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Biomedical subjects

K Katsumata

Publications and source records attributed to K Katsumata.

At least 19 recordsLinked to original sources
PubMed1997

Fragile mitochondrial DNA: the missing link in the apoptotic neuronal cell death in Parkinson's disease.

The oxidative stress theory, the mitochondrial (mt) hypothesis, and the apoptosis hypothesis are proposed as the cause of neuronal cell death in Parkinson's disease (PD). However, the direct link between them has remained unknown. Recently, the mt control of nuclear apoptosis is documented that collapse of mt transmembrane potential due to energy crisis leads to release of apoptotic protease activating-factors into cytosol and subsequently nuclear DNA fragmentation. However, an endogenous factor responsible for the energy crisis under physiological conditions is missing. Here we report the missing factor as that mtDNA in the striatum of a parkinsonian patient fragments into 134 types of deleted pieces, being detected by the total detection system for mtDNA deletion. The system has documented that the mtDNA is extremely susceptible to hydroxyl radical damage, hence to oxidative stress, enough to cause the cellular energy crisis. The extensive fragility of mtDNA in brain stem could link the oxidative stress up with the apoptotic neuronal cell-death of PD.

Adolescent↗
PubMed1997

Hydrogen-exchange kinetics of reduced alpha-lactalbumin bound to the chaperonin GroEL.

alpha-Lactalbumin in which all the disulfide bonds are fully reduced (RLA) is known to bind strongly to the chaperonin GroEL. Although RLA is more unfolded than the native state and the molten globule state of alpha-lactalbumin, the CD spectrum of RLA in the far-UV region shows that RLA is not fully unfolded but has an appreciable amount of secondary structure. To investigate whether the secondary structure elements present in RLA are responsible for the recognition of RLA by GroEL or not, we have examined the hydrogen-exchange kinetics of RLA in the presence and absence of GroEL. Our results show that the hydrogen-exchange kinetics of RLA bound to GroEL is identical to that of free RLA. This implies that the secondary structure elements in RLA are not important for the recognition by GroEL, but the unstructured parts of RLA that are not relevant to the stability of the secondary structure provide strong recognition sites of RLA.

Chaperonin 60↗
PubMed1997

Suppressed cardiac and electroencephalographic arousal on apnea/hypopnea termination in elderly patients with cerebral infarction.

The goal of the present investigation is to show the clinical significance of arousal response at termination of apnea/hypopnea in patients with sleep apnea syndrome (SAS) after cerebral infarction. We polygraphically assessed "cardiac arousal," which is defined as an abrupt increase in heart rate at a termination of sleep apnea/hypopnea, and electroencephalographic (EEG) arousal. There were six elderly subjects, bedridden after cerebral infarction, with SAS aged 71-87 years (mean 72.3 years) and 11 age-matched patients with SAS aged 61-78 years (mean 62.3 years) as controls. The following sleep parameters were measured: number of apneas per hour (apnea index [AI]), number of hypopneas per hour (hypopnea index [HI]), summation of the two (apnea/hypopnea index [AHI]), and duration in which nocturnal oxygen saturation was decreased below 90% (duration of SaO2 < 90%). We calculated the ratio of apnea/hypopnea per hour with cardiac arousal to total apnea/hypopneas (XI) (% cardiac arousal [XI/AHI x 100]) and the ratio of that with EEG arousal (YI) (% EEG arousal [YI/AHI x 100]). Between the two groups, we found no significant difference in body mass index, the ratio of central apnea to total apnea/hypopnea, AHI, duration of apnea/hypopnea, lowest SaO2, and duration of SaO2 < 90%. Compared with controls, % cardiac and % EEG arousals were significantly lower in patients with cerebral infarction. In contrast, the ratio of HI to AHI was significantly higher in patients with cerebral infarction than in control subjects. Our findings indicate that cardiac and EEG arousals at termination of apnea/hypopnea are significantly suppressed in elderly patients with SAS after cerebral infarction, which may provide useful information on the pathophysiology of SAS in patients with cerebrovascular disease.

Aged↗
PubMed1997

[Clinical analysis of adjuvant chemotherapy using 5-fluorouracil, leucovorin and cis-diamminedichloroplatinum for patients with advanced and recurrent gastric cancer].

The chemotherapy combining 5-FU, CDDP, and LV was conducted in 17 patients with advanced and recurrent gastric cancer. The regimen consisted of 5-FU (by continual infusion 600 mg/m2/day for 5 days), CDDP (low-dose consecutive drip infusion, 2 hours 20 mg/m2/day for 3 days) and LV (by bolus infusion 20 mg/ m2/day for 5 days). Advanced gastric cancer was found in 12 cases (operation performed in 9 cases and 7 cases resectable) and recurrent in 5 cases. Macroscopic judgment of efficacy in 10 recurrent and inoperable cases revealed CR in 1 patient, PR in 5 patients, NL in 2, and PD in 2 patients. The overall response rate was 60.0%. There were 7 resectable cases, 4 PR patients, 1 MR and 2 NC patients. The overall response rate was 57.1%. Operations were done in 9 of 12 patients with advanced gastric cancer. The histological effects in 7 cases with resectable cases were as follows: 1 patient of grade 0, 2 patients of grade 1a, 3 patients of grade 1b, and 1 patient of grade 2. The main adverse reactions were gastrointestinal symptoms, but in 3 cases thrombocytopenia was found. This chemotherapy for advanced and recurrent gastric cancer shows excellent clinical efficacy.

Adenocarcinoma↗
PubMed1997

[Endogenous retroviruses in autoimmune diseases].

Endogenous retroviruses (ERVs) and those related genes are thought to be originated from integration of infectious retroviruses to germ cells or evolved from transposable genetic elements. Some of them can make biological effects on activities of hosts, by promoting the expression of flanking genes or producing certain regulatory proteins. If those mechanisms occur on cells in immune networks, immunological dysregulation including autoimmunity will develop. ERVs can also produce proteins serving as auto-antigens, followed by autoimmune responses. In this article, studies up to date on ERVs of animals and humans are shortly reviewed, related to immunological disorders to autoimmune diseases, showing some examples.

Animals↗
PubMed1997

[Efficacy of combination chemotherapy with mitoxantrone, vincristine, doxifluridine and prednisolone for recurrence of breast cancer].

We treated fifteen patients with recurrent breast cancer by a combination of mitoxantrone (8 mg/m i.v., day 1), vincristine (1.2 mg/m i.v., day 1), doxifluridine (800 mg/body po, everyday) and prednisolone (30 mg/body po, day 1-7). Cycles were repeated every 3 weeks and all patients received more than 2 cycles. A response to treatment was observed in 9 of 15 evaluable patients (60.0%) with 4 complete remissions and 5 partial remissions. Eight patients were previously exposed to anthracyclines. In 5 of 7 cases with no previous chemotherapy, treatment was effective, and in 4 of 8 cases previous chemotherapy was effective. The toxicity was primarily leucopenia (86.7%), and 9 patients received G-CSF therapy. Other toxicities (alopecia, neurologic and general fatigue) were mild. Two patients with heart failure were recognized and treated with other therapy. This chemotherapy is effective for the treatment of recurrent breast cancer.

Administration, Oral↗
PubMed1997

[Tissue-specific expression of human endogenous retrovirus mRNA and its regulation by cytokines in vitro].

To investigate biological roles of human endogenous retroviruses (ERVs), the author examined the viral mRNA expression in the normal systemic organs in vivo and its regulation by cytokines in cultured cells. The following evidence suggesting biological activities of a human ERV, ERV3, was obtained. First, the ERV3 mRNA was demonstrated at different levels in organs, and at consistently high levels in adrenal glands from all individuals and in all adrenocortical adenomas examined, by Northern hybridization. In situ hybridization revealed that the ERV3 expression was localized in all three layers of the adrenal cortex, but not in the medulla. These results suggest that the ERV3 expression may relate to the cellular differentiation and/or steroid production of adrenocortical cells. Second, the amount of ERV3 mRNA in cultured endothelial cells from human umbilical vein was significantly increased with any of TNF-alpha, IL-1 beta or IL-1 alpha stimulation but decreased with IFN-gamma treatment, by a quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) with competitive PCR. The collective evidence suggests that the ERV3 expression may be upregulated at the inflammatory sites of vessels in vivo, and that the ERV3 expression may, therefore, play certain pathogenic roles in diseases, including collagen and vascular diseases in man.

Adrenal Cortex↗
PubMed1996

Dominant forces in the recognition of a transient folding intermediate of alpha-lactalbumin by GroEL.

GroEL is known to retard the refolding of apo-alpha-lactalbumin by interacting with the molten globule state of the protein. In order to investigate the dominant forces in this interaction, the GroEL-affected kinetic refolding of apo-alpha-lactalbumin from its acidic molten globule state was studied at different temperatures and in the presence of different kinds of monovalent cations at a fixed temperature (25 degrees C), by stopped-flow fluorescence measurements. The binding constant between GroEL and alpha-lactalbumin in the molten globule state was evaluated quantitatively from the kinetic refolding curves in the absence and presence of GroEL. The binding was found to be entropy-driven at room temperature and the heat capacity change for the binding was found to be largely negative (-3.6 kJ mol-1.K-1), indicating that GroEL binds to alpha-lactalbumin through hydrophobic interactions. The study of the effect of different monovalent cations at various ionic strengths shows that the binding is strengthened by electrostatic screening by ions, demonstrating the importance of electrostatic interactions. The relationship of these results with a putative target recognition site of GroEL will be discussed.

Binding Sites↗
PubMed1996

Age-related extensive fragmentation of mitochondrial DNA into minicircles.

In normal human hearts, a progressive age-related fragmentation of mitochondrial (mt) DNA into various-sized deleted (delta) mtDNA up to 358 types was documented by a novel total-detection system for deletions. The delta mtDNA lacking replication origin(s), minicircles, accumulated up to 280 types out of the 358, suggesting a yet unknown replication mechanism in human. Wild-type mtDNA decreased linearly down to 11% of the total with age negatively correlated with delta mtDNA and oxidized nucleoside, 8-hydroxydeoxyguanosine. A remarkable mirror image observed in delta mtDNA size distribution as well implies that random hydroxyl-radical attacks resulted in double-strand break and rejoining of mtDNA as a preferable mechanism to form various delta mtDNA of closed circular duplex. These facts support the 'redox mechanism of aging.'

Adolescent↗
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↗