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Biomedical subjects

T Tamaki

Publications and source records attributed to T Tamaki.

At least 19 recordsLinked to original sources
PubMed2001

Biallelic inactivation of retinoic acid receptor beta2 gene by epigenetic change in breast cancer.

A growing body of evidence supports the hypotheses that retinoic acid receptor beta2 (RAR beta2) is a tumor suppressor gene. Although the loss of RAR beta2 expression has been reported in many malignant tumors, including breast cancer, the molecular mechanism is still poorly understood. We hypothesized that loss of RAR beta2 activity could result from multiple factors, including epigenetic modification and loss of heterozygosity (LOH). Using methylation-specific polymerase chain reaction and LOH analysis, we found that biallelic inactivation via epigenetic changes of both maternal and paternal alleles, or epigenetic modification of one allele combined with genetic loss of the remaining allele, could completely suppress RAR beta2 expression in breast cancer. Thus, it is possible that substantial numbers of human cancers arise through suppressor gene silencing via epigenetic mechanisms that inactivate both alleles. Because of this, chromatin-remodeling drugs may provide a novel strategy for cancer prevention and treatment.

Alleles↗
PubMed2001

Hypolipidemic effect of NK-104 and other 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in guinea pigs.

Hypolipidemic effects of various HMG-CoA reductase inhibitors (statins) were examined in guinea pigs. After 2-week administration of NK-104 ((+)-monocalcium bis((3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3, 5-dihydroxy-6-heptenoate), CAS 147526-32-7), simvastatin (SV), pravastatin (PV), fluvastatin (FV), cerivastatin (CV) and atorvastatin (AV) to guinea pigs at various doses, which did not affect body weight, plasma and liver lipids were measured. Liver endoplasmic reticulum (ER) was isolated and measured for lipid content and activity of ER enzymes (NK-104: 3 mg/kg, SV: 30 mg/kg). Each statin except CV dose-dependently lowered total cholesterol (TC), with NK-104 showing the greatest effect. Only NK-104 and AV, long-acting statins, significantly lowered triglycerides (TG). A significant reduction of the liver cholesterol content was observed for NK-104 and AV. The liver TG content increased with dose for SV or PV, but not for NK-104 or AV. The TG content in ER and activity of diacylglycerol acyltransferase of ER, increased with SV and slightly with NK-104. Activity of microsomal triglyceride transfer protein, which is necessary for both apoB particle formation at rough ER and TG droplet production at smooth ER, increased by SV but not by NK-104. It is suggested that statins with prolonged action lower TG by decreasing cholesterol ester supply necessary for very low density lipoprotein formation and by attenuating an increase in TG production at ER after HMG-CoA reductase inhibition.

Acyltransferases↗
PubMed2000

Effect of endothelin-1(1-31) on p38 mitogen-activated protein kinase in cultured human mesangial cells.

It was reported that human chymase cleaves big endothelins (ETs) at the Tyr31-Gly32 bond and produces 31-amino acid ETs(1-31). In this study, we investigated the effect of ET-1(1-31) on p38 mitogen-activated protein kinase (p38-MAPK) activity in human mesangial cells (HMCs). By measuring the kinase activity, we demonstrated that ET-1 (1-31) activated the p38-MAPK dose-dependently (10(-9) M to 10(-7) M), which was inhibited by SB203580. The p38-MAPK activation induced by ET-1(1-31) peaked at 10 minutes. BQ123 almost abolished ET-1(1-31)-induced p38-MAPK activation, whereas BQ788 failed to inhibit it. These findings suggest that the stimulatory effect of ET-1(1-31) on p38-MAPK activation is mediated through ET(A) or ET(A)-like receptor. In conclusion, ET-1(1-31) induced increase in p38-MAPK activation in cultured HMCs.

Blotting, Western↗
PubMed2000

An immunosuppressive and anti-inflammatory HLA class I-derived peptide binds vascular cell adhesion molecule-1.

BACKGROUND: A synthetic peptide corresponding to residues 75-84 of HLA-B2702 modulates immune responses in rodents and humans both in vitro and in vivo. METHODS: We used a yeast two-hybrid screening, an in vitro biochemical method, and an in vivo animal model. RESULTS: Two cellular receptors for this novel immunomodulatory peptide were identified using a yeast two-hybrid screen: immunoglobulin binding protein (BiP), a member of the heat shock protein 70 family, and vascular cell adhesion molecule (VCAM)-1. Identification of BiP as a ligand for this peptide confirms earlier biochemical findings, while the interaction with VCAM-1 suggests an alternative mechanism of action. Binding to the B2702 peptide but not to closely related variants was confirmed by ligand Western blot analysis and correlated with immunomodulatory activity of each peptide. In mice, an ovalbumin-induced allergic pulmonary response was blocked by in vivo administration of either the B2702 peptide or anti-VLA-4 antibody. CONCLUSIONS: We propose that the immunomodulatory effect of the B2702 peptide is caused, in part, by binding to VCAM-1, which then prevents the normal interaction of VCAM-1 with VLA-4.

Amino Acid Sequence↗
PubMed2000

Prior induction of heat shock proteins by a nitric oxide donor attenuates cardiac ischemia/reperfusion injury in the rat.

BACKGROUND: Recent studies have demonstrated that nitric oxide (NO) releasers considerably increase heat shock proteins (HSPs) in the in vitro cell system, providing resistance to oxidant damage. This study was designed to examine the cellular responses of HSPs induced by prior administration of an NO releaser, FK409 (FK), in an in vivo transplantation model. METHODS: Lewis rats received either saline or FK solution intravenously administered at different time points before graft harvesting (10 micromol/kg) or for 15 min during reperfusion (0.66 micromol/kg/min). Tissue specimens were taken to determine HSP70 and heme oxygenase-1/HSP32 (HO-1) expression, and glutathione content. After 24-hr preservation with University of Wisconsin solution, heterotopic cardiac transplantations were performed, and graft survival was determined at 14 days. Tissue samples for end labeling of nuclear DNA fragments (TdT-mediated d-uridine triphosphate biotin nick end labeling; TUNEL) and propidium iodide staining were taken 15 min after reperfusion. RESULTS: The gene and protein expression of HSP70 after FK administration peaked at 12 min and 60-90 min, whereas those of HO-1 peaked at 6 min and 90 min, respectively. Then, representative cardiac grafts taken 60 min after FK treatment were examined for further assay. Localization of induced HSP70 and HO-1 molecules were observed in the myocardium and vascular endothelium, respectively. Prior treatment of FK was effective in preventing the reduction of tissue glutathione contents compared with control (P<0.05). Fewer TUNEL and propidium iodide-positive cells were also observed in the FK group (P<0.0005, vs. control). The graft survival rate was higher in the FK group (9/10 vs. 1/10 of control; P<0.001), whereas the groups either harvested 10 min after FK pretreatment or continuously infused for 15 min during reperfusion were inferior, similar to that of control. CONCLUSION: Prior induction of HSP70 and HO-1 with a relatively low dose of FK administration attenuates ischemia and reperfusion injury, which was due to antioxidant and antiapoptotic activities augmented by such stress proteins. Thus, NO releasers as a pharmacological maneuver may provide an innovative approach for the prevention of ischemia and reperfusion injury.

Animals↗
PubMed2000

Mechanical compression of the lumbar nerve root alters pain-related behaviors induced by the nucleus pulposus in the rat.

The purpose of this study was to refine a method of nerve-root injury in the rat to produce hyperalgesia, a pain-related behavior, and to determine if there were any relationships between the histological extent of nerve-root injury and the magnitude of hyperalgesia. Three methods were used to produce hyperalgesia: irritation of a nerve root by ectopic nucleus pulposus, silk loop alone, or both silk loop and ectopic nucleus pulposus. Autologous nucleus pulposus obtained from coccygeal intervertebral discs was relocated on the lumbar nerve roots after laminectomy. Two loops of 4-0 silk were placed around the exposed nerve roots. Hyperalgesia was measured preoperatively and postoperatively. The distribution of myelinated axons in the dorsal nerve roots was evaluated histologically. Mechanical hyperalgesia was detected in rats in which autologous nucleus pulposus was applied to the nerve root but not in those in which silk loops were used. Silk loops around the nerve root resulted in thermal hyperalgesia only in rats in which autologous nucleus pulposus was applied to the nerve root. Fewer large myelinated fibers were seen in the rats in which silk loops were used. Although a silk loop around the nerve root was not sufficient to produce hyperalgesia, supplemental application of autologous nucleus pulposus to the nerve root produced thermal hyperalgesia. It is possible that mechanical constriction of the nerve root alters the pain-related behavior elicited by chemical factors from the nucleus pulposus.

Animals↗
PubMed2000

Thymidine phosphorylase expression correlates with tumor differentiation and Bcl-2 in invasive breast cancer.

BACKGROUND: Angiogenesis plays an important role in the growth and metastasis of solid tumors. Several angiogenic factors have been identified, and thymidine phosphorylase (TP) is thought to be one such factor. To date, little information is available on the relationship between TP and other clinicopathological variables. METHODS: Formalin-fixed, paraffin-embedded materials from 116 primary breast carcinomas were used. The expression of TP, estrogen receptor, Bcl-2, Bax, p53, c-erbB-2 and MIB-1 was examined by immunohistochemical methods. RESULTS: Nuclear and/or cytoplasmic TP expression was observed in the neoplastic cells, and accentuation of TP was often present at the infiltrating tumor edge and intraductal spread region. Tumor cell TP expression was significantly inversely correlated with histological grade (p< 0.05) and positively correlated with Bcl-2 expression, but no association with other tumor variables was found. CONCLUSIONS: TP is associated with Bcl-2 expression and tumor differentiation in breast cancer. TP may be a new prognostic parameter for breast cancer.

Breast Neoplasms↗
PubMed2000

Biomechanical functions of the iliolumbar ligament in L5 spondylolysis.

Abiomechanical study of the functions of the iliolumbar ligament in L5 spondylolysis was performed. Five fresh cadaveric specimens were used. The bilateral ilia and sacrum were fixed. Four kinds of pure moments (10 Nm) were applied to the specimens at the top (L4) vertebra: flexion, extension, and right and left axial rotations. The three-dimensional position of the L5 vertebra was measured after serial transections in: (1) the intact condition; (2) bilateral pars interarticulares of L5 transected; (3) anterior bands of the iliolumbar ligaments transected; and (4) posterior bands of the iliolumbar ligaments transected. In L5 spondylolysis, flexion and axial rotation of L5 on S1 are significantly regulated by the anterior and posterior bands of the iliolumbar ligaments (especially by the posterior bands of the ligaments). The integrity of the ligament may determine the stability of the lumbosacral junction and the amount of forward slipping of the L5 vertebra.

Aged↗
PubMed2000

Novel polymorphisms of prostate-specific antigen (PSA) gene associated with PSA mRNA expression in breast cancer.

A growing body of evidence suggests that prostate-specific antigen (PSA) is a novel prognostic factor for breast cancer. The molecular mechanism of variant PSA expression in breast cancer has remained poorly understood in spite of intensive research. Previous studies have shown that the coding region of the PSA gene is not a target for mutations in prostate cancer and breast cancer. The purpose of this study was to analyze genetic variations in the promoter region of the PSA gene, and to detect whether such variations are correlated with PSA mRNA expression in breast tumors. We identified two polymorphisms in the proximal promoter region of the PSA gene. These polymorphisms are located at positions -252 (G or A) and -205 (A or AA), and generate three genotypes. The genotypes were associated with PSA mRNA expression. Our findings suggest that these polymorphisms identified in the proximal promoter region may affect the transcriptional activity of PSA.

Breast Neoplasms↗
PubMed2000

Serum levels of tissue inhibitor of metalloproteinases 2 in patients with systemic sclerosis.

BACKGROUND: The serum tissue inhibitor of metalloproteinases 1 (TIMP-1) level was reported to be a useful indicator of disease activity, especially of lung fibrosis in patients with systemic sclerosis. TIMP-2 is also an important inhibitor of matrix metalloproteinases (MMPs), such as interstitial collagenase, gelatinase, and stromelysin, which control the metabolism of the extracellular matrix. However, serum levels of TIMP-2 in patients with systemic sclerosis (SSc) have not been investigated. OBJECTIVE: We sought to determine the clinical significance of serum levels of TIMP-2 and MMP-2 in patients with SSc. METHODS: Serum samples were obtained from 128 patients with SSc (68 with limited cutaneous SSc and 60 with diffuse cutaneous SSc). Twenty-seven serum samples from healthy age- and sex-matched individuals were also examined as controls. The TIMP-2 and MMP-2 levels were determined by means of sandwich enzyme-linked immunosorbent assays. RESULTS: The serum TIMP-2 levels were elevated in 29 (22.7%) of the 128 patients with SSc and were significantly higher than those of the healthy control subjects. The serum TIMP-2 levels were significantly correlated with the extent of skin sclerosis in the patients with SSc. The incidence of decreased percentage of the diffusing capacity of lung for carbon monoxide (DLCO ) and that of an elevated erythrocyte sedimentation rate were significantly greater in the patients with elevated TIMP-2 levels compared with the patients with normal TIMP-2 levels (P <.05). When these patients were classified into 2 groups by disease activity, TIMP-2 levels were significantly more elevated in the high active group than in those low active group (P <.001). The serum MMP-2 levels of the patients with SSc were not significantly higher than those of the healthy control subjects. CONCLUSION: These findings suggest that the serum TIMP-2 level is a useful marker of the extent of skin sclerosis and disease activity in patients with SSc. The balance of TIMP-2 and MMP-2 may play an important role in patients with SSc. Furthermore, TIMP-2 may be thought to contribute to the development of disease in patients with SSc.

Adolescent↗
PubMed2000

Alteration in synaptic inputs through C-afferent fibers to substantia gelatinosa neurons of the rat spinal dorsal horn during postnatal development.

The change in synaptic inputs through primary afferent C- and A-fibers during postnatal development was examined in substantia gelatinosa neurons of a rat spinal cord slice with an attached L5 dorsal root by use of the blind whole-cell patch-clamp technique; the synaptic responses were compared between the slices obtained from immature (postnatal days 21-23) and mature (postnatal days 56-60) male rats. The mono- and/or polysynaptic afferent inputs were monitored by recording glutamatergic excitatory postsynaptic currents and potentials evoked by stimulating C- and A-fibers, the identification of which was based on the values of threshold stimulus intensity and of the conduction velocity of the fibers, determined by intracellular recordings from dorsal root ganglion neurons. Immature substantia gelatinosa neurons received synaptic inputs through Abeta-, Adelta- and C-afferents, with proportions of 51%, 46% and 36%, respectively. In mature substantia gelatinosa neurons, C- and Adelta-afferent inputs were increased in number (to 84% and 86%, respectively), while Abeta-inputs were decreased to 9%. In both immature and mature rats, repetitive stimulation of C-afferents did not elicit any slow responses, which are longer in duration than the monosynaptic excitatory postsynaptic currents, although C-fibers are known to contain not only excitatory amino acids, but also neuropeptides such as substance P, which is thought to be involved in the production of slow responses. These results indicate that both C- and Adelta-afferents innervating substantia gelatinosa neurons are reorganized following maturation, accompanied by a withdrawal or elimination of Abeta-fibers from the substantia gelatinosa, probably due to a competition among the fibers during development. In spite of the developmental increase in C-fiber inputs, mature as well as immature substantia gelatinosa neurons did not display any slow synaptic responses, which appear to be mediated by transmitters other than excitatory amino acids.

Action Potentials↗
PubMed2000

Intracranial malignant meningioma with abdominal metastases associated with hypoglycemic shock: a case report.

A thirty-year-old male with an intracranial malignant meningioma, first diagnosed 9 years ago, with three recurrences was admitted with a hypoglycemic shock. The blood glucose level was 17 mg/dl, requiring treatment with high doses of intravenous and oral dextrose for improvement. A large metastatic tumor in the liver was noted. All hormones and peptides influencing blood glucose levels were in their normal levels. Chemo-embolization and injection of anti-cancer drugs was employed in the management of the metastatic tumor. Positron emission tomography was performed to measure the glucose metabolism of the abdominal tumor and it indicated that glucose consumption within the tumor was much elevated than the surrounding abdominal organs. Hypoglycemia secondary to primary hepatoma or islet-cell cancer has been frequently described, but a complication of metastatic meningioma is an exceedingly rare event. Elevated glucose consumption within the tumor might be addressed as one of the reasons for hypoglycemia, not due to the elevated serum levels of insulin or IGF, but due to the closely related blood glucose level.

Abdominal Neoplasms↗
PubMed2000

Expression of Bcl-2 but not Bax or p53 correlates with in vitro resistance to a series of anticancer drugs in breast carcinoma.

Programmed cell death is an important determinant of the response to chemotherapy. Among the factors controlling this process, a significant role is played by bcl-2, bax and p53. The in vitro chemosensitivity of the 177 breast carcinomas was assessed by the histoculture drug response assay (HDRA) using mitomycin C (MMC), 5-fluorouracil (5-Fu), adriamycin (ADM), cisplatin (CDDP), and cyclophosphamide (CPA). The susceptibility of Bcl-2-negative tumors to all the drugs killing was significantly higher than that of Bcl-2-positive tumors. No relationship between Bax or p53 immunoreactivity and sensitivity for any of anticancer drugs studied was demonstrated. Immunohistochemical results regarding Bcl-2 are promising in the evaluation of the sensitivity of cancer cells to a series of anticancer drugs and might be therapeutically useful as an indicator of response to adjuvant chemotherapy for breast cancer.

Antineoplastic Agents↗
PubMed2000

Lipid-lowering and antiatherosclerotic effect of NK-104, a potent 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, in Watanabe heritable hyperlipidemic rabbits.

NK-104 ((+)-monocalcium bis(3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy- 6-heptenoate), CAS 147526-32-7) an inhibitor of 3-hydroxy-3-metylglutaryl coenzyme A reductase, was administered in drinking water (0.5 mg/kg equivalent) to Watanabe heritable hyperlipidemic (WHHL) rabbits for 26 weeks. It lowered plasma total cholesterol (TC, 7-20%) and triglyceride (TG, 16-39%) levels throughout the experimental period due to a significant reduction of very low density lipoprotein cholesterol (VLDL-C, 61-62%, p < 0.05), intermediate density lipoprotein cholesterol (IDL-C, 49-60%, p < 0.05), VLDL-TG (40-53%, p = 0.06-0.08) and IDL-TG (29-59%, p = 0.06-0.14); low density lipoprotein cholesterol (LDL-C) was not affected. The pattern of the lipoprotein reduction along with a decrease in liver cholesteryl ester (CE, 33.1%, p < 0.01) suggests an intense reduction of VLDL secretion and a marginal induction of LDL-receptor. Enhanced expression of LDL receptor-related protein (LRP) in the liver was observed at mRNA levels (49.5% increase, P = 0.13), which might play a role in the lipoprotein reduction. Histological analyses of aorta revealed that aortic arch showed the most advanced lesions with larger lesion area (70.0 vs 41.3%) and much greater CE content (more than 2 fold) with less macrophages than thoracic aorta. NK-104 decreased the surface lesion area at the arch (23.1%, p = 0.054) and reduced the degeneration of media in the thoracic aorta (69.9% increase in medial smooth muscle cells, p < 0.01). Thus NK-104 preferentially reduced TG-rich lipoproteins (VLDL and IDL) without affecting LDL-C levels and prevented progression of atherosclerosis in WHHL rabbits.

Animals↗