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Biomedical subjects

K Takeuchi

Publications and source records attributed to K Takeuchi.

At least 217 records · Page 12Linked to original sources
PubMed2000

Diamino benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors. Part 6: further focus on the contracted C4'-side chain analogues.

Novel benzo[b]thiophene diamine thrombin inhibitors were investigated, focusing on a contracted C4'-side chain series. SAR studies identified compounds with either a pyrrolidino or morpholino group as potent, active site directed thrombin inhibitors when the amino group was connected to the C3-phenyl ring with a methylene linker at the C4' position of the phenyl ring.

Antithrombins↗
PubMed2000

Retinoic acid is a negative regulator for the differentiation of cord blood-derived human mast cell progenitors.

We examined the effects of retinoids on the human mast cell development using a serum-deprived culture system. When 10-week cultured mast cells derived from CD34(+) cord blood cells were used as target cells, both all-trans retinoic acid (ATRA) and 9-cis RA inhibited the progeny generation under stimulation with stem cell factor (SCF) in a dose-dependent manner (the number of progeny grown by SCF plus RA at 10(-7) mol/L was one tenth of the value obtained by SCF alone). The early steps in mast cell development appear to be less sensitive to RA according to the single CD34(+)c-kit(+) cord blood cell culture study. The optimal concentration of RAs also reduced the histamine concentration in the cultured mast cells (3.00 +/- 0.47 pg per cell in SCF alone, 1.44 +/- 0.18 pg per cell in SCF+ATRA, and 1.41 +/- 0.10 pg per cell in SCF+9-cis RA). RT-PCR analyses showed the expression of RARalpha, RARbeta, RXRalpha, and RXRbeta messenger ribonucleic acid (mRNA) in 10-week cultured mast cells. The addition of an RAR-selective agonist at 10(-10) mol/L to 10(-7) mol/L decreased the number of mast cells grown in SCF, whereas an RXR-selective agonist at up to 10(-8) mol/L was inactive. Among RAR subtype selective retinoids used at 10(-9) mol/L to 10(-7) mol/L, only the RARalpha agonist was equivalent to ATRA at 10(-7) mol/L in its ability to inhibit mast cell growth. Conversely, the addition of excess concentrations of a RARalpha antagonist profoundly counteracted the retinoid-mediated suppressive effects. These results suggest that RA inhibits SCF-dependent differentiation of human mast cell progenitors through a specific receptor. (Blood. 2000;95:2821-2828)

Alitretinoin↗
PubMed2000

A hyperosmotic stress-induced mRNA of carp cell encodes Na(+)- and Cl(-)-dependent high affinity taurine transporter.

A cDNA clone encoding a Na(+)- and Cl(-)-dependent high affinity taurine transporter was isolated from a common carp cell line, Epithelioma papulosum cyprini (EPC), as a hyperosmotic stress-inducible gene by RNA arbitrarily primed PCR. The clone contained a 2.5-kb cDNA fragment including an open reading frame of 1878 bp encoding a protein of 625 amino acids. The deduced amino acid sequence of carp taurine transporter shows 78-80% identity to those of cloned mammalian taurine transporters. The functional characteristics of the cloned transporter were analyzed by expression in COS-7 cells. Transfection with the cDNA induced Na(+)- and Cl(-)-dependent taurine transport activity with an apparent K(m) of 56 microM. The Na(+)/Cl(-)hepatopancreas. Taurine transporter mRNA level increased up to 7.5-fold on raising the ambient osmolality from 300 to 450 mosmol/kgH(2)O. These data suggest the significant role of taurine as an osmolyte in carp cells.

Amino Acid Sequence↗
PubMed2000

Solvolysis of 2-Bicyclo

The solvolysis rate of 2-bicyclo[3.2.2]nonyl p-toluenesulfonate (6-OTs) was nearly equal to that of cycloheptyl p-toluenesulfonate in 2,2,2-trifluoroethanol (TFE). This indicates that the ethylene bridge in 6-OTs does not significantly enhance the rate and that 6-OTs ionizes without anchimeric assistance. The solvolysis of [1-(13)C]-2-bicyclo[3.2.2]nonyl p-toluenesulfonate in methanol or TFE gave 2-substituted bicyclo[3.2.2]nonane, exo-2-substituted bicyclo[3.3.1]nonane, 2-bicyclo[3.2.2]nonene (10), and 2-bicyclo[3.3.1]nonene (11), whose distributions of (13)C labels were determined by quantitative (13)C NMR analysis using a relaxation reagent. The (13)C labels were exclusively placed at only two positions, the ratios of them were not unity, and the labels in 10 were less extensively scrambled than those in other products. These results indicate that the 2-bicyclo[3.2.2]nonyl cation is classical and that 10 is formed at a former ionization stage than 2-substituted bicyclo[3.2.2]nonane. The (13)C redistributions for both exo-2-substituted bicyclo[3.3.1]nonane and 11, which are yielded via 1,3-hydride shift, were similar to that of 2-substituted bicyclo[3.2.2]nonane, suggesting that 1,3-hydride shift occurs mainly at the solvent-separated ion pair.

Journal Article↗
PubMed2000

Treatment of intractable autoimmune diseases in MRL/lpr mice using a new strategy for allogeneic bone marrow transplantation.

A new bone marrow transplantation (BMT) method for treating severe autoimmune diseases in chimeric resistant MRL/lpr mice is presented. The method consists of fractionated irradiation (5.5 Gy x 2), followed by portal venous (PV) injection of whole bone marrow cells (BMCs) from allogeneic normal C57BL/6 (B6) mice and intravenous (IV) injection of whole B6 BMCs 5 days after the PV injection (abbreviated as 5.5 Gy x 2 + PV + IV). All recipients survived more than 1 year after this treatment (more than 64 weeks after birth). Abnormal T cells (Thy1.2(+)/B220(+)/CD3(+)/CD4(-)/CD8(-)) present in MRL/lpr mice before the treatment disappear, and hematolymphoid cells are reconstituted with donor-derived cells. The treated mice are free from autoimmune diseases. Levels of autoantibodies (IgG/IgM anti-ssDNA antibodies and IgG/IgM rheumatoid factors) decrease to normal levels. Successful cooperation is achieved among T cells, B cells, and antigen-presenting cells (APCs) of the treated MRL/lpr mice when evaluated by in vitro anti-SRBC responses. Newly developed T cells are tolerant to both donor (B6)-type and host (MRL/lpr)-type major histocompatibility complex (MHC) determinants. These findings clearly indicate that severe autoimmune diseases in MRL/lpr mice are completely ameliorated by the treatment without recourse to immunosuppressants, and that the treated MRL/lpr mice show normal immune functions, strongly suggesting that this strategy would be applicable to humans. (Blood. 2000;95:1862-1868)

Animals↗
PubMed2000

Diamino benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors. 5. Potency, efficacy, and pharmacokinetic properties of modified C-3 side chain derivatives.

A systematic investigation of the structure-activity relationships of the C-3 side chain of the screening hit 1a led to the identification of the potent thrombin inhibitors 23c, 28c, and 31c. Their activities (1240, 903, and 1271 x 10(6) L/mol, respectively) represent 2200- and 2900-fold increases in potency over the starting lead 1a. This activity enhancement was accomplished with an increase of thrombin selectivity. The in vitro anticoagulant profiles of derivatives 28c and 31c were determined, and they compare favorably with the clinical agent H-R-1-[4aS, 8aS]perhydroisoquinolyl-prolyl-arginyl aldehyde (D-Piq-Pro-Arg-H; 32). The more potent members of this series have been studied in an arterial/venous shunt (AV shunt) model of thrombosis and were found to be efficacious in reducing clot formation. However, their efficacy is currently limited by their rapid and extensive distribution following administration.

Animals↗
PubMed2000

Expression of L1 and TAG-1 in the corticospinal, callosal, and hippocampal commissural neurons in the developing rat telencephalon as revealed by retrograde and in situ hybridization double labeling.

In the telencephalon, the corticospinal (CS), callosal, and hippocampal commissural neurons are the major types of neurons that have axons crossing the midline of the brain. To understand the mechanisms involved in crossing the midline structure and to examine whether the expression patterns of L1 and TAG-1 in the commissural neurons are similar to those in the spinal cord, we investigated L1 and TAG-1 expression in these neurons in rats by using a double-labeling technique involving retrograde labeling and in situ hybridization. Expression of L1 messenger RNA was detected in the retrogradely labeled CS projection neurons by 1,1;-dioctadecyl-3,3, 3;,3;-tetramethylindocarbocyanine perchlorate (DiI) injection into the pons at embryonic day (E) 19, but expression of TAG-1 messenger RNA was not detected in these neurons. Also, after their axons crossed the pyramidal decussation, continued expression of L1 but no expression of TAG-1 in the CS projection neurons was shown by an additional double-labeling experiment involving DiI injection into the spinal cord at postnatal day (P) 1. An immunohistochemical study showed that L1 was continuously present in each level of the CS tract at E21 and P3, but TAG-1 immunoreactivity was not found in any level at any stage. Finally, we examined the expression of L1 and TAG-1 messenger RNAs in the callosal and hippocampal commissure neurons after their axons had crossed the midline by using the double-labeling technique. In both cases, hybridization signals of the L1 and TAG-1 messenger RNAs were observed in the retrogradely labeled neurons at P3. These results suggest that the roles of L1 and TAG-1 in the formation of the commissures in the forebrain are different from their roles in the spinal cord.

Animals↗
PubMed2000

Local levels of soluble tumor necrosis factor receptors in patients with allergic rhinitis are regulated by amount of antigen.

OBJECTIVES: To examine the possible correlation between the amount of antigen and the level of soluble tumor necrosis factor receptor (sTNFR), and to assess its biologic significance in allergic reactions. DESIGN: Randomized control trial. SUBJECTS: Twelve volunteers with Japanese cedar pollinosis and 10 healthy volunteers. INTERVENTIONS: The levels of p55 sTNFR (sTNFR1) and p75 sTNFR (sTNFR2) in samples of serum and nasal epithelial lining fluid (ELF) from 12 subjects with pollinosis and 10 healthy subjects were measured 4 times (preseason, early season, midseason, and postseason) in low (total, 415/cm( 2) per season) and high (total, 19,935/cm(2) per season) pollen-count periods, and the results were compared among the 4 groups. RESULTS: In the low-pollen-count period, increased levels of sTNFR1 and sTNFR2 were observed in ELF samples from the allergic subjects during the midseason. In contrast, in the high-pollen-count period, those levels were already elevated during the preseason and reduced during the midseason. Especially, the levels of sTNFR2 in ELF samples from the allergic subjects during the midseason in the high-pollen-count period were significantly lower than those in the low-pollen-count period. Moreover, a significant negative correlation (sTNFR1, R = -0.82; sTNFR2, R = -0. 73) was found between the levels of sTNFR1 and sTNFR2 in ELF samples and the scores of symptoms in the allergic subjects in the high-pollen-count period, but not in the low-pollen-count period. CONCLUSION: In patients with pollinosis, the amounts of antigen regulate the local levels of sTNFRs, possibly inhibiting nasal allergic inflammation.

Adult↗
PubMed2000

Pancreatic arteriovenous malformation presenting as cysts: Doppler sonographic diagnosis.

A 50-year-old man presented with multiple lesions resembling cysts throughout the pancreas on gray-scale sonography. Pulsatile blood flow detected within the lesions on color Doppler sonography led to the diagnosis of pancreatic arteriovenous malformation (PAVM). Most previously reported PAVMs have been described as having a poorly defined, reticular, or mosaic-like hypoechoic appearance on gray-scale sonography; the cystic appearance of the PAVM seen in our case is unusual.

Arteriovenous Malformations↗
PubMed2000

Immunohistochemical detection of parathyroid hormone-related protein in a squamous cell carcinoma arising from mature cystic teratoma causing humoral hypercalcemia of malignancy.

BACKGROUND: Humoral hypercalcemia of malignancy is a cancer-related hypercalcemia caused by the production of humoral factors by malignant cells in patients without bone metastases. Squamous cell carcinomas are the tumors most frequently associated with humoral hypercalcemia of malignancy, and parathyroid hormone-related protein (PTH-rP) is the main humoral factor implicated. Squamous cell carcinoma arising from mature cystic teratoma is a rare diagnosis itself, much less the description of associated hypercalcemia, despite the fact that the normal keratinocytes produce parathyroid hormone-related protein. CASE: We present a well-documented case of squamous cell carcinoma arising from mature cystic teratoma of the ovary, complicated by hypercalcemia in a patient with high levels of plasma parathyroid hormone-related protein and immunohistochemical evidence of parathyroid hormone-related protein expression by the tumor cells. CONCLUSION: In this case, the carcinoma cells had already produced PTH-rP in the primary tumor although the serum calcium levels had not been significantly high at surgery. It is therefore suggested that hypercalcemia may have occurred after PTH-rP production had overcome the homeostatic level during the terminal stage.

Aged↗
PubMed2000

Angiotensin blockade inhibits SIF DNA binding activities via STAT3 after myocardial infarction.

The in vivo activation of transcription factors, which is important for cell regulation by gene expression, has not been well examined in myocardial infarcted heart. The purpose of this study was to determine whether myocardial signal transducer and activator of transcription (STAT) pathway is activated as sis-inducing factor (SIF) in infarcted heart, and to assess the angiotensin blockade on SIF activity in ischemic and non-ischemic myocardium of rat. Myocardial infarction was made by ligation of the coronary artery in Wistar rats. In electrophoretic mobility shift assay, myocardial SIF DNA binding activities gradually increased and reached to peak at 1 week in infarcted and non-infarcted regions after myocardial infarction. Imidapril and candesartan cilexitil significantly prevented the increase in SIF DNA binding activity in infarcted and non-infarcted regions. This increased SIF DNA complex was supershifted by specific anti-STAT3 antibody, indicating that increased SIF complex at least contained activated STAT3 proteins in myocardial infarcted heart. Furthermore, immunoprecipitation-Western blot analysis revealed that STAT3 of infarcted and non-infarcted regions were tyrosine-phosphorylated at 1 week after myocardial infarction. Imidapril and candesartan cilexitil prevented the increase in phosphorylated STAT3. Thus, the transcriptional activation of STAT3 through AT1 receptor may be partially involved in cardiac remodeling after myocardial infarction.

Angiotensin Receptor Antagonists↗
PubMed2000

Exogenous insulin-like growth factor (IGF)-1 improves the impaired healing of gastric mucosal lesions in diabetic rats.

BACKGROUND: We examined the influence of diabetes mellitus (DM) on the healing of HCl-induced gastric lesions and the healing promoting effect of IGF-1 on these lesions. METHODS: Experiments were performed on rats injected with streptozotocin (STZ, 70 mg kg(-1), i.p.) 5 weeks prior to the experimental session. Diabetic animals had blood glucose levels (BGLs) higher than 350 mg dl(-1). Randomly chosen rats were treated with insulin (4 IU day(-1) rat(-1)) starting 1 week after STZ. Animals were given 1 ml of 0.6 m HCl by gavage following 18 h of fasting. Normal feeding was started 1 h later. Animals were killed at various time points after HCl. Recombinant human IGF-1 (rhIGF-1) at doses 10-400 microg kg(-1) was injected subcutaneously twice daily for 4 days following HCl treatment. RESULTS: Gastric lesions induced by HCl healed macroscopically within 10 days. DM and insulin regimen did not affect the development of HCl-invoked gastric lesions. However, DM significantly delayed the healing of such lesions. Daily administration of insulin returned the high BGLs to significantly lower ranges (190-210 mg dl(-1)) and markedly antagonized the delayed healing. Likewise, the repeated administration of rhIGF-1 (>/=10 microg kg(-1)) significantly enhanced the healing of gastric lesions in diabetic rats, without any notable effect on BGLs or gastric acid secretion. The mucosal expression of IGF-1 mRNA was lower in diabetic rat stomachs as compared to normal rats, although the expression was apparently restored after insulin treatment. CONCLUSION: These results suggest that DM has a deleterious influence on the healing of acute gastric lesions in both insulin- and IGF-1-sensitive manner. The systemic administration of rhIGF enhanced the rate of healing of gastric lesions observed in the healing-impaired STZ-diabetic animals.

Animals↗
PubMed2000

Point mutations in mitochondrial DNA of patients with alcoholic cardiomyopathy.

The pathogenesis of alcoholic cardiomyopathy (ACM) is not well understood. However, recent reports have shown that mutations in mitochondrial DNA (mtDNA) were associated with mitochondrial encephalomyopathy and cardiomyopathy. Our objective was to explore point mutations in mtDNA and the pathogenesis of ACM. We obtained heart biopsy specimens from ten male habitual drinkers with congestive heart failure. We amplified the total mtDNA obtained from these specimens using a two-step polymerase chain reaction method and analyzed the products using automated fluorescence-based direct sequencing. The sequences were compared with those of controls. MtDNA from the ACM patients contained multiple point mutations. Specifically, four of the ten patients carried five point mutations that had been detected previously in several other mitochondrial diseases. These point mutations were not observed in controls. These results suggest that mtDNA abnormalities are involved in the pathogenesis of ACM.

Adult↗
PubMed2000

Prognostic value of Doppler transmittal flow patterns and cardiac natriuretic peptides in patients with chronic congestive heart failure admitted for episodes of acute decompensation.

This study was designed to determine whether the restrictive filling transmitral flow velocity pattern is associated with increased plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). It was also designed to evaluate the prognostic value of these parameters from patients with chronic congestive heart failure (CHF) admitted for episodes of acute decompensation. We performed Doppler echocardiography, measured plasma levels of ANP and BNP in 33 patients at the time of admission, and assessed the subsequent cardiac mortality for 3 months. Eleven patients (33%) had a restrictive filling pattern of deceleration time (DcT) < 120ms. Plasma ANP and BNP levels were markedly increased in all patients to 189 +/- 145 pg/ml and 865 +/- 559 pg/ml, respectively. Seventeen patients (52%) showed more than 700 pg/ml of plasma levels of BNP. There was a significant correlation of DcT with the plasma ANP level (r = -0.41, P = 0.017), and a better correlation of DcT with the plasma BNP level (r =-0.50, P = 0.003). The combined index of both shorter DcT (< 120 ms) and higher plasma BNP levels (>700 pg/ml) was the best predictor of cardiac mortality by Cox univariate analysis (chi2 = 5.87, P = 0.015). Furthermore, the sensitivity and specificity of this index for the detection of cardiac mortality were 80% and 86%, respectively. In conclusion, the combined analysis of the Doppler transmitral flow velocity pattern and measurement of the plasma BNP level is noteworthy since it is noninvasive and convenient. Moreover, it is extremely useful in predicting the prognosis for patients with chronic CHF admitted for episodes of acute decompensation.

Acute Disease↗
PubMed2000

Differences in time course of myocardial mRNA expression in non-infarcted myocardium after myocardial infarction.

In non-infarcted myocardium after myocardial infarction, the change of cardiac phenotypic modulation of contractile protein, extracellular matrix and intracellular Ca2+ transport protein, such as sarcoplasmic reticulum Ca2+(SR-Ca2+)-ATPase, Na+-Ca2+ exchanger, have a important role during cardiac remodeling. However, the time course in this gene expression in the adjacent and remote left ventricular, or right ventricular myocardium after myocardial infarction has not been well examined. The purpose of this study was to examine the left ventricular function and regional cardiac gene expression after myocardial infarction. Myocardial infarction was produced in Wistar rats by the ligation of the left anterior descending coronary artery. After 3 weeks, 2 months and 4 months from myocardial infarction, we performed Doppler echocardiography and measured the systolic and diastolic function. Then, we analyzed the contractile protein, extracellular matrix and intracellular Ca2+ transport protein mRNAs of cardiac tissues in the adjacent and the remote noninfarcted myocardium, and right ventricular myocardium by Northern blot hybridization. Fractional shortening of infarcted heart progressively decreased. Peak early diastolic filling wave (E wave) velocity increased, and the deceleration rate of the E wave velocity was more rapid in myocardial infarction areas. Atrial filling wave (A wave) velocity decreased, resulting in a marked increase in the ratio of E wave to A wave velocity. Expression of myocardial alpha-skeletal actin, beta-MHC and ANP mRNA, or collagen I and III mRNA were higher at 3 weeks after myocardial infarction. SR Ca2+-ATPase mRNA in the adjacent non-infarcted myocardium was decreased at 2 months, and that in remote myocardium was decreased at 4 months after infarction. Na+-Ca2+ exchanger mRNA levels were increased at 3 weeks, but was decreased at 2 months in the adjacent non-infarcted myocardium and at 4 months in the remote myocardium. These findings suggest that the compensation for myocardial infarction by myocardial gene expression in non-infarcted myocardium may occur at an early phase after myocardial infarction, and myocardial dysfunction may begin from adjacent to remote non-infarcted myocardium during progressive cardiac remodeling.

Animals↗
PubMed2000

Recent advances in bilirubin metabolism research: the molecular mechanism of hepatocyte bilirubin transport and its clinical relevance.

Bilirubin is taken up from blood into hepatocytes by sinosuidal membrane transporters and then excreted into bile through the bile canalicular membrane mainly as bilirubin glucuronides. (1) Mechanism of bilirubin uptake into hepatocytes: many organic anions are incorporated into hepatocytes by organic anion transporting polypeptides (rat, oatp1, oatp2, oatp3; human, OATP), liver-specific transporter (rlst/HLST), and/or by organic anion transporters (OAT2, OAT3). Oatp1 and HLST transport bilirubin monoglucuronide. However, a transporter of unconjugated bilirubin in the sinusoidal membrane has not as yet been identified. Unconjugated bilirubin may also go across the hepatocyte sinusoidal membrane by a diffusion process. (2) Intrahepatic transport and conjugation of bilirubin: ligandin carries bilirubin to the endoplasmic reticulum (ER) of hepatocytes. In the ER, bilirubin is conjugated by bilirubin uridine diphosphate (UDP)-glycosyltransferase (bilirubin UGT; UGT1A1) to form mono- and diglucuronides of bilirubin. (3) Transport mechanism of bilirubin glucuronides across the hepatocyte canalicular membrane: at the canalicular membrane, bilirubin glucuronides are excreted into bile by multidrug resistance-associated protein 2 (MRP2), a member of the ATP-binding cassette transporter family. (4) Regurgitation of bilirubin glucuronides into blood: MRP3, which is located in the lateral membrane, transports bilirubin glucuronides into blood under conditions of impaired biliary bilirubin excretion.

Anion Transport Proteins↗
PubMed2000

An uncommon case of simultaneous malignant tumors: bronchioloalveolar cancer and Ewing's sarcoma in a 17-year-old girl: report of a case.

This report describes a 17-year-old girl with a simultaneous occurrence of bronchioloalveolar cancer and Ewing's sarcoma of the femur, which is a previously unreported association. This case emphasizes the existence of multiple primary malignant neoplasms even in adolescents. Primary lung cancer should therefore be considered in patients under 19 years of age who present with abnormal pulmonary lesions.

Adolescent↗