperlipidemic subjects using a novel ELISA system. The distribution of fasting serum apoB-48 levels in normolipidemic subjects varied widely, ranging from <1 to >24 microgram/ml (mean, 5.2 +/- 3.8 microgram/ml; median, 3.9 microgram/ml). Serum apoB-48 levels correlated with serum triglyceride (TG) concentrations (r = 0.45, P < 0.001), but not with total cholesterol levels. Serum apoB-48 levels were 7 to 18 times higher in patients with Type I, Type V, and Type III hyperlipidemia, and only slightly higher in patients with Type IIa, Type IIb, and Type IV hyperlipidemia, compared with normolipidemic subjects. The calculated apoB-48/TG ratio was elevated only in patients with dysbetalipoproteinemia (apoE2/2 phenotype). In normolipidemic subjects, oral fat loading resulted in about 2-fold increase in serum apoB-48 levels, with a peak level recorded at 3-4 h postloading, and then returned to the baseline level within 6 h. On the other hand, in patients with dysbetalipoproteinemia, serum apoB-48 levels did not change considerably. Our results indicate that serum apoB-48 is a very useful parameter for evaluating lipoprotein metabolism in exogenous pathways.

Adult↗
PubMed2003

Reciprocal association of C-reactive protein with adiponectin in blood stream and adipose tissue.

BACKGROUND: High-sensitive C-reactive protein (hs-CRP) is a well-known risk factor for coronary artery disease (CAD). Recently, we have demonstrated that adiponectin served as an antiatherogenic plasma protein which was secreted specifically from adipocytes. The present study investigated the association between adiponectin and CRP in the blood stream and adipose tissue. METHODS AND RESULTS: We studied a total of 101 male patients, 71 of whom had angiographically documented coronary atherosclerosis. As a control group, 30 patients with normal coronary angiogram were included. The plasma hs-CRP levels were negatively correlated with the plasma adiponectin levels (r=-0.29, P<0.01). The plasma adiponectin concentrations were significantly lower and the hs-CRP levels were significantly higher in the CAD patients compared with control subjects. The mRNA levels of CRP and adiponectin were analyzed by quantitative real-time polymerase chain reaction method. We found that the CRP mRNA was expressed in human adipose tissue. A significant inverse correlation was observed between the CRP and adiponectin mRNA levels in human adipose tissue (r=-0.89, P<0.01). In addition, the CRP mRNA level of white adipose tissue in adiponectin deficient mice was higher than that of wild-type mice. CONCLUSIONS: The reciprocal association of adiponectin and CRP levels in both human plasma and adipose tissue might participate in the development of atherosclerosis.

Adiponectin↗
PubMed2003

Association of hypoadiponectinemia with coronary artery disease in men.

BACKGROUND: Adiponectin is an adipocyte-derived plasma protein that accumulates in the injured artery and has potential antiatherogenic properties. This study was designed to determine whether a decreased plasma adiponectin level (hypoadiponectinemia) can be independently associated with the prevalence of coronary artery disease (CAD). METHODS AND RESULTS: The consecutive 225 male patients were enrolled from inpatients who underwent coronary angiography. Voluntary blood donors (n=225) matched for age served as controls. Plasma adiponectin levels in the CAD patients were significantly lower than those in the control subjects. Multiple logistic regression analysis including plasma adiponectin level, diabetes mellitus, dyslipidemia, hypertension, smoking habits, and body mass index revealed that hypoadiponectinemia was significantly and independently correlated with CAD (P<0.0088). The entire study population was categorized in quartiles based on the distribution of plasma adiponectin levels. The interquartile cutoff points were 4.0, 5.5, and 7.0 microg/mL. The multivariate-adjusted odds ratios for CAD in the first, second, and third quartiles were 2.051 (95% confidence interval [CI], 1.288 to 4.951), 1.221 (95% CI, 0.684 to 2.186), and 0.749 (95%CI, 0.392 to 1.418), respectively. CONCLUSIONS: Male patients with hypoadiponectinemia (<4.0 microg/mL) had a significant 2-fold increase in CAD prevalence, independent of well-known CAD risk factors.

Adiponectin↗
PubMed2003

Localized relapse in bone marrow in a posttransplantation patient with t(6;9) acute myeloid leukemia.

We report a 38-year-old woman with t(6;9) acute myeloid leukemia who relapsed with localized leukemic cell growth in the bone marrow after she had undergone allogeneic bone marrow transplantation. The localized cell growth was first recognized by an apparent discrepancy in the DEK-CAN fusion transcript levels between the aspirates from the left and right iliac bone marrow. Magnetic resonance imaging of the iliac bone revealed localized cell accumulation in the left side. The nonhomogeneous and localized leukemic cell growth in this case may have been due to the graft-versus-leukemia effect following allogeneic transplantation with donor lymphocyte infusion. Serial monitoring of molecular markers for leukemia at different sites or magnetic resonance imaging of the bone marrow may be of value in detecting this type of relapse.

Adult↗
PubMed2003

A decreased number of c- kit-expressing cells in a patient with afferent loop syndrome.

Following gastrectomy, stasis in the afferent jejunal loop accompanied by an overgrowth of bacteria leads to a number of clinical symptoms, including the so-called afferent loop syndrome. The disturbances in intestinal motility may be related to stagnation of the intestinal contents in the afferent loop. The pacemaker cells for the basic contractile activity of the intestine are thought to be the interstitial cells of Cajal (ICCs). We and others have reported that ICCs express the c- kit receptor, and that a decreased number of c- kit-expressing ICCs is generally thought to result in disturbed intestinal motility. We report here a patient with postgastrectomy afferent loop syndrome with a decreased number of c- kit-expressing cells in the external muscle layer of the dilated intestine, suggesting damage to the ICCs.

Afferent Loop Syndrome↗
PubMed2003

Prevalence and phenotypic spectrum of cholesteryl ester transfer protein gene mutations in Japanese hyperalphalipoproteinemia.

A patient with cholesteryl ester transfer protein (CETP) deficiency presents with marked hyperalphalipoproteinemia (HALP). To investigate the contribution of CETP deficiency to the cause of HALP (HDL-C> or =1.94 mmol/l, 75 mg/dl), we investigated the CETP activities and the prevalence of genetic CETP mutations among 624 Japanese HALP subjects. The subjects were screened for four known genetic CETP mutations (intron 14 splicing defect (In14), exon 15 missense mutation (Ex15), intron 10 splicing defect (In10) and exon 6 nonsense mutation (Ex6)). We found the frequency of the patients with reduced CETP activity (<75% of normal controls) to be 55.5 and 64.1% in a high HDL group (1.94< or =HDL-C<2.59 mmol/l) and a marked HALP group (HDL-C> or =2.59 mmol/l, 100 mg/dl), respectively. At least one of the four mutations was identified in 65.7% of subjects with reduced CETP activities and 57.5% of subjects with marked HALP. The In14 and Ex15 mutations were very common in HALP subjects and the frequency of In10 mutation and Ex6 mutation was quite low. To investigate the impact of genetic CETP mutation on the phenotypes, we compared the plasma lipid levels and CETP activities between the subjects with two common mutations. All In14 homozygotes showed marked HALP, while marked HALP is less frequent (64.3%) in Ex15 homozygotes. HDL-C levels in Ex15 heterozygotes were significantly higher than those of In14 heterozygotes, suggesting the mutation has dominant negative effects on CETP activity in vivo. Some cases with In14 (5.7%) or Ex15 (7.2%) mutation showed low HDL-C levels. We conclude that CETP deficiency is a major cause of HALP; nevertheless CETP deficiency is not necessarily HALP.

Adult↗
PubMed2003

Atorvastatin markedly improves type III hyperlipoproteinemia in association with reduction of both exogenous and endogenous apolipoprotein B-containing lipoproteins.

Remnant lipoproteins are known to promote atherosclerosis especially in patients with type III hyperlipoproteinemia (HLP). In the current study, the effects of atorvastatin were investigated with special reference to the exogenous and endogenous apolipoprotein (apo) B-containing lipoprotein metabolism in type III HLP. Four Japanese male patients with type III HLP associated with homozygous apoE2 were studied. One-month administration of atorvastatin (20 mg once daily), after a 4-week dietary run-in, strikingly reduced serum total cholesterol and triglyceride (TG) levels by 52 (P<0.01) and 56% (P<0.05), respectively. Atorvastatin further decreased remnant-like particle (RLP)-cholesterol by 73% and RLP-TG by 65% (P<0.05), respectively. Distribution analysis by polyacrylamide gel disc electrophoresis clearly showed that atorvastatin diminished very low-, intermediate- and low-density lipoprotein particles. The relative particle diameter of intermediate-density lipoprotein became smaller after atorvastatin treatment (P<0.01). Furthermore, ultracentrifugal analysis demonstrated that atorvastatin significantly decreased cholesterol, TG and phospholipid concentrations in all apoB-containing lipoprotein fractions and very low-density lipoprotein (VLDL)-cholesterol/serum TG ratio (P<0.05), implying atorvastatin-induced reduction of beta-VLDL. Finally, newly developed assays of apoB-48 and apoB-100 revealed that atorvastatin markedly reduced these apolipoproteins by 43 and 52%, respectively (P<0.01), suggesting that atorvastatin decreased the number of both exogenous and endogenous apoB-containing lipoproteins. Taken together, atorvastatin improves remnant lipoprotein metabolism in type III HLP both in quality and in quantity. Atorvastatin can be one of the optimal options for the treatment of patients with type III HLP.

Aged↗
PubMed2003

Disappearance of intraglomerular lipoprotein thrombi and marked improvement of nephrotic syndrome by bezafibrate treatment in a patient with lipoprotein glomerulopathy.

Lipoprotein glomerulopathy (LPG) is a hereditary disorder characterized by intraglomerular lipoprotein thrombi and increased serum apolipoprotein (apo) E. Patients with LPG usually manifest with nephrotic syndrome, and some progress to renal failure; however, no effective therapeutic regimen has been established for this disease. We experienced a patient with LPG for whom bezafibrate treatment was very effective. This 30-year-old Japanese woman had nephrotic syndrome and type III hyperlipoproteinemia. Renal biopsy showed markedly dilated capillary lumina containing massive lipoprotein thrombi. Plasma apo E concentration was elevated to twice that of normal controls. She was proved to be a heterozygote of apo E2 Kyoto (Arg25Cys). After 2 years treatment with bezafibrate (400 mg/day), her plasma albumin gradually increased from 2.1 to 4.0 mg/dl, and intraglomerular lipoprotein thrombi disappeared almost completely. Bezafibrate decreased plasma apo E and dramatically increased high density lipoprotein (HDL)-cholesterol. The decrease in apo E was observed mainly in the pre-beta-fraction, not in the alpha fraction. Lipidological analyses of our patient suggest that the origin her lipoprotein thrombi may be mainly from pre-beta-lipoproteins and that HDL might be involved in resolving lipoprotein thrombi. Our case suggests that administration of fibrates such as bezafibrate may be a novel therapeutic strategy for resolving intraglomerular thrombi and improving nephrotic syndrome in patients with LPG.

Adult↗
PubMed2003

Expression of ephrin-B1 in hepatocellular carcinoma: possible involvement in neovascularization.

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) is, in general, a hypervascular tumor. Ephrin/Eph molecules have recently been reported as possible regulators of angiogenesis. We aimed to clarify the role of ephrin-Bs (B1-B3) in the progression of HCC. METHODS: Ephrin-Bs transcripts in 26 HCC and their corresponding non-tumor liver tissues were analyzed by the quantitative reverse transcription-polymerase chain reaction. We established ephirn-B1 overexpressing cell in a human HCC cell line, PLC/PRF/5 cell, and their in vivo growth monitored after subcutaneous injection into nude mice. Neovascularization in the inoculated tumors was evaluated by the immunohistochemical staining of CD31. The migration and proliferation of human umbilical vein endothelial cells (HUVECs) in response to soluble ephrin-B1-Fc was examined. RESULTS: The expression of the ephrin-B1 transcript but not -B2 and -B3 transcripts was significantly higher in HCC tissues than in non-tumor tissues (P<0.05). The ephrin-B1 overexpressing cells developed tumors more rapidly than controls in vivo (P<0.05), although in vitro cell growth was not affected. The tumor vessel number significantly increased in the ephrin-B1 overexpressing tumors (P<0.0001). In addition, in vitro studies revealed that ephrin-B1 induced migration and proliferation of HUVECs. CONCLUSIONS: Ephrin-B1 may be involved in in vivo tumor progression by promoting neovascularization in HCC.

Animals↗
PubMed2003

Decreased plasma adiponectin concentration in patients with essential hypertension.

Adipocytes secrete several biologically active substances that are presumed to be involved in obesity-related hypertension. There are no reports that deal with the relationship between plasma adiponectin concentration and blood pressure (BP). To evaluate the role of adiponectin in essential hypertension 33 patients with essential hypertensive (EHP) (12 women, 21 men) and 33 body mass index-matched normotensive healthy subjects (NHS) (13 women, 20 men) were studied. In EHP plasma adiponectin concentration was significantly lower than in NHS (9.1 +/- 4.5 v 13.7 +/- 5.2 microg/mL, respectively). In all subjects a significant negative correlation was found between plasma adiponectin concentration and mean, systolic, and diastolic BP, suggesting that adiponectin contributes to the clinical course of essential hypertension.

Adiponectin↗
PubMed2003

Pathophysiology of human genetic CD36 deficiency.

CD36, originally identified as glycoprotein IV on platelets, is an 88-kDa integral membrane protein that has multiple ligands and is expressed in the cardiovascular system (ie, blood vessel walls and the heart). Human genetic CD36 deficiency is relatively frequent in Asian and African populations. Investigation into the pathophysiology of this disorder has shown that CD36 may play an important role as a major scavenger receptor for oxidized low-density lipoproteins and as a crucial transporter for long-chain fatty acids. The CD36 deficiency may be related to the phenotypic expression of the "metabolic syndrome," which is frequently associated with atherosclerotic cardiovascular diseases. It also has been reported that CD36 deficiency might be linked with cardiomyopathy. These data raised the possibility that CD36 deficiency might be an important genetic background for these life-threatening human cardiovascular diseases.

Animals↗
PubMed2003

Angiotensin II stimulates the nuclear translocation of Smad2 and induces PAI-1 mRNA in rat hepatic stellate cells.

It has recently been reported that angiotensin II (ANGII) stimulates gene expression of transforming growth factor-beta1 (TGF-beta1) and is involved in hepatic fibrosis. This effect is thought to be caused through ANGII type 1 receptor (ATR1). However, a role of ANGII at the postreceptor levels of TGF-beta1 signaling has not been identified. To clarify the role of ANGII on hepatic fibrosis, we investigated the effect of ANGII on rat hepatic stellate cells (HSCs). HSCs were isolated from male Sprague-Dawley rats. TGF-beta1 and matrix protein gene expression in HSCs was assessed by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) using SYBR Green I. The nuclear translocation of Smad2 in HSCs after 20 min ANGII stimulation was analyzed by Western blotting. ANGII was found to induce TGF-beta1 and matrix protein gene expression in HSCs. The nuclear translocation of Smad2 in HSCs was also induced by ANGII stimulation. These effects of ANGII were almost completely blocked by the ATR1 antagonist, CS-866. ANGII induces TGF-beta1 and matrix protein mRNA, and stimulates rapid nuclear translocation of Smad2 in rat HSCs through ATR1, which indicates that the ATR1 blockade represents a novel approach for the possible prevention of hepatic fibrosis.

Journal Article↗
PubMed2003

c-kit gene mutation at exon 17 or 13 is very rare in sporadic gastrointestinal stromal tumors.

BACKGROUND AND AIM: Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the human gut. They frequently have gain-of-function mutations of the c-kit gene, which encodes a receptor, tyrosine kinase. The mutations were found at exon 11 in most cases, and either at exon 9 or at exon 13 in rare cases. Recently, we found a family with multiple GIST and a gain-of-function mutation at exon 17. The family was the first reported GIST case with c-kit gene mutation at exon 17 including sporadic GIST. Although we previously reported that the c-kit gene mutation at exon 17 was not detected in 124 sporadic GIST by single-strand conformation polymorphism (SSCP) analysis, the mutation at exon 17 observed in the familial GIST was detectable by the use of direct sequencing but not by our SSCP method. In the present study, we examined the mutations at exon 17 and exon 13 by using direct sequencing. METHODS: Genomic DNA was extracted from formalin-fixed, paraffin-embedded GIST tissues. We could obtain 143 sporadic GIST cases appropriate for DNA analysis at exon 17 and 141 at exon 13. Exons 17 and 13 were amplified by using polymerase chain reaction and direct sequencing was conducted. RESULTS: No mutation was found at exon 17, and only one case with the mutation at exon 13 was observed. The GIST with the mutation at exon 13 was large and showed frequent mitosis, and the patient died of the recurrent GIST 3 years after the first operation. CONCLUSION: The mutation at exons 17 or 13 was considered to be very rare in sporadic GIST.

Aged↗
PubMed2003

Helicobacter pylori-induced enlarged-fold gastritis is associated with increased mutagenicity of gastric juice, increased oxidative DNA damage, and an increased risk of gastric carcinoma.

BACKGROUND AND AIM: The severe inflammation, increased cell proliferation and marked acid inhibition observed in subjects with Helicobacter pylori-associated enlarged-fold gastritis suggest that enlarged-fold gastritis may be a risk factor for gastric carcinoma. The purpose of the present study was to determine whether a relationship exists between enlarged-fold gastritis and gastric carcinoma. METHODS: One hundred and thirty-five H. pylori-positive patients with early gastric carcinoma and 141 age- and sex-matched H. pylori-positive controls without gastric carcinoma were involved in the study. The widths of gastric body folds were measured by double-contrast radiographs. The mutagenicity of gastric juice was assayed using the Ames test and Salmonella typhimurium TA-98 or TA-100 with S9-mix. Levels of 8-hydroxydeoxyguanosine (8-OHdG) in gastric mucosa were examined using high-performance liquid chromatographic-electrochemical detection. RESULTS: An upward shift in the distribution of gastric fold widths in H. pylori-positive patients with early gastric carcinoma was found. Enlarged-fold gastritis (fold width >/=5 mm) was observed in 81% of the patients with gastric carcinoma, compared with 46% of H. pylori-positive controls. The odds ratio for gastric carcinoma increased with increasing fold width to a maximum of 35.5 in persons with fold width >/=7 mm. The prevalence of diffuse-type early gastric carcinoma in the body region increased with increasing fold width. The mutagenicity of gastric juice from the patients with enlarged-fold gastritis was significantly higher than that in H. pylori-negative controls and H. pylori-positive patients without enlarged folds. Mucosal 8-OHdG levels in the body region of patients with enlarged-fold gastritis were significantly higher than in H. pylori-negative controls and H. pylori-positive patients without enlarged-fold gastritis. Eradication of H. pylori significantly decreased the mutagenicity of gastric juice and 8-OHdG levels in the gastric mucosa from patients with enlarged-fold gastritis. CONCLUSION: A significant association is suggested between enlarged-fold gastritis and gastric carcinoma.

Adult↗
PubMed2003

Adiponectin is markedly increased in patients with nephrotic syndrome and is related to metabolic risk factors.

BACKGROUND: Adiponectin (ADPN), the gene product of apM1, is the most abundant secretory protein of the adipose tissue in human plasma. Altered regulation (reduced synthesis) of this substance may be relevant to endothelial dysfunction and cardiovascular complications in patients with ESRD. METHODS: We investigated the relationship between plasma ADPN, glomerular filtration rate (GFR) (plasma iohexol clearance), and metabolic risk factors in 16 patients with nephrotic syndrome, in 25 patients with chronic nephropathies without nephrotic syndrome, and in 31 healthy subjects. RESULTS: Plasma ADPN was much higher (P < 0.01) in patients with nephrotic syndrome (24.4 +/- 14.9 microg/mL) than in patients with chronic nephropathies without nephrotic syndrome (12.3 +/- 7.2 microg/mL) and healthy subjects (5.9 +/- 2.6 microg/mL). In the aggregate 24-hour, proteinuria (r = 0.53, P < 0.01) and serum cholesterol (r = 0.53, P < 0.01) were strong and direct correlates of plasma ADPN, while serum albumin correlated inversely (r = -0.46, P < 0.01) with this protein. Proteinuria appeared to be an important confounder of the relationship between ADPN and the GFR because in the whole patient population (with and without nephrotic syndrome), this relationship emerged only after data adjustment for 24-hour proteinuria (partial r = -0.31, P = 0.05), while no such relationship was demonstrable on crude data analysis (r = 0.03, P = 0.87). CONCLUSIONS: ADPN is markedly increased in patients with nephrotic syndrome, and proteinuria is strongly related to circulating ADPN in patients with nephrotic and non-nephrotic renal diseases. The relationships between plasma ADPN, serum cholesterol, and serum albumin suggest that this adipocyte protein may serve to mitigate endothelial damage triggered by dyslipidemia and other risk factors in patients with chronic renal diseases.

Adiponectin↗
PubMed2003

Liver regeneration in heparin-binding EGF-like growth factor transgenic mice after partial hepatectomy.

BACKGROUND & AIMS: Heparin-binding epidermal growth factor-like growth factor (HB-EGF), a member of the EGF family, is synthesized in the form of a membrane-anchored precursor (proHB-EGF), which subsequently is processed proteolytically to mature HB-EGF. This study describes the effects of HB-EGF on liver regeneration after 70% partial hepatectomy in proHB-EGF transgenic mice with liver-specific expression. METHODS & RESULTS: No significant differences in liver/body weight ratios and in bromodeoxyuridine (BrdU)-labeling index (the ratios of BrdU-positive hepatocyte nuclei) were found between adult transgenic and wild-type mice. However, in regenerating liver after partial hepatectomy, transgenic mice had higher liver/body weight ratios than wild-type mice and at 120 hours reached a level equal to that before partial hepatectomy. The BrdU-labeling index was about 5 times higher in the livers of transgenic mice compared with the wild type (51.5% vs. 10.2%, respectively; P < 0.01) at 48 hours after partial hepatectomy. Activation of microtubule-associated protein kinase after partial hepatectomy was higher and earlier in the transgenic mice as compared with the wild-type mice. Soluble HB-EGF was increased in the liver (at 8 min) after partial hepatectomy, indicating that the shedding of proHB-EGF occurred after partial hepatectomy. CONCLUSIONS: The transgenic expression of HB-EGF accelerates the proliferation of hepatocytes after partial hepatectomy, suggesting that HB-EGF functions as a hepatotrophic factor in vivo.

Animals↗