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Biomedical subjects

Y Kuroki

Publications and source records attributed to Y Kuroki.

At least 19 recordsLinked to original sources
PubMed2005

Structural analysis of leucine-rich-repeat variants in proteins associated with human diseases.

A number of human diseases have been shown to be associated with mutation in the genes encoding leucine-rich-repeat (LRR)-containing proteins. They include 16 different LRR proteins. Mutations of these proteins are associated with 19 human diseases. The mutations occur frequently within the LRR domains as well as their neighboring domains, including cysteine clusters. Here, based on the sequence analysis of the LRR domains and the known structure of LRR proteins, we describe some features of different sequence variants and discuss their adverse effects. The mutations in the cysteine clusters, which preclude the formation of sulfide bridges or lead to a wrong paring of cysteines in extracellular proteins or extracellular domains, occur with high frequency. In contrast, missense mutations at some specific positions in LRRs are very rare or are not observed at all.

Genetic Diseases, Inborn↗
PubMed2004

DNA sequence and comparative analysis of chimpanzee chromosome 22.

Human-chimpanzee comparative genome research is essential for narrowing down genetic changes involved in the acquisition of unique human features, such as highly developed cognitive functions, bipedalism or the use of complex language. Here, we report the high-quality DNA sequence of 33.3 megabases of chimpanzee chromosome 22. By comparing the whole sequence with the human counterpart, chromosome 21, we found that 1.44% of the chromosome consists of single-base substitutions in addition to nearly 68,000 insertions or deletions. These differences are sufficient to generate changes in most of the proteins. Indeed, 83% of the 231 coding sequences, including functionally important genes, show differences at the amino acid sequence level. Furthermore, we demonstrate different expansion of particular subfamilies of retrotransposons between the lineages, suggesting different impacts of retrotranspositions on human and chimpanzee evolution. The genomic changes after speciation and their biological consequences seem more complex than originally hypothesized.

Animals↗
PubMed2004

Effects of ageing and smoking on SP-A and SP-D levels in bronchoalveolar lavage fluid.

Surfactant protein (SP)-A and SP-D are collagen-like glycoproteins that are synthesised in the distal pulmonary epithelium. This study examined the effects of ageing and long-term smoking on SP-A and SP-D in the lungs. The possible links to the development of pulmonary emphysema were also investigated. Sequential lavage was performed in young and middle-aged or elderly nonsmokers and asymptomatic current smokers with various smoking histories. Middle-aged or elderly smokers were further categorised according to the presence of emphysema by high-resolution computed tomography. Levels of SP-A and SP-D in bronchial lavage (BL) fluid and in bronchoalveolar lavage (BAL) fluid were quantified by ELISA. Significant decreases in SP-A were seen with age in nonsmokers in BL fluid, but not in BAL fluid. Middle-aged or elderly smokers with emphysema had lower levels of SP-A in both BL and BAL fluids when compared with young subjects, and in BL fluid when compared with middle-aged or elderly smokers without emphysema. SP-D did not change with age alone, however, it was decreased in middle-aged or elderly smokers when compared with similarly aged nonsmokers. In conclusion, surfactant protein-A may decrease with age alone or due to the cumulative effects of long-term smoking and development of emphysema, while surfactant protein-D decreases due to long-term smoking.

Adolescent↗
PubMed2003

Longitudinal growth and height velocity of Japanese children with Down's syndrome.

AIM: To determine the natural growth pattern of Japanese children with Down's syndrome. METHODS: Longitudinal height data of 85 patients (43 males, 42 females) from birth to final height were analyzed. Based on these data, semi-longitudinal standard growth curves and height velocity curves for Down's syndrome were drawn. RESULTS: The means +/- SD of final height of males and females with Down's syndrome were 153.2 +/- 5.6 and 141.9 +/- 4.2 cm, respectively. They were -3.0 SD and -2.8 SD for Japanese standards. Mean peak height velocities were 8.9 and 7.5 cm y(-1), and the ages at peak height velocity were 11.6 and 10.2 y for males and females, respectively. CONCLUSION: The mean height of patients with Down's syndrome was around -2 SD for normal children before puberty. Their pubertal growth spurt starts about 1 y earlier and their peak height velocity was about 1.3-1.4 cm shorter than for normal children.

Asian People↗
PubMed2002

Serum surfactant proteins-A and -D as biomarkers in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) has a high mortality rate, and current therapies are only marginally effective. A serum biomarker that predicts clinical outcome would be useful to stage disease, indicate prognosis and the need for aggressive therapy, and help stratify patients for clinical trials. The goals of this study were to determine whether serum levels of surfactant protein-A (SP-A) or surfactant protein-D (SP-D) would distinguish between IPF and other types of interstitial lung disease and whether serum SP-A or SP-D levels predict outcome in patients with IPF. The authors found that serum SP-A and SP-D levels were significantly elevated in patients with IPF and systemic sclerosis compared to sarcoidosis, beryllium disease and normal controls, and that SP-D correlated with radiographic abnormalities in patients with IPF. In addition, the authors found that both serum SP-A and SP-D levels were highly predictive of survival in patients with IPF. This is the largest North American data set of surfactant protein measurements in idiopathic pulmonary fibrosis and the first report using multivariate analysis comparing serum surfactant proteins-A and -D to other commonly measured predictors of survival in idiopathic pulmonary fibrosis. Based on these results, the authors propose that serum surfactant proteins may prove to be useful biomarkers in patients with idiopathic pulmonary fibrosis.

Adult↗
PubMed2001

Extracellular Toll-like receptor 2 region containing Ser40-Ile64 but not Cys30-Ser39 is critical for the recognition of Staphylococcus aureus peptidoglycan.

Toll-like receptor 2 (TLR2) and CD14 function as pattern recognition receptors for bacterial peptidoglycan (PGN). TLRs and CD14 possess repeats of the leucine-rich motif. To address the role of the extracellular domain of TLR2 in PGN signaling, we constructed CD14/TLR2 chimeras, in which residues 1-356 or 1-323 of CD14 were substituted for the extracellular domain of TLR2, and five deletion mutants of TLR2, in which the progressively longer regions of extracellular TLR2 regions were deleted. PGN induced NF-kappaB activation in HEK293 cells expressing TLR2 but not in cells expressing CD14/TLR2 chimeras. The cells transfected with a deletion mutant TLR2(DeltaCys30-Ile64) as well as TLR2(DeltaCys30-Asp160) and TLR2(DeltaCys30-Asp305) failed to respond to PGN, indicating the importance of the TLR2 region Cys(30)-Ile(64). Although TLR2(DeltaCys30-Ser39) conferred cell responsiveness to PGN, the cells expressing TLR2(DeltaSer40-Ile64) failed to induce NF-kappaB activation. In addition, NF-kappaB activity elicited by PGN was significantly attenuated in the presence of synthetic peptide corresponding to the TLR2 region Ser(40)-Ile(64). From these results, we conclude that; 1) CD14 cannot functionally replace the extracellular domain of TLR2 in PGN signaling; 2) the TLR2 region Cys(30)-Ser(39) is not required for PGN recognition; 3) the TLR2 region containing Ser(40)-Ile(64) is critical for PGN recognition.

Amino Acid Sequence↗
PubMed2001

Thrombin activates p38 mitogen-activated protein kinase in vascular smooth muscle cells.

Thrombin is a potent mitogen for vascular smooth muscle cells. However, the signaling pathways by which thrombin mediates its mitogenic response are not fully understood. The ERK (extracellular signal-regulated protein kinase) and JNK (c-Jun N-terminal kinase) members of the mitogen-activated protein kinase (MAPK) family are reported to be activated by thrombin. We have investigated the response to thrombin of another member of the MAPK family, p38 MAPK, which has been suggested to be activated by both stress and inflammatory stimuli in vascular smooth muscle cells. We found that thrombin induced time- and dose-dependent activation of p38 MAPK. Maximal stimulation of p38 MAPK was observed after a 10-min incubation with 1 unit ml(-1) thrombin. GF109203X, a protein kinase C inhibitor, and prolonged treatment with phorbol 12-myristate 13-acetate partially inhibited p38 MAPK activation. A tyrosine kinase inhibitor, genistein, also inhibited p38 MAPK activation in a dose-dependent manner. p38 MAPK activation was inhibited by overexpression of betaARK1ct (beta-adrenergic receptor kinase I C-terminal peptide). p38 MAPK activation was also inhibited by expression of dominant-negative Ras, not by dominant-negative Rac. We next examined the effect of a p38 MAPK inhibitor, SB203580, on thrombin-induced proliferation. SB203580 inhibited thrombin-induced DNA synthesis in a dose-dependent manner. These results suggest that thrombin activates p38 MAPK in a manner dependent on Gbetagamma, protein kinase C, a tyrosine kinase, and Ras, that p38 MAPK has a role in thrombin-induced mitogenic response in the cells.

Animals↗
PubMed2001

Differential lipid specificities of the repeated domains of annexin IV.

The roles of the four domains of annexin IV in binding to phospholipids and glycolipids were assessed by analyzing the binding of a group of mutant annexins IV in which one or more of the four domains was inactivated by replacing a critical amino residue(s) (Asp or Glu) with the neutral residue Ala. The data reveal that individual annexin domains may have characteristic affinities for different lipids. In particular, inactivation of the fourth domain inhibits the binding to phosphatidylserine (PS) and phosphatidylinositol (PI) but not to phosphatidylglycerol (PG), suggesting that this domain specifically can accommodate the larger head groups of PS and PI whereas the other three domains may form more restricted binding pockets. In order to block binding to PG, domain 1, or both domains 2 and 3 must be inactivated in addition to domain 4, suggesting that all four domains may be able to accommodate the headgroup of PG to some extent. Binding to acidic glycolipids (sulfatides) was also sensitive to inactivation of domain 4. However, in the case of sulfatides the nature of the binding reaction is fundamentally different compared with the binding to phospholipids since the interaction with sulfatides was highly sensitive to an increase in ionic strength. The binding to sulfatides may depend therefore on charge-charge interactions whereas the binding to phospholipid may involve a more specific interaction between the lipid headgroup and the protein surface, and/or interaction of the protein with the hydrophobic portion of a lipid bilayer.

Alanine↗
PubMed2001

Identification of human antitumor cytotoxic T lymphocytes epitopes of recoverin, a cancer-associated retinopathy antigen, possibly related with a better prognosis in a paraneoplastic syndrome.

Cancer-associated retinopathy (CAR) is a rare paraneoplastic syndrome, and the recoverin-specific autoantibody is suggested to contribute to the pathogenesis of retinopathy, including apoptosis of retinal cells. Because it is known that CAR(+) cancer patients have a preferable prognosis, we hypothesized that aberrantly expressed recoverin in cancer cells can become a target of cytotoxic T lymphocytes (CTL). Here we tested nine recoverin-derived HLA-A24-binding peptides for their capacity to elicit antitumor CTL. We observed recoverin-specific CTL responses in two HLA-A24(+) CAR(+) cancer patients. In addition, the CTL responses were obtained from three of ten CAR(-) cancer patients and two of six healthy individuals. The CTL precursor frequency of CAR(+) cancer patients and that of CAR(-) cancer patients was higher than that of healthy individuals. Of nine recoverin peptides, R49 (QFQSIYAKF), R49.2 (QFQSIYAKFF), and R64 (AYAQHVFRSF) were discovered to induce the peptide-specific CTL. Taken together, our present data suggest that peripheral activation of recoverin-specific antitumor CTL is likely to contribute to the preferable prognosis of CAR(+) cancer patients. Moreover, in cases other than CAR(+) cancer patients, recoverin may offer the opportunity to design epitope-based immunotherapeutic approaches for treating HLA-A24(+) cancer patients with a recoverin-expressing tumor.

Antigens, Neoplasm↗
PubMed2001

Disseminated peritoneal adenomucinosis associated with a panperitonitis-like onset: report of a case.

A 59-year-old man was admitted to our department due to a fever of unknown origin. Abdominal ultrasonography and computed tomography showed a large cystic mass in the lower abdomen and a massive amount of abdominal fluid. A laparotomy was performed under a diagnosis of panperitonitis. Diffuse pyogenic gelatinous ascites and a large cystic mass with a grayish wall, and a hard solid lesion in part were found. The microscopic findings of the hard solid lesion showed calcification, osteogenesis, and focal epithelial proliferation in a tiny area consisting of mucinous cells with no significant cytologic atypia. The remaining part of the cystic wall and small cystic lesions were hyalinized, fibrous, or necrotic tissue. Since a total resection of the masses was not possible, the patient received adjuvant chemotherapy with cisplatin followed by the administration of mitomycin C and 5-fluorouracil. An abdominal fistula with the excretion of pyogenic gelatinous fluid occurred, but the patient is still alive and doing well over 2 years postoperatively. The primary site of this tumor could unfortunately not be identified.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Y chromosome compound haplotypes with the microsatellite markers DXYS265, DXYS266, and DXYS241.

Two newly developed microsatellite markers on Yp11 (DXYS265) and Yq11.21 (DXYS266) and our previously reported marker, on Yp11 (DXYS241), were typed by triplex polymerase chain reaction (PCR) in 102 Japanese, 18 white American, and 17 black American males. The DXYS265 locus revealed three alleles, the DXYS266 locus showed two alleles, while the DXYS241 locus showed five alleles. Nine different compound haplotypes were observed among the males. Of these, two haplotypes were common to all groups, while four were limited to Japanese. Pedigree analysis of 61 Japanese families revealed no mutations of these loci. The triplex PCR developed in this study, as well as the new loci, are useful for tracing paternal lineages in human migration studies and population analysis, in addition to Y chromosome evolutionary studies.

Alleles↗
PubMed2001

Thrombin-induced p38 mitogen-activated protein kinase activation is mediated by epidermal growth factor receptor transactivation pathway.

Thrombin is a potent mitogen for vascular smooth muscle cells (VSMC) and has been implicated its pathogenic role in vascular remodelling. However, the signalling pathways by which thrombin mediates its mitogenic response are not fully understood. We have previously reported that thrombin activates p38 mitogen-activated protein kinase (p38 MAPK) by a tyrosine kinase-dependent mechanism, and that p38 MAPK has a role in thrombin-induced mitogenic response in rat VSMC. In the present study, we examine the involvement of epidermal growth factor (EGF) receptor in thrombin-induced p38 MAPK activation. We found that thrombin induced EGF receptor tyrosine phosphorylation (transactivation) in A10 cells, a clonal VSMC cell line. A selective inhibitor of EGF receptor kinase (AG1478) inhibited the p38 MAPK activation in a dose-dependent manner, whereas it had no effect on the response to platelet-derived growth factor (PDGF). EGF receptor phosphorylation induced by thrombin was inhibited by BAPTA-AM and GF109203X, which suggest a requirement for intracellular Ca(2+) increase and protein kinase C. We next examined the effect of AG1478 on thrombin-induced DNA synthesis. AG1478 inhibited thrombin-induced DNA synthesis in a dose-dependent manner. In contrast, PDGF-induced DNA synthesis was not affected by AG1478. In conclusion, these data suggest that the EGF receptor transactivation and subsequent p38 MAPK activation is required for thrombin-induced proliferation of VSMC.

Blotting, Western↗
PubMed2001

Neuroprotection by estrogen via extracellular signal-regulated kinase against quinolinic acid-induced cell death in the rat hippocampus.

Extracellular signal-regulated kinase (ERK) belongs to the family of mitogen-activated protein kinases (MAPKs), which are serine-threonine kinases activated by phosphorylation in response to a variety of mitogenic signals. We previously reported that 17 beta-estradiol rapidly activates ERK in the rat hippocampus. However, the physiological role of this rapid activation of ERK by estrogen in vivo has not yet been elucidated. This study investigated whether ERK may participate in mediating the neuroprotective effects of estrogen against quinolinic acid (QA) toxicity in the rat hippocampus in vivo. Injection of QA into the hippocampi of male rats produced a loss of Nissl-stained neurons in the CA1 after 24 h. Prior administration of 17 beta-estradiol (50 pmol/animal) to the ventricles prevented the QA-induced decrease in Nissl-stained neurons. Pretreatment with U0126, an inhibitor of MAPK/ERK kinase, inhibited the rapid activation of ERK by 17 beta-estradiol in the rat hippocampus. Moreover, the neuroprotective effects of 17beta-estradiol against QA toxicity were blocked by the pretreatment with U0126. U0126 alone did not produce a loss of neurons. These results indicate that ERK mediates estrogen neuroprotection after QA toxicity in the rat hippocampus.

Animals↗
PubMed2001

Binding of annexins to lung lamellar bodies and the PMA-stimulated secretion of annexin V from alveolar type II cells.

To identify lung lamellar body (LB)-binding proteins, the fractions binding to LB-Sepharose 4B in a Ca(2+)-dependent manner from the lung soluble fractions were analyzed with Mono Q column. Four annexins (annexins III, IV, V, and VIII) were identified by partial amino acid sequence analyses as the LB-binding proteins in the lung soluble fractions. A control experiment using phospholipid (phosphatidylserine/phosphatidylglycerol/phosphtidylcholine) liposome-Sepharose 4B revealed that annexins III, IV and V were the Ca(2+)-dependent proteins binding to the column in the lung soluble fractions, while annexin VIII was not detected. Thus, annexin VIII might preferentially bind to LB. On the other hand, the only Ca(2+)-dependent LB-binding protein identified in the bronchoalveolar lavage fluids was annexin V. It was further demonstrated that annexin V was secreted by isolated alveolar type II cells from rats and that the secretion was stimulated by the addition of phorbol ester (PMA), a potent stimulator of surfactant secretion. The PMA-dependent stimulation of annexin V was attenuated by preincubation with surfactant protein-A (SP-A), a potent inhibitor of surfactant secretion. As LB is thought to be an intracellular store of pulmonary surfactant, which is secreted by alveolar type II cells, annexin V is likely to be secreted together with the lamellar body.

Animals↗
PubMed2001

Alteration of annexin IV expression in alcoholics.

Western blot analysis was performed by using a specific antibody to measure annexin IV in human postmortem brain samples from alcoholic subjects. The analysis showed a significantly augmented expression in the hippocampus compared with controls, whereas the expression in the frontal cortex was equivalent in both groups. Annexin IV expression in the occipital cortex tended to increase in alcoholics. It was shown further that autoantibodies to annexin IV were increased significantly in alcoholic patients compared with controls. Thus, annexin IV may become a novel biological marker for alcoholics.

Adult↗