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Biomedical subjects

Susumu Itoh

Publications and source records attributed to Susumu Itoh.

At least 19 recordsLinked to original sources
PubMed2006

Methylation of Smad6 by protein arginine N-methyltransferase 1.

Signal transduction pathways utilize posttranslational modifications to regulate the activity of their components in a temporal-spatial and efficient fashion. Arginine methylation is one of the posttranslational modifications that can result in monomethylated-, asymmetric dimethylated- and/or symmetric dimethylated-arginine residues in proteins. Here we demonstrate that inhibitory-Smads (Smad6 and Smad7), but not receptor-regulated- (R-)Smads and the common-partner Smad4, can be methylated by protein arginine N-methyltransferase (PRMT)1. Using mass-spectrometric analysis, we found that PRMT1 dimethylates arginine(74) (Arg(74)) in mouse Smad6. PRMT1 interacts with the N-terminal domain of Smad6 in which Arg(74) residue is located. Assays examined so far have shown no significant differences between the functions of Smad6 and those of methylation-defective Smad6 (Smad6R74A). Both wild-type and Smad6R74A were equally efficient in blocking BMP-induced growth arrest upon their ectopic expression in HS-72 mouse B-cell hybridoma cells.

Alanine↗
PubMed2006

Smad7 and protein phosphatase 1alpha are critical determinants in the duration of TGF-beta/ALK1 signaling in endothelial cells.

BACKGROUND: In endothelial cells (EC), transforming growth factor-beta (TGF-beta) can bind to and transduce signals through ALK1 and ALK5. The TGF-beta/ALK5 and TGF-beta/ALK1 pathways have opposite effects on EC behaviour. Besides differential receptor binding, the duration of TGF-beta signaling is an important specificity determinant for signaling responses. TGF-beta/ALK1-induced Smad1/5 phosphorylation in ECs occurs transiently. RESULTS: The temporal activation of TGF-beta-induced Smad1/5 phosphorylation in ECs was found to be affected by de novo protein synthesis, and ALK1 and Smad5 expression levels determined signal strength of TGF-beta/ALK1 signaling pathway. Smad7 and protein phosphatase 1alpha (PP1alpha) mRNA expression levels were found to be specifically upregulated by TGF-beta/ALK1. Ectopic expression of Smad7 or PP1alpha potently inhibited TGF-beta/ALK1-induced Smad1/5 phosphorylation in ECs. Conversely, siRNA-mediated knockdown of Smad7 or PP1alpha enhanced TGF-beta/ALK1-induced signaling responses. PP1alpha interacted with ALK1 and this association was further potentiated by Smad7. Dephosphorylation of the ALK1, immunoprecipitated from cell lysates, was attenuated by a specific PP1 inhibitor. CONCLUSION: Our results suggest that upon its induction by the TGF-beta/ALK1 pathway, Smad7 may recruit PP1alpha to ALK1, and thereby control TGF-beta/ALK1-induced Smad1/5 phosphorylation.

Activin Receptors↗
PubMed2005

Structure-based design of P3 moieties in the peptide mimetic factor VIIa inhibitor.

Selective factor VIIa-tissue factor complex (FVIIa/TF) inhibition is seen as a promising target for developing new anticoagulant drugs. Structure-based designs of the P3 moiety in the peptide mimetic factor VIIa inhibitor successfully lead to novel inhibitors with selectivity for FVIIa/TF and extrinsic coagulation the same as or even higher than those of previously reported peptide mimetic factor VIIa inhibitors. X-ray crystal structure analysis reveals that one of the novel inhibitors shows improved selectivity by forming interactions between the inhibitor and FVIIa as expected. Another of the novel inhibitors achieves improved selectivity through an unexpected hydrogen bond with Gln217, with a unique bent conformation in FVIIa/TF accompanied by conformational changes of the inhibitor and the protein.

Amino Acid Sequence↗
PubMed2005

Novel interactions of large P3 moiety and small P4 moiety in the binding of the peptide mimetic factor VIIa inhibitor.

Selective factor VIIa-tissue factor complex (FVIIa/TF) inhibition is seen as a promising target for developing new anticoagulant drugs. A novel peptide mimetic factor VIIa inhibitor, ethylsulfonamide-d-biphenylalanine-Gln-p-aminobenzamidine, shows 100-fold selectivity against thrombin in spite of its large P3 moiety, unlike previously reported FVIIa/TF selective inhibitors. X-ray crystal structure analysis reveals that the large P3 moiety, d-biphenylalanine, and the small P4 moiety, ethylsulfonamide, make novel interactions with the 170-loop and Lys192 of FVIIa/TF, respectively, accompanying ligand-induced conformational changes of the 170-loop, Gln217, and Lys192. Structural comparisons of FVIIa with thrombin and amino acid sequence comparisons among coagulation serine proteases suggest that these interactions play an important role in achieving selective inhibition for FVIIa/TF.

Amino Acid Sequence↗
PubMed2005

Structure of human factor VIIa/tissue factor in complex with a peptide-mimetic inhibitor: high selectivity against thrombin by introducing two charged groups in P2 and P4.

The crystal structure of human factor VIIa/soluble tissue factor (FVIIa/sTF) in complex with a highly selective peptide-mimetic FVIIa inhibitor which shows 1670-fold selectivity against thrombin inhibition has been solved at 2.6 A resolution. The inhibitor is bound to FVIIa/sTF at the S1, S2 and S3 sites and at the additional S1 subsite. Two charged groups, the amidino group in P2 and the carboxylate group in P4, form ionic interactions with Asp60 and Lys192 of FVIIa, respectively. Structural comparisons between factor VIIa and thrombin show that thrombin has oppositely charged residues, Lys60F and Glu192, in the S2 site and the S1 subsites, respectively. These data suggest that the utilization of the differences of charge distribution in the S2 site and the S1 subsites between FVIIa and thrombin is critical for achieving high selectivity against thrombin inhibition. These results will provide valuable information for the structure-based drug design of specific inhibitors for FVIIa/TF.

Anticoagulants↗
PubMed2005

Developmental changes in serum half-life of (EZ)-cyclobilirubin.

BACKGROUND: Phototherapy has been a standard treatment for neonatal hyperbilirubinemia for more than 40 years, but it has remained sub-optimal. AIMS: To clarify the developmental changes in parameters of (4E, 15Z)-cyclobilirubin ((EZ)-C) elimination in order to obtain basic data for establishing optimal phototherapy. STUDY DESIGN: Blood samples were taken at regular intervals after stopping phototherapy, and bilirubin fractions were analyzed by high-performance liquid chromatography. SUBJECTS AND METHODS: The subjects were 46 infants with hyperbilirubinemia who underwent phototherapy. The gestational age and birth weight of the subjects ranged from 25.0 to 41.0 weeks and from 656 to 3810 g, respectively, and the age at cessation of phototherapy was a median of 5 days. A kinetic model of (EZ)-C elimination was established, and the serum half-life of (EZ)-C was calculated on the basis of the determined model. Relationships of the half-life of (EZ)-C with birth weight and gestational age were investigated. RESULTS: Serum (EZ)-C elimination followed a first-order kinetic model in 43 infants and a zero-order kinetic model in three extremely low birth weight infants. The half-life of (EZ)-C calculated on the basis of a first-order elimination model in serum ranged from 68 to 274 min and showed weak negative correlations with birth weight and gestational age. CONCLUSIONS: Serum (EZ)-C excretion followed a first-order kinetic model in most of the neonates. The half-life of (EZ)-C becomes more prolonged in the very low birth weight infant and early gestational age.

Bilirubin↗
PubMed2005

Preoperative administration of FTY720 prolonged renal allograft survival.

BACKGROUND: FTY729 is an immunomodulator obtained by chemical modification of Myriocin(ISI-1) which exists in the culture filtrate of an ascomycete, Isaria sinclairii. It has been reported that postoperative administration of FTY720 prolonged survival of various kinds of transplanted organs. In the present study, we evaluated the effect of 2-day preoperative administration of FTY 720 on graft survival. MATERIALS AND METHODS: We used a rat renal transplantation model in which Wistar King Aptekman Hokkaido (WKAH, RT1K) served as the organ donor and Lewis (LEW, RTl) as the recipient. FTY720 was given to the recipients consecutively 2 days (day-2, day-1) before transplantation at the doses of 1, 3 or 5 mg/kg/day. Renal allograft survivals, hematological parameters of recipient blood and phenotypic analysis of recipient splenic cells and graft infiltrate were evaluated. RESULTS: Consecutive 2-day preoperative oral administration of FTY 720 at the doses of 1, 3 or 5 mg/kg/day significantly prolonged WKAH allograft survivals compared with those of the untreated recipients. The number of peripheral blood lymphocytes was markedly decreased in the recipients treated with FTY720 at the doses of 3 mg/kg/day or 5 mg/kg/day on the 5th postoperative day. Preoperative FTY 720 administration significantly decreased the number of CD4 positive cells and the percentage of interleukin 2 receptor (IL-2 R) positive cells infiltrating both spleen and allograft at the dose of 3 mg/kg/day or 5 mg/kg/day. CONCLUSION: FTY 720 could act as a safe and potent immunomodulator by decreasing the number of peripheral lymphocytes, especially CD4 positive cells and IL-2R positive cells when it is given to the recipient preoperatively.

Animals↗
PubMed2005

Cortisol levels in umbilical vein and umbilical artery with or without antenatal corticosteroids.

BACKGROUND: The developmental changes of the umbilical cortisol levels in neonates at gestational age of 23-41 weeks were studied and the effect of antenatal steroid administration on the umbilical cortisol levels were examined. METHODS: Cortisol levels in the umbilical vein (UV) and the umbilical artery (UA) were studied in 35 neonates at the gestational age (GA) of 23-41 weeks with or without antenatal administration of corticosteroids. Serum cortisol concentrations were measured by the high performance liquid chromatography method. RESULTS: The correlation between cortisol levels in UV and birthweight (BW) was weak and negative in premature infants. UV cortisol levels in the neonates with antenatal corticosteroid were lower than those in the neonates without antenatal corticosteroid, but the relation was not significant. The developmental changes of UV cortisol levels were the same as those in Murphy's study (spontaneous-onset labor). The cortisol levels in UV and UA had a significantly positive correlation and both had almost equal concentrations. There were no correlations between cortisol levels in UV and placental weight, Apgar Score at 1 and 5 min. CONCLUSIONS: In the neonates whose birthweight was less than 2000 g without antenatal corticosteroid, there was a negative correlation between cortisol levels in UV and BW but there was no correlation between cortisol levels in UV and GA. That the neonates with antenatal corticosteroid would have a suppressed adrenocortical function after birth could not be proved.

Adrenal Cortex Hormones↗
PubMed2005

Estimation of circulating blood volume in infants using the pulse dye densitometry method.

BACKGROUND: Estimation of hemodynamics is important for critically ill infants. Pulse dye densitometry (PDD) using indocyanine green (ICG), which enables measurements of circulating blood volume at the bedside, has recently been developed for adults. METHODS: We conducted a basic investigation to determine whether this method can be applied to infants and measured circulating blood volume in 25 infants whose gestational ages ranged from 24 to 40 weeks (median, 32 weeks). At first, to validate the accuracy of measurements, arterial ICG concentrations determined by blood sample measurements were compared using a spectrophotometer ([ICG blood]) and by noninvasive measurement using PDD ([ICG pdd]) in seven infants. Next, blood volumes in 25 infants were estimated by the PDD method. RESULTS: There was a positive relationships between [ICG blood] and [ICG pdd] (r = 0.913, P < 0.0001). Using Bland Altman analysis, the bias between the two methods was 0.24 +/- 0.30 mg.l(-1) (95% confidence interval: 0.39-0.09 mg.l(-1)) and the limits of agreement (2 sd) were -0.36 and 0.84 mg.l(-1), respectively. Mean (sd) blood volume was 94.9 ml.kg(-1) (24.3). The values obtained by this study are almost the same as previously reported values obtained by using other methods. CONCLUSIONS: PDD using ICG can be used to monitor of hemodynamics in infants.

Blood Pressure↗
PubMed2005

Vastus lateralis oxygenation and blood volume measured by near-infrared spectroscopy during whole body vibration.

The purpose of this study was to investigate the effects of whole body vibration (WBV) on oxygenation of vastus lateralis muscle during squatting exercise. Eighteen male subjects [mean age, 27.3 +/- 6.0 (SD) years; mean height, 171.8 +/- 4.9 cm; mean weight, 64.4 +/- 6.1 kg] performed squatting exercise on a vibration platform for 3 min with and without vibration, and changes in oxygenation of the vastus lateralis muscle were determined by near-infrared spectroscopy. The muscle oxygenation levels and total haemoglobin and myoglobin levels (total Hb/Mb) decreased during squatting exercise with and without vibration. After exercise, the muscle oxygenation level and total Hb/Mb rapidly increased from the minimum value during exercise and remained constant for latter 10 min. The muscle oxygenation levels with vibration from 90 to 180 s after the start of squatting exercise were significantly lower than those without vibration. Total Hb/Mb with vibration from 90 s after the squatting exercise to 540 s were significantly higher than those without vibration. This study demonstrated that WBV exercise affects the oxygenation level of vastus lateralis muscle and reduces muscle oxygenation level compared to that with no WBV. Therefore, WBV exercise may be an efficient training stimulus for muscle deoxygenation.

Adult↗
PubMed2005

Developmental changes of optical properties in neonates determined by near-infrared time-resolved spectroscopy.

Near-infrared spectroscopy has been used for measurement of changes in cerebral Hb concentrations in infants to study cerebral oxygenation and hemodynamics. In this study, measurements by time-resolved spectroscopy (TRS) were performed in 22 neonates to estimate the values of light absorption coefficient and reduced scattering coefficient (mu'(s)), cerebral Hb oxygen saturation (SCO2), cerebral blood volume (CBV), and differential pathlength factor (DPF), and the relationships between postconceptional age and mu'(s), SCO2, CBV, and DPF were investigated. A portable three-wavelength TRS system with a probe attached to the head of the neonate was used. The mean mu'(s) values at 761, 795, and 835 nm in neonates were estimated to be (mean +/- SD) 6.46 +/- 1.21, 5.90 +/- 1.15 and 6.40 +/- 1.16/cm, respectively. There was a significant positive relationship between postconceptional age and mu'(s) at those three wavelengths. The mean SCO2 value was calculated to be 70.0 +/- 4.6%, and postconceptional age and SCO2 showed a negative linear relationship. The mean value of CBV was 2.31 +/- 0.56 mL/100 g. There was a significant positive relationship between postconceptional age and CBV. The mean DPF values at 761, 795, and 835 nm were estimated to be 4.58 +/- 0.41, 4.64 +/- 0.46, and 4.31 +/- 0.42, respectively. There was no relationship between postconceptional age and DPF at those three wavelengths. The results demonstrated that our near-infrared TRS method can be used to monitor mu'(s), SCO2, CBV, and DPF in the neonatal brain at the bedside in an intensive care unit.

Blood Volume↗
PubMed2004

Crystal structure of human factor VIIa/tissue factor in complex with peptide mimetic inhibitor.

The 3D structure of human factor VIIa/soluble tissue factor in complex with a peptide mimetic inhibitor, propylsulfonamide-D-Thr-Met-p-aminobenzamidine, is determined by X-ray crystallography. As compared with the interactions between thrombin and thrombin inhibitors, the interactions at S2 and S3 sites characteristic of factor VIIa and factor VIIa inhibitors are revealed. The S2 site has a small pocket, which is filled by the hydrophobic methionine side chain in P2. The small S3 site fits the small size residue, D-threonine in P3. The structural data and SAR data of the peptide mimetic inhibitor show that these interactions in the S2 and S3 sites play an important role for the improvement of selectivity versus thrombin. The results will provide valuable information for the structure-based drug design of specific inhibitors for FVIIa/TF.

Anticoagulants↗
PubMed2004

Synergy and antagonism between Notch and BMP receptor signaling pathways in endothelial cells.

Notch and bone morphogenetic protein signaling pathways are important for cellular differentiation, and both have been implicated in vascular development. In many cases the two pathways act similarly, but antagonistic effects have also been reported. The underlying mechanisms and whether this is caused by an interplay between Notch and BMP signaling is unknown. Here we report that expression of the Notch target gene, Herp2, is synergistically induced upon activation of Notch and BMP receptor signaling pathways in endothelial cells. The synergy is mediated via RBP-Jkappa/CBF-1 and GC-rich palindromic sites in the Herp2 promoter, as well as via interactions between the Notch intracellular domain and Smad that are stabilized by p/CAF. Activated Notch and its downstream effector Herp2 were found to inhibit endothelial cell (EC) migration. In contrast, BMP via upregulation of Id1 expression has been reported to promote EC migration. Interestingly, Herp2 was found to antagonize BMP receptor/Id1-induced migration by inhibiting Id1 expression. Our results support the notion that Herp2 functions as a critical switch downstream of Notch and BMP receptor signaling pathways in ECs.

Animals↗
PubMed2004

Noninvasive optical imaging in the visual cortex in young infants.

During the developmental stage, the brain undergoes anatomic, functional, and metabolic changes necessary to support the complex adaptive behavior of a mature individual. Estimation of developmental changes occurring in different regions of the brain would provide a means of relating various behavioral phenomena to maturation-specific brain structures, thereby providing useful information on structure-function relationships in both normal and disease states. We used multichannel near-infrared spectroscopy (MNIRS), a new noninvasive imaging technique for revealing the course of neural activity in selected brain regions, to monitor the activities of the visual cortex as mirrored by hemodynamic responses in infants subjected to photostimulation during natural sleep. In the infants, oxyhemoglobin and total hemoglobin decreased and deoxyhemoglobin increased in the visual cortex with photostimulation. This pattern of responses was different from the response pattern in adults reported previously. The different patterns of responses to photostimulation in the visual cortices of infants and adults might reflect developmental and behavioral differences. It may reflect a different functional organization of the visual cortex in infants or ongoing retinal development. Our results demonstrated that regional hemodynamic change could be detected in a small area around the visual cortex. MNIRS offers considerable potential for research and noninvasive clinical applications.

Adult↗
PubMed2004

IgM AL amyloidosis due to B cell lymphoproliferative disorder: efficacy of high-dose melphalan followed by autologous stem cell transplantation.

This report concerns a patient with IgM AL amyloidosis due to a B cell lymphoproliferative disorder who was successfully treated with VAD and subsequent high-dose melphalan followed by autologous stem cell support. After this chemotherapeutic regimen, the patient showed complete hematological remission and improvement in nephrotic syndrome. These findings suggest that high-dose melphalan may also be effective for lymphoplasmacytoid cells producing monoclonal IgM which are phenotypically distinct from plasma cells. Myeloablative therapies, such as high-dose melphalan, should definitely be considered as a treatment option for AL amyloidosis, irrespective of the type of precursor immunoglobulin.

Amyloidosis↗
PubMed2004

Change of bilirubin photoisomers in the urine and serum before and after phototherapy compared with light source.

BACKGROUND: The clinical effect of phototherapy for neonatal hyperbilirubinemia is based on the production and elimination of cyclobilirubin. Generally, the clinical effect of light sources is estimated by the reduction in the total serum bilirubin level. One procedure with less invasiveness than blood collecting is urine collection. Whether the effectiveness of light sources used for phototherapy could be assessed using measurements of bilirubin photoisomers in urine was studied. METHODS: This study was a retrospective analysis of 38 term infants with hyperbilirubinemia who underwent phototherapy. Bilirubin fractions in serum and urine before and 24 h after the phototherapy were measured by high-performance liquid chromatography. The light sources used for the phototherapy were blue-white light (n = 11), Biliblanket plus high output (n = 13) or green light (n = 14). The relationships between serum and urine bilirubin photoisomers after phototherapy and whether the levels of urine bilirubin photoisomer are affected by the light sources with different wavelength characteristic were analyzed. RESULTS: There was no correlation between serum (ZE)-bilirubin and urine configurational isomers, but a weak positive correlation between serum (EZ)-cyclobilirubin and urine structural isomers after phototherapy. Although serum (ZE)-bilirubin levels depended on the wavelength characteristic of each light source during phototherapy, the urine configurational isomer levels did not depend on it. The increase in serum (EZ)-cyclobilirubin levels and the urine structural isomer levels were mostly in agreement. CONCLUSIONS: The urine bilirubin structural isomers may be used to estimate the serum (EZ)-cyclobilirubin levels and to evaluate the clinical effects of light sources.

Bilirubin↗
PubMed2004

Giant hydronephrosis with increased carbohydrate antigen 19-9 both in serum and fluid.

We report a case of right giant hydronephrosis. A 68-year-old man was admitted to our hospital with chief complaints of general fatigue, loss of appetite and a one-year history of progressive fullness on whole abdomen. Abdominal computed tomography scan exhibited a huge, homogeneous, low density mass originating from the right kidney. We performed right percutaneous nephrostomy and drained over 6,500 ml bloody fluid. Cytological examination of the drained fluid revealed atypical nuclear appearance defined as class III. Increased values of carbohydrate antigen 19-9 were observed both in the fluid as well as in the serum. We performed right nephrectomy. Macroscopic appearance of the resected kidney showed marked stenosis at the portion of ureteropelvic junction. Histological analysis of the stenotic portion demonstrated marked fibrosis without findings of malignancy.

Aged↗