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Biomedical subjects

F Suzuki

Publications and source records attributed to F Suzuki.

At least 19 recordsLinked to original sources
PubMed2006

Increased expression of cyclooxygenase-2 in the renal cortex of human prorenin receptor gene-transgenic rats.

Increased macula densa cyclooxygenase-2 (COX-2) is observed in diabetic rats and may contribute to hyperfiltration states. However, the signals mediating increased COX-2 expression in diabetic rats remain undetermined. We recently found that non-proteolytic activation of prorenin by site-specific binding proteins, such as prorenin receptor, plays a pivotal role in the development of diabetic nephropathy. The present study was designed to determine the contribution of prorenin receptor to renal cortical COX-2 expression. The COX-2 mRNA and protein levels of six 4-week-old male wild-type rats and six human prorenin receptor gene-transgenic (hProRenRcTg) rats were measured by real-time polymerase chain reaction methods, Western blotting, and immunohistochemistry, and compared. There were no differences between the two groups in arterial pressure measured by telemetry, urinary sodium excretion, or renal levels of rat prorenin receptor mRNA. The renal cortical COX-2 mRNA levels of the hProRenRcTg rats were significantly higher than those of the wild-type rats, and the renal cortical COX-2 protein levels were also higher in hProRenRcTg rats than in the wild-type rats. Immunohistochemical analysis revealed that COX-2 immunostaining was predominantly present in the macula densa cells, and significantly more COX-2-positive cells were present in the hProRenRcTg rats than in the wild-type rats. In addition, COX-2 inhibition with NS398 significantly decreased renal cortical blood flow in the hProRenRcTg rats but not in the wild-type rats. These results strongly suggest that human prorenin receptor directly or indirectly contributes to the regulation of renal cortical COX-2 expression.

Animals↗
PubMed2005

Immunological control of methicillin-resistant Staphylococcus aureus (MRSA) infection in an immunodeficient murine model of thermal injuries.

Staphylococcus aureus, especially methicillin-resistant S. aureus (MRSA), is a major cause of sepsis in patients who are immunosuppressed by their burns. In this study, an immunological regulation of MRSA infection was attempted in a mouse model of thermal injury. SCIDbg mice were resistant to MRSA infection, while SCIDbgMN mice (SCIDbg mice depleted of neutrophils and macrophages (Mphi)) were susceptible to the same infection. Also, thermally injured SCIDbg mice were shown to be susceptible to MRSA infection. On the other hand, the resistance of SCIDbgMN mice to the infection was completely recovered after an inoculation with Mphi from normal mice. However, anti-MRSA resistance was not shown in SCIDbgMN mice inoculated with Mphi from thermally injured mice. Mphi from MRSA-infected thermally injured mice were identified as alternatively activated Mphi, and Mphi from MRSA-infected unburned mice were characterized as classically activated Mphi. Mphi from thermally injured SCIDbg mice previously treated with 2-carboxyethylgermanium sesquioxide (Ge-132) protected SCIDbgMN mice against MRSA infection. Ge-132 has been described as an inhibitor of alternatively activated Mphi generation. These results suggest that MRSA infection in thermally injured patients is controlled immunologically through the induction of anti-MRSA effector cells and elimination of burn-associated alternatively activated Mphi, which are cells that inhibit the generation of classically activated Mphi.

Animals↗
PubMed2005

Serum prorenin levels and diabetic retinopathy in type 2 diabetes: new method to measure serum level of prorenin using antibody activating direct kinetic assay.

AIM: To investigate the serum levels of prorenin and its correlation with the severity of diabetic retinopathy (DR). METHODS: 248 patients with diabetes and 108 control subjects were divided into four groups: no-DR (n = 146), no proliferative diabetic retinopathy (no-PDR) (n = 78), PDR (n = 24), and controls (n = 108). Serum levels of prorenin from all subjects were measured using the new antibody activating direct kinetic (AAD-PR) assay. The serum prorenin levels were compared among the groups. RESULTS: The serum levels of prorenin in the control, no-DR, no-PDR, and PDR groups, respectively, were 109.1 (66.1), 194.6 (160.4), 271.5 (220.3), and 428.4 (358.4) pg/ml (mean (SD)). Prorenin in the PDR group was remarkably high compared with the control and no-DR groups (p<0.0001) and with the no-PDR group (p = 0.002). Serum levels of prorenin increased with increasingly severe retinopathy. No correlation was found between the prorenin level and the duration of disease or HbA(1c). CONCLUSIONS: The serum levels of prorenin in patients with PDR were found to be markedly high using the AAD-PR assay. Increased levels of prorenin in diabetes may have an important role in the pathogenesis of DR.

Antibodies↗
PubMed2004

Wild-type precore and core promoter sequences in patients with acute self-limited or chronic hepatitis B.

BACKGROUND: Mutations in the precore region and core promoter were compared between patients with acute and chronic hepatitis B. METHODS: There were 69 patients with acute self-limited hepatitis B and 210 with chronic hepatitis B who had been followed for > 15 years. The hepatitis B virus (HBV) of genotypes A, B and C was detected in 14 (23%), 8 (13%) and 28 (45%) of the patients with acute self-limited hepatitis, respectively, in contrast to 11 (5%), 25 (12%) and 167 (80%) of those with chronic hepatitis. RESULTS: At presentation, hepatitis B e antigen (HBeAg) in serum was the more common (82% versus 65%, P < 0.05), and the wild-type sequences of the precore region (100% versus 74%, P < 0.001) and core promoter (88% versus 36%, P < 0.00001) were more frequent in the 50 patients with acute self-limited hepatitis than the 203 patients with chronic hepatitis B who were infected with HBV of genotype A, B or C. Wild-types of both the precore region and core promoter persisted in acute self-limited hepatitis, while they decreased from 28% to 10% in chronic hepatitis over the course of > 15 years. CONCLUSION: HBV with the wild-type sequences of the precore region and core promoter prevails in patients with acute self-limited hepatitis, unlike in patients with chronic hepatitis.

Acute Disease↗
PubMed2004

Single nucleotide polymorphism of the MxA gene promoter influences the response to interferon monotherapy in patients with hepatitis C viral infection.

The biological activity of interferon (IFN) is mediated by the induction of intracellular antiviral proteins, such as 2'-5' oligoadenylate synthetase, dsRNA-activated protein kinase and MxA protein. Among these, MxA protein is assumed to be the most specific surrogate parameter for IFN action. This study was performed to elucidate whether a single nucleotide polymorphism (SNP) (G/T at nt-88) in the promoter region of the MxA gene influences the response to IFN therapy in patients with chronic hepatitis C virus (HCV) infection. Polymorphisms of the MxA gene in 235 HCV patients were determined by polymerase chain reaction-restriction fragment length polymorphism. The frequency of SNP was compared between sustained-responders (n = 78) and nonresponders (n = 157), as determined by biochemical and virological responses to IFN. Multivariate analysis showed that among all patients, HCV genotype, HCV RNA level and the SNP of the MxA gene were independent and significant determinants of the outcome of IFN therapy [odds ratio 3.8 (95% confidence interval 2.0-7.0), P < 0.0001; 0.27 (0.15-0.50), P < 0.0001; 1.8 (1.0-3.4), P = 0.0464, respectively]. Furthermore, among patients with a low viral load (< or =2.0 Meq/mL), MxA-T-positive patients were more likely to show a sustained response compared with MxA-T-negative patients [2.87 (1.3-6.3); 62%vs 36%; P = 0.0075]. Our findings suggested that the SNP of the MxA gene is one of the important host factors that independently influences the response to IFN in patients with chronic HCV infection, especially those with a low viral load.

Adult↗
PubMed2003

Progress in pursuit of therapeutic A2A antagonists: the adenosine A2A receptor selective antagonist KW6002: research and development toward a novel nondopaminergic therapy for Parkinson's disease.

Research and development of the adenosine A2A receptor selective antagonist KW6002 have focused on developing a novel nondopaminergic therapy for Parkinson's disease (PD). Salient pharmacologic features of KW6002 were investigated in several animal models of PD. In rodent and primate models, KW6002 provides symptomatic relief from parkinsonian motor deficits without provoking dyskinesia or exacerbating existing dyskinesias. The major target neurons of the A2A receptor antagonist were identified as GABAergic striatopallidal medium spiny neurons. A possible mechanism of A2A receptor antagonist action in PD has been proposed based on the involvement of striatal and pallidal presynaptic A2A receptors in the "dual" modulation of GABAergic synaptic transmission. Experiments with dopamine D2 receptor knockout mice showed that A2A receptors can function and anti-PD activities of A2A antagonists can occur independent of the dopaminergic system. Clinical studies of KW6002 in patients with advanced PD with L-dopa-related motor complications yielded promising results with regard to motor symptom relief without motor side effects. The development of KW6002 represents the first time that a concept gleaned from A2A biologic research has been applied successfully to "proof of concept" clinical studies. The selective A2A antagonist should provide a novel nondopaminergic approach to PD therapy.

Adenosine A2 Receptor Antagonists↗
PubMed2002

Duodenal wall cysts may be derived from a ductal component of ectopic pancreatic tissue.

AIMS: To clarify the mechanism of origin of duodenal wall cysts in patients with chronic pancreatitis, developing into duodenal stenosis. METHODS AND RESULTS: Specimens from 12 pancreatoduodenectomized patients with chronic pancreatitis and 51 controls were studied histopathologically and immunohistochemically. Variously shaped cystic lesions, averaging about 15 mm in diameter, were found in the duodenum in six of the 12 patients with chronic pancreatitis, but were not observed in the controls. Each case had an average of two cysts, which were located mainly in the muscularis propria of the duodenum with or without submucosal or extraduodenal-peripancreatic extensions. The inner part of the cyst wall consisted of a moderate rim of granulation tissue, with both myofibroblasts and smooth muscle proliferation in the tissue surrounding the cyst and the submucosal layer of the duodenum, occasionally accompanied by an epithelial lining. A ductal structure in the muscularis propria of the duodenum, possibly a ductal component of ectopic pancreatic tissue, was found in five of the six cases. Some of these structures showed cystic changes. Three of the six patients had accompanying duodenal stenosis. CONCLUSIONS: Duodenal wall cysts occur mainly in the muscularis propria of the duodenum associated with both myofibroblasts and smooth muscle proliferation, and may result in duodenal stenosis. These cysts may be derived from a ductal component of ectopic pancreatic tissue.

Adult↗
PubMed2001

Rapid acid extrusion response triggered by alpha(1) adrenoceptor in CHO cells.

1. Using a microphysiometer with synchronized valve switching, we investigated real-time acid extrusion from Chinese hamster ovary (CHO) cells in which human alpha(1) adrenoceptor (AR) is stably expressed, in response to noradrenaline (NA). 2. In the cells expressing alpha(1a) AR, the time course of extracellular acidification after stimulation had two phases; in the first phase it transiently reached a rate several times greater than the base rate with a peak at around 10 s, and in the second it increased to 2 times the base rate and reached a plateau in 2 min. Both phases showed a concentration-dependent increase of acidification rate in response to NA, but had distinct pEC(50) values; 5.6 for the transient phase and 7.2 for the steady phase. 3. In the cells expressing alpha(1b) AR, the transient phase was not detected but the steady phase was observed. The pEC(50) value was 7.1, although the magnitude of the response was much smaller than that with alpha(1a) AR. 4. Both 5-(N-ethyl-N-isopropyl)amiloride (EIPA) and HOE642 inhibited the acid extrusion response by either AR in a concentration-dependent manner. EIPA and HOE642 had high pIC(50) values (7.4 and 7.3, respectively) for inhibition of the transient phase response via alpha(1a) AR. In the inhibition of the steady phase response via alpha(1a) AR, both drugs revealed the presence of two components in the response; one had high pIC(50) values (8.1 and 8.2 for EIPA and HOE642, respectively) and the other had low pIC(50) values (5.6 and 6.0, respectively). In contrast, the steady phase response via alpha(1b) AR was inhibited by EIPA and HOE642 with low pIC(50) values (5.3 and 5.9, respectively). 5. As Ca2+ was depleted, the alpha(1a) AR-induced transient phase disappeared, while the steady phase was not affected. 6. These results suggest that alpha(1a) AR drives two acid extrusion systems in CHO cells upon stimulation; one elicits the transient response, which is largely mediated by an EIPA/HOE642-sensitive and Ca(2+)-dependent Na(+)-H(+) exchanger (NHE), presumably NHE1, and the other induces the steady acid extrusion that is mediated by NHE1 and another NHE which has low sensitivity to both EIPA and HOE642. alpha(1b) AR drives only the steady phase acid extrusion response, which is mainly mediated by NHEs other than NHE1.

Acids↗
PubMed2001

Glycyrrhizin restores the impaired IL-12 production in thermally injured mice.

Mice 6 days after thermal injury (TI-mice) did not respond to lipopolysaccharide (LPS) stimulation for production of serum interleukin 12 (IL-12; 2 h after LPS stimulation, <20 pg/ml in TI-mice; 1091+/-162 pg/ml in normal mice). However, 2 h after LPS stimulation, 1456+/-118 pg/ml of IL-12 were demonstrated in sera of TI-mice previously treated with a 10 mg/kg i.p. dose of glycyrrhizin (GR). IL-12 was not induced by LPS in sera of normal mice inoculated with burn-associated type 2 T cells (IL-4/IL-10-producing CD8+CD11b+TCRgamma/delta+T cells isolated from spleens of TI-mice). However, IL-12 production was induced by LPS in sera of these mice previously treated with GR or a mixture of monoclonal antibodies (mAbs) for type 2 cytokines. Also, IL-12 production was induced by LPS in TI-mice inoculated with CD4+T cells from spleens of GR-treated normal mice (GR-CD4+T cells, 5x10(6)cells/mouse). Since GR-CD4+T cells have been shown to be antagonistic cells against production of type 2 cytokines by burn-associated type 2 T cells, these results indicate that IL-12 unresponsiveness shown in TI-mice is recovered by GR through the regulation of burn-associated type 2 T cell responses.

Adoptive Transfer↗
PubMed2001

DOPA cyclohexyl ester, a competitive DOPA antagonist, protects glutamate release and resultant delayed neuron death by transient ischemia in hippocampus CA1 of conscious rats.

In rat striata, DOPA released is a causal factor for glutamate release and resultant delayed neuron death by four-vessel occlusion. Nanomolar DOPA cyclohexyl ester (CHE), a potent and relatively stable competitive DOPA antagonist, protects these events. We tried to clarify whether DOPA CHE protects these events in hippocampal CA1 pyramidal cell layers most vulnerable against ischemia. Five to 10 min ischemia caused slight to mild glutamate release in 10 min samples during microdialysis and mild to severe neuron death 96 h after reperfusion. DOPA and dopamine were under assay limit in this design, but were basally detected by 20 min sampling and released by 20 min ischemia. In 10 min samples, intrahippocampal perfusion of 100 nM DOPA CHE 10 min before ischemia for 70 min did not inhibit glutamate release by 10 min ischemia, while it abolished glutamate release and protected delayed neuron death by 5 min ischemia. DOPA CHE is neuroprotective under a mild ischemic condition in rat hippocampus CA1.

Animals↗
PubMed2001

Efficacy of IFN therapy based on duration period of negative HCV-RNA during IFN administration.

We assessed the relationship between the duration period of negative hepatitis C virus (HCV)-RNA during interferon (IFN) therapy and the efficacy after prolonged IFN therapy in patients with HCV-genotype 1b and high virus load of more than 1 mega equivalents/ml (Meq/ml) retrospectively. A total of 100 patients who had HCV-genotype 1b and a high virus load of more than 1 Meq/ml and were treated with natural IFN-alpha for more than 12 months were enrolled in this trial. These patients were given 6 MU of IFN daily for 8 weeks, followed by three times weekly for another more than 44 weeks. The HCV-RNA pattern during IFN therapy according to negative or positive of the serum HCV-RNA by reverse transcription nested polymerase chain reaction (RT-nested PCR) from 2 months after the initiation of IFN to the termination of IFN were classified as follows: group 1: constant negative HCV-RNA (n=41 cases), group 2: constant positive HCV-RNA (n=35 cases), group 3: HCV-RNA pattern except for group 1 or group 2 (n=24 cases). A complete response (CR) was defined as negative HCV-RNA by RT-nested PCR at two points, 3 and 6 months after the completion of IFN therapy. CR rate was 58.5% (24 cases) in group 1, but CR rate in group 2 or group 3 was 0%. In group 1, the CR rate was 100% (10/10) in patients with negative HCV-RNA constantly for period of more than 24 months during IFN therapy. On the other hand, all patients who had positive HCV-RNA 2 months after the initiation of IFN did not get CR. In conclusion, it seems to us that the attainment of constantly negative HCV-RNA for the period of more than 24 months during IFN therapy is highly related to CR.

Journal Article↗
PubMed2001

Risk factors of hepatitis C virus-related liver cirrhosis in young adults: positive family history of liver disease and transporter associated with antigen processing 2(TAP2)*0201 Allele.

The aim of this study was to clinically characterize young patients with hepatitis-C-related cirrhosis. We compared 27 patients with liver cirrhosis (Group LC) who were anti-HCV positive, aged 40 years or less at the time of diagnosis, with 323 consecutive patients with HCV-related chronic hepatitis (Group CH) matched for age and gender. Furthermore, Group LC was divided into two arbitrary groups (29-35 years, n = 8 /36-40 years, n = 19), based on the age of patients at the time of diagnosis of liver cirrhosis. Patients' characteristics and family history were investigated, and the frequency of transporter associated with antigen processing 2 (TAP2) was determined. A family history of liver disease was present in 40.7% of Group LC but in 18.0% of Group CH (P < 0.05). The younger the age of diagnosis of cirrhosis in Group LC, the higher the frequency of a positive family history (29-35 years, 87.5%; 36-40 years, 21.1%, P < 0.05). The frequency of TAP2*0201 was significantly higher in young adult patients with HCV-related liver cirrhosis than in HCV carriers with normal ALT (P < 0.05), and tended to be higher than in uninfected normal subjects (P = 0.05). The cumulative survival rate of cirrhosis patients with family history of liver diseases was significantly lower than that of cirrhosis patients without such history (P < 0.05). Our findings suggest that a positive family history of liver disease and TAP2*0201 polymorphism may be risk factors for HCV-related liver cirrhosis in young adults.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

A mechanism of interleukin-12 unresponsiveness associated with thermal injury.

An unresponsive state for the production of interleukin-12 (IL-12) is commonly observed in animals and patients with severe thermal injuries. In the present study, the participation of corticosteroids, prostaglandin E(2) (PGE(2)), and type 2 cytokines, which appeared in association with thermal injury, on the burn-associated IL-12 unresponsiveness was studied. These substances have been described as inhibitors of IL-12 production. Less than 20 pg/ml serum IL-12 was produced in thermally injured mice (TI-mice) after stimulation with lipopolysaccharide (LPS), while 1037 pg/ml IL-12 was detected in sera of unburned mice equally stimulated with LPS. Almost complete restoration of the impaired IL-12 production was witnessed in TI-mice after treatment with soluble IL-4 receptor (50 ng/mouse, 2 h and 2 days after thermal injury). However, IL-12 was not induced by LPS stimulation in TI-mice treated with an inhibitor of PGE(2) (indomethacin, 0.1-5 mg/kg) or an inhibitor of corticosteroid production (ketoconazole, 10 mg/kg). LPS-stimulated IL-12 production was also impaired in normal mice inoculated with burn-associated type 2 T cells. In addition, in the presence of 1 microg/ml LPS, naive macrophages cocultured with burn-associated type 2 T cells did not produce IL-12 in their culture fluids, while IL-12 was produced by LPS-stimulated naive macrophages that were cocultured with naive splenic CD8(+) T cells. These results suggest that the IL-12-unresponsive state demonstrated in TI-mice is associated mainly with type 2 cytokines released from burn-associated type 2 T cells.

Adrenal Cortex Hormones↗
PubMed2001

Incidence of the appearance of the red color sign on esophageal varices and its predictive factors: long-term observations of 359 patients with cirrhosis.

PURPOSE: The red color sign observed by endoscopic examination is a reliable predictive factor for variceal bleeding. The aim of this study was to calculate the incidence of the appearance of the red color sign and to evaluate its predictive factors. METHODS: Endoscopic examination was repeatedly performed in 359 consecutive patients diagnosed as having liver cirrhosis with or without esophageal varices, during a median follow-up period of 2651 days. RESULTS: The incidence of the appearance of the red color sign on esophageal varices at the end of the tenth year was compared among patients without varices (11.4%), those with small varices (45.4%), and those with mid-size varices (65.0%). The difference was significant (P < 0.0001). The number of varices (P = 0.0010), size of varices (P = 0.0064), platelet count (P = 0.0168), and alpha-fetoprotein level (P = 0.0207) were significantly correlated with the appearance of the red color sign, as estimated by the multivariate Cox hazard model. To exclude the influence of carcinogenesis, observation was stopped when hepatocellular carcinoma was discovered. Additive predictive factors with significance were: number of varices (P = 0.001), size of varices (P = 0.027), and platelet count (P = 0.0315). CONCLUSIONS: Endoscopic signs of esophageal varices and platelet count were significant predictors for the appearance of the red color sign.

Color↗
PubMed2001

Twice-daily administration of interferon-beta for chronic hepatitis C is not superior to a once-daily regimen.

PURPOSE: Although interferon (IFN) is commonly used for the treatment of chronic hepatitis C virus (HCV) infection, eradication of the virus occurs in only a small proportion of patients with genotype 1b and a high virus titer. Modified IFN therapies have been tried, with only limited benefit. Recently, the administration of IFN-beta twice per day has been reported to be more effective than the usual once-daily administration regimen. The aim of this study was to evaluate whether twice-daily IFN results in a sustained response in patients with chronic HCV infection with genotype 1b, and a high virus titer. METHODS: Twenty patients with genotype 1b and high HCV RNA level (more than 1 MEq/ml by branched DNA probe assay) were randomly assigned to receive either twice-daily 3 MU of IFN beta (group A) or once-daily 6 MU of IFN-beta (group B) for 4 weeks. All patients received a further daily dose of 6 MU IFN-beta for 12 weeks, followed by IFN-alfa three times a week for 16 weeks. RESULTS: Although a rapid fall in HCV RNA levels was noted in group A, a sustained response was observed in only one of nine patients in this group, and none of group B. Adverse effects of IFN were more frequent and pronounced in group A than in group B. CONCLUSIONS: We conclude that further modification, which combines the early strong anti-viral effects of the twice-daily regimen with long-term sustained response, is necessary for effective therapy of HCV patients with genotype 1b and high HCV RNA levels.

Adult↗
PubMed2001

Interferon therapy for flare-up of hepatitis B virus infection after emergence of lamivudine-induced YMDD motif mutant.

A 61-year-old man with chronic hepatitis B was treated with interferon (IFN)-alpha for flare-up after the emergence of a lamivudine-induced YMDD motif mutant. The YMDD mutant emerged 13 months after the initiation of lamivudine therapy. Despite this, lamivudine therapy was continued. Acute exacerbation occurred 25 months after the emergence of the YMDD mutant. Treatment with IFN-alpha resulted in rapid loss of hepatitis, B virus DNA, resolution of hepatitis, and clinical recovery.

Amino Acid Motifs↗
PubMed2001

Evaluation of quantitative measurements of hepatitis C virus RNA to predict sustained response to interferon by genotype.

Hepatitis C virus (HCV) virus load is one of the most important predictive factors for the outcome of interferon (IFN) therapy. Recent technological advances have allowed a more precise measurement of HCV load. However, the exact cutoff values that could be used to predict the outcome of IFN have not been established for each assay. Five recent quantitative assays were evaluated for the measurement of HCV (Amplicor monitor ver 1.0, Amplicor monitor ver 2.0 (GT), Amplicor monitor ver 2.0 (Cobas), Quantiplex branched DNA amplification (bDNA) ver 2.0 and HCV core protein level by enzyme immunosorbent assay) in 209 consecutive patients with chronic hepatitis C, who received IFN therapy. The results of the two second generation Amplicor monitor tests (GT and Cobas) showed the best correlation (r = 0.930), but the other tests also showed relatively good correlations (r = 0.646-0.925). Each method predicted the effect of IFN with comparable predictive efficacy, ranging from 77.0 to 80.8%. Receiver operating characteristic (ROC) curve analysis showed that Amplicor monitor ver 2.0 and bDNA ver 2.0 are superior in predicting the response in genotype 2a. The best cutoff value for predicting the response to IFN was different by genotype, which should be considered in selecting candidates for IFN treatment.

Adult↗