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Biomedical subjects

Y Kido

Publications and source records attributed to Y Kido.

At least 19 recordsLinked to original sources
PubMed2006

Predictive assay of neoadjuvant chemotherapy in management of oral cancer.

Neoadjuvant chemotherapy (NAC) for oral squamous cell carcinoma has a positive impact on organ preservation and/or survival only in patients who achieve an excellent anti-tumour effect with this therapy. Predictive assay for NAC can play an important role in establishing tailor-made treatments for oral squamous cell carcinoma. In this retrospective study, the anti-tumour effects of cisplatin-based NAC in 70 patients with oral squamous cell carcinoma were reviewed in relation to biological markers of tumour cell proliferation activity: tumour grade, cellular DNA content, mitotic index, apoptotic index, ki-67 positive rate, and p53 and Bax expression. Tumour grade, Bax expression, apoptotic index and cellular DNA content were significantly correlated with the anti-tumour effects of NAC in univariate analysis. Tumour grade, Bax expression and apoptotic index were selected as independent predictive factors by means of multiple logistic analysis. Using the regression equation from these results, the prediction rate for anti-tumour effects was 70%. For patients in whom NAC is predicted to be ineffective, it may be necessary to choose another treatment option in order to improve their survival and quality of life.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Unique role of SNT-2/FRS2beta/FRS3 docking/adaptor protein for negative regulation in EGF receptor tyrosine kinase signaling pathways.

The membrane-linked docking protein SNT-2/FRS2beta/FRS3 becomes tyrosine phosphorylated in response to fibroblast growth factors (FGFs) and neurotrophins and serves as a platform for recruitment of multiple signaling proteins, including Grb2 and Shp2, to FGF receptors or neurotrophin receptors. We previously reported that SNT-2 is not tyrosine phosphorylated significantly in response to epidermal growth factor (EGF) but that it inhibits ERK activation via EGF stimulation by forming a complex with ERK2. In the present report, we show that expression of SNT-2 suppressed EGF-induced cell transformation and proliferation, and expression level of SNT-2 is downregulated in cancer. The activities of the major signaling molecules in EGF receptor (EGFR) signal transduction pathways, including autophosphorylation of EGFR, were attenuated in cells expressing SNT-2 but not in cells expressing SNT-2 mutants lacking the ERK2-binding domain. Furthermore, SNT-2 constitutively bound to EGFR through the phosphotyrosine binding (PTB) domain both with and without EGF stimulation. Treatment of cells with MEK inhibitor U0126 partially restored the phosphorylation levels of MEK and EGFR in cells expressing SNT-2. On the basis of these findings, we propose a novel mechanism of negative control of EGFR tyrosine kinase activity with SNT-2 by recruiting ERK2, which is the site of negative-feedback loop from ERK, ultimately leading to inhibition of EGF-induced cell transformation and proliferation.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Antihypertensive effect of gamma-amino butyric acid enriched soy products in spontaneously hypertensive rats.

The effect of gamma-amino butyric acid (GABA)-enriched soybean on blood pressure was investigated in male spontaneously hypertensive rats. Ten-week-old rats were given diets containing graded levels of GABA-enriched soybean powder for 8 weeks. The systolic blood pressure in rats fed 0.15% GABA diet was significantly lower at 1st week and maintained lower values for 4 weeks as compared with 0% GABA controls. No effect on blood pressure was found in those of 0.03 and 0.3% GABA. The results suggest that there exist appropriate dietary GABA level to get the blood pressure lowering effect.

Animals↗
PubMed2002

Analyses of serum lipoprotein(a) and the relation to phenotypes and genotypes of apolipoprotein(a) in type 2 diabetic patients with retinopathy.

To elucidate the association of lipoprotein(a) (Lp(a)) with diabetic retinopathy (DR), we studied the serum Lp(a) concentrations (n = 412), apolipoprotein(a) (apo(a)) phenotypes expressed by the number of kringle 4 (K4) repeats (n = 150), apo(a) gene genotypes (n = 161) of type 2 diabetes with or without DR. The 5'-untranslated region of apo(a) gene was classified into seven haplotypes (A to G) and 18 genotypes by PCR-RFLP at three distinct sites. The serum Lp(a) concentrations were significantly higher in diabetic patients than in normal controls. Furthermore, the patients with DR, especially proliferative retinopathy showed higher serum Lp(a) concentrations than those without DR. Although a negative correlation was found between the serum Lp(a) concentrations and the number of K4 repeats in total diabetic patients, no difference was seen in the distribution of the number of K4 repeats between those with and without DR. In the same apo(a) phenotypes, the patients with DR had higher Lp(a) concentrations than those without DR. Among the genotypes, type CC showed significantly higher serum Lp(a) concentrations than the other genotypes. However, there was no difference in the ratios of the type CC between the patients with and without DR. In conclusion, other factors than phenotypes and genotypes in the 5'-untranslated region of apo(a) may be responsible for the elevation of serum Lp(a) in diabetic patients with retinopathy.

5' Untranslated Regions↗
PubMed2001

Analysis of the serological response to Chlamydia pneumoniae in patients with ischemic heart disease by recombinant MOMP-ELISA.

To investigate the humoral immune response to the major outer membrane protein (MOMP) of Chlamydia pneumoniae, a fusion protein, thioredoxin-(His)6-MOMP (rMOMP) was produced in Escherichia coli and purified; this served as an antigen to establish an enzyme-linked immunosorbent assay (ELISA). Specific IgG and IgA antibodies against rMOMP were determined in sera from patients with ischemic heart disease. The findings were compared with those obtained by ELISA using the outer membrane protein complex (Hitazyme). The positivity rates for IgG antibody by rMOMP-ELISA were low (28%) compared with those by Hitazyme (72%). However, the positivity rates of IgA antibody by rMOMP-ELISA were similar to those by Hitazyme (76%). Interestingly, antigen positivity by immunohistochemical staining in the atherosclerotic lesions of coronary arteries was high in the groups with a high IgA titer of rMOMP-ELISA.

Aged↗
PubMed2001

Functional relevance of carnitine transporter OCTN2 to brain distribution of L-carnitine and acetyl-L-carnitine across the blood-brain barrier.

Transport of L-[3H]carnitine and acetyl-L-[3H]carnitine at the blood-brain barrier (BBB) was examined by using in vivo and in vitro models. In vivo brain uptake of acetyl-L-[3H]carnitine, determined by a rat brain perfusion technique, was decreased in the presence of unlabeled acetyl-L-carnitine and in the absence of sodium ions. Similar transport properties for L-[3H]carnitine and/or acetyl-L-[3H]carnitine were observed in primary cultured brain capillary endothelial cells (BCECs) of rat, mouse, human, porcine and bovine, and immortalized rat BCECs, RBEC1. Uptakes of L-[3H]carnitine and acetyl-L-[3H]carnitine by RBEC1 were sodium ion-dependent, saturable with K(m) values of 33.1 +/- 11.4 microM and 31.3 +/- 11.6 microM, respectively, and inhibited by carnitine analogs. These transport properties are consistent with those of carnitine transport by OCTN2. OCTN2 was confirmed to be expressed in rat and human BCECs by an RT-PCR method. Furthermore, the uptake of acetyl-L-[3H]carnitine by the BCECs of juvenile visceral steatosis (jvs) mouse, in which OCTN2 is functionally defective owing to a genetical missense mutation of one amino acid residue, was reduced. The brain distributions of L-[3H]carnitine and acetyl-L-[3H]carnitine in jvs mice were slightly lower than those of wild-type mice at 4 h after intravenous administration. These results suggest that OCTN2 is involved in transport of L-carnitine and acetyl-L-carnitine from the circulating blood to the brain across the BBB.

Acetylcarnitine↗
PubMed2001

Preserved pancreatic beta-cell development and function in mice lacking the insulin receptor-related receptor.

Receptors of the insulin/insulinlike growth factor (IGF) family have been implicated in the regulation of pancreatic beta-cell growth and insulin secretion. The insulin receptor-related receptor (IRR) is an orphan receptor of the insulin receptor gene (Ir) subfamily. It is expressed at considerably higher levels in beta cells than either insulin or IGF-1 receptors, and it has been shown to engage in heterodimer formation with insulin or IGF-1 receptors. To address whether IRR plays a physiologic role in beta-cell development and regulation of insulin secretion, we have characterized mice lacking IRR and generated a combined knockout of Ir and Irr. We report that islet morphology, beta-cell mass, and secretory function are not affected in IRR-deficient mice. Moreover, lack of IRR does not impair compensatory beta-cell hyperplasia in insulin-resistant Ir(+/-) mice, nor does it affect beta-cell development and function in Ir(-/-) mice. We conclude that glucose-stimulated insulin secretion and embryonic beta-cell development occur normally in mice lacking Irr.

Animals↗
PubMed2001

Is D2 lymphadenectomy in gastrectomy safe with regard to the skill of the operator?

BACKGROUND/AIMS: D2 gastrectomy has been regarded as an inconvenient procedure with high morbidity and no survival benefit in the West. Recent western studies, however, especially from specialist centers, have shown a survival benefit and the safety of D2 gastrectomy. The aim of this study is to clarify the safety of D2 gastrectomy (defined by the Japanese Research Society for the Study of Gastric Cancer), even if carried out by a junior surgeon, and to show that it is not a particularly difficult or special procedure. METHODS: Patients who underwent a typical distal gastrectomy (DG) with D2 resection (n = 344) and total gastrectomy (TG) with D2 resection (n = 111) were analyzed. The subjects were divided into 3 groups according to the postgraduate year of the operator (group I = the surgeon's postgraduate experience was less than 5 years; group II = surgeons with more than 5 years and less than 10 years postgraduate experience; group III = surgeons with more than 10 years postgraduate experience). The rate of postoperative complications and the 5-year survival rate were compared among the 3 groups. RESULTS: The overall operative mortality rate, hospital death rate and the overall rate of postoperative complications were 1.2, 2.0 and 10.2% in DG patients, and 14.4, 0 and 1.8% in TG patients, respectively. There was no significant difference in the operative blood loss, the rate of operative mortality, hospital death rate and postoperative complications among the 3 groups. There was no significant difference in the 5-year survival rate among the 3 groups in each stage. CONCLUSION: The postoperative mortality rate, morbidity rate and 5-year survival rate after a typical D2 gastrectomy were independent of the experience of the operator. It is considered to be a safe and useful procedure in view of the rate of postoperative complications and the long-term survival rate, even if performed by a junior trainee under the supervision of experienced surgeons in a nonspecialized hospital.

Adult↗
PubMed2001

Distinct and overlapping functions of insulin and IGF-I receptors.

Targeted gene mutations have established distinct, yet overlapping, developmental roles for receptors of the insulin/IGF family. IGF-I receptor mediates IGF-I and IGF-II action on prenatal growth and IGF-I action on postnatal growth. Insulin receptor mediates prenatal growth in response to IGF-II and postnatal metabolism in response to insulin. In rodents, unlike humans, insulin does not participate in embryonic growth until late gestation. The ability of the insulin receptor to act as a bona fide IGF-II-dependent growth promoter is underscored by its rescue of double knockout Igf1r/Igf2r mice. Thus, IGF-II is a true bifunctional ligand that is able to stimulate both insulin and IGF-I receptor signaling, although with different potencies. In contrast, the IGF-II/cation-independent mannose-6-phosphate receptor regulates IGF-II clearance. The growth retardation of mice lacking IGF-I and/or insulin receptors is due to reduced cell number, resulting from decreased proliferation. Evidence from genetically engineered mice does not support the view that insulin and IGF receptors promote cellular differentiation in vivo or that they are required for early embryonic development. The phenotypes of insulin receptor gene mutations in humans and in mice indicate important differences between the developmental roles of insulin and its receptor in the two species.

Alternative Splicing↗
PubMed2001

Mitogenic and metabolic effects of type I IGF receptor overexpression in insulin receptor-deficient hepatocytes.

We have previously shown that hepatocytes lacking insulin receptors (Ir-/-) fail to mediate metabolic responses, such as stimulation of glycogen synthesis, while retaining the ability to proliferate in response to IGFs. In this study we have asked whether overexpression of type I IGF receptors would rescue the metabolic response of Ir-/- hepatocytes. After IGF-I stimulation, insulin receptor substrate-1 and -2 phosphorylation and PI3K activity were restored to levels similar to or greater than those seen in wild-type cells. Rates of cell proliferation in response to IGF-I increased approximately 2-fold, whereas glycogen synthesis was restored to wild-type levels, but was comparatively smaller than that elicited by overexpression of insulin receptors. In summary, overexpression of IGF-I receptors in Ir-/- hepatocytes normalized insulin receptor substrate-2 phosphorylation and glycogen synthesis to wild-type levels, whereas it increased cell proliferation above wild-type levels. Moreover, stimulation of glycogen synthesis was submaximal compared with the effect of insulin receptor overexpression. We conclude that IGF-I receptors are more efficiently coupled to cell proliferation than insulin receptors, but are less potent than insulin receptors in stimulating glycogen synthesis. The data are consistent with the possibility that there exist intrinsic signaling differences between insulin and IGF-I receptors.

Animals↗
PubMed2001

Clinical review 125: The insulin receptor and its cellular targets.

The pleiotropic actions of insulin are mediated by a single receptor tyrosine kinase. Structure/function relationships of the insulin receptor have been conclusively established, and the early steps of insulin signaling are known in some detail. A generally accepted paradigm is that insulin receptors, acting through insulin receptor substrates, stimulate the lipid kinase activity of phosphatidylinositol 3-kinase. The rapid rise in Tris-phosphorylated inositol (PIP(3)) that ensues triggers a cascade of PIP(3)-dependent serine/threonine kinases. Among the latter, Akt (a product of the akt protooncogene) and atypical protein kinase C isoforms are thought to be involved in insulin regulation of glucose transport and oxidation; glycogen, lipid, and protein synthesis; and modulation of gene expression. The presence of multiple insulin-regulated, PIP(3)-dependent kinases is consistent with the possibility that different pathways are required to regulate different biological actions of insulin. Additional work remains to be performed to understand the distal components of insulin signaling. Moreover, there exists substantial evidence for insulin receptor substrate- and/or phosphatidylinositol 3-kinase-independent pathways of insulin action. The ultimate goal of these investigations is to provide clues to the pathogenesis and treatment of the insulin resistant state that is characteristic of type 2 diabetes.

Animals↗
PubMed2001

Molecular and functional identification of large neutral amino acid transporters LAT1 and LAT2 and their pharmacological relevance at the blood-brain barrier.

We present here the evidence of molecular and functional expression of LAT1 and LAT2, subunits of the large neutral amino acid transporter system L, in cultured brain capillary endothelial cells of the rat. By means of the RT-PCR method, transcripts of LAT1, LAT2 and heavy chain of 4F2 antigen (4F2hc) were detected in rat primary cultured brain capillary endothelial cells (BCECs) and immortalized subline, RBEC1. The uptake properties of RBEC1, such as [3H]leucine and L-[3H]DOPA uptake, were similar to those of primary cultured BCECs. So, RBEC1 may retain almost native properties of the large neutral amino acid uptake activities. [3H]Leucine uptake by RBEC1 showed two saturable components and the Km values of the high- and low-affinity components were 8.92+/-3.18 and 119+/-45 microM, respectively. The Km value of the high-affinity component agreed well with that of LAT1 and the amino acid transport selectivity of RBEC1 was similar to that of LAT1. Therefore, it is suggested that LAT1 is important at the blood-brain barrier of rats. Additionally, the Km value of the low-affinity component was similar to that of LAT2. These observations indicate that LAT1 and LAT2 are involved as transporters for large neutral amino acids at the blood-brain barrier. Additionally, we concluded that RBEC1 is useful as an in-vitro model for evaluation of the pharmacological relevance of system L at the blood-brain barrier.

Amino Acid Transport Systems↗
PubMed2001

Genetics of type 2 diabetes: insight from targeted mouse mutants.

Diabetes affects millions of people worldwide, and its chronic complications are a leading cause of death in many industrialized countries. In a minority of patients, diabetes is brought about by the auto-immune destruction of insulin-producing pancreatic beta cells (Type 1 diabetes). In the vast majority of patients, diabetes is brought about by a combination of genetic and environmental factors that affect the organism's ability to respond to insulin (Type 2 diabetes). This impairment is due to a complex abnormality involving insulin action at the periphery and insulin production in the beta cell. Genetic factors play a key role in the development of type 2 diabetes. However, the inheritance of diabetes is non-Mendelian in nature, due to genetic heterogeneity, polygenic pathogenesis and incomplete penetrance. For these reasons, many laboratories have developed "designer" mice bearing targeted mutations in genes of the insulin action and insulin secretion pathways in order to develop a better model for the inheritance and pathogenesis of type 2 diabetes. These mutant mice are beginning to challenge established paradigms in the pathogenesis of type 2 diabetes and to shed light onto the genetic interactions underlying its complex inheritance. Here we review recent progress in the field and assess its impact on human studies of the genetics, prevention and treatment of type 2 diabetes.

Animals↗
PubMed2001

Vascular endothelial growth factor (VEGF) serum concentration changes during chemotherapy in patients with lung cancer.

Vascular endothelial growth factor (VEGF) is one of the most important angiogenic factors. This study aimed at clarifying the clinical significance of the changes in the serum VEGF (S-VEGF) concentrations in patients with lung cancer during anticancer chemotherapy. Subjects comprised 29 patients with lung cancer (13 adenocarcinomas, 7 squamous cell carcinomas, and 9 small cell carcinomas) who were treated with cisplatin-based chemotherapy. S-VEGF was measured by ELISA. We compared the S-VEGF concentrations between the responders and nonresponders to anticancer chemotherapy. S-VEGF concentrations before treatment of the chemotherapy (pretreatment S-VEGF concentrations) were correlated with the number of WBC, neutrophil count, monocyte count and platelet count but not the lymphocyte count. The mean pretreatment S-VEGF concentrations in responders and those in nonresponders were not significantly different, 509.7 pg/ml in the former and 382.8 pg/ml in the latter, respectively., The S-VEGF concentrations in the responders decreased to a mean of 356.0 pg/ml and 304.1 pg/ml during and at the end of therapy, respectively while those in the nonresponders increased to a mean of 474.2 pg/ml and 598.4 pg/ml during and at the end of therapy. The S-VEGF concentration changes in the responders were significantly different from those in the nonresponders (p = .006). The S-VEGF concentration may relate to tumor burden, however it may not be a good marker for tumor burden, because it can be influenced by various factors such as neutrophil which increases during infection. A decrease in S-VEGF concentrations may improve neoangiogenesis and the immune response, and may correlate with improvements in the quality of life and survival of patients.

Adult↗
PubMed2001

Tissue-specific insulin resistance in type 2 diabetes: lessons from gene-targeted mice.

Type 2 diabetes is caused by genetic and environmental factors that affect the ability of the organism to respond to insulin. This impairment results from decreased insulin action in target tissues and insulin production in beta cells. Genetic factors play a key role in the development of type 2 diabetes. However, the inheritance of diabetes is non-Mendelian in nature because of genetic heterogeneity, polygenic pathogenesis, and incomplete penetrance. Novel insight into this complex process has been obtained from 'designer' mice bearing targeted mutations in genes of the insulin action and insulin secretion pathways. These mutant mice are beginning to challenge established paradigms in the pathogenesis of type 2 diabetes and to shed light on the genetic interactions underlying its complex inheritance. Here we review recent progress in the field and assess its relevance to the pathogenesis of diabetes in humans.

Animals↗
PubMed2000

Functional clarification of MCT1-mediated transport of monocarboxylic acids at the blood-brain barrier using in vitro cultured cells and in vivo BUI studies.

PURPOSE: To prove the functional significance of monocarboxylic acid transporter, MCT1 at the blood-brain barrier (BBB) for the passage of both endogenous and exogenous monocarboxylic acids into the central nervous system. METHODS: Monocarboxylic acid transport at the BBB was studied in rats by using a newly established immortalized brain capillary endothelial cell (BCEC) line, RBEC1, and the results were compared with those obtained by using primary cultured BCECs, cells stably expressed with rat MCT1, and the in vivo brain uptake index (BUI) method. RESULTS: The cell line, RBEC1 meets various morphological and enzymatic criteria of BCECs and appears to be suitable for the study of BBB transport of monocarboxylic acids. The presence of MCT1-transcript in RBEC1 was confirmnned by the RT-PCR method, as previously observed in isolated brain capillaries. A typical substrate of MCT1, lactic acid, was taken up by RBEC1 in a stereospecific and saturable manner. The value of the kinetic parameter Km showed good agreement with values previously obtained in studies using an in vivo BUI and in vitro MCT1-transfected cells. An organic weak acid, benzoic acid, which has been considered to cross biological membranes by passive diffusion, exhibited carrier-mediated transport properties, such as saturation, pH dependence, and stereospecific inhibition in RBEC1, similar to those we observed in primary cultured rat BCECs. The Km values in RBEC1, in primary cultured BCECs and in the in vivo BUI method were comparable and well agreed with that obtained in MCT1-transfected cells, suggesting that the transport features of benzoic acid observed by in vitro methods well reflect the in vivo transport activity. Furthermore, hybrid depletion of MCT1 in RBEC1 using an antisense oligonucleotide against rat MCT1 abolished the saturable transport of benzoic acid. CONCLUSIONS: These observations show that MCT1 plays a significant role in the transport of monocarboxylic acids, including the exogenous organic weak acid benzoic acid, as well as native lactic acid.

Animals↗