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Makoto Arai

Publications and source records attributed to Makoto Arai.

At least 19 recordsLinked to original sources
PubMed2007

Synaptotagmin XI as a candidate gene for susceptibility to schizophrenia.

Synaptotagmin XI (Syt11) is a member of the synaptotagmin family, which is localized in cells either in synaptic vesicles or the cellular membrane, and is known to act as a calcium sensor. The Syt11 gene is located on chromosome locus 1q21-q22, which was previously reported as a major susceptibility locus of familial schizophrenia. Here, we present evidence for an association between the number of 33-bp repeats in the promoter region of the Syt11 gene and schizophrenia. We found that the transcriptional activity of the gene is affected by the number of 33-bp repeats, which include an Sp1 binding site, suggesting that the excessive expression of Syt11 can be associated with schizophrenia. Another (single nucleotide) polymorphism in the Syt11 5'UTR region, where the potent transcription factor YY1 can bind, also affects the transcriptional activity of Syt11.

Base Sequence↗
PubMed2007

A resistance gene in disguise for schizophrenia?

We examined the hypothesis that -485 T, a novel polymorphism in the promoter region of the neuropeptide Y gene which was shown to be associated with schizophrenia in our previous paper, confers susceptibility to the disease. For a case-control association study, 331 unrelated Japanese schizophrenics (S(1): milder cases in the previous study, n = 212; and S(2): additional severer cases, n = 119) and 199 unrelated normal controls were recruited. Contribution of -485 T to the risk and the severity of the illness was examined by (1) comparing the risk in each genotype in the general population, (2) testing correlations between the gene-dose of -485 T, and the severity of chronic outcome in S(2) assessed with the Positive and Negative Symptom Scale, and (3) comparing the distribution of age at onset in S(1) + S(2) among the three genotypes. -485 T was significantly associated with schizophrenia in S(1) + S(2). Significant negative correlations were observed between the gene-dose and the symptom assessment scores in all items. The homozygote of -485 T showed a second peak frequency in the late-onset group both in males and females, while the homozygote of the alternative allele showed a single peak in the early-onset group. The higher risk of schizophrenia in the heterozygote than in the homozygote of -485 T in the general population did not support the possibility of linkage disequilibrium with a susceptibility gene. -485 T most likely confers resistance but not susceptibility to schizophrenia. An interaction between a nuclear resistance gene and a presumptive pathogenic gene in the mitochondrial DNA was suggested.

Age Distribution↗
PubMed2006

Monoallelic and unequal allelic expression of the HTR2A gene in human brain and peripheral lymphocytes.

BACKGROUND: The 102T/C polymorphism of the serotonin 2A receptor (HTR2A) gene is reported to be associated with schizophrenia and other diseases and phenotypes. Altered HTR2A expression has been found in relation to several neuropsychiatric conditions, including depression and schizophrenia. Studies of expression of HTR2A messenger RNA (mRNA) and protein in postmortem brains suggest that the 102C allele might be less transcriptionally active than the T allele. However, equal expression of both alleles has also been reported. METHODS: We performed primer extension assays to measure relative expression of allele-specific HTR2A transcripts in mRNAs isolated from the prefrontal cortex of 31 individuals with schizophrenia and from peripheral lymphocytes (PBLs) of 31 healthy individuals heterozygous for 102T/C. We also examined the allele transmission pattern of HTR2A in PBLs of nine families. RESULTS: Analyses of DNA and mRNA revealed that 102C is expressed but at lower levels than 102T in brains. In contrast to the biallelic expression observed in brains, monoallelic expression of HTR2A was common in PBLs. However, a family study revealed that imprinting was not responsible for the monoallelic expression in PBLs. CONCLUSIONS: The present study revealed a tissue-specific modification of HTR2A expression, which makes allelic and epiallelic analyses necessary for genetic epidemiologic and pharmacogenomic studies of HTR2A.

Aged↗
PubMed2006

Analysis of genes upregulated by the demethylating agent 5-aza-2'-deoxycytidine in gastric cancer cell lines.

In gastric cancer, increasing numbers of genes have been reported to be silenced by aberrant methylation. However, global analysis of epigenetic inactivation in cancer cells has rarely been performed. For screening the genes upregulated by the demethylating agent 5-aza-2'-deoxycytidine (DAC), cDNA microarray analysis (AceGene(R), containing 30,000 genes) was performed using gastric cancer cell lines (AGS, MKN74, MKN1, MKN45 and Kato3) treated with DAC. The candidate upregulated genes were confirmed by real-time PCR, and the methylation status of 5'CpG islands was determined by bisulfite DNA sequencing or methylation-specific PCR. Among the upregulated genes considered to have CpG island in their promoter regions, we selected 5 genes (BCL2L10, DKK1, DNAJD1, GAGED2 and NMU) that exhibited a greater than 3-fold increase in at least 2 cell lines. Of these, we could determine the methylation status of 5'CpG islands of BCL2L10, DKK1 and DNAJD1. 5'CpG of BCL2L10 and DNAJD1 was hypermethylated in 4 of 5 gastric cancer cell lines, whereas 5'CpG of DKK1 was hypermethylated in only 1 cell line. MSP analysis for BCL2L10 revealed that the CpG island was demethylated after DAC treatment. In addition, we observed that overexpression of BCL2L10 could promote apoptosis and growth-inhibitory effect in gastric cancer cell lines. In conclusion, some of the genes upregulated by DAC treatment may be transcriptionally repressed by promoter hypermethylation. These genes might be related to gastric carcinogenesis. In particular, the suppression of BCL2L10, which could induce apoptosis and inhibit proliferation of cancer cells, might be one of the underlying mechanisms for gastric carcinogenesis.

Azacitidine↗
PubMed2006

Sequential gene expression changes in cancer cell lines after treatment with the demethylation agent 5-Aza-2'-deoxycytidine.

BACKGROUND: 5-Aza-2'-deoxycytidine (5-AzaC) is known well for its demethylation effect and is a promising anticancer agent. However, to the authors' knowledge, serial changes in gene expression over time after 5-AzaC treatment have not been studied to date. To clarify the categories of genes that are up-regulated or down-regulated after 5-AzaC treatment, the authors surveyed the genes that had expression levels changed by 5-AzaC treatment in 6 hepatoma cell lines (Hep3B, HLE, Huh7, HepG2, PLC/PRF/5, and Huh6). METHODS: Cell lines were grown in medium that contained 1 microM of 5-AzaC. Changes in messenger RNA levels were monitored from 24 hours up to 120 hours after 5-AzaC treatment using an in-house microarray that consisted of 4608 combinational DNAs. Using clustering analysis to identify the genes that had gradually changed expression levels and to exclude the substantial experimental noise by microarray analysis, the authors focused on 206 up-regulated genes and 248 down-regulated genes. RESULTS: According to their functional characterization, genes that were involved in the cytoskeleton and the extracellular matrix were enriched significantly in the up-regulated genes. Conversely, genes that were involved in metabolism were enriched significantly in the down-regulated genes. CONCLUSIONS: The current results demonstrated that 5-AzaC can regulate the expression of groups of genes with characteristic functions.

Azacitidine↗
PubMed2006

Molecular biology of hepatitis B virus: effect of nucleotide substitutions on the clinical features of chronic hepatitis B.

Hepatitis B virus (HBV) is a major cause of liver disease worldwide. It is covered with envelope (surface antigen) proteins with the nucleocapsid (core antigen) inside. In the nucleocapsid, there is an incomplete double-stranded DNA and a DNA polymerase. Four genes, S, C, X, and P, are encoded, and these partially overlap. Mutations have been reported in each gene and in their promoter regions, and these mutations can change the efficiency of HBV replication and the clinical course of patients. In this article, we review the relationship between the molecular biology of HBV and its clinical outcome.

Base Pairing↗
PubMed2006

Serum osteopontin levels in patients with acute liver dysfunction.

OBJECTIVE: Fulminant hepatic failure (FHF) is a clinical syndrome of sudden and severe liver dysfunction accompanied by encephalopathy in a previously healthy person. In FHF, hepatocytes are severely damaged and ordinary liver regeneration is impaired. We demonstrated that the expression of osteopontin (OPN), a multifunctional cytokine, was up-regulated in mouse oval cell (a stem-cell progenitor) induction models. MATERIAL AND METHODS: Based on this finding, serum OPN levels were examined in 43 patients with FHF and in 45 patients with acute self-limited hepatitis (AH). To determine the cellular source of OPN, the expression of OPN was studied in a liver specimen derived from an FHF patient. RESULTS: The mean OPN level of patients with FHF was 2.80+/-0.48 ng/ml (log(10), +/-SD), which was significantly higher than that of the patients with AH (2.42+/-0.39 ng/ml) (p=0.003, unpaired t-test). Patients with elevated serum OPN levels had a significantly poorer prognosis than patients whose serum OPN levels were not elevated. In the FHF patient's liver, OPN protein was expressed not only in inflammatory cells but also in regenerating hepatocytes and bile ductular structures. CONCLUSIONS: Our current study indicates that serum OPN levels increased in patients with FHF and that OPN might play an important role in liver regeneration due to activation of hepatic stem cells.

Acute Disease↗
PubMed2005

A 200-kb region of human chromosome 22q11.2 confers antipsychotic-responsive behavioral abnormalities in mice.

Human chromosome 22q11.2 has been implicated in various behavioral abnormalities, including schizophrenia and other neuropsychiatric/behavioral disorders. However, the specific genes within 22q11.2 that contribute to these disorders are still poorly understood. Here, we show that an approximately 200-kb segment of human 22q11.2 causes specific behavioral abnormalities in mice. Mice that overexpress an approximately 200-kb region of human 22q11.2, containing CDCrel, GP1Bbeta, TBX1, and WDR14, exhibited spontaneous sensitization of hyperactivity and a lack of habituation. These effects were ameliorated by antipsychotic drugs. The transgenic mice were also impaired in nesting behavior. Although Tbx1 has been shown to be responsible for many physical defects associated with 22q11.2 haploinsufficiency, Tbx1 heterozygous mice did not display these behavioral abnormalities. Our results show that the approximately 200-kb region of 22q11.2 contains a gene(s) responsible for behavioral abnormalities and suggest that distinct genetic components within 22q11.2 mediate physical and behavioral abnormalities.

Abnormalities, Multiple↗
PubMed2005

Association between polymorphisms in the promoter region of the sialyltransferase 8B (SIAT8B) gene and schizophrenia.

BACKGROUND: Sialyltransferase 8B (SIAT8B) and 8D (SIAT8D) are two polysialyltransferases that catalyze the transfer of polysialic acid (PSA) to the neural cell adhesion molecule 1 (NCAM1). PSA modification of NCAM1 plays an important role in neurodevelopment of the brain and disruption of this process is postulated as an etiologic factor in psychiatric disorders. Altered levels of the PSA-NCAM1 in the brain of schizophrenics have been reported, suggesting a role for this molecule in the disorder. METHODS: We performed an association study of single nucleotide polymorphisms (SNPs) within SIAT8B and SIAT8D, using 188 schizophrenics and 156 age and gender matched controls. All genotypes were determined by polymerase chain reaction (PCR) amplification and direct sequencing. RESULTS: Two polymorphisms, -1126T > C and -851T > C, located in the promoter region of SIAT8B showed nominally significant association with schizophrenia (allelic associations, p = .014 and p = .007, respectively), and haplotypes constructed from three additional SNPs located in the same linkage disequilibrium block were associated with schizophrenia. Furthermore an in vitro promoter assay revealed that a reporter construct containing a risk haplotype for SIAT8B had significantly higher transcriptional activity compared with one containing a protective haplotype (p = .021). In contrast, no significant association was observed between any variations in SIAT8D and schizophrenia. CONCLUSIONS: The present study suggests that functional promoter SNPs of SIAT8B could confer a risk for schizophrenia in the Japanese population.

Alleles↗
PubMed2005

A polymorphism in the PDLIM5 gene associated with gene expression and schizophrenia.

BACKGROUND: Results of recent DNA microarray analyses of postmortem brains of patients with schizophrenia revealed that expression of the PDZ and LIM domain 5 gene (PDLIM5) is increased. In the present study, we examined whether polymorphisms in PDLIM5 are associated with schizophrenia. METHODS: We screened for mutations in PDLIM5 in 24 Japanese patients with schizophrenia and evaluated the associations of the identified polymorphisms with schizophrenia in a Japanese case-control population (total samples, 278 schizophrenia patients and 462 control subjects). Expression of PDLIM5 was quantified by real-time quantitative polymerase chain reaction (PCR) in postmortem prefrontal cortex of 34 schizophrenia patients. Electrophoretic mobility shift assay (EMSA) was performed to examine whether a polymorphism influences nuclear protein binding. RESULTS: We identified 27 polymorphisms in PDLIM5 and found associations between polymorphisms (rs2433320 and rs2433322) in the 5' region of the gene and schizophrenia (p = .004). Real-time quantitative PCR revealed that these polymorphisms influenced gene expression (p = .007). An EMSA showed that the different alleles of the rs2433320 polymorphism bound differently to nuclear proteins. CONCLUSIONS: These results suggest that PDLIM5 might play a role in genetic susceptibility to schizophrenia.

Adult↗
PubMed2005

Enhanced sensitivity of human hepatoma cells to 5-fluorouracil by small interfering RNA targeting Bcl-2.

This study was designed to reveal whether the apoptosis induced in human hepatocellular carcinoma (HCC) cell lines by 5-fluorouracil (5-FU) could be enhanced by transfecting Bcl-2 small interfering RNA (siRNA). Bcl-2 siRNA and control siRNA were transfected into cells following treatment with or without 5-FU. Suppression of Bcl-2 expression was confirmed by Western blotting; cell viability was evaluated by MTS assay, and the occurrence of apoptosis in cells was evaluated by apoptosis assay. Expression of Bcl-2 protein after transfection of 20 nM Bcl-2 siRNA was significantly lower than that of control. Incubation of all cell lines with Bcl-2 siRNA reduced cell viability 96 h after 5-FU treatment compared with all other controls: Huh-7 (P < 0.01), Huh-7 with hepatitis C replicon (P < 0.01), HepG2 (P < 0.01), HLE (P < 0.05). Moreover, the proportion of apoptosis in control siRNA, Bcl-2 siRNA, control siRNA prior to 5-FU treatment, and Bcl-2 siRNA prior to 5-FU treatment groups were (4.6 +/- 2.3)%, (7.5 +/- 0.5)%, (6.0 +/- 2.1)%, and (19.5 +/- 0.86)%, respectively. The Bcl-2 siRNA prior to 5-FU treatment group showed the strongest effect of inducing apoptosis. In conclusion, the combination Bcl-2 siRNA and 5-FU might represent a new therapeutic option for HCC.

Antimetabolites, Antineoplastic↗
PubMed2004

Association study of polymorphisms in the 5' upstream region of human DISC1 gene with schizophrenia.

Disrupted-in-Schizophrenia-1 (DISC1) is a gene in which a mutant truncation by a balanced t(1;11)(p42.1;q14.3) translocation is segregated with major psychiatric illness with a predominance of schizophrenic symptomatology in a large Scottish family. However, no functional polymorphisms have been detected that are associated with schizophrenia in general populations. As prior polymorphism searches in DISC1 have been focused on coding exons and flanking introns, the present study examined sequence variations in the 5' upstream region of DISC1. Screening of exon 1 through to approximately 1.0 kb upstream of exon 1 identified 6 polymorphisms, including 2 novel variants, -94C>A and -199(CG)(n). We tested these variants for associations with schizophrenia in the first set of a case (n = 198) and control (n = 198) panel, and found significant results with -274G>C (genotypic P = 0.01) and -215(TG)(n) (genotypic P = 0.039). However, we failed to replicate these associations in a second, larger independent patient (n = 532) and control (n = 519) sample. These results suggest that the genomic interval of DISC1 probably involved in transcriptional regulation does not display major genetic relevance in Japanese schizophrenia patients.

5' Flanking Region↗
PubMed2004

Gene expression profiles in liver regeneration with oval cell induction.

The liver has the unique ability to regenerate even in adulthood. While mature hepatocytes can proliferate by themselves, stem cells also play a critical role in liver regeneration and oval cells are considered to be the progeny of activated hepatic stem cells. We herein investigated the gene expression profiles in the conditions inducing oval cells, using microarray analysis. Two approaches were used to induce oval cells. In the first, animals were treated with a combination of an N-2-acetylaminofluorene (AAF)-containing diet and partial hepatectomy (PHx). In the second, animals were supplied with chow containing a 1:1 mixture of choline-deficient and normal diets, as well as 0.075% ethionine in drinking water. Using in-house cDNA microarrays consisting of 2304 cDNA clones from the mouse liver, 69 and 89 genes, respectively, were found to be up-regulated in these two models. Six genes, i.e., those for insulin-like growth factor binding protein-1, CYP4a14, carnitine octanoyltransferase, osteopontin, and two expressed sequence tags (ESTs) were up-regulated in these models but not in ordinary model with PHx alone. They might be specifically activated in the induction of oval cells, and help to clarify the nature of stem cell stimulation that occurs during liver regeneration.

2-Acetylaminofluorene↗
PubMed2004

Association of neural cell adhesion molecule 1 gene polymorphisms with bipolar affective disorder in Japanese individuals.

BACKGROUND: Although the pathogenesis of mood disorders remains unclear, heritable factors have been shown to be involved. Neural cell adhesion molecule 1 (NCAM1) is known to play important roles in cell migration, neurite growth, axonal guidance, and synaptic plasticity. Disturbance of these neurodevelopmental processes is proposed as one etiology for mood disorder. We therefore undertook genetic analysis of NCAM1 in mood disorders. METHODS: We determined the complete genomic organization of human NCAM1 gene by comparing complementary deoxyribonucleic acid and genomic sequences; mutation screening detected 11 polymorphisms. The genotypic, allelic, and haplotype distributions of these variants were analyzed in unrelated control individuals (n = 357) and patients with bipolar disorder (n = 151) and unipolar disorder (n = 78), all from central Japan. RESULTS: Three single nucleotide polymorphisms, IVS6+32T>C, IVS7+11G>C and IVS12+21C>A, displayed significant associations with bipolar disorder (for allelic associations, nominal p =.04, p =.02, and p =.004, respectively, all p >.05 after Bonferroni corrections). Furthermore, the haplotype located in a linkage disequilibrium block was strongly associated with bipolar disorder (the p value of the most significant three-marker haplotype is .005). CONCLUSIONS: Our results suggest that genetic variations in NCAM1 or nearby genes could confer risks associated with bipolar affective disorder in Japanese individuals.

Adult↗
PubMed2004

Effects of antithrombin III on spinal cord-evoked potentials and functional recovery after spinal cord injury in rats.

STUDY DESIGN: From the view of motor function, spinal cord-evoked potentials, and histology, we evaluated the effects of antithrombin III on a spinal cord injury resulting in incomplete paraplegia. OBJECTIVES: To investigate the effect of antithrombin III on the recovery process after acute incomplete rat spinal cord injury. SUMMARY OF BACKGROUND DATA: Antithrombin III is used for treating disseminated intravascular coagulation by its anticoagulant effect and is also reported to reduce organ damage by the release of prostaglandin I2 from endothelial cells, induced by antithrombin III. Therefore, antithrombin III has potential as a therapeutic agent for spinal cord damage. METHODS: The spinal cord injury was induced by placing a 25 g weight on the dorsal surface of the spinal cord at the 10th thoracic spine level for 20 minutes. Antithrombin III (250 U/kg) was administered intravenously 5 minutes before the compression, whereas 2 mL of physiologic saline solution was administered to the control group. We recorded the spinal cord-evoked potentials at the T13 level after stimulation of the brain and C7 level. For 12 weeks after the injury, we observed the recovery course of waveform and motor function. The recovery of motor function was evaluated by using inclined table and modified Tarlov scores. We also examined the histology of the compressed site in the spinal cord. RESULTS: There were statistically significant differences in the motor recovery process between the two groups. Evoked potentials of the antithrombin III group recovered earlier than those of the control group. Histologically, hemorrhage and tissue defects in the spinal cord were less in the antithrombin III group. CONCLUSION: Because antithrombin III facilitated the recovery of behavior and evoked potentials, these findings suggest that antithrombin III may have a positive effect on the recovery of incomplete spinal cord injury.

Animals↗
PubMed2004

A case of severe acute hepatitis of unknown etiology treated with the Chinese herbal medicine Inchinko-to.

A prolonged severe hepatitis of unknown etiology was treated with Inchinko-to, a Chinese herbal medicine, and this case is herein described. Inchinko-to was given with ursodeoxycholic acid (UDCA) and glycyrrhizin. The improvement in the patient's liver function seemed to be accelerated after the treatment, especially after stopping the administration of kanamycin sulfate which might possibly inhibit the conversion of geniposide, one of the constituents of Inchinko-to, to an active ingredient through the suppression of the bacterial growth in intestinal flora, suggesting the usefulness of Inchinko-to for treatment of severe hepatitis.

Journal Article↗
PubMed2004

Identification of genes up-regulated by histone deacetylase inhibition with cDNA microarray and exploration of epigenetic alterations on hepatoma cells.

BACKGROUND/AIMS: Epigenetics is the key factor in the regulation of gene expression. We conducted cDNA microarray analysis to screen for genes induced by histone deacetylase (HDAC) inhibition and examined epigenetic alterations. METHODS: Microarray analysis was performed in six hepatoma cell lines and primary hepatocytes treated with trichostatin A (TSA). mRNA expression of several genes was examined by reverse transcription-polymerase chain reaction in TSA-treated cells and hepatoma samples. Acetylated histones and methylation status in 5'CpG islands was assessed by chromatin immunoprecipitation (ChIP) assay and bisulfite genomic sequencing, respectively. RESULTS: Fifty-seven genes showed greater than 2-fold change after TSA treatment in multiple cell lines. Among them, four genes including p21(WAF1) exhibited substantial induction (greater than 5-fold changes). Decreased mRNA levels of these genes in hepatoma tissues were observed in more than half of patients. ChIP assay, in general, demonstrated a good correlation between mRNA expression and histone acetylation, but only a limited correlation with the methylated DNA in the promoter region. CONCLUSIONS: We identified 57 up-regulated genes by TSA treatment in hepatoma cells and some of them appeared to be cancer-related genes in hepatomas. The alterations in acetylated histones are likely closely associated with gene expression.

Acetylation↗