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Biomedical subjects

Y Omori

Publications and source records attributed to Y Omori.

At least 37 records · Page 2Linked to original sources
PubMed1999

Connexins in tumour suppression and cancer therapy.

Malignant cells usually show altered gap junctional intercellular communication and are often associated with aberrant expression or localization of connexins. Transfection of connexin genes into tumorigenic cells restores normal cell growth, suggesting that connexins form a family of tumour suppressor genes. Some studies have also shown that specific connexins may be necessary to control growth of specific cell types. Although we have found that genes encoding connexin32 (Cx32; beta 1), Cx37 (alpha 4) and Cx43 (alpha 1) are rarely mutated in tumours, our recent studies suggest that methylation of the connexin gene promoter may be a mechanism by which connexin gene expression is down-regulated in certain tumors. We have produced various dominant negative mutants of the genes encoding Cx26 (beta 2), Cx32 and Cx43, some of which prevent the growth control exerted by the corresponding wild-type genes. A decade ago, we proposed a method to enhance killing of cancer cells by diffusion of therapeutic agents through gap junctions. Recently, we and others have shown that gap junctional intercellular communication is responsible for the bystander effect seen in herpes simplex virus thymidine kinase/ganciclovir gene therapy. Thus, connexin genes can exert dual effects in tumour control: tumour suppression and a bystander effect for cancer therapy.

Animals↗
PubMed1999

Differences between bulimia nervosa and binge-eating disorder in females with type 1 diabetes: the important role of insulin omission.

This study explored the differences between bulimia nervosa ("BN," n=22) and binge-eating disorder ("BED," n=11) in type 1 diabetic females and the factors most predictive of poor glycemic control in patients suffering from these disorders. These two groups and a control group without eating disorders (n=32) were compared across a number of demographic, psychological, and medical variables. BN manifested significantly more severe disturbances related to eating disorders, depression, anxiety, a higher rate of co-occurring mental disorders, and poorer psychosocial functioning compared with BED. BN also showed poorer glycemic control. Multivariate analysis indicated that higher serum glycosylated hemoglobin (HbA1c) levels were most associated with the presence of severe insulin omission in type 1 diabetic females with binge eating. Clinicians may be able to determine the psychological/medical severity of illness in these patients by identifying the presence of compensatory behaviors to prevent weight gain such as severe insulin omission, as described in the DSM-IV.

Adolescent↗
PubMed1999

Polymorphism of the beta3-adrenergic receptor gene and weight gain in pregnant diabetic women.

Inappropriate body weight gain during pregnancy has critical effects on the outcome for both mother and fetus. Therefore, body weight gain is an important issue in the management of pregnancy in women with diabetes. A Trp64Arg substitution in the beta3-AR gene has been reported to be associated with body weight gain and obesity in non-insulin-dependent diabetes mellitus (NIDDM) subjects. The aim of this study was to elucidate the contribution of the beta3-AR gene to body weight gain during pregnancy in subjects with diabetes. We analyzed 199 diabetic patients (NIDDM/IDDM; 131/68) and patient data was obtained from the first delivery of each individual. The mean age at diagnosis of diabetes was 22.9 +/- 7.5 years (mean +/- S.D.) and the mean age at delivery was 29.8 +/- 4.5 years. A polymorphism of the beta3-AR gene was detected by PCR-RFLP using Bst OI, which recognizes a Trp64Arg substitution. The frequency of the Trp64Arg allele was 0.15 in NIDDM and 0.17 in IDDM. Among the NIDDM subjects, excess weight gain during pregnancy, as defined by maximum BMI during pregnancy minus basal BMI before pregnancy exceeding five, was observed in 12.2% of the wild-type patients, 19.2% of heterozygotes and 28.6% of homozygotes. Homozygous subjects with NIDDM tended to show excess weight gain during pregnancy, however, this trend did not reach significance. None of the IDDM homozygotes showed excess weight gain. From our study, this beta3-AR gene polymorphism cannot be excluded as a contributing factor to excess weight gain during pregnancy in NIDDM subjects.

Adult↗
PubMed1999

Genetic polymorphism of renin-angiotensin system is not associated with diabetic vascular complications in Japanese subjects with long-term insulin dependent diabetes mellitus.

In a hospital cohort study, we examined whether or not ACE (Angiotensin-I converting enzyme) and AGT (Angiotensinogen) gene polymorphisms were associated with the development of nephropathy in long-term Japanese insulin-dependent diabetes mellitus (IDDM) patients with or without proliferative retinopathy, and whether or not the polymorphisms were associated with an arteriosclerotic family history in first degree relatives of the patients. A total of 201 patients with IDDM for more than 10 years and 159 patients with IDDM for more than 15 years were randomly selected in our hospital. All patients received uniform diabetes management and were divided into three groups, no nephropathy, incipient nephropathy and clinical nephropathy groups. There were no differences in clinical characteristics excluding urinary albumin to creatinine ratio and systolic blood pressure between the three groups. ACE I/D polymorphism was related to plasma ACE activity, but there were no associations between ACE I/D polymorphism and the development of diabetic nephropathy, nor was renal deterioration observed in patients with proliferative retinopathy even in those with a history of diabetes for more than 15 years. The AGT polymorphism did not have an additive effect on the association between ACE polymorphism and the development of diabetic nephropathy in patients with or without retinopathy. Development of diabetic nephropathy in the patients with or without proliferative retinopathy did not result in ACE or AGT polymorphisms. On the other hand, the ACE DD genotype was associated with a family history of ischemic heart disease in first degree relatives (X2 score = 9.04, P < 0.05). ACE and AGT gene polymorphisms may not play a role in the protective or accelerative effect against the development of diabetic nephropathy in the patients with or without proliferative retinopathy, but ACE gene polymorphism might be related to an arteriosclerotic family history in Japanese IDDM patients.

Adult↗
PubMed1999

Genetic and epigenetic changes of intercellular communication genes during multistage carcinogenesis.

During multistage carcinogenesis, the functions of several key genes involved in cell growth control must be damaged. Such genes include not only those involved in cell cycle control of individual cells, but also those involved in the coordination of cell growth throughout a given tissue through cell-cell communication. The most intimate form of intercellular communication is mediated by gap junctions. Gap junctional intercellular communication (GJIC) is known to transfer small water soluble molecules, including cAMP and IP3, from the cytoplasm of one cell to that of its neighbors; the growth of a given GJIC-associated cell is thus kept in check by other GJIC-connected cells. Most tumor cells have a reduced ability to communicate among themselves and/or with surrounding normal cells, confirming the importance of intact GJIC in growth control. When connexin (gap junction protein) genes are transfected into such cells, normal cell growth control is often recovered. Certain dominant-negative mutant connexin genes can reverse such tumor suppression. While these results suggest that connexin genes form a family of tumor suppressor genes, so far we have found no connexin gene mutations in human tumors; only two connexin gene mutations were found in chemically induced rat tumors. On the other hand, our recent studies suggest that connexin genes may be inactivated by hypermethylation of their promoter regions, suggesting that epigenetic inactivation of connexin genes may be a mechanism of GJIC disturbance in certain tumors. However, in many tumor cells connexins are normally expressed but aberrantly localized. The mechanisms of aberrant localization of connexins include lack of an appropriate cell-cell recognition apparatus and aberrant phosphorylation of connexins. These results suggest that GJIC disorders may occur not only because of aberrant expression of connexin genes themselves, but also as a result of disruption of various control mechanisms of the protein functions.

Animals↗
PubMed1999

Gap junction proteins connexin32 and connexin43 partially acquire growth-suppressive function in HeLa cells by deletion of their C-terminal tails.

Our laboratory has previously reported that transfection of a connexin26 (Cx26) gene, but not connexin40 nor connexin43 (Cx43), into HeLa cells expressing no detectable level of connexins suppressed the tumorigenic phenotype of the HeLa cells both in vitro and in vivo, although all of these connexins induced gap junctional intercellular communication in HeLa cells to a similar extent. The most remarkable structural difference between connexin proteins is the length of the C-terminal cytoplasmic tail, Cx26 having almost no tail, while Cx43 and connexin32 (Cx32) have long and intermediate ones, respectively. When Cx32 and Cx43 lose their C-terminal tails, they seem to resemble Cx26 in structure. To examine whether such truncated connexins become tumor suppressive in HeLa cells, we introduced a stop codon into each of the Cx32 and Cx43 cDNAs to remove their C-terminal tails and transfected these constructs (DeltaCx) into HeLa cells. Both DeltaCx cDNAs induced GJIC as efficiently as the wild-type counterparts. Although none of the truncated connexins affected proliferation rate, the truncated Cx32 and Cx43 proteins suppressed anchorage-independent cell growth in soft agar. Furthermore, when the transfectants were injected into the backs of nude mice, tumor appearance was delayed by 7 days in animals given cells expressing truncated connexins, i.e. tumors became detectable on days 11 and 18 after injection of vector and DeltaCx transfectants, respectively. Although throughout these experiments the truncated connexins did not completely eliminate the tumorigenicity of HeLa cells, as Cx26 did, it was evident that deletion of the C-terminal tails gave both Cx32 and Cx43 a capacity for negative growth control, suggesting that the C-terminal tails of these two connexins function as a regulatory region for connexin-mediated growth control in HeLa cells.

Animals↗
PubMed1998

Mutated connexin43 proteins inhibit rat glioma cell growth suppression mediated by wild-type connexin43 in a dominant-negative manner.

Many lines of evidence support the hypothesis that connexins form a family of tumor-suppressor genes. Transfection of connexin43 (Cx43) into rat C6 glioma cells have revealed that Cx43 functions as a growth- and tumor-suppressor in C6 cells. In previous studies, we and others have reported that several mutant connexins can inhibit gap junctional intercellular communication (GJIC) realized by the wild type in a dominant-negative manner. We have now examined dominant-negative effects of Cx43 mutants on cell growth control exerted by wild-type Cx43 in C6 cells. When 2 Cx43 mutants (L160M and A253V) were transfected into Cx43-transfected C6 cells, they restored anchorage-independent growth capacity and reinforced the tumorigenicity of these cells, meaning that these 2 mutants can inhibit growth-suppressive function of wild-type Cx43 in a dominant-negative manner. Neither of the mutants appeared to affect phosphorylation states and subcellular localization of Cx43 proteins. Intriguingly, the mutant A253V did not suppress GJIC capacity, implying a growth-suppressive pathway mediated by Cx43 may not be related to GJIC.

Animals↗
PubMed1998

Growth control of 3T3 fibroblast cell lines established from connexin 43-deficient mice.

Connexins are considered to be involved in cell growth control, on the basis of studies mainly with tumorigenic cells. To study the role of connexin genes in normal cell growth control, we established fibroblast cell lines from connexin 43 (Cx43)-deficient mice and characterized their growth. Embryonic fibroblasts from wild-type mice (Cx43+/+) and those with heterozygous (Cx43+/-) and homozygous (Cx43+/-) deficiencies of the Cx43 gene were cultured and passaged by a 3T3 protocol (every 3 d, 3 x 10(5) cells/60-mm dish). All cell lines showed a growth crisis during passages 6-15 and then started to grow well. All cell lines grew at similar rates under the 3T3 protocol, but Cx43-deficient (Cx43-/-) cell lines tended to grow faster when they were plated at 10(5) cells per dish. Cx43-/- cells did not express Cx43 and showed little gap-junctional intercellular communication (GJIC), confirming that Cx43 is the major connexin responsible for GJIC of these fibroblasts. While all Cx43+/+ and Cx43+/- cell lines expressed Cx43 protein, some of them showed very little GJIC. Those cell lines with high GJIC showed higher levels of the P2 form of Cx43 protein, and more Cx43 was localized in the plasma membrane than in cell lines with lower GJIC levels. We investigated effects of serum concentration on cell growth in these cell lines. Although different cell lines responded differentially to these agents, there was no clear relationship between Cx43 expression and cell growth stimulation by them. This suggests that Cx43 expression alone is not a strong regulator of mouse fibroblast growth.

3T3 Cells↗
PubMed1998

Association of distal chromosome 2q with IDDM in Japanese subjects.

An insulin-dependent diabetes mellitus (IDDM)-susceptibility gene (IDDM13) has recently been mapped to a region of distal chromosome 2q, which is syntenic to the region of mouse chromosome 1 containing a murine susceptibility gene for IDDM, Idd5. To determine the contribution of this region to IDDM disease susceptibility further and to narrow the region for positional cloning of susceptibility genes, we have studied the association of distal chromosome 2q with IDDM in the genetically distinct Japanese population. A 137 mobility unit (mu) allele at D2S137 locus was significantly associated with IDDM (odds ratio 1.92, p = 0.0016). Other markers, D2S301 and D2S143, located in the same region were not associated with IDDM, indicating that IDDM13 is in linkage disequilibrium with D2S137, but not with D2S301 or D2S143. The association of D2S137 with IDDM was observed in patients lacking one of two high risk HLA alleles, DQBI*0303 and DQBI*0401, but not in patients with either of these alleles. The frequency of high risk HLA alleles was significantly lower in patients with the susceptible allele at D2S137, suggesting that IDDMI3 contributes to IDDM susceptibility in subjects without high risk genotypes at IDDM1. Demonstration of allelic association of D2S137 with IDDM localizes IDDM13 in the close vicinity (<2 centiMorgans) of D2S137, greatly facilitating fine structure mapping and positional cloning of IDDM13.

Adolescent↗
PubMed1998

Cloning and chromosomal mapping of a novel ABC transporter gene (hABC7), a candidate for X-linked sideroblastic anemia with spinocerebellar ataxia.

We isolated a novel human ATP-binding cassette (ABC) transporter cDNA, determined its nucleotide sequence, and designated it human ABC7 (hABC7). The nucleotide sequence was highly homologous to the ATM1 gene in yeast, which encodes an ABC transporter (yAtm1p) located in the mitochondrial inner membrane. The deduced human product, a putative half-type transporter, consists of 752 amino acids that are 48.9% identical to those of yAtm1p. A computer-assisted protein structural and localization analysis revealed that the mitochondrial targeting signal of yAtm1p is conserved in the N-terminal region of the primary sequence of the hABC7 protein, and therefore this product is also likely to be located in the mitochondrial inner membrane. The evidence strongly suggests that the hABC7 gene is a counterpart of ATM1 and that its product is probably involved in heme transport. We mapped the hABC7 gene to chromosome Xq13.1-q13.3 by fluorescence in-situ hybridization. As band Xq13 has been implicated in X-linked sideroblastic anemia with spinocerebellar ataxia, hABC7 becomes a candidate gene for this heritable disorder.

5-Aminolevulinate Synthetase↗
PubMed1998

Expression and chromosomal localization of KIAA0369, a putative kinase structurally related to Doublecortin.

Neuropathy in vertebrates can be a consequence of failure of genes involved in the nervous system to be expressed at the correct times and levels during embryonic life. Recently, a brain specific gene, Doublecortin, was cloned and was shown to have mutations in X-linked lissencephaly and double cortex syndrome. KIAA0369 is a putative kinase that is structurally related to Doublecortin. We compared the expression of KIAA0369 with that of Doublecortin, both of which were expressed specifically or predominantly in fetal brain among 20 different tissues examined. The deduced products of both genes contain a unique domain (the Doublecortin [DC] domain), but KIAA0369 also contains a calmodulin-dependent kinase (CaM kinase)-like domain following the DC domain. We found at least four splicing variants of KIAA0369: KIAA0369-AS (type A, short version), KIAA0369-AL (type A, long version), KIAA0369-BS (type B, short version), and KIAA0369-BL (type B, long version). KIAA0369-B, which lacked the DC domain and maintained the kinase domain, was expressed in adult as well as fetal brain, but the variants that included the DC domain, KIAA0369-A, were expressed predominantly in fetal brain. These results suggest that the DC domain plays an important role in the development of the nervous system. In the adult brain, KIAA0369 was expressed in all 15 different regions examined, more intensely in cerebral cortex, occipital pole, frontal lobe, amygdala, and hippocampus, and less intensely in corpus callosum and thalamus. The murine homologs of Doublecortin and KIAA0369 were not detectable in 7-day mouse embryos, but both genes were expressed extensively in 11-day embryos. Human KIAA0369 was mapped by fluorescence in situ hybridization (FISH) to chromosome 13q13-q14.1. The presence of genes related to neuropathy has been reported in this locus.

Adult↗
PubMed1998

Plasma concentration of immunoreactive vascular endothelial growth factor and its relation to smoking.

We determined the plasma concentration of immunoreactive vascular endothelial growth factor (IR-VEGF) and searched for a relationship between it and the degree of microangiopathy. The plasma VEGF level was measured using an enzyme immunoassay in 110 non-insulin-dependent diabetes mellitus (NIDDM) patients with varying degrees of nephropathy or retinopathy (RP) and in 39 healthy controls and 30 nondiabetic patients for comparison. One fourth of the control subjects, 60% of whom were currently smokers, had plasma levels of IR-VEGF higher than the lower limit (15.6 pg/mL) of detection for this assay, whereas this was the case in half of the NIDDM patients. Plasma IR-VEGF was detectable in all patients with cerebral infarction, chronic renal failure, and severe infection, suggesting that tissue hypoxia might be a common cause for the elevation of plasma VEGF in these disorders. The prevalence of measurable plasma IR-VEGF levels increased in parallel with increases in the urinary albumin excretion rate ([UAER] 35.1% for UAER <30 mg/24 h, 54.8% for UAER 30 to 300 mg/24 h, and 61.3% for UAER >300 mg/24 h; P < .05 v UAER <30 mg/24 h). The mean measurable plasma concentration tended to increase with increasing UAER. However, there was no such correlation with the severity of RP. Smoking caused an acute increase of plasma IR-VEGF in only 22.6% (12 of 53) of the patients with a smoking habit. In conclusion, these findings suggest that circulating IR-VEGF may be linked to the progression of nephropathy, and smoking may facilitate this process by causing tissue hypoxia in susceptible patients.

Adult↗
PubMed1998

Circulating proinsulin levels in insulin-dependent diabetic patients after whole pancreas-kidney transplantation.

Disproportional hyperproinsulinemia is a sensitive marker for beta-cell dysfunction. The objective of this study was to assess the proinsulin profile in persons with insulin-dependent diabetes mellitus (IDDM) after pancreas-kidney transplantation. We determined serum insulin, C-peptide, and proinsulin concentrations during an oral glucose challenge in five pancreas-kidney transplant recipients, nine nondiabetic kidney transplant recipients, and 17 normal subjects. Basal proinsulin concentrations were significantly increased in pancreas-kidney recipients (geometric mean [+/-1 SE range], 6.0 [5.5 to 6.4] pmol/L) and kidney recipients (6.4 [5.4 to 7.5] pmol/L) compared with the normal subjects (2.8 [2.5 to 3.2] pmol/L). Integrated proinsulin concentrations during the oral glucose load were also higher in pancreas-kidney recipients (1.4 [1.1 to 1.8] nmol/L x min) and kidney recipients (1.5 [1.2 to 2.0] nmol/L x min) versus normal subjects (0.8 [0.7 to 0.9] nmol/L x min). There was no difference in basal or integrated proinsulin concentrations between the two transplant groups. Even after adjustment for the glomerular filtration rate (GFR), basal and incremental proinsulin concentrations continued to be higher in the transplant groups than in the normal subjects. Proinsulin to C-peptide molar ratios both before and after the glucose load were similar in the three groups. From these findings, we conclude that pancreas-kidney transplantation provokes proportional hyperproinsulinemia, which is closely associated with its reduced clearance in the kidneys.

Adult↗
PubMed1998

Onset age-dependent variations of three islet specific autoantibodies in Japanese IDDM patients.

The age related incidence rate of insulin-dependent diabetes mellitus shows a bimodal distribution, not only in Caucasians but also in Japanese. To evaluate the onset age-related autoimmune profile at presentation in insulin-dependent diabetes mellitus (IDDM), glutamic acid decarboxylase (GAD) autoantibody, islet cell antibody (ICA), and insulin autoantibody (IAA) were measured in 137 newly diagnosed Japanese IDDM patients with onset ages between 0-29 years. The prevalence of GAD autoantibody was significantly increased from the lowest (32%) in the 0-5 years onset age group to 75% in the 13-19 years onset age group (P < 0.05), whereas the IAA prevalence significantly decreased from the peak (48%) in the 6-12 years onset age group to 10% in the 20-29 years onset age group (P < 0.05). The ICA prevalence was increased from the lowest (32%) in the 0-5 years onset age group to the highest (53%) in the 20-29 years onset age group similar to that for the GAD autoantibody. Such results demonstrate that there was age-related autoimmune characteristics at presentation of IDDM in Japanese as well as in Caucasians.

Adolescent↗