H Hishigaki

Otsuka Pharmaceutical Group, Edo, Tōkyō, Japan

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Publications (30)132.09 Total impact

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    ABSTRACT: Aspirin prevents the production of thromboxane A2 (TXA2) by irreversibly inhibiting platelet cyclooxygenase, exhibiting antiplatelet actions. This agent has been reported to prevent relapse in patients with ischemic heart disease or cerebral infarction via this action mechanism. However, there are individual differences in this action, and aspirin is not effective in some patients, which is referred to as 'aspirin resistance'. In this study, we analyzed laboratory aspirin resistance by platelet aggregation in 110 healthy adult Japanese males using 24 single-nucleotide polymorphisms (SNPs) of nine genes involved in platelet aggregation/hemorrhage. Among SNPs involved in platelet aggregation, aspirin was less effective for 924T homozygote of a TXA2 receptor, 924T>C, and 1018C homozygote of a platelet membrane glycoprotein GPIbalpha, 1018C>T, suggesting that 924T and 1018C alleles are involved in aspirin resistance.
    The Pharmacogenomics Journal 01/2008; 7(6):395-403. · 5.13 Impact Factor
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    ABSTRACT: The etiology of osteoarthritis (OA) is multifactorial and current research attributes it to a complex network of biochemical factors. We attempted to identify important molecules in OA joint destruction. Synovium was collected from 2 women with hip OA. Total RNA was extracted from the combined synovium. Messenger RNAs (mRNAs) were randomly sequenced for identification with the oligo-capping method. mRNA expression of 9 genes that were found to be frequently expressed was compared in synovium from 7 OA patients and 2 control patients with no signs of arthritis. We sequenced 7,339 mRNAs in total and identified 4,247 different kinds, which were ranked in order of frequency. Fibronectin was the protein most frequently expressed (230/7,339), followed by matrix metalloproteinases (MMPs) 1 and 3. The 9 genes selected were those encoding fibronectin 1, MMP1, MMP3, tissue inhibitor of metalloproteinase 3, apolipoprotein L-I (APOL1), syndecan binding protein, insulin-like growth factor binding protein 5, heat shock protein 90, and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5). We investigated expression of these 9 genes in synovium from the 7 individual patients with OA. All 9 genes were expressed in OA and control synovium. Expression of MMP1 mRNA was weak in OA samples, however, while expression of ADAMTS5 and APOL1 mRNAs was weak in the controls and some of the OA samples. ADAMTS5 and APOL1 may have important roles in the mechanism of OA.
    Acta Orthopaedica 11/2007; 78(5):687-92. · 2.74 Impact Factor
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    Toshihide Ono, Haretsugu Hishigaki
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    ABSTRACT: Understanding the coupling specificity between G protein-coupled receptors (GPCRs) and specific classes of G proteins is important for further elucidation of receptor functions within a cell. Increasing information on GPCR sequences and the G protein family would facilitate prediction of the coupling properties of GPCRs. In this study, we describe a novel approach for predicting the coupling specificity between GPCRs and G proteins. This method uses not only GPCR sequences but also the functional knowledge generated by natural language processing, and can achieve 92.2% prediction accuracy by using the C4.5 algorithm. Furthermore, rules related to GPCR-G protein coupling are generated. The combination of sequence analysis and text mining improves the prediction accuracy for GPCR-G protein coupling specificity, and also provides clues for understanding GPCR signaling.
    Genomics Proteomics & Bioinformatics 12/2006; 4(4):238-44.
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    ABSTRACT: 1. We have confirmed the Diabetes Mellitus OLETF type I (Dmo1) effect on hyperphagia, dyslipidaemia and obesity in the Otsuka Long-Evans Tokushima Fatty (OLETF) strain. The critical interval was narrowed down to 570 kb between D1Got258 to p162CA1 by segregation analyses using congenic lines. 2. Within the critical 570 kb region of the Dmo1 locus, we identified the G-protein-coupled receptor gene GPR10 as the causative gene mutated in the OLETF strain. The ATG translation initiation codon of GPR10 is changed into ATA in this strain and, so, is unavailable for the initiation of translation. 3. The GPR10 protein has a cognate ligand, namely prolactin-releasing peptide (PrRP). Centrally administered PrRP suppressed the food intake of congenic rats that have a Brown Norway derived Dmo1 region (i.e. with wild-type GPR10), but did not suppress that of the OLETF strain, indicating that GPR10 is without function and could explain hyperphagia in the OLETF strain. 4. Moreover, when restricted in food volume to the same level consumed by the congenic strain, OLETF rats showed few differences in the parameters of dyslipidaemia and obesity compared with congenic strains. 5. Taken together, these results demonstrate that the mutated GPR10 receptor is responsible for the hyperphagia leading to obesity and dyslipidaemia in the obese diabetic strain rat.
    Clinical and Experimental Pharmacology and Physiology 01/2005; 32(5-6):355-66. · 2.41 Impact Factor
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    ABSTRACT: As a base for human transcriptome and functional genomics, we created the "full-length long Japan" (FLJ) collection of sequenced human cDNAs. We determined the entire sequence of 21,243 selected clones and found that 14,490 cDNAs (10,897 clusters) were unique to the FLJ collection. About half of them (5,416) seemed to be protein-coding. Of those, 1,999 clusters had not been predicted by computational methods. The distribution of GC content of nonpredicted cDNAs had a peak at approximately 58% compared with a peak at approximately 42%for predicted cDNAs. Thus, there seems to be a slight bias against GC-rich transcripts in current gene prediction procedures. The rest of the cDNAs unique to the FLJ collection (5,481) contained no obvious open reading frames (ORFs) and thus are candidate noncoding RNAs. About one-fourth of them (1,378) showed a clear pattern of splicing. The distribution of GC content of noncoding cDNAs was narrow and had a peak at approximately 42%, relatively low compared with that of protein-coding cDNAs.
    Nature Genetics 02/2004; 36(1):40-5. · 35.21 Impact Factor
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    ABSTRACT: 1. Dmo1 (Diabetes Mellitus OLETF type I) is a major quantitative trait locus for dyslipidaemia, obesity and diabetes phenotypes of male Otsuka Long Evans Tokushima Fatty (OLETF) rats. 2. Our congenic lines, produced by transferring Dmo1 chromosomal segments from the non-diabetic Brown Norway (BN) rat into the OLETF strain, have confirmed the strong, wide-range therapeutic effects of Dmo1 on dyslipidaemia, obesity and diabetes in the fourth (BC4) and fifth (BC5) generations of congenic animals. Analysis of a relatively small number of BC5 rats (n = 71) suggested that the critical Dmo1 interval lies within a < 4.9 cM region between D1Rat461 and D1Rat459. 3. To confirm the assignment of the Dmo1 critical interval, we intercrossed BC5 animals to produce a larger study population (BC5:F1 males; n = 406). For the present study, we used bodyweight at 18 weeks of age as an index of obesity; this phenotype is representative of the closely associated dyslipidaemia and hyperglycaemia phenotypes. 4. Interval mapping assigned logarithm of odds (LOD) peaks at the D1Rat90 marker (LOD = 9.11). One LOD support interval lies within the < 1.7 cM region between D1Rat461 and D1Rat459. 5. This large intercross study confirms that Dmo1 is likely localized within the interval.
    Clinical and Experimental Pharmacology and Physiology 01/2004; 31(1-2):110-2. · 2.41 Impact Factor
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    ABSTRACT: Dmo1 (Diabetes Mellitus OLETF type I) is a major quantitative trait locus for dyslipidaemia, obesity and diabetes phenotypes in the Otsuka Long Evans Tokushima Fatty (OLETF) rat strain. To evaluate possible metabolic and pathological improvements generated by correction of the Dmo1 genetic pathway, we produced congenic lines, in which both OLETF Dmo1 alleles are replaced by the F344-derived genome. Congenic animals were produced by introgressing F344-derived Dmo1 alleles into the OLETF rat. Congenic animals of the fourth generation (BC4) were intercrossed to obtain F1 animals (BC4:F1). Animals of the next generation, BC4:F2, were used for this study. We used 23 BC4:F2 males harbouring homozygous replacement of the OLETF Dmo1 region with the F344-derived genome. Seven animals with OLETF-derived Dmo1 alleles were used as controls. Dmo1-F344/F344 congenic rats showed significant decreases in body weight, abdominal fat weight, serum triacylglycerols, total cholesterol, food consumption and blood glucose after glucose loading (13%, 39%, 45%, 27%, 18% and 27% respectively; p < 0.05) compared with Dmo1-OLETF/OLETF animals. Furthermore, histopathological analysis of the kidney showed that mesangial sclerosis, hyalin deposits and deposition of PAS-positive substance were significantly lower in Dmo1-F344/F344 animals (p < 0.05). Improvements in metabolic parameters and histopathological scores show that correction of the Dmo1 genetic pathway in the diabetic and mildly obese OLETF rat strain produces wide-ranging therapeutic effects. Thus, this pathway might represent a new drug target also applicable to humans.
    Diabetes Obesity and Metabolism 09/2002; 4(5):309-18. · 5.18 Impact Factor
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    ABSTRACT: Whole-genome scans have identified Dmo1 as a major quantitative trait locus (QTL) for obesity and dyslipidaemia in the Otsuka Long Evans Tokushima Fatty (OLETF) rat. We have produced congenic rats for the Dmo1 locus, using marker-assisted speed congenic protocols, enforced by selective removal of other QTL regions (QTL-marker-assisted counterselection), to efficiently transfer chromosomal segments from non-diabetic Fischer 344 (F344) rats into the OLETF background. In the third generation of congenic animals, we observed a substantial therapeutic effect of the Dmo1 locus on lipid metabolism, obesity control and plasma glucose homeostasis. We conclude that single-allele correction of an impaired genetic pathway can generate a substantial therapeutic effect, despite the complex polygenic nature of type II diabetic syndromes.
    Genetics Research 05/2001; 77(2):183-90. · 2.00 Impact Factor
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    H Hishigaki, K Nakai, T Ono, A Tanigami, T Takagi
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    ABSTRACT: Functional prediction of open reading frames coded in the genome is one of the most important tasks in yeast genomics. Among a number of large-scale experiments for assigning certain functional classes to proteins, experiments determining protein-protein interaction are especially important because interacting proteins usually have the same function. Thus, it seems possible to predict the function of a protein when the function of its interacting partner is known. However, in vitro experiments often suffer from artifacts and a protein can often have multiple binding partners with different functions. We developed an objective prediction method that can systematically include the information of indirect interaction. Our method can predict the subcellular localization, the cellular role and the biochemical function of yeast proteins with accuracies of 72.7%, 63.6% and 52.7%, respectively. The prediction accuracy rises for proteins with more than three binding partners and thus we present the open prediction results for 16 such proteins.
    Yeast 05/2001; 18(6):523-31. · 1.96 Impact Factor
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    ABSTRACT: An Otsuka Long-Evans Tokushima Fatty (OLETF) strain of rat spontaneously developed hyperglycemia, hyperinsulinemia, insulin resistance and mild obesity, which had been studied as animal model for type II diabetes mellitus (T2DM). Recently, we observed that this strain coincidentally developed atypical hyperplasia of the choledocho-pancreatic ductal epithelium with a complete incidence. In an effort to locate genes responsible for this hyperplasia, we prepared 288 backcross progeny from a mating between OLETF rats and BN rats (which do not develop hyperplasia), and performed a genome-wide scan using 207 polymorphic genetic markers. We observed a prominent association of hyperplasia with a region involving a marker locus D14Mit4 (P = 0.00020, Fisher's exact test) and Cckar (the cholecystokinin-A receptor gene; P = 0.00025, Fisher's exact test) which is known to be disrupted in an OLETF strain. Our findings indicated that epithelial hyperplasia of the choledocho-pancreatic duct is associated with a region on rat chromosome 14 around the Cckar gene in an additive fashion with another two susceptible loci, each on chromosome 9 and 7. This implied the possibility that Cckar deficiency could result in a predisposition towards pancreatic duct hyperplasia.
    Pathology International 04/2001; 51(3):133-9. · 1.72 Impact Factor
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    T Ono, H Hishigaki, A Tanigami, T Takagi
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    ABSTRACT: To understand biological process, we must clarify how proteins interact with each other. However, since information about protein-protein interactions still exists primarily in the scientific literature, it is not accessible in a computer-readable format. Efficient processing of large amounts of interactions therefore needs an intelligent information extraction method. Our aim is to develop an efficient method for extracting information on protein-protein interaction from scientific literature. We present a method for extracting information on protein-protein interactions from the scientific literature. This method, which employs only a protein name dictionary, surface clues on word patterns and simple part-of-speech rules, achieved high recall and precision rates for yeast (recall = 86.8% and precision = 94.3%) and Escherichia coli (recall = 82.5% and precision = 93.5%). The result of extraction suggests that our method should be applicable to any species for which a protein name dictionary is constructed. The program is available on request from the authors.
    Bioinformatics 03/2001; 17(2):155-61. · 5.32 Impact Factor
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    ABSTRACT: Whole-genome scans have identified Dmo1 as a major quantitative trait locus (QTL) for obesity and dyslipidaemia in the Otsuka Long Evans Tokushima Fatty (OLETF) rat. We have produced congenic rats for the Dmo1 locus, using marker-assisted speed congenic protocols, enforced by selective removal of other QTL regions (QTL-marker-assisted counterselection), to efficiently transfer chromosomal segments from non-diabetic Fischer 344 (F344) rats into the OLETF background. In the third generation of congenic animals, we observed a substantial therapeutic effect of the Dmo1 locus on lipid metabolism, obesity control and plasma glucose homeostasis. We conclude that single-allele correction of an impaired genetic pathway can generate a substantial therapeutic effect, despite the complex polygenic nature of type II diabetic syndromes.
    Genetics Research 01/2001; 77(02):183 - 190. · 2.00 Impact Factor
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    ABSTRACT: SUMMARY1. Whole-genome scans have identified Dmo1 as a major quantitative trait locus for dyslipidaemia and obesity in the Otsuka Long Evans Tokushima Fatty (OLETF) rat.2. We have produced congenic rats for the Dmo1 locus through successive back-cross breeding with diabetic OLETF rats. Marker-assisted speed congenic protocols were applied to efficiently transfer chromosomal segments from non-diabetic Brown Norway (BN) rats into the OLETF background.3. In the fourth generation of congenic animals, we observed a substantial therapeutic effect of the Dmo1 locus on lipid metabolism, obesity control and plasma glucose homeostasis.4. We have concluded that Dmo1 primarily affects lipid homeostasis, obesity control and/or glucose homeostasis at fasting and is secondarily involved in glucose homeostasis after loading.5. The results of the present study show that single-allele correction of a genetic defect of the Dmo1 locus can generate a substantial therapeutic effect, despite the complex polygenic nature of type II diabetic syndromes.
    Clinical and Experimental Pharmacology and Physiology 12/2000; 28(1‐2):28 - 42. · 2.41 Impact Factor
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    ABSTRACT: We constructed the comparative cytogenetic maps of X chromosomes in three rodent species, Indian spiny mouse (Mus platythrix), Syrian hamster and Chinese hamster, using 26 mouse cDNA clones. Twenty-six, 22 and 22 out of the 26 genes, which were mapped to human, mouse and rat X chromosomes in our previous study, were newly localized to X chromosomes of Indian spiny mouse, and Syrian and Chinese hamsters, respectively. The order of the genes aligned on the long arm of human X chromosome was highly conserved in rat and the three rodent species except mouse. The present results suggest a possibility that the rat X chromosome retains the ancestral form of the rodent X chromosomes.
    Chromosome Research 12/2000; 9(1):61-67. · 3.47 Impact Factor
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    ABSTRACT: 1. The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is a model of type II diabetes with accompanying dyslipidaemia and obesity. 2. To define chromosomal intervals associated with obesity (abdominal fat weight and plasma leptin levels), dyslipidaemia (plasma triglyceride, cholesterol and free fatty acids) and hyperglycaemia (plasma glucose levels), we have performed genome-wide quantitative traits loci (QTL) analyses of 115 male OLETF x (OLETF x Fischer 344) backcross animals at 16 weeks of age. 3. The Diabetes Mellitus OLETF type I (Dmo1) locus on rat chromosome 1 showed statistically significant involvement in elevations of plasma levels of triglycerides (P = 4.87 x 10(-6) at D1Rat90) and total cholesterol (P = 1.16 x 10(-5) at D1Rat306). 4. No other loci produced significant linkage to these observed phenotypes. 5. These analyses have confirmed the importance of Dmo1 in lipid homeostasis at younger ages as well as during overt diabetes, which appears later. Thus, alterations at the Dmo1 locus are a major risk factor for pathogenesis in the strain, a finding that agrees with physiological studies that indicate a role for dyslipidaemia in the type II diabetic syndrome of OLETF rats.
    Clinical and Experimental Pharmacology and Physiology 12/2000; 27(11):881-6. · 2.41 Impact Factor
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    ABSTRACT: The rat is a widely used model organism in medical and pharmaceutical research, and its physiology is better understood than that of any other vertebrate with the exception of human. The rat is a particularly useful model for investigating polygenic diseases, yet rat genetics has remained under-researched compared with that of the mouse (Jacob 1999; James and Lindpaintner 1997). This is being redressed with the publication of genome-spanning genetic maps, the production of many thousands of genetic markers (Steen et al. 1999; Watanabe et al. 1999), and construction of large-insert clone libraries (loc.cit.). With the availability of these new genetic and genomic resources, an efficient means of deploying them in the various disease model studies is required. Radiation hybrid (RH) mapping is a powerful tool to achieve this goal because it is rapid, has 100% genome coverage, higher resolution than meiotic maps, allows for integration of genetic and gene-based markers, and provides a single resource that can be distributed to any laboratory (McCarthy 1996). Furthermore, non-polymorphic markers may be RH mapped, a particular advantage for the rat because genetic maps have limitations because only approximately 50% of genetic markers are polymorphic in a cross between any two inbred strains.
    Mammalian Genome 08/2000; 11(9):791-795. · 2.42 Impact Factor
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    ABSTRACT: We have isolated more than 12,000 clones containing microsatellite sequences, mainly consisting of (CA)n dinucleotide repeats, using genomic DNA from the BN strain of laboratory rat. Data trimming yielded 9636 non-redundant microsatellite sequences, and we designed oligonucleotide primer pairs to amplify 8189 of these. PCR amplification of genomic DNA from five different rat strains yielded clean amplification products for 7040 of these simple-sequence-length-polymorphism (SSLP) markers; 3019 markers had been mapped previously by radiation hybrid (RH) mapping methods (Nat Genet 22, 27-36, 1998). Here we report the characterization of these newly developed microsatellite markers as well as the release of previously unpublished microsatellite marker information. In addition, we have constructed a genome-wide linkage map of 515 markers, 204 of which are derived from our new collection, by genotyping 48 F2 progeny of (OLETFxBN)F2 crosses. This map spans 1830.9 cM, with an average spacing of 3.56 cM. Together with our ongoing project of preparing a whole-genome radiation hybrid map for the rat, this dense linkage map should provide a valuable resource for genetic studies in this model species.
    Mammalian Genome 05/2000; 11(4):300-5. · 2.42 Impact Factor
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    A Nakaya, H Hishigaki, S Morishita
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    ABSTRACT: Although the synergetic effects of multiple marker loci regarding quantitative traits such as blood glucose level have attracted interest, previous conclusions have been based on assumptions that each marker locus behaves independently of the other, leading to approximation. To cope with this problem, this paper focuses on the effects of multiple genetic factors and tries to find significant marker combinations by using conjunctive rules regarding genotypes at multiple marker loci. Application of the proposed method on the OLETF model rat of non-insulin dependent diabetes mellitus (NIDDM) has found significant combinations of marker loci with respect to oral glucose tolerance (OGT).
    Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing 02/2000;
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    ABSTRACT: We have isolated more than 12,000 clones containing microsatellite sequences, mainly consisting of (CA)n dinucleotide repeats, using genomic DNA from the BN strain of laboratory rat. Data trimming yielded 9636 non-redundant microsatellite sequences, and we designed oligonucleotide primer pairs to amplify 8189 of these. PCR amplification of genomic DNA from five different rat strains yielded clean amplification products for 7040 of these simple-sequence-length-polymorphism (SSLP) markers; 3019 markers had been mapped previously by radiation hybrid (RH) mapping methods (Nat Genet 22, 27–36, 1998). Here we report the characterization of these newly developed microsatellite markers as well as the release of previously unpublished microsatellite marker information. In addition, we have constructed a genome-wide linkage map of 515 markers, 204 of which are derived from our new collection, by genotyping 48 F2 progeny of (OLETFxBN)F2 crosses. This map spans 1830.9 cM, with an average spacing of 3.56 cM. Together with our ongoing project of preparing a whole-genome radiation hybrid map for the rat, this dense linkage map should provide a valuable resource for genetic studies in this model species.
    Mammalian Genome 01/2000; 11(4):300-305. · 2.42 Impact Factor
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    ABSTRACT: To identify genetic determinants relevant to non-insulin-dependent diabetes mellitus (NIDDM), we performed a genome-wide analysis for quantitative trait loci (QTLs) using 359 backcross progeny of the Otsuka Long-Evans Tokushima Fatty (OLETF) rat. The OLETF strain is a well-studied animal model of obese NIDDM, with features of hyperinsulinemia, hyperglycemia, insulin resistance, and abundant abdominal fat. Our extensive genomic scanning with 218 markers revealed nine significant QTLs, including a strong determinant of obesity on chromosome 1 (Dmo1: LOD = 13.99, for body weight). Two highly significant QTLs for glucose homeostasis were found, one on chromosome 1 (Dmo4 LOD = 7.16, for postprandial glucose level) and the other on chromosome X (Dmo11/Odb1: LOD = 7.81, for postprandial glucose level). These data are comparable to results of our previous studies of the OLETF rat.
    Genomics 07/1999; 58(3):233-9. · 3.01 Impact Factor