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Junxia Yan,
Tsutomu Takahashi,
Toshihiro Ohura,
Hiroyuki Adachi,
Ikuko Takahashi,
Eishin Ogawa,
Hiroko Okuda, Hatasu Kobayashi,
Toshiaki Hitomi,
Wanyang Liu,
Kouji H Harada,
Akio Koizumi
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ABSTRACT: Familial goiter is a genetic disease showing heterogeneous expression. To identify causative genes, we investigated three multigenerational goiter families with an autosomal dominant inheritance pattern. We performed genome-wide linkage analysis on all the families, combined with whole-exome sequencing in two affected individuals from each family. For linkage analysis, we considered loci with logarithm of odds (LOD) scores >1.5 as candidate regions for identification of rare variants. In one of the families, we found two rare heterozygous missense variants, p.V56M in RGS12 and p.G37D in GRPEL1, which segregate with goiter and are both located within the same haplotype on 4p16. This haplotype was not observed in 150 controls. In the other two families, we identified two additional rare missense variants segregating with goiter, p.A551T in CLIC6 on 21q22.12 and p.V412A in WFS1 on 4p16. In controls, the minor allele frequency (MAF) of p.V412A in WFS1 was 0.017 while p.A551T in CLIC6 was not detected. All identified genes (RGS12, GRPEL1, CLIC6 and WFS1) show expression in the human thyroid gland, suggesting that they may play a role in thyroid gland function. Moreover, these four genes are novel with regard to their involvement in familial goiter, supporting genetic heterogeneity of this disease.Journal of Human Genetics advance online publication, 28 March 2013; doi:10.1038/jhg.2013.20.
Journal of Human Genetics 03/2013; · 2.57 Impact Factor
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Hatasu Kobayashi,
Satoru Yamazaki,
Seiji Takashima,
Wanyang Liu,
Hiroko Okuda,
Junxia Yan,
Yukiko Fujii,
Toshiaki Hitomi,
Kouji H Harada,
Toshiyuki Habu,
Akio Koizumi
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ABSTRACT: Moyamoya disease (MMD) and moyamoya syndrome are vasculopathies characterized by progressive stenosis in the circle of Willis and its branches. The RNF213 gene, which encodes a novel class of proteins, characterized by both E3 ligase and AAA+ATPase activities, has been identified as the susceptibility gene for MMD. However, its physiological functions remain unknown. MMD and moyamoya syndrome are often accompanied by diabetes mellitus. In this study, we generated Rnf213 knockout (KO) C57BL/6 mice (Rnf213-/-; Ins2+/+), which were mated with Akita (C57BL/6 Rnf213+/+; Ins2+/C96Y) mice, a strain that develops diabetes spontaneously by 5weeks of age, to obtain mice lacking Rnf213 and carrying the Akita mutation (KO/Akita, Rnf213-/-; Ins2+/C96Y). Body weight and blood glucose concentration were measured from 6 to 20weeks. Glucose tolerance, insulin resistance, plasma insulin and leptin concentrations, food consumption, pancreatic insulin content and histopathology were evaluated at 18weeks of age. We found that glucose tolerance, as indicated by AUC, was 20% lower (p<0.05) and insulin contents in pancreas were 150% higher (p<0.05), in KO/Akita than in Akita mice. The number of CHOP positive β-cells assayed by histopathological examination was 30% lower and food consumption was 34% lower in KO/Akita than in Akita mice (p<0.05 each). These findings indicated that the disruption of Rnf213 improved glucose tolerance by protecting islet β cells.
Biochemical and Biophysical Research Communications 02/2013; · 2.48 Impact Factor
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Akio Koizumi, Hatasu Kobayashi,
Wanyang Liu,
Yukiko Fujii,
S T M L D Senevirathna,
Shanika Nanayakkara,
Hiroko Okuda,
Toshiaki Hitomi,
Kouji H Harada,
Katsunobu Takenaka,
Takao Watanabe,
Shinichiro Shimbo
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ABSTRACT: BACKGROUND: Moyamoya disease-an idiopathic vascular disorder of intracranial arteries-is often accompanied by hypertension. RNF213 has been identified as a susceptibility gene for moyamoya disease. In the present study, the association of p.R4810K (G>A) with blood pressure (BP) was investigated in a Japanese population. METHODOLOGY/PRINCIPAL FINDINGS: Three independent study populations, the Nyukawa (n = 984), Noshiro (n = 2,443) and Field (n = 881) studies, joined this study. BP, body weight and height were measured. Past and present symptoms and disease and medication histories were assessed by interview. Associations of p.R4810K (rs112735431, ss179362673) of RNF213 with BP were investigated. Two linkage disequilibrium blocks were constructed for moyamoya patients with p.R4810K (n = 140) and the general population (n = 384) using 39 single nucleotide polymorphisms (SNPs) spanning 390 kb around RNF213. A total of 60 carriers (3 for AA genotype and 57 for GA genotype) were found in these samples, and the minor allele frequencies were 1.4 % in the Nyukawa and Field studies and 0.2 % in the Noshiro study. Regression analyses adjusted for age, sex and body mass index based on an additive model demonstrated significant associations with systolic BP (mmHg/allele): β (standard error) was 8.2 (2.9) in the Nyukawa study (P = 4.7 × 10(-3)), 18.7 (5.4) in the Noshiro study (P = 4.6 × 10(-4)) and 8.9 (2.0) (P = 1.0 × 10(-5)) in the three populations. In contrast, diastolic BP showed significant associations only in the Noshiro study. Linkage disequilibrium blocks contained none of the BP-associated proxy SNPs reported by previous studies. CONCLUSIONS/SIGNIFICANCE: Our study suggests that p.R4810K of RNF213 is associated strongly with systolic BP.
Environmental Health and Preventive Medicine 08/2012;
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ABSTRACT: To characterize the phenotype of spinocerebellar ataxia type 36 (SCA36), a novel dominant disorder (nicknamed "Asidan") caused by a hexanucleotide GGCCTG repeat expansion in intron 1 of the NOP56 gene.
We investigated the clinical, genetic, and neuropathologic characteristics of 18 patients with SCA36. We performed histologic evaluation of a muscle biopsy specimen from 1 patient with SCA36, and neuropathologic evaluation of an autopsied brain from another patient with SCA36.
The (GGCCTG)n expansion was found in 18 ataxic patients from 9 families. The age at onset of ataxia was 53.1 ± 3.4 years, with the most frequent symptoms being truncal ataxia (100% of patients), ataxic dysarthria (100%), limb ataxia (93%), and hyperreflexia (79%). Tongue fasciculation and subsequent atrophy were found in 71% of cases, particularly in those of long duration. Skeletal muscle fasciculation and atrophy of the limbs and trunk were found in 57% of cases. Lower motor involvement was confirmed by EMG and muscle biopsy. The neuropathologic study revealed significant cerebellar Purkinje cell degeneration with obvious loss of lower motor neurons. Immunohistochemical analysis showed that NOP56 was localized to the nuclei of various neurons. Cytoplasmic or intranuclear inclusion staining of NOP56, TDP-43, and ataxin-2 was not observed in the remaining neurons.
This is the first description of the unique clinical features of SCA36, a relatively pure cerebellar ataxia with progressive motor neuron involvement. Thus, SCA36 is a disease that stands at the crossroads of SCA and motor neuron disease.
Neurology 06/2012; 79(4):333-41. · 8.31 Impact Factor
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No shinkei geka. Neurological surgery 02/2012; 40(2):105-18. · 0.13 Impact Factor
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ABSTRACT: Moyamoya disease is an idiopathic vascular disorder of the intracranial arteries. Ring finger 213 (RNF213) was previously identified as the strongest susceptibility gene for moyamoya disease in East Asian people by a genome-wide linkage analysis and exome analysis. The coding variant p.R4810K in RNF213 was strongly associated with moyamoya disease in the Japanese (odds ratio: 338.94, p = 1.05 × 10(-100)) and Korean (odds ratio: 135.63, p = 7.59 × 10(-27)) populations, and much less strongly associated in the Chinese population (odds ratio: 14.70, p = 2.63 × 10(-5)). The present study investigated the distribution of variant p.R4810K in RNF213 in 2,508 participants from East and Southeast Asian countries using a TaqMan probe. p.R4810K was detected at an allele frequency of about 1.00% in 4 of 11 investigated locations in China. In contrast, p.R4810K was detected homogeneously at relatively high frequencies of 1.00-1.72% in all investigated locations in Korea and Japan, including Okinawa. p.R4810K was not detected in Southeast Asian populations. The population susceptible to moyamoya disease was estimated to be 16.16 million people in East Asian countries, including 11.41 million Chinese, 1.36 million Korean, and 3.39 million Japanese people. The number of patients with moyamoya disease, which was estimated at approximately one per 300 carriers of p.R4810K, was considered to be 53,800 in East Asian populations.
Neurologia medico-chirurgica 01/2012; 52(5):299-303. · 0.61 Impact Factor
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ABSTRACT: This study aims to estimate the ecological exposure of adult residents of Fukushima Prefecture to ¹³⁴cesium (Cs) and ¹³⁷Cs through ingestion and inhalation between July 2 and July 8, 2011.
Fifty-five sets of meals with tap water, each representing one person's daily intake, were purchased in local towns in Fukushima Prefecture. Locally produced cow's milk (21 samples) and vegetables (43 samples) were also purchased. In parallel, air sampling was conducted at 12 different sites using a high-volume sampler. Nineteen sets of control meals were collected in Kyoto in July 2011. ¹³⁴Cs and ¹³⁷Cs levels in the samples were measured using a germanium detector.
Radioactivity was detected in 36 of the 55 sample meals from Fukushima, compared with one of 19 controls from Kyoto. The median estimated dose level (μSv/year) was 3.0, ranging from not detectable to 83.1. None of the cow's milk (21) or vegetable (49) samples showed levels of contamination above the current recommended limits (Bq/kg) of 200 for milk and 500 for vegetables. The total effective dose levels by inhalation were estimated to be <3 μSv/year at nine locations, but samples at three other locations close to the edge of the 20-km radius from the crippled nuclear power plant showed higher levels of contamination (μSv/year): 14.7 at Iitate, 76.9 at Namie, and 27.7 at Katsurao.
Levels of exposure to ¹³⁴Cs and ¹³⁷Cs in Fukushima by ingestion and inhalation are discernible, but generally within recommended limits.
Environmental Health and Preventive Medicine 11/2011; 17(4):292-8.
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Ning Ma,
Raynoo Thanan, Hatasu Kobayashi,
Olfat Hammam,
Mohamed Wishahi,
Tarek El Leithy,
Yusuke Hiraku,
El-Karef Amro,
Shinji Oikawa,
Shiho Ohnishi,
Mariko Murata,
Shosuke Kawanishi
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ABSTRACT: To investigate whether mutant stem cells participate in inflammation-related carcinogenesis, we performed immunohistochemical analysis to examine nitrative and oxidative DNA lesions (8-nitroguanine and 8-oxodG) and a stem cell marker Oct3/4 in bladder tissues obtained from cystitis and bladder cancer patients infected with Schistosomahaematobium (S. haematobium). We also detected the expression of nuclear factor-κB (NF-κB) and inducible nitric oxide synthase (iNOS), which lead to 8-nitroguanine formation. The staining intensity of 8-nitroguanine and 8-oxodG was significantly higher in bladder cancer and cystitis tissues than in normal tissues. iNOS expression was colocalized with NF-κB in 8-nitroguanine-positive tumor cells from bladder cancer patients. Oct3/4 expression was significantly increased in cells from S. haematobium-associated bladder cancer tissues in comparison to normal bladder and cancer tissues without infection. Oct3/4 was also expressed in epithelial cells of cystitis patients. Moreover, 8-nitroguanine was formed in Oct3/4-positive stem cells in S. haematobium-associated cystitis and cancer tissues. In conclusion, inflammation by S.haematobium infection may increase the number of mutant stem cells, in which iNOS-dependent DNA damage occurs via NF-κB activation, leading to tumor development.
Biochemical and Biophysical Research Communications 09/2011; 414(2):344-9. · 2.48 Impact Factor
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ABSTRACT: Autosomal-dominant spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative disorders. In this study, we performed genetic analysis of a unique form of SCA (SCA36) that is accompanied by motor neuron involvement. Genome-wide linkage analysis and subsequent fine mapping for three unrelated Japanese families in a cohort of SCA cases, in whom molecular diagnosis had never been performed, mapped the disease locus to the region of a 1.8 Mb stretch (LOD score of 4.60) on 20p13 (D20S906-D20S193) harboring 37 genes with definitive open reading frames. We sequenced 33 of these and observed a large expansion of an intronic GGCCTG hexanucleotide repeat in NOP56 and an unregistered missense variant (Phe265Leu) in C20orf194, but we found no mutations in PDYN and TGM6. The expansion showed complete segregation with the SCA phenotype in family studies, whereas Phe265Leu in C20orf194 did not. Screening of the expansions in the SCA cohort cases revealed four additional occurrences, but none were revealed in the cohort of 27 Alzheimer disease cases, 154 amyotrophic lateral sclerosis cases, or 300 controls. In total, nine unrelated cases were found in 251 cohort SCA patients (3.6%). A founder haplotype was confirmed in these cases. RNA foci formation was detected in lymphoblastoid cells from affected subjects by fluorescence in situ hybridization. Double staining and gel-shift assay showed that (GGCCUG)n binds the RNA-binding protein SRSF2 but that (CUG)(6) does not. In addition, transcription of MIR1292, a neighboring miRNA, was significantly decreased in lymphoblastoid cells of SCA patients. Our finding suggests that SCA36 is caused by hexanucleotide repeat expansions through RNA gain of function.
The American Journal of Human Genetics 06/2011; 89(1):121-30. · 10.60 Impact Factor
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Wanyang Liu,
Daisuke Morito,
Seiji Takashima,
Yohei Mineharu, Hatasu Kobayashi,
Toshiaki Hitomi,
Hirokuni Hashikata,
Norio Matsuura,
Satoru Yamazaki,
Atsushi Toyoda, [......],
Asao Fujiyama,
Roman Herzig,
Boris Krischek,
Liping Zou,
Jeong Eun Kim,
Masafumi Kitakaze,
Susumu Miyamoto,
Kazuhiro Nagata,
Nobuo Hashimoto,
Akio Koizumi
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ABSTRACT: Moyamoya disease is an idiopathic vascular disorder of intracranial arteries. Its susceptibility locus has been mapped to 17q25.3 in Japanese families, but the susceptibility gene is unknown.
Genome-wide linkage analysis in eight three-generation families with moyamoya disease revealed linkage to 17q25.3 (P<10(-4)). Fine mapping demonstrated a 1.5-Mb disease locus bounded by D17S1806 and rs2280147. We conducted exome analysis of the eight index cases in these families, with results filtered through Ng criteria. There was a variant of p.N321S in PCMTD1 and p.R4810K in RNF213 in the 1.5-Mb locus of the eight index cases. The p.N321S variant in PCMTD1 could not be confirmed by the Sanger method. Sequencing RNF213 in 42 index cases confirmed p.R4810K and revealed it to be the only unregistered variant. Genotyping 39 SNPs around RNF213 revealed a founder haplotype transmitted in 42 families. Sequencing the 260-kb region covering the founder haplotype in one index case did not show any coding variants except p.R4810K. A case-control study demonstrated strong association of p.R4810K with moyamoya disease in East Asian populations (251 cases and 707 controls) with an odds ratio of 111.8 (P = 10(-119)). Sequencing of RNF213 in East Asian cases revealed additional novel variants: p.D4863N, p.E4950D, p.A5021V, p.D5160E, and p.E5176G. Among Caucasian cases, variants p.N3962D, p.D4013N, p.R4062Q and p.P4608S were identified. RNF213 encodes a 591-kDa cytosolic protein that possesses two functional domains: a Walker motif and a RING finger domain. These exhibit ATPase and ubiquitin ligase activities. Although the mutant alleles (p.R4810K or p.D4013N in the RING domain) did not affect transcription levels or ubiquitination activity, knockdown of RNF213 in zebrafish caused irregular wall formation in trunk arteries and abnormal sprouting vessels.
We provide evidence suggesting, for the first time, the involvement of RNF213 in genetic susceptibility to moyamoya disease.
PLoS ONE 01/2011; 6(7):e22542. · 4.09 Impact Factor
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ABSTRACT: We previously reported a novel peptide, Hippocampal Cholinergic Neurostimulating Peptide (HCNP), which induces acetylcholine synthesis by increasing the amount of choline acetyltransferase (ChAT) in medial septal nuclei. The HCNP precursor protein (HCNP-pp), composed of 186 amino acids, is an inhibitory factor of the c-Raf/MEK cascade and may be involved in fetal rat brain development via the inhibition of phosphorylation of Erk. To clarify the involvement of HCNP in hippocampal cholinergic circuitry, we previously generated HCNP-pp transgenic (HCNP-pp Tg) mice using the promoter of the α subunit of Ca(2+) calmodulin-dependent protein kinase II (CaMKIIα). These mice showed increased levels of ChAT in medial septal nuclei at 12 weeks of age, and the phenotype of depressive mood at 30 weeks of age. Here, through proteomic analysis we investigated the alteration of protein expression in the hippocampus of HCNP-pp Tg mice compared with wild-type littermate mice. We demonstrate that the activation of collapsin response mediator protein-2 (CRMP-2) is increased in the transgenic mice at 12 weeks of age when compared with wild-type littermate mice.
Brain research 10/2010; 1355:180-8. · 2.46 Impact Factor
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Wanyang Liu,
Hirokuni Hashikata,
Kayoko Inoue,
Norio Matsuura,
Yohei Mineharu, Hatasu Kobayashi,
Ken-Ichiro Kikuta,
Yasushi Takagi,
Toshiaki Hitomi,
Boris Krischek,
Li-Ping Zou,
Fang Fang,
Roman Herzig,
Jeong-Eun Kim,
Hyun-Seung Kang,
Chang-Wan Oh,
David-Alexandre Tregouet,
Nobuo Hashimoto,
Akio Koizumi
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ABSTRACT: In an earlier study, we identified a locus for Moyamoya disease (MMD) on 17q25.3.
Linkage analysis and fine mapping were conducted for two new families in additional to the previously studied 15 families. Three genes, CARD14, Raptor, and AATK, were selected based on key words, namely, "inflammation", "apoptosis", "proliferation", and "vascular system", for further sequencing. A segregation analysis of 34 pedigrees was performed, followed by a case-control study in Japanese (90 cases vs. 384 controls), Korean (41 cases vs. 223 controls), Chinese (23 cases and 100 controls), and Caucasian (25 cases and 164 controls) populations.
Linkage analysis increased the LOD score from 8.07 to 9.67 on 17q25.3. Fine mapping narrowed the linkage signal to a 2.1-Mb region. Sequencing revealed that only one newly identified polymorphism, ss161110142, which was located at position -1480 from the transcription site of the Raptor gene, was common to all four unrelated sequenced familial affected individuals. ss161110142 was then shown to segregate in the 34 pedigrees studied, resulting in a two-point LOD score of 14.2 (P = 3.89 × 10(-8)). Its penetrance was estimated to be 74.0%. Among the Asian populations tested (Japanese, Korean, and Chinese), the rare allele was much more frequent in cases (26, 33, and 4%, respectively) than in controls (1, 1, and 0%, respectively) and was associated with an increased odds ratio of 52.2 (95% confidence interval 27.2-100.2) (P = 2.5 × 10(-49)). This allele was, however, not detected in the Caucasian samples. Its population attributable risk was estimated to be 49% in the Japanese population, 66% in the Korean population, and 9% in the Chinese population.
ss161110142 may confer susceptibility to MMD among East Asian populations.
The online version of this article (doi:10.1007/s12199-009-0116-7) contains supplementary material, which is available to authorized users.
Environmental Health and Preventive Medicine 11/2009; 15(2):94-104.
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ABSTRACT: Reactive oxygen species (ROS) are known to participate in neurodegeneration after ischemia-reperfusion. With the aid of ROS, the calpain-induced lysosomal rupture provokes ischemic neuronal death in the cornu Ammonis (CA) 1 of the hippocampus; however, the target proteins of ROS still remain unknown. Here a proteomic analysis was done to identify and characterize ROS-induced carbonyl modification of proteins in the CA1 of the macaque monkey after transient whole-brain ischemia followed by reperfusion. We found that carbonyl modification of heat shock 70-kDa protein 1 (Hsp70-1), a major stress-inducible member of the Hsp70 family, was extensively increased before the neuronal death in the CA1 sector, and the carbonylation site was identified to be Arg469 of Hsp70-1. The CA1 neuronal death conceivably occurs by calpain-mediated cleavage of carbonylated Hsp70 that becomes prone to proteolysis with the resultant lysosomal rupture. In addition, the carbonyl levels of dihydropyrimidinase-like 2 isoform 2, glial fibrillary acidic protein, and beta-actin were remarkably increased in the postischemic CA1. Therefore, ischemia-reperfusion-induced oxidative damage to these proteins in the CA1 may lead to loss of the neuroprotective function, which contributes to neuronal death.
Free radical biology & medicine 04/2009; 46(11):1472-7. · 5.42 Impact Factor
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ABSTRACT: Aspirin has been proposed as a possible chemopreventive agent. On the other hand, a recent cohort study showed that aspirin may increase the risk for pancreatic cancer. To clarify whether aspirin is potentially carcinogenic, we investigated the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), which is correlated with the incidence of cancer, in cultured cells treated with 2,3-dihydroxybenzoic acid (2,3-DHBA), a metabolite of aspirin. 2,3-DHBA induced 8-oxodG formation in the PANC-1 human pancreatic cancer cell line. 2,3-DHBA-induced DNA single-strand breaks were also revealed by comet assay using PANC-1 cells. Flow cytometric analyses showed that 2,3-DHBA increased the levels of intracellular reactive oxygen species (ROS) in PANC-1 cells. The 8-oxodG formation and ROS generation were also observed in the HL-60 leukemia cell line, but not in the hydrogen peroxide (H(2)O(2))-resistant clone HP100 cells, suggesting the involvement of H(2)O(2). In addition, an hprt mutation assay supported the mutagenicity of 2,3-DHBA. We investigated the mechanism underlying the 2,3-DHBA-induced DNA damage using (32)P-labeled DNA fragments of human tumor suppressor genes. 2,3-DHBA induced DNA damage in the presence of Cu(II) and NADH. DNA damage induced by 2,3-DHBA was enhanced by the addition of histone peptide-6 [AKRHRK]. Interestingly, 2,3-DHBA and histone peptide-6 caused base damage in the 5'-ACG-3' and 5'-CCG-3' sequences, hotspots of the p53 gene. Bathocuproine, a Cu(I) chelator, and catalase inhibited the DNA damage. Typical hydroxyl radical scavengers did not inhibit the DNA damage. These results suggest that ROS derived from the reaction of H(2)O(2) with Cu(I) participate in the DNA damage. In conclusion, 2,3-DHBA induces oxidative DNA damage and mutations, which may result in carcinogenesis.
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 01/2009; 661(1-2):93-100. · 2.85 Impact Factor
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ABSTRACT: Tetrahydroisoquinoline (TIQ) derivatives are putative neurotoxins that may contribute to the degeneration of dopaminergic neurons in Parkinson's disease. One TIQ, norsalsolinol (NorSAL), is present in dopamine-rich areas of human brain, including the substantia nigra. Here, we demonstrate that NorSAL reduces cell viability and induces apoptosis via cytochrome c release and caspase 3 activation in SH-SY5Y human neuroblastoma cells. Cytochrome c release, caspase 3 activation, and apoptosis induction were all inhibited by the antioxidant N-acetylcysteine. Thus, reactive oxygen species (ROS) contribute to apoptosis induced by NorSAL. Treatment with NorSAL also increased levels of oxidative damage to DNA, a stimulus for apoptosis, in SH-SY5Y. To clarify the mechanism of intracellular DNA damage, we examined the DNA damage caused by NorSAL using (32)P-5'-end-labeled isolated DNA fragments. NorSAL induced DNA damage in the presence of Cu(II). Catalase and bathocuproine, a Cu(I) chelator, inhibited this DNA damage, suggesting that ROS such as the Cu(I)-hydroperoxo complex derived from the reaction of H(2)O(2) with Cu(I), promote DNA damage by NorSAL. In summary, NorSAL-generated ROS induced oxidative DNA damage, which led to caspase-dependent apoptosis in neuronal cells.
Journal of Neurochemistry 11/2008; 108(2):397-407. · 4.06 Impact Factor
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ABSTRACT: 6-Hydroxydopamine (6-OHDA) is a neurotoxin to produce an animal model of Parkinson's disease. 6-OHDA increased the formation of 8-oxo-7, 8-dihydro-2'-deoxyguanosine (8-oxodG), a biomarker of oxidatively damaged DNA, and induced apoptosis in human neuroblastoma SH-SY5Y cells. Iron or copper chelators inhibited 6-OHDA-induced 8-oxodG formation and apoptosis. Thus, iron and copper are involved in the intracellular oxidatively generated damage to DNA, a stimulus for initiating apoptosis. This study examined DNA damage caused by 6-OHDA plus metal ions using (32)P-5'-end-labelled DNA fragments. 6-OHDA increased levels of oxidatively damaged DNA in the presence of Fe(III)EDTA or Cu(II). Cu(II)-mediated DNA damage was stronger than Fe(III)-mediated DNA damage. The spectrophotometric detection of p-quinone and the scopoletin method showed that Cu(II) more effectively accelerated the 6-OHDA auto-oxidation and H(2)O(2) generation than Fe(III)EDTA. This study suggests that copper, as well as iron, may play an important role in 6-OHDA-induced neuronal cell death.
Free radical research 07/2008; 42(7):651-60. · 2.22 Impact Factor
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ABSTRACT: Tetrahydropapaveroline (THP), a metabolite of dopamine, has been suspected to be associated with dopaminergic neurotoxicity of L-DOPA. THP induced apoptosis in human leukemia cell line HL-60 cells, but did not in its hydrogen peroxide (H(2)O(2))-resistant clone HP100. THP-induced DNA ladder formation in HL-60 cells was inhibited by a metal chelator. THP induced damage to (32)P-labeled DNA fragments in the presence of metals. In the presence of Fe(III)EDTA, THP caused DNA damage at every nucleotide. The DNA damage was inhibited by free hydroxy radical ((.)OH) scavengers and catalase, suggesting that the Fe(III)EDTA-mediated DNA damage is mainly due to (.)OH generation. In the presence of Cu(II), THP caused DNA damage mainly at T and G of 5'-TG-3' sequence. The inhibitive effect of catalase and bathocuproine on Cu(II)-mediated DNA damage suggested that H(2)O(2) and Cu(I) participate in the DNA damage. This study demonstrated that THP-induced apoptosis via reactive oxygen species generated from reaction of H(2)O(2) and metals plays an important role in cytotoxicity of L-DOPA.
Neurochemical Research 05/2006; 31(4):523-32. · 2.24 Impact Factor
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ABSTRACT: Propyl gallate (PG), widely used as an antioxidant in foods, is carcinogenic to mice and rats. PG increased the amount of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), a characteristic oxidative DNA lesion, in human leukemia cell line HL-60, but not in HP100, which is hydrogen peroxide (H2O2)-resistant cell line derived from HL-60. Although PG induced no or little damage to 32P-5'-end-labeled DNA fragments obtained from genes that are relevant to human cancer, DNA damage was observed with treatment of esterase. HPLC analysis of the products generated from PG incubated with esterase revealed that PG converted into gallic acid (GA). GA induced DNA damage in a dose-dependent manner in the presence of Fe(III)EDTA or Cu(II). In the presence of Fe(III) complex such as Fe(III)EDTA or Fe(III)ADP, GA caused DNA damage at every nucleotide. Fe(III) complex-mediated DNA damage by GA was inhibited by free hydroxy radical (*OH) scavengers, catalase and an iron chelating agent. These results suggested that the Fe(III) complex-mediated DNA damage caused by GA is mainly due to *OH generated via the Fenton reaction. In the presence of Cu(II), DNA damage induced by GA occurred at thymine and cytosine. Although *OH scavengers did not prevent the DNA damage, methional inhibited the DNA damage. Cu(II)-mediated DNA damage was inhibited by catalase and a Cu(I) chelator. These results indicated that reactive oxygen species formed by the interaction of Cu(I) and H2O2 participates in the DNA damage. GA increased 8-oxodG content in calf thymus DNA in the presence of Cu(II), Fe(III)EDTA or Fe(III)ADP. This study suggested that metal-mediated DNA damage caused by GA plays an important role in the carcinogenicity of PG.
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 04/2004; 558(1-2):111-20. · 2.85 Impact Factor
