Biomedical subjects

M Yoneda

Publications and source records attributed to M Yoneda.

At least 19 recordsLinked to original sources

PubMed1992

Marked replicative advantage of human mtDNA carrying a point mutation that causes the MELAS encephalomyopathy.

The segregation of mutant and wild-type mtDNA was investigated in transformants constructed by transferring human mitochondria from individuals belonging to four pedigrees with the MELAS encephalomyopathy-associated mtDNA mutation (MELAS is mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) into human mtDNA-less (rho 0) cells. Five of 13 clonal cell lines containing mixtures of wild-type and mutant mtDNAs were found to undergo a rapid shift of their genotype toward the pure mutant type. The other 8 cell lines, which included 6 exhibiting nearly homoplasmic mutant mtDNA, on the contrary, maintained a stable genotype. Subcloning experiments and growth rate measurements clearly indicated that an intracellular replicative advantage of mutant mtDNA was mainly responsible for the dramatic shift toward the mutant genotype observed in the unstable cell lines.

Cell Division↗

PubMed1992

Central action of sigma receptor ligand, JO 1784, to suppress CRF-induced inhibition of gastric function in conscious rats.

The central interaction between the sigma receptor ligand, JO 1784, and corticotropin-releasing factor (CRF)-induced inhibition of gastric acid secretion and emptying was investigated in conscious rats. Intracisternal (i.c.) injection of CRF (5 micrograms) inhibited by 95% gastric acid secretion. JO 1784 (0.05-0.5 micrograms) given i.c. immediately before i.c. injection of CRF partially reversed CRF antisecretory action whereas JO 1784 (5 micrograms) given i.v. had no effect. CRF (0.6 micrograms i.c.)-induced 83% inhibition of gastric emptying was reversed by 45% by JO 1784 (5 micrograms i.c.). JO 1784 (5-50 micrograms i.c.) did not influence basal gastric function. These data demonstrate a centrally mediated antagonistic action of the sigma receptor ligand, JO 1784, on i.c. CRF-induced inhibition of gastric function.

Animals↗

PubMed1992

MELAS mutation in mtDNA binding site for transcription termination factor causes defects in protein synthesis and in respiration but no change in levels of upstream and downstream mature transcripts.

The pathogenetic mechanism of the mitochondrial tRNA(LeuUUR) gene mutation responsible for the MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) syndrome was investigated in transformants obtained by transfer of mitochondria from three genetically unrelated MELAS patients into human mitochondrial DNA (mtDNA)-less (rho 0) cells. Marked defects in mitochondrial protein synthesis and respiratory activity were observed in transformants containing virtually pure mutant mtDNA, as compared to the parent of the rho 0 cells (the 143B cell line) or to transformants containing exclusively wild-type mtDNA, derived from one of the patients or a maternally related asymptomatic individual. A striking protective effect against the mutation was exerted in the transformants by levels of residual wild-type mtDNA above 6%. The MELAS mutation occurs within the mtDNA binding site for a protein factor (mTERF) that promotes termination of transcription at the 16S rRNA/tRNA(LeuUUR) gene boundary. A marked decrease in affinity of purified mTERF for the mutant target sequence was observed in in vitro assays. By contrast, RNA transfer hybridization experiments failed to show any significant change in the steady-state amounts of the two rRNA species, encoded upstream of the termination site, and of the mRNAs encoded downstream, in the transformants carrying the MELAS mutation.

Acidosis, Lactic↗

PubMed1992

Central thyrotropin-releasing factor analog prevents ethanol-induced gastric damage through prostaglandins in rats.

The effects of intracisternal injection of the stable thyrotropin-releasing factor (TRH) analog RX 77368 on gastric lesions induced by 60% ethanol and gastric prostaglandin E2 (PGE2) release were studied in rats. RX 77368 (1.0 and 1.5 ng) injected intracisternally inhibited (by 58% and 78%, respectively) macroscopic gastric damage induced by ethanol. Higher doses (3 and 300 ng) inhibited ethanol-induced gastric injury only in rats pretreated with omeprazole (20 mg/kg SC). Gastric acid output measured in conscious rats 2 hours after pylorus ligation was not modified by intracisternal injection of RX 77368 at 1.5 ng but was significantly increased by 54% at the 3-ng dose. The protective effect of TRH analog (1.5 ng) was completely abolished by indomethacin (5 mg/kg IP) and atropine (2 mg/kg SC) pretreatment. In pylorus-ligated rats, intracisternal RX 77368 (1.5 ng) inhibited ethanol-induced gastric lesions by 64%. Intracisternal injection of RX 77368 (1.5 ng) increased PGE2 levels measured in the effluent of dialysis fibers implanted into the corpus submucosa of urethane-anesthetized rats. Peripheral administration of omeprazole, atropine, indomethacin, or RX 77368 (1.5 ng IV) did not influence gastric damage induced by ethanol. These data show that the stable TRH analog, RX 77368, injected intracisternally at low non-secretory doses acts in the brain to protect against ethanol lesions through prostaglandin and cholinergic pathways. These findings suggest that central vagal activation induced by TRH may play a role in the control of mucosal integrity against ethanol through cholinergic prostaglandin release.

Animals↗

PubMed1992

Inhibitory effect of 17 beta -estradiol on prostaglandin E2-induced phosphoinositide hydrolysis in osteoblast-like cells.

We examined the effect of estradiol on PGE2-induced phosphoinositide hydrolysis and cAMP production in cloned osteoblast-like MC3T3-E1 cells. 17 beta -Estradiol pretreatment significantly inhibited the formation of inositol phosphates induced by 10 microM PGE2 in a dose-dependent manner between 1 pM and 10 nM. This effect of 17 beta -estradiol was dependent on the time of pretreatment and submaximum inhibition was observed at 4 h. However, 17 beta -estradiol had little effect on the formation of inositol phosphates induced by 20 mM NaF, a GTP-binding protein activator. The cAMP production induced by PGE2 was not influenced by 17 beta -estradiol. These results suggest that 17 beta -estradiol modulates the signal transduction by PGE2 and that the effect seems to be exerted between PGE2 receptor and the GTP-binding protein coupled to phospholipase C in osteoblast-like MC3T3-E1 cells.

Animals↗

PubMed1992

Central neuropeptide Y and the sigma ligand, JO 1784, reverse corticotropin-releasing factor-induced inhibition of gastric acid secretion in rats.

1. The central interactions between the sigma ligand, JO 1784, [(+)-N-cyclopropylmethyl-N-methyl-1,4-diphenyl-1-ethylbut-3- en-1-ylamine hydrochloride], or neuropeptide Y (NPY) and corticotropin-releasing factor (CRF)-induced inhibition of gastric acid secretion were investigated in rats anaesthetized with urethane. Drugs were injected intracisternally (i.c.) or into specific hypothalamic nuclei. Gastric acid secretion was measured by the flushed technique under basal and pentagastrin (10 micrograms kg-1 h-1, i.v.) stimulated conditions. 2. Intracisternal injection of CRF (10 micrograms), bombesin (0.1 microgram) and human recombinant interleukin-1 beta (hIL-1 beta, 0.1 microgram) inhibited gastric acid response to pentagastrin by 72%, 56% and 62%, respectively. NPY (0.5 microgram) or JO 1784 (0.5 microgram) injected i.c. did not alter acid secretion but completely prevented the inhibitory effect of CRF. The antagonistic effect of NPY and JO 1784 against CRF was dose-related (0.01-0.5 microgram) and peptide-specific since NPY and JO 1784 did not alter the antisecretory action of bombesin or hIL-1 beta. 3. The putative sigma receptor antagonist, BMY 14802, (1 mg kg-1, s.c.) did not influence pentagastrin-stimulated acid secretion nor CRF-induced inhibition of gastric acid secretion; however, BMY 14802 administered s.c. 20 min before JO 1784 or NPY, abolished the antagonistic effect of both JO 1784 and NPY. 4. CRF (3 micrograms) microinjected into the hypothalamic paraventricular nucleus (PVN) and the lateral hypothalamus (LH) inhibited pentagastrin-stimulated gastric acid secretion by 61% and 51%; NPY (0.03 micrograms) or JO 1784 (0.03 micrograms) microinjected into the PVN had no effect by themselves but blocked CRF antisecretory action.There were more VPBs (220 +/- 75), a higher incidence of VT (60%) and more episodes of VT (11.5 +/- 6.0 compared to 0.7 +/- 0.3 episodes in the preconditioned dogs not given L-NAME); none of the animals survived reperfusion (incidence of VF 100%). The improvement in the severity of the degree of inhomogeneity which resulted from preconditioning was abolished by L-NAME administration.5. L-NAME itself elevated blood pressure (from 96 +/- 5 mmHg diastolic to 119 +/- 7 mmHg), reduced heart rate (from 155 +/- 7 to 144 +/- 4 beats min-') but did not change LVEDP, LVdP/dt,,,,, coronary blood flow, ST-segment elevation or the degree of inhomogeneity of conduction. When given 10 min before the prolonged coronary artery occlusion in dogs not subjected to preconditioning, L-NAME had no significant effect on the severity of arrhythmias except for more periods of VT (a mean of 11.7 +/- 4.7 episodes per dog).6. It is concluded from these studies that the generation of nitric oxide contributes to the marked antiarrhythmic effects of preconditioning in the canine myocardium, probably through elevation of cyclic GMP.

Animals↗

PubMed1992

Influence of endothelin on human platelet aggregation and prostacyclin generation from human vascular endothelial cells in culture.

The effects of endothelin (ET) on the function of cultured human umbilical vein endothelial cells (HUVEC) and that of human platelets were investigated with reference to endothelium-derived relaxing factor (EDRF) and PGI2. Considering the platelets, ET had no effect on platelet-rich plasma (PRP) aggregation, the generation of thromboxane A2 ([TXA2]) from platelets, and cytosolic free calcium ion concentration ([Ca++]i), cAMP content ([cAMP]i) or cGMP content ([cGMP]i) in platelets. In contrast, the addition of the solution in which HUVEC had been incubated with ET to PRP produced a decrease in PRP aggregation, [TXA2], and [Ca++]i, and an increase not only in [cAMP]i but also in [cGMP]i in platelets. In the HUVEC pretreated with acetylsalicylic acid (aspirin), this increase of [cGMP]i was not affected, but the HUVEC-mediated decrease in PRP aggregation, [TXA2], and [Ca++]i induced by ET were not completely abolished. However, the pretreatment of HUVEC with a combination of aspirin and L-NG-monomethyl arginine (LNMMA) as an inhibitor of EDRF completely abolished the HUVEC-mediated decrease in PRP aggregation, [TXA2] and [Ca++]i induced by ET, and also abolished the enhancement of [cGMP]i and [cAMP]i in platelets. The PGI2 of HUVEC was enhanced by ET with no changes in [Ca++]i, [cAMP]i and [cGMP]i. The ET-induced enhancement was remarkably attenuated by pretreating the HUVEC with aspirin, but not with LNMMA. We conclude that ET attenuates the aggregation of platelets through a decrease in [TXA2] by an increase in [cAMP]i via the increase in PGI2 of HUVEC, and by an increase in [cGMP]i via EDRF.

Blood Platelets↗

PubMed1992

Granulomatous hypophysitis with meningitis and hypopituitarism.

We report an unusual case of granulomatous hypophysitis in which visual impairment, meningitis and hypopituitarism in a 76-year-old female were associated with radiological evidence of a pituitary mass. The sellar lesion was indistinguishable from pituitary tumor on neuroimaging studies, but the recovery of visual acuity and visual field abnormalities together with the improvement of pituitary function after steroid administration indicated that the mass lesion was due to an inflammatory disease of the pituitary gland. The pituitary tissue obtained by transsphenoidal hypophysectomy revealed granulomatous inflammatory cell infiltration with epithelioid cells and scattered multinucleated giant cells. Although a causal relationship with meningitis was not ascertained, possible exposure of the CSF space to the autoimmune inflammatory process of the pituitary gland was likely in view of the positive pituitary antibody reaction and radiological evidence of suprasellar extension. This entity should be considered when evaluating patients with a pituitary mass, hypopituitarism and meningitis.

Aged↗

PubMed1992

[Evaluation of hypercoagulable state in patients with malignancies by using prothrombin fragment F1 + 2].

In order to elucidate the activation of the coagulation cascade in patients with malignant neoplasms, we measured the levels of plasma prothrombin fragment F1 + 2, which is liberated in the process of thrombin generation. Twenty healthy adults (Group A), 29 patients with malignancies not complicated with DIC (Group B) and 4 patients with DIC (Group C) were evaluated. The values of F1 + 2 in Group C (2.38 +/- 0.55 nmol/l) were significantly higher (p < 0.01) than those in Group A (0.52 +/- 0.19 nmol/l) and B (0.86 +/- 0.68 nmol/l). Many patients in Group B showed higher levels of F1 + 2 compared to normal subjects, however, no significant differences were found between Group A and B. With respect to other coagulation molecular markers such as TAT, D-Dimer and PIC, F1 + 2 levels revealed positive correlation to those levels. Concerning the clinical course of DIC, elevated levels of F1 + 2 normalized much rapidly than those of TAT and D-Dimer by continuous administration of heparin. In conclusion, the measurement of plasma F1 + 2 is important in monitoring the activation of coagulation system in patients with malignancies, especially with respect to early detection and treatment of DIC.

Aged↗

PubMed1991

Quantitation of mitochondrial DNA carrying tRNALys mutation in MERRF patients.

An A to G transition at nucleotide position 8,344 in tRNALys of mitochondrial DNA has been recently identified as a causative mutation of myoclonus epilepsy associated with ragged-red fibers (MERRF). To investigate if the degree of heteroplasmy of mitochondrial DNA is correlated with the severity of MERRF, we have developed a novel method for quantitation of the mutant mitochondrial DNA by polymerase chain reaction using a mismatched primer. With the method, populations of mutant mtDNAs from 5 cases of MERRF carrying the tRNALys mutation were analyzed. The tight linkage of the severity of symptoms and the degree of heteroplasmies is not necessarily observed for all cases, though there is a tendency that patients with less wild type mtDNAs show severer clinical symptoms and earlier onset.

Adolescent↗

PubMed1991

Distinct clustering of point mutations in mitochondrial DNA among patients with mitochondrial encephalomyopathies and with Parkinson's disease.

The total sequence data for mitochondrial DNA (mtDNA) revealed distinct clustering of point mutations (pms) in mtDNA among one patient with myoclonus epilepsy with ragged-red fibers (MERRF), two patients with Parkinson's disease (PD), two patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), and one patient with fatal infantile cardiomyopathy (FICM). Among 33 to 62 pms found in each patients, sequentially diverged five clusters of pms were detected and designated as C-1 to C-5. C-1, consisted of fourteen pms, existed in the MERRF patient, C-1 and C-2 (nine pms) in one PD patient, C-1 to C-3 (seven pms) in another PD patient, C-1 to C-4 (one pm) in one MELAS patient and C-1 to C-5 (three pms) in another MELAS patient and the FICM patient. From these clustering of pms, a phylogenetic tree of mitochondrial encephalomyopathies (ME) was constructed. This tree clearly indicated that the ME and PD patients are members of the same gene family, and the MELAS and FICM patients are each others' closest relative. Each patient's unique pms (14 to 28 pms) were detected and, from their characteristic features, the types of the mutations specific for the disease were classified as mit- + syn- for MERRF, mit- + p- for PD, and syn- + mit- for MELAS. An inverse relation was found between the total number of pms and life span of the MELAS and FICM patients.

Adolescent↗

PubMed1991

Vagal afferent innervation and regulation of gastric function.

In this article, we have presented evidence that vagal capsaicin-sensitive afferent fibers are involved in the regulation of gastric mucosal and motor function. Gastric acid secretion stimulated by gastric distension, histamine and central injection of TRH analog are all partly dependent on vagal capsaicin-sensitive afferent mechanisms. It is possible that as vagal efferent activity releases histamine, the common final pathway is the reduction in the response to histamine. At present, it is unclear as to the mechanism by which capsaicin-sensitive afferents are involved in the secretory response to histamine. With regard to the gastric acid and mucosal blood flow responses to TRH, it is not clear whether the sensory neurons represent a component of the efferent pathway that is activated by TRH or whether their role is to set the sensitivity of, or exert feedback control on this efferent pathway. As perineural capsaicin application decreases peptide content in the peripheral terminal fields of sensory neurons and these peptides may produce local effector functions within the tissue, it is possible that alterations in the gastric responses to TRH result from a decrease in the local effector functions of vagal neurons. From the experiments on electrical stimulation of the vagus nerve, it is evident that antidromic stimulation of vagal afferents can stimulate gastric mucosal blood flow, although under these experimental conditions there was no evidence for a capsaicin-sensitive stimulation of gastric acid secretion. The physiological relevance of this stimulation of gastric mucosal blood flow is at present unclear, but it is possible that physiological stimuli, such as distension or nutrients, may stimulate afferents and signal for an increase in gastric mucosal blood flow. In addition, pathophysiological or noxious stimulation of vagal afferents may also signal for an increase in gastric mucosal blood flow and may play a role in the response of the mucosa to injury.

Animals↗

PubMed1991

Initiation of DNA replication cycle in fertilized eggs of the starfish, Asterina pectinifera.

Starfish oocytes or eggs were inseminated at various times between first prometaphase and pronuclear stage, and were subsequently labeled with the thymidine analogue 5-bromo-2'-deoxyuridine (BrdU) in order to detect the onset of DNA synthesis phase (S phase) during the first cell cycle using a monoclonal antibody against BrdU. The interval between fertilization and the first S phase was found to be constant (30-45 min, depending on batches) in eggs fertilized after formation of the first polar body. Eggs fertilized before first polar body formation, however, always entered the S phase 10-20 min after the second polar body formation. On the basis of these observations we conclude that (i) the chain of events triggered by fertilization, collectively called "postactivation process" for the first S phase, goes on in parallel with the process of maturation and (ii) only the final step of the postactivation process is arrested until the termination of meiosis. In eggs that had been fertilized before the first polar body formation, the female and male pronuclei exhibited uniformly distributed chromatin soon after the second polar body formation. In eggs that had been fertilized after the second polar body formation, however, the chromatin of the pronuclei remained fibrillar even during the S phase. Thus full decondensation of chromatin appears to depend on a certain advance in the postactivation process.

Animals↗

PubMed1991

Muscle histopathology in myoclonus epilepsy with ragged-red fibers (MERRF).

Histopathologic findings were examined in skeletal muscle biopsies from 6 patients with myoclonus epilepsy with ragged-red fibers (MERRF) who had an A to G base substitution at mitochondrial DNA (mtDNA) nucleotide pair 8344. In addition to variation in fiber size and ragged-red fibers, all specimens in cross sections showed focal cytochrome c oxidase (CCO) deficiency, suggesting that this finding is crucial in elucidating the role of the mutant mtDNA in the pathogenesis of this disorder. Along the length of single muscle fibers, defects in CCO activity were distributed segmentally with blurred borders in 5 patients which were in contrast with segmental defects with sharply delineated borders seen in chronic progressive external ophthalmoplegia with deleted mtDNA. These morphologically heterogeneous defects in CCO activity may in part be due to differing populations of and distributions of wild and mutants mtDNAs.

Adolescent↗

PubMed1991

Effects of hypergravity on proliferation and differentiation of osteoblast-like cells.

We investigated the effects of hypergravity on DNA synthesis and alkaline phosphatase (ALP) activity in cloned osteoblast-like cells, MC3T3-E1. Hypergravity (5 x g) stimulated DNA synthesis in these cells in a time-dependent manner and increased it approximately up to 150% of that of the control (1 x g). 12-O-Tetra-decanoylphorbol-13-acetate (TPA), a protein kinase C activator, and insulin-like growth factor I (IGF-I) enhanced DNA synthesis additively with hypergravity (5 x g). An increase in ALP activity induced by 10% fetal calf serum (FCS) was suppressed by hypergravity (2 x g, 5 x g). Five x g completely suppressed the increase in ALP activity. TPA and hypergravity (2 x g) suppressed the increase in ALP activity induced by FCS additively. Hypergravity (5 x g) showed no significant effect on cAMP nor cGMP production in these cells, but increased prostaglandin E2 (PGE2) production. Exogenous PGE2 stimulated DNA synthesis in these cells but had little effect on 10% FCS-induced ALP activity. These results suggest that hypergravity stimulates proliferation but suppresses differentiation of osteoblast-like cells through a pathway independent of the activation of protein kinase C and the production of cyclic nucleotides, and that hypergravity and IGF-I stimulate proliferation of these cells through an independent signal transduction pathway. Moreover, our data strongly suggest that PGE2 mediates the signalling of hypergravity on the proliferation of osteoblast-like cells.

Alkaline Phosphatase↗

PubMed1991

Effects of changes in angiotensin converting enzyme activity on renin release: pretreatment with dexamethasone enhances a plasma renin activity response to captopril in normal subjects.

Healthy adults were given captopril (25 mg and 75 mg) po with or without dexamethasone (DXM) pretreatment (1 mg po 2 h before and simultaneously with the captopril). We determined the serum potassium and sodium concentrations, plasma prostaglandin E2 level, PRA, serum angiotensin converting enzyme (ACE) activity, and aldosterone level from 20 min before to 120 min after administration of captopril. DXM pretreatment stimulated the PRA response to captopril. This stimulation was suppressed by indomethacin. However, the administration of DXM did not induce a consistent rise in the prostaglandin E2 level. The administration of DXM induced a significant rise in the potassium concentration, but since simultaneous administration of indomethacin with captopril induced the suppression of PRA without affecting the potassium level, the PRA increase in response to captopril with DXM was not caused directly by the potassium increase. There were no significant differences in the PRA increase between 25 mg captopril and 75 mg captopril, or between DXM-25 mg captopril and DXM-75 mg captopril, though the inhibitions of ACE activity by captopril differed according to dose. The PRA increases, but not the captopril-induced inhibition of ACE activity, were significantly different between captopril alone and captopril with DXM pretreatment at either dose of captopril. Thus, the inhibition of ACE activity perhaps allows PRA to increase in response to captopril. These results suggest that the DXM stimulation of PRA may have been dependent on the inhibition of ACE activity by captopril.

Adult↗

PubMed1991

Simple detection of tRNA(Lys) mutation in myoclonus epilepsy associated with ragged-red fibers (MERRF) by polymerase chain reaction with a mismatched primer.

We developed a simple method for the detection of a tRNA(Lys) mutation in myoclonus epilepsy associated with ragged-red fibers (MERRF) by polymerase chain reaction with use of a mismatched primer. Although the tRNA(Lys) mutation does not alter recognition sequences for commercially available restriction enzymes, we have successfully changed two nucleotides flanking the A to G mutation at nucleotide position 8344 in a tRNA(Lys) gene of a mitochondrial genome. As a result, the mutation can be detected as a Nae I restriction fragment length polymorphism. With this method, all eight MERRF patients and an asymptomatic mother of a MERRF patient, from six independent families, had the same tRNA(Lys) mutation. Our method is simple and should also be useful for the quantitation of heteroplasmies.

Base Sequence↗

PubMed1991

Cytotoxic activity of marine algae and a cytotoxic principle of the brown alga Sargassum tortile.

Partition fractions of hexane, CCl4 and CHCl3 from methanolic extracts of marine algae were each examined for cytotoxic activities against cultured P-388 lymphocytic leukemia cells. Cytotoxic activities were found for partition fractions of 21 species of seaweed. Bioactivity-guided fractionation of the CCl4 partition fraction from Sargassum tortile, exhibiting the most prominent activity, afforded dihydroxysargaquinone (1) and sargatriol (2) previously isolated from this alga. The former was evaluated as a cytotoxic principle, and the latter, showing moderate activity, was suggested to be an artifact derived from 1 during the isolation procedure.

Animals↗