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Biomedical subjects

K Katsumata

Publications and source records attributed to K Katsumata.

At least 55 records · Page 3Linked to original sources
PubMed1996

Accumulation of deletions and point mutations in mitochondrial genome in degenerative diseases.

Accumulation of various mutations in the mitochondrial genome is proposed as an important contributor to aging and degenerative diseases. Extensive fragmentation of mtDNA was detected in association with increased 8-hydroxydeoxyguanosine content in the heart mitochondrial DNA (mtDNA) from a patient with premature aging and mitochondrial cardiomyopathy, who carried a mutation within the mitochondrial tRNA(Asp) gene. This result suggests that damage to mtDNA by hydroxyl radical and accumulation of deleted mtDNA can be accelerated by a specific mitochondrial genotype. Similarly, extensive fragmentation of mtDNA was also detected in cultured cells exposed to a high oxygen concentration atmosphere, implying that mtDNA is vulnerable to reactive oxygen species. To clarify the role of point mutations accumulated in mtDNA, we examined the sequence heterogeneity of mtDNA in the skeletal muscle of a MELAS patient who carried a mutation within the mitochondrial tRNA(leu)(UUR) gene. The analysis revealed that the frequency of mutant clones in the MELAS muscle was significantly higher than those in an age-matched control muscle and a control placenta. Some of these nucleotide substitutions were missense and nonsense mutations, which potentially have deleterious effects on the mitochondrial function. The frequency of nucleotide substitutions in the striatum of three patients with Parkinson's disease was also significantly higher than that in control tissues. We also observed increased protein modification by 4-hydroxy-2-nonenal, a lipid peroxidation by-product, in Parkinson's disease. These results suggests that a vicious cycle contributes to the progression of degenerative process. In this cycle, first a primary mitochondrial mutation(s) induces a mitochondrial respiratory defect, which increases the leakage of reactive oxygen species (ROS) from the respiratory chain. Then the ROS would trigger accumulation of secondary mtDNA mutations in postmitotic cells, leading to further aggravation of mitochondrial respiratory defects and increased production of ROS and lipid peroxides from mitochondria, and thus resulting in degeneration of cellular components.

Aged↗
PubMed1996

Effect of GroEL on the re-folding kinetics of alpha-lactalbumin.

The effect of GroEL on the re-folding kinetics of apo- and holo-alpha-lactalbumin from the acidic molten globule state has been investigated by stopped-flow fluorescence measurements. GroEL retards the re-folding of apo-alpha-lactalbumin by interacting with the molten globule state of the protein. The binding constant was estimated to be in the order of 10(5) M-1 by analyzing the kinetic data quantitatively and was found to be much weaker than the binding between GroEL and disulfide-bond reduced alpha-lactalbumin, whose binding constant is in the order of 10(7) M-1. Our present results, together with the previous results, suggest that the state recognized by GroEL is not unique and that the binding strength varies with the state of a target protein. The binding between GroEL and the molten globule state of apo-alpha-lactalbumin becomes stronger with an increasing salt concentration; the binding constant is increased tenfold (from 10(5) to 10(6) M-1) by an increase in salt concentration from 0.05 to 0.25 M. The study of the effect of GroEL on the re-folding kinetics of holo-alpha-lactalbumin, which is represented by a bi-phasic process, shows that the slow phase is affected by GroEL in the same manner as observed in the apo-alpha-lactalbumin re-folding but that the fast phase is not affected by GroEL at all. This indicates that the binding rate of GroEL is faster than the slow phase but slower than the fast phase of the re-folding, and the bi-molecular rate constant of GroEL binding to the molten globule state of alpha-lactalbumin was estimated to be in the order of 10(6) M-1S-1.

Animals↗
PubMed1996

[Evaluation of chemotherapy in the treatment of advanced colorectal cancer--pilot study of 5-FU by biochemical modulation].

We undertook a randomized trial in patients with advanced colorectal cancer, comparing 5-fluorouracil and leucovorin versus combination of these agents with additional cisplatin. Between July 1991 and October 1994, 21 patients with advanced measurable colorectal cancer previously unexposed to chemotherapy were randomly assigned to treatment with either 5-FU (500-750 mg/body) and LV (30 mg/body) for 5 days, or the combination of 5-FU and LV in the same daily dose plus cisplatin (10 mg/body). The overall responses were 30% and 36.3% for the 5-FU/LV and the 5-FU/LV/CDDP treatment arms, respectively. The three-drug combination appeared superior to 5-FU/LV for response duration. A comparative analysis of the toxicities experienced by the patients in the two treatment groups showed a comparable rate, although moderate leukocytopenia was prolonged in one patient treated with 5-FU/LV for 5 days. We conclude that the 5-FU/LV/CDDP treatment arm is an effective therapy for advanced colorectal cancer, but further attempts should be made to increase response rate, prolong response duration and assure effective therapy.

Adult↗
PubMed1995

Mitochondrial DNA minicircles, lacking replication origins, exist in the cardiac muscle of a young normal subject.

This is the first report that mitochondrial (mt) DNA 'minicircles,' lacking replication origins, exist in the heart mtDNA of a young normal subject. A total detection system using 180 kinds of PCR primer pairs was recently devised to detect all possible deletions in mtDNA. To assess the reliability of the system, template mtDNAs were prepared from the heart muscle by three different methods including DNAase digestion. The methods for mtDNA preparation and the nuclear DNA contaminants were demonstrated to have few influences on the analysis. With not less than 95% accuracy, 52 types of deletions including 36 types of minicircles were detected in the subject's mtDNA. These results will give an insight to the mechanism of mtDNA deletion and to the relevance of the deletion with normal aging.

Adult↗
PubMed1995

Oxygen stress induces an apoptotic cell death associated with fragmentation of mitochondrial genome.

We have investigated the role of mitochondria on an active cell death, a feature of apoptosis, under the oxygen stress. An immortalized human fibroblast cell line (rho+) carrying normal mitochondrial genome (mtDNA) underwent an active cell death in 95% oxygen; 68% and 84% of the cells died on the 3rd and 4th days, respectively. By contrast, its derivative lacking mtDNA (rho 0) exhibited a marked resistance to cell death. PCR analyses using 180 primer pairs covering the entire regions of the mtDNA revealed extensive fragmentations of the mtDNA; 49 types of deletions increased up to 187 on the 3rd day. These results indicate that mtDNA and its fragmentation are the underlying molecular lesions in a cell death pathway induced by the oxygen stress.

Apoptosis↗
PubMed1995

Genotype and phenotype of severe mitochondrial cardiomyopathy: a recipient of heart transplantation and the genetic control.

Comprehensive analyses of mitochondrial (mt)DNA of a recipient of heart transplantation at age 7 because of severe cardiomyopathy revealed three germ line point mutations, each one in the 12S rRNA gene, in the CO1 gene and in the cytochrome b gene, respectively. As the somatic mutation, extensive fragmentation of mtDNA associated with 212 kinds of deletions was detected in contrast to 5 kinds in an age-matched negative control. A recipient's positive control having almost the same base-substitutions and mutations with the recipient except one in the CO1 gene also developed severe cardiomyopathy died at age 20. The close relation between phenotype and mtDNA genotype provides the basis of our understanding of cell death and premature ageing.

Adult↗
PubMed1995

Expression of endogenous retroviruses, ERV3 and lambda 4-1, in synovial tissues from patients with rheumatoid arthritis.

We addressed the question of whether or not expression of human endogenous retroviruses (ERV), ERV3 and lambda 4-1, is related to the pathogenesis of rheumatoid arthritis (RA). In genomic Southern hybridization, there were no significant differences between RA patients and healthy volunteers with regard to frequencies of restriction fragment length polymorphism (RFLP) patterns, for either ERV3 or lambda 4-1. By Northern blot analysis using fresh synovial tissues, cultured synovial cells, and peripheral blood mononuclear cells (PBMC) from patients with RA, we noted two molecular species of ERV3 mRNAs of 3.5 kb and 9.0 kb sizes, and one single molecular species of lambda 4-1 mRNAs of 4.2 kb size. The expression was detected not only in RA patients but also in synovial cells from osteoarthritis (OA) as a non-RA control and PBMC from healthy volunteers, and was not related to RA activities or treatments. Although ERV3 and lambda 4-1 expression may not be directly associated with the pathogenic pathway of RA, the possibility exists that human ERV may have a causative role in autoimmune diseases, including RA. We also examined the effect of cytokines on the transcriptional regulation of ERV3. Although the level of ERV3 expression in cultured synovial cells did not change with IL-1 beta treatment, the level for cultured proximal tubular epithelial cells (hKEC) was up-regulated.

Arthritis, Rheumatoid↗
PubMed1995

A rare case of disseminated intravascular coagulation caused by the nonionic contrast medium iohexol.

Nonionic contrast media are reported to cause serious adverse reactions less often than ionic contrast media. However, we treated an otherwise healthy woman with a left ureteral stone in whom disseminated intravascular coagulation developed due to intravenous administration of the nonionic contrast medium iohexol. We discuss the clinical course and possible causes of disseminated intravascular coagulation. Our case emphasizes that nonionic contrast media are not free from serious adverse reactions although the incidence seems extremely low.

Disseminated Intravascular Coagulation↗
PubMed1994

Evidence for the uptake of a vitamin D analogue (OCT) by a human carcinoma and its effect of suppressing the transcription of parathyroid hormone-related peptide gene in vivo.

The present study was undertaken to clarify the pharmacokinetics of 22-oxa-1,25-dihydroxyvitamin D3 (22-oxa-1,25-(OH)2D3, OCT), a vitamin D3 analogue with little calcemic activity, and its effect on the transcription of parathyroid hormone-related peptide (PTHRP) gene in nude mice bearing a human carcinoma (FA-6) associated with humoral hypercalcemia. FA-6 tumor expressed vitamin D receptor (VDR) mRNA, and its nuclear extract contained a specific and saturable 1,25-(OH)2D3 binding activity. Although [3H]OCT administered intravenously into FA-6 tumor-bearing nude mice was cleared from the circulation more rapidly than [3H]1,25-(OH)2D3, the uptake of [3H]OCT into the tumor tissue, relative to the radioactivity in the circulation, was greater than that of [3H]1,25-(OH)2D3. Intravenous or oral administration of OCT reduced the steady-state levels of PTHRP mRNA in FA-6 tumor, and nuclear run-off assays demonstrated that the effect of OCT on PTHRP gene expression occurred at a transcriptional level. RNase mapping analysis revealed that both upstream and downstream promoters of the human PTHRP gene were down-regulated by OCT. Finally, OCT exerted a preventive as well as therapeutic effect on cancer-associated hypercalcemia with a marked prolongation of the survival time in tumor-bearing animals. These results suggest that OCT is effectively taken up by a VDR-positive human carcinoma in vivo and has a therapeutic potential for cancer-associated hypercalcemia through suppression of PTHRP gene transcription.

Animals↗
PubMed1994

Comparison of antagonistic effects of sendide and CP-96,345 on a spinally mediated behavioural response in mice.

Intrathecal administration of the tachykinin NK1 receptor agonists, substance P, physalaemin, septide and [Sar9, Met(O2)11]substance P, elicited a characteristic behavioural response consisting of scratching, biting and licking in mice. The behavioural response induced by substance P was significantly inhibited by simultaneous intrathecal injection of a tachykinin NK1 receptor antagonist, [Tyr6,D-Phe7,D-His9]substance P-(6-11) (sendide), and a non-peptide antagonist, [(2S,3S)-cis-2-(di-phenylmethyl)-N-[(2- methoxyphenyl)-methyl]-1-azabicyclo[2.2.2]octan-3-amine](CP-96,345). The duration of the antagonistic effect of sendide was similar to that of CP-96,345. The antagonistic effect of sendide on the response induced by tachykinin NK1 receptor agonists was approximately 1000 times more potent than that of CP-96,345. Neither antagonist inhibited neurokinin A-, D-septide-, neurokinin B- and eledoisin-induced scratching, biting and licking responses. Sendide was without effect on motor performance as measured by the rotarod test, while motor incoordination was elicited only 2 min after intrathecal injection of CP-96,345. These results indicate that sendide and CP-96,345 are selective antagonists of tachykinin NK1 receptors with a long duration of action.

Analgesics↗
PubMed1994

Fragmentation of human heart mitochondrial DNA associated with premature aging.

Point mutations, oxygen damage and deletions in the heart mitochondrial (mt) DNA of a 19-year-old male patient with premature aging, who died of mitochondrial cardiomyopathy, were comprehensively analyzed. With total base-sequencing, one syn- mutation in the tRNA(Asp) gene and one mit-mutation in the ND3 gene were demonstrated. Using microHPLC/MS, 0.20% of the total deoxyguanosine (dG) were proved to be converted into its hydroxy-radical adduct, 8-hydroxy-dG, of which amount corresponds to that in normal subjects of 78 years old. The total detection system for mtDNA deletions, using 180 kinds of primer pairs, revealed extensive fragmentation of mtDNA; 235 types of deletions existed with various sizes, 97 of which yielded mtDNA minicircles lacking both of the replication origins of light- and heavy-strands. Deleted mtDNA accounted for 84% of the total mtDNA. In a man died from an accident at age 28 having almost the same mtDNA genotype except syn-, 50 types of deleted mtDNA, accounting for 15% of the total, were detected in his heart mtDNA. These results will present a clue to an unidentified mechanism of somatic mtDNA replication and the molecular basis of aging heart.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1994

Differential antinociceptive effects of sendide, a NK1-receptor antagonist, and morphine in the capsaicin test.

The peptide NK1-receptor antagonists, sendide and [D-Trp7]sendide, have been evaluated for antinociceptive activity in the capsaicin test. Both peptides, injected intrathecally (i.t.) 5 min prior to intraplantar capsaicin, produced a dose-dependent reduction of the capsaicin-induced paw licking response. Naloxone (4.0 mg/kg) pretreatment did not affect sendide- and [D-Trp7]sendide-induced antinociception, whereas naloxone at a dose of 0.5 mg/kg antagonized the antinociceptive effect of i.t. administered morphine. Conversely, the antinociceptive action induced by both NK1-receptor antagonists was reduced significantly by i.t. co-administration of substance P. Morphine-induced antinociception was not antagonized by co-administration of substance P. These results led us to the understanding of differential action mechanism of NK1-receptor antagonist- and morphine-induced antinociception as assayed by the capsaicin test.

Analgesics↗