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Yuji Tanaka

Publications and source records attributed to Yuji Tanaka.

At least 19 recordsLinked to original sources
PubMed2025

SLC25A11 Is Associated with KDM2A-Dependent Reduction in rRNA Transcription Induced by Aminooxyacetic Acid.

The malate-aspartate shuttle (MAS) is an NADH shuttle that transports cytoplasmic reducing equivalents to the mitochondria for producing energy. We previously demonstrated that K-demethylase 2A (KDM2A), a jmjC-type histone demethylase, decreases ribosomal RNA (rRNA) transcription via demethylation of H3K36me2 in the rRNA gene promoter region in response to energy reduction in MCF-7 cells. However, whether MAS inhibition is involved in KDM2A activity has not been investigated. In this study, we demonstrate that aminooxyacetic acid (AOA), which inhibits aspartate transaminase (AST/GOT) in MAS, decreased intracellular ATP levels and reduced rRNA transcription via KDM2A-dependent reduction in H3K36me2 levels in the rRNA gene promoter in MCF-7 cells. On the other hand, N-phenylmaleimide (NPM), which inhibits the mitochondrial αKG/malate carrier SLC25A11 in MAS, also decreased intracellular ATP levels but did not induce KDM2A activity. Additionally, NPM pretreatment or knockdown of SLC25A11 inhibited AOA-induced KDM2A activity. Dimethyl αKG, a cell-permeable αKG, restored KDM2A activity inhibited by NPM-pretreatment in AOA-treated cells. These results demonstrate that AOA and NPM have different abilities to induce a decrease in rRNA transcription via KDM2A. Furthermore, the αKG/malate carrier SLC25A11 is associated with KDM2A-dependent reduction in rRNA transcription via demethylation under MAS inhibition.

Humans↗
PubMed2006

Hepatic ischemia-reperfusion induces renal heme oxygenase-1 via NF-E2-related factor 2 in rats and mice.

Hepatic ischemia-reperfusion (IR) results in Kupffer cell activation and subsequent tumor necrosis factor (TNF) alpha release, leading to localized hepatic injury and remote organ dysfunction. Heme oxygenase (HO)-1 is an enzyme that is induced by various stimuli, including proinflammatory cytokines, and exerts antioxidative and anti-inflammatory functions. Up-regulation of HO-1 is known to protect against hepatic IR injury, but the effects of hepatic IR on the kidney are poorly understood. Thus, the purpose of this study was to determine whether hepatic IR and resultant Kupffer cell activation alters renal HO-1 expression. Male Sprague-Dawley rats and wild-type and NF-E2-related factor 2 (Nrf2)-null mice were subjected to 60 min of partial hepatic ischemia, and at various times thereafter, blood, liver, and kidneys were collected. After reperfusion, 1) creatinine clearance decreased; 2) HO-1 mRNA and protein expression in liver and kidney markedly increased; 3) renal NAD(P)H: quinone oxidoreductase 1 mRNA expression was induced; 4) serum TNFalpha levels increased; 5) Nrf2 translocation into the nucleus of renal tissue increased; and 6) renal and urinary 15-deoxy-Delta(12,14)-prostaglandin J2 (15-d-PGJ2) levels increased. Kupffer cell depletion by pretreating with gadolinium chloride 1) attenuated increased mRNA expression of HO-1 in kidney; 2) attenuated the increase in TNFalpha; 3) inhibited the increase in Nrf2 nuclear translocation; and 4) tended to attenuate renal 15-d-PGJ2 levels. Whereas renal HO-1 mRNA expression increased in wild-type mice, it was attenuated in Nrf2-null mice. These results suggest that renal HO-1 is induced via Nrf2 to protect the kidney from remote organ injury after hepatic IR.

Animals↗
PubMed2006

Transcriptional repression of the mouse wee1 gene by TBP-related factor 2.

TBP-related factor 2 (TRF2), one of the TBP family proteins, is involved in various cellular functions through its transcription stimulation activity. We previously reported that TRF2 is involved in reduction of wee1 mRNA in genotoxin-treated chicken cells. In this study, we investigated the role of TRF2 in wee1 gene expression. It was found that wee1 mRNA was decreased in hydroxyurea-treated NIH3T3 cells. Mouse wee1 promoter activity was repressed by TRF2 in mouse and chicken cells. Chromatin immunoprecipitation and plasmid immunoprecipitation analyses revealed that TRF2 is recruited to the wee1 promoter in accordance with the transcriptional repression. A mutant TRF2 that lacks TFIIA-binding capacity lost its repressive function. This mutant was less recruited to the wee1 promoter than was the wild-type one, and provided a decline in promoter-recruited TFIIA. Data in this study suggest that transcription repressive activity of TRF2 to wee1 promoter needs association with the promoter and TFIIA.

Animals↗
PubMed2006

TATA-binding protein-related factor 2 is localized in the cytoplasm of mammalian cells and much of it migrates to the nucleus in response to genotoxic agents.

TBP (TATA-binding protein)-related factor 2 (TRF2) regulates transcription during a nuber of cellular processes. We previously demonstrated that it is localized in the cytoplasm and is translocated to the nucleus by DNA-damaging agents. However, the cytoplasmic localization of TRF2 is controversial. In this study, we reconfirmed its cytoplasmic localization in various ways and examined its nuclear migration. Stresses such as heat shock, redox agents, heavy metals, and osmotic shock did not affect localization whereas genotoxins such as methyl methanesulfonate (MMS), cisplatin, etoposide, and hydroxyurea caused it to migrate to the nucleus. Adriamycin, mitomycin C and gamma-rays had no obvious effect. We determined optimal conditions for the nuclear migration. The proportions of cells with nuclei enriched for TRF2 were 25-60% and 5-10% for stressed cells and control cells, respectively. Nuclear translocation was observed after 1 h, 4 h and 12 h for cisplatin, etoposide and MMS and hydroxyurea, respectively. The association of TRF2 with the chromatin and promoter region of the proliferating cell nuclear antigen (PCNA) gene, a putative target of TRF2, was increased by MMS treatment. Thus TRF2 may be involved in genotoxin-induced transcriptional regulation.

Active Transport, Cell Nucleus↗
PubMed2006

A genetic variant of the serine racemase gene is associated with schizophrenia.

BACKGROUND: Serine racemase (SRR) is a brain-enriched enzyme that converts L-serine to D-serine, which acts as an endogenous ligand of N-methyl D-aspartate (NMDA) receptors. Dysfunction of SRR may reduce the function of NMDA receptors and susceptibility to schizophrenia. METHODS: We genotyped three single-nucleotide polymorphisms (SNPs) of the 5' region of the SRR gene in 525 patients with schizophrenia and 524 healthy controls. Effects of SNPs on the promoter activity and on serum levels of total and D-serine were examined. RESULTS: We found a significant excess of the IVS1a+465C allele of the SRR gene in schizophrenia, especially in the paranoid subtype (p = .0028). A reporter assay showed that the IVS1a+465C allele had 60% lower promoter activity than did the IVS1a+465G allele. CONCLUSIONS: The IVS1a+465C allele of the SRR gene, which reduces expression of the gene, is a risk factor for schizophrenia, especially the paranoid subtype.

Adult↗
PubMed2006

Successful engraftment of mismatched unrelated cord blood transplantation following reduced intensity preparative regimen using fludarabine and busulfan.

We conducted a pilot study to evaluate the feasibility of reduced-intensity cord blood transplantation (RI-CBT) using a non-total body irradiation (TBI) regimen in adult patients with advanced hematologic malignancies. Seventeen patients with a median age of 58 years (range, 38-74) underwent RI-CBT at Tsukuba Memorial Hospital between April 2004 and November 2005. Preparative regimens were fludarabine 30 mg/m(2) for 6 days, and busulfan 4 mg/kg for 2 days. Tacrolimus was used for prophylaxis of graft-vs-host disease (GVHD). Median numbers of infused total nucleated were 2.6 x 10(7)/kg (range, 2.0-3.3). HLA disparity was found in 2/6 antigens (n=16) and 1/6 antigens (n=1). Underlying diseases progressed despite preparative regimens in four patients. Of the remaining 13 patients, nine patients achieved engraftment at a median of day 18 (range, 17-28). Six of the nine patients with engraftment achieved complete donor-type chimerism by day 100. Six patients were alive in remission at median follow-up of 13.1 months (range, 1.0-19.0). This study demonstrated the feasibility of RI-CBT using a non-TBI regimen in adults. When disease progression is controlled by the preparative regimen, RI-CBT carries a clinically significant graft-vs-tumor effect. Further studies are required to identify patients who benefit from this regimen.

Adult↗
PubMed2006

Parkinson's disease genetic mutations increase cell susceptibility to stress: mutant alpha-synuclein enhances H2O2- and Sin-1-induced cell death.

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by selective loss of dopaminergic neurons and the presence of Lewy bodies. Alpha-synuclein is a major component of Lewy bodies in sporadic PD, and genetic alterations in alpha-synuclein cause autosomal-dominant hereditary PD. The pathogenesis of PD remains incompletely understood, but it appears to involve both genetic susceptibility and environmental factors. Here we investigated the effect of alpha-synuclein expression on cell susceptibility to proteasome inhibition, oxidative and nitrative stresses by using a PC 12-Tet-off regulatory system. We found that inducible expression of A30P or A53T mutant alpha-synuclein decreased the proteasome activity, increased intracellular ROS levels, and enhanced lactacystin- and H2O2-induced cell death. Furthermore, 3-nitrotyrosine levels increased in cells expressing alpha-synuclein, and further increased after Sin-1 (a NO donor) treatment compared with untreated or treated non-induced cells. Expression of alpha-synuclein (mutant more than wild type) significantly enhances Sin-1 toxicity. These results indicate that genetic mutations in alpha-synuclein may increase neuronal vulnerability to cellular stress in aging and PD pathogenesis.

Animals↗
PubMed2006

Kupffer cell-mediated downregulation of hepatic transporter expression in rat hepatic ischemia-reperfusion.

BACKGROUND: Hepatic ischemia-reperfusion (IR) injury is frequently followed by cholestatic liver disease. Cytokines released by Kupffer cells following hepatic IR injury may subsequently regulate hepatic transporter expression. The purpose of this study was to determine whether hepatic IR injury and the resultant Kupffer cell activation alters hepatic transporter expression. METHODS: Rats were subjected to 60 minutes of partial hepatic ischemia followed by 0, 3, 6, 24, or 48 hours of reperfusion. After IR surgery, the following were determined: 1) serum bilirubin and bile acid levels; 2) serum levels of cytokines, such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL6; 3) expression of several hepatic transporters; and 4) nuclear protein levels of hepatocyte nuclear factor (HNF)-1alpha and retinoid X receptor (RXR)-alpha to investigate whether altered expression of hepatic transporters following IR is associated with decreases in these transcription factors. RESULTS: After reperfusion: 1) serum bilirubin and bile acids increased; 2) levels of all three cytokines increased; 3) mRNA expression of hepatic transporters organic anion transporting polypeptide (Oatp) 1a1, Oatp1a4, Oatp1b2, sodium taurocholate cotransporting polypeptide, multidrug resistance-associated protein (Mdr) 2, and bile salt export pump decreased, whereas Mdr1b expression increased; and 4) nuclear protein levels of HNF1alpha decreased, whereas RXRalpha was not altered. Pretreatment with gadolinium chloride to deplete Kupffer cells before IR: 1) blocked the increase in serum bile acids, 2) attenuated TNFalpha but not IL1beta/IL6 levels, 3) inhibited the altered hepatic transporter expression, and 4) blocked the decrease in HNF1alpha nuclear protein levels. CONCLUSIONS: These results suggest that alterations in hepatic transporter expression during IR occur through Kupffer cell-mediated events, possibly involving a decrease in nuclear HNF1alpha.

Alanine Transaminase↗
PubMed2006

Genetic variant of prodynorphin gene is risk factor for methamphetamine dependence.

Previous studies have indicated that genetic factors substantially affect development of substance use disorders, including methamphetamine dependence. Prodynorphin (PDYN) is an opioid peptide precursor that yields dynorphins, endogenous kappa opioid-receptor agonists that play important roles in substance abuse. A physiologically active polymorphism of 1-4 repeats of a 68-bp element in the promoter region of the PDYN gene has been identified. We analyzed this polymorphism of the PDYN gene by a case-control association study in 143 patients with methamphetamine dependence and 209 healthy controls in the Japanese population. A 3- or 4-repeat allele in the PDYN gene promoter was found significantly more frequently in patients with methamphetamine dependence than in controls (chi(2)=9.45, p=0.0021). A 3- or 4-repeat allele in the PDYN gene promoter, which was shown to produce significantly higher transcription activity of the PDYN gene than a 1- or 2-repeat allele, is a genetic risk factor for development of methamphetamine dependence (odds ratio: 1.83, 95% CI=1.24-2.68).

Adult↗
PubMed2006

Myeloablative allogeneic hematopoietic stem cell transplantation for non-Hodgkin lymphoma: a nationwide survey in Japan.

We retrospectively surveyed the data of 233 patients who underwent myeloablative allogeneic hematopoietic stem cell transplantation (allo-HSCT) for non-Hodgkin lymphoma (NHL). Donors were HLA-matched relatives in 154 patients (66%) or unrelated volunteers in 60 (26%). Ninety patients (39%) were in complete remission. One hundred ninety-three (83%) received a total body irradiation (TBI)-based regimen, and 40 (17%) received a non-TBI-based regimen. Acute graft-versus-host disease (GVHD) occurred in 155 (67%) of the 233 evaluable patients; grade II to IV in 90 (39%), and grade III to IV in 37 (16%). Treatment-related mortality (TRM) was observed in 98 patients (42%), and 68% of them were related to GVHD. In a multivariate analysis, chemoresistance, prior autograft, and chronic GVHD were identified as adverse prognostic factors for TRM. Relapse or progression of lymphoma was observed in 21%. The 2-year overall survival rates of the patients with indolent (n = 38), aggressive (n = 111), and lymphoblastic lymphoma (n = 84) were 57%, 42%, and 41%, respectively. In a multivariate analysis, chemoresistance, prior autograft, and prior radiotherapy were identified as adverse prognostic factors for overall survival. Although myeloablative allo-HSCT represents an effective therapeutic option for patients with NHL, more work is still needed to decrease TRM and relapse.

Acute Disease↗
PubMed2006

Hepatic injury following reduced intensity unrelated cord blood transplantation for adult patients with hematological diseases.

Liver injury is a common complication in allogeneic hematopoietic stem cell transplantation. Its major causes comprise graft-versus-host disease (GVHD), infection, and toxicities of preparative regimens and immunosuppressants; however, we have little information on liver injuries after reduced intensity cord blood transplantation (RICBT). We reviewed medical records of 104 recipients who underwent RICBT between March 2002 and May 2004 at Toranomon Hospital. Preparative regimen and GVHD prophylaxis comprised fludarabine/melphalan/total body irradiation and cyclosporine or tacrolimus. We assessed the etiology of liver injuries based on the clinical presentation, laboratory results, comorbid events, and imaging studies in 85 patients who achieved primary engraftment. The severity of liver dysfunction was assessed according to the National Cancer Institute Common Toxicity Criteria version 2.0. Hyperbilirubinemia was graded according to a report by Hogan et al (Blood. 2004;103:78-84). Moderate to very severe liver injuries were observed in 36 patients. Their causes included cholestatic liver disease (CLD) related to GVHD or sepsis (n = 15), GVHD (n = 7), cholangitis lenta (n = 5), and others (n = 9). Median onsets of CLD, GVHD, and cholangitis lenta were days 37, 40, and 22, respectively. Frequencies of grade 3-4 alanine aminotransferase elevation were comparable across the 3 types of hepatic injuries. Serum gamma-glutamil transpeptidase was not elevated in any patients with cholangitis lenta, whereas 27% and 40% of patients with CLD and GVHD, respectively, developed grade 3-4 gamma-glutamil transpeptidase elevation. Multivariate analysis identified 2 risk factors for hyperbilirubinemia; grade II-IV acute GVHD (relative risk, 2.23; 95% confidential interval, 1.11-4.47; P = .024) and blood stream infection (relative risk, 3.77; 95% confidential interval, 1.91-7.44; P = .00013). In conclusion, the present study has demonstrated that the hepatic injuries are significant problems after RICBT, and that GVHD and blood stream infection contribute to their pathogenesis.

Adolescent↗
PubMed2006

Usefulness and cost effectiveness of cardiovascular screening of young adolescents.

OBJECTIVES: This study was conducted to assess the usefulness of a screening system for cardiovascular disease in Kagoshima, Japan, and to compare its cost-effectiveness with that of a similar system reported in the United States. BACKGROUND: Preparticipation screening of young athletes has been implemented in many countries to prevent sudden death, but sudden death in young nonathletes remains a problem. In Japan, both athletes and nonathletes have been screened for the presence or absence of cardiovascular diseases for more than 20 yr. METHODS: From 1989 to 1997, all seventh graders in schools in Kagoshima, Japan, were screened for cardiovascular disease using a questionnaire and electrocardiogram before physical examination. They were screened again in the same way 3 yr later. One subject newly diagnosed with cardiovascular disease and recommended to limit athletic participation was defined as "high-risk." Situations leading to cases of sudden death were verified with a report from the school in question. RESULTS: Of the initial study population, 99% participated in the program every year. A total of 37,807 subjects, including nine high-risk subjects, were evaluated consecutively for 6 yr. Of these nine subjects, six, including three patients with hypertrophic cardiomyopathy, were nonathletes. Three sudden deaths occurred during the study period; one student was from the high-risk group. The cost of this screening system was lower than that reported in the United States. CONCLUSIONS: Population-based screening for heart disease in this age range is limited by various factors. To analyze the mechanisms of sudden death in adolescents, we, therefore, are in need of a nationwide registry that includes autopsies for all deadly events.

Adolescent↗
PubMed2006

[Callosal disconnection syndrome due to acute disseminated enchephalomyelitis].

We have reported a very rare case of a patient with callosal disconnection syndrome due to acute disseminated enchephalomyelitis (ADEM). A 54-year-old right-handed woman developed sudden consciousness disturbance and fever after 2 weeks when she had common cold. She did not have a history of stuttering. On admission, the neurological finding showed consciousness disturbance, and exaggerated muscle stretch reflex in four extremities without meningeal irritation. The cerebrospinal fluid examination revealed the cell counts of 273/mm3, the protein of 348 mg/dl and the myelin basic protein 18.3 pg/ml. The brain MRI demonstrated a focal high signal intensity in the right cerebellar peduncle, right temporal lobe, left occipital lobe and corpus callosum on the T2-weighted and FLAIR images. The lesion of corpus callosum was the trunk and splenium, sparing the dorsal side of splenium. Her diagnosis was ADEM. The steroid pulse therapy (metylpredinisolone 1 g/day for 3 days) improved the consciousness disturbance. After 6 weeks from the onset, the neuropsycological examination was performed. The remarkable findings included pure alexia without color naming defects, the acquired stuttering and one-way disturbance of somesthetic transfer from the left hand to the right. This patient may contribute to the study of functional localization of the corpus callosum.

Apraxias↗
PubMed2005

Endoplasmic reticulum stress and mitochondrial cell death pathways mediate A53T mutant alpha-synuclein-induced toxicity.

Parkinson's disease (PD) is a neurodegenerative movement disorder characterized by selective loss of dopaminergic neurons and the presence of Lewy bodies. Alpha-synuclein is a major component of Lewy bodies in sporadic PD, and mutations in alpha-synuclein cause autosomal-dominant hereditary PD. Here, we generated A53T mutant alpha-synuclein-inducible PC12 cell lines using the Tet-off regulatory system. Inducing expression of A53T alpha-synuclein in differentiated PC12 cells decreased proteasome activity, increased the intracellular ROS level and caused up to approximately 40% cell death, which was accompanied by mitochondrial cytochrome C release and elevation of caspase-9 and -3 activities. Cell death was partially blocked by cyclosporine A [an inhibitor of the mitochondrial permeability transition (MPT) process], z-VAD (a pan-caspase inhibitor) and inhibitors of caspase-9 and -3 but not by a caspase-8 inhibitor. Furthermore, induction of A53T alpha-synuclein increased endoplasmic reticulum (ER) stress and elevated caspase-12 activity. RNA interference to knock down caspase-12 levels or salubrinal (an ER stress inhibitor) partially protected against cell death and further reduced A53T toxicity after treatment with z-VAD. Our results indicate that both ER stress and mitochondrial dysfunction contribute to A53T alpha-synuclein-induced cell death. This study sheds light into the pathogenesis of alpha-synuclein cellular toxicity in PD and provides a cell model for screening PD therapeutic agents.

Animals↗
PubMed2005

Genomewide high-density SNP linkage analysis of 236 Japanese families supports the existence of schizophrenia susceptibility loci on chromosomes 1p, 14q, and 20p.

The Japanese Schizophrenia Sib-Pair Linkage Group (JSSLG) is a multisite collaborative study group that was organized to create a national resource for affected sib pair (ASP) studies of schizophrenia in Japan. We used a high-density single-nucleotide-polymorphism (SNP) genotyping assay, the Illumina BeadArray linkage mapping panel (version 4) comprising 5,861 SNPs, to perform a genomewide linkage analysis of JSSLG samples comprising 236 Japanese families with 268 nonindependent ASPs with schizophrenia. All subjects were Japanese. Among these families, 122 families comprised the same subjects analyzed with short tandem repeat markers. All the probands and their siblings, with the exception of seven siblings with schizoaffective disorder, had schizophrenia. After excluding SNPs with high linkage disequilibrium, we found significant evidence of linkage of schizophrenia to chromosome 1p21.2-1p13.2 (LOD=3.39) and suggestive evidence of linkage to 14q11.2 (LOD=2.87), 14q11.2-q13.2 (LOD=2.33), and 20p12.1-p11.2 (LOD=2.33). Although linkage to these regions has received little attention, these regions are included in or partially overlap the 10 regions reported by Lewis et al. that passed the two aggregate criteria of a meta-analysis. Results of the present study--which, to our knowledge, is the first genomewide analysis of schizophrenia in ASPs of a single Asian ethnicity that is comparable to the analyses done of ASPs of European descent--indicate the existence of schizophrenia susceptibility loci that are common to different ethnic groups but that likely have different ethnicity-specific effects.

Chromosomes, Human, Pair 1↗