Ataxia with isolated vitamin E deficiency and retinitis pigmentosa.
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Ataxia↗
Biomedical subjects
K Hirota
Publications and source records attributed to K Hirota.
Misuse of infusion pump during propofol anaesthesia.
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Anesthesia, Intravenous↗
Mature and immature myeloid cells decrease the granulocyte colony-stimulating factor level by absorption of granulocyte colony-stimulating factor.
We studied the effects of polymorphonuclear neutrophils (PMN) and immature myeloid cells on the granulocyte colony-stimulating factor (G-CSF) level in vitro to better understand the regulatory mechanisms of neutropoiesis. Intact normal PMN decreased the G-CSF level after incubation with recombinant human (rh) G-CSF in a time- and dose-dependent manner. The percent reduction decreased as the concentration of rhG-CSF increased. However, the cell-free PMN-conditioned medium (PMN-CM) did not decrease the G-CSF level. The intact PMN also decreased the granulocyte-macrophage (GM)-CSF level after culture with rhGM-CSF, but did not affect the monocyte (M)-CSF level after culture with rhM-CSF. Normal bone marrow (BM) immature neutrophilic cells and G-CSF-dependent acute myeloid leukemic cells (OCI/AML la) also decreased the G-CSF level, whereas K-562 cells, which have no detectable G-CSF receptors, did not affect it. Phenylarsine oxide (PhAsO), an inhibitor of endocytosis of ligand receptor complex, abrogated this decreasing effect of intact PMN and OCI/AML la cells. These findings suggest that mature and immature myeloid cells negatively regulate neutropoiesis by, at least in part, decreasing the G-CSF level probably through receptor-mediated continual absorption and metabolism of G-CSF.
Absorption↗
In vitro adherence of Streptococcus constellatus to dense hydroxyapatite and titanium.
Bacterial adherence to dense hydroxyapatite (HA) and titanium (Ti) rods was examined in vitro using Streptococcus constellatus ATCC27832. Streptoccus constellatus is associated with dental abscess and was isolated from the peri-implantitis. The dense HA was etched with 5% hydrofluoric acid for 0, 10, 20, 30, 40, and 50 s Adherence to the untreated dense HA was twice as high as the adherence to the Ti. The adherence to saliva-treated Ti was 13% higher than that to untreated Ti. The adherence was increased by acid-treatment of the dense HA, following a sigmoid curve from 20 to 50 s of treatment time. The dense HA has the capacity to receive more bacterial adherence than Ti and furthermore, the etched dense HA becomes more adherent.
Abscess↗
Ketamine inhibits the tonic response to carbachol and histamine in the guinea pig trachea.
The contractile response of smooth muscles to spasmogens can be divided into two components by modifying the extracellular Ca2+ concentration. The phasic component depends on the mobilization of Ca2+ from intracellular stores whereas the tonic component depends, to a large extent, on the influx of extracellular Ca2+. The present study was designed to investigate the effect of ketamine on the tonic response to carbachol or histamine in the guinea pig trachea. Tracheal spirals from female guinea pigs were mounted in organ baths filled with aerated physiological buffer, and their isometric tension was measured. The phasic response to 10(-7) M carbachol or 10(-5) M histamine in Ca(2+)-free, ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid-containing buffer and the tonic response to each spasmogen after restoring [Ca2+] in the buffer was measured in the absence or presence of ketamine. In the presence of normal physiological buffer, ketamine decreased the contractions induced by carbachol or histamine in a dose-dependent fashion. No measurable phasic response to either carbachol or histamine was obtained in our preparation. Ketamine (5 x 10(-5) M-10(-3) M) reduced the tonic response to 10(-7) M carbachol to 79.5 +/- 2.7-4.3 +/- 0.7% of the response without ketamine. Similarly, ketamine (5 x 10(-4) M-2 x 10(-3) M) decreased the tonic response to 10(-5) M histamine to 80.7 +/- 3.9-23.0 +/- 3.2% of the response in the absence of ketamine. Our findings support the hypothesis that ketamine inhibits the paracrine agent-induced contractions of smooth muscles by interfering with the influx of extracellular Ca2+ or with an intracellular event(s) requiring extracellular Ca2+.
Anesthetics, Dissociative↗
In vivo spasmolytic effect of ketamine and adrenaline on histamine-induced airway constriction. Direct visualization method with a superfine fibreoptic bronchoscope.
BACKGROUND: Ketamine (K) has been reported to produce bronchodilation in patients suffering from asthma. Although most researchers have used indirect measurements to study the effect of K in vivo, the reliability of these indirect methods are controversial. We have developed a new technique to measure the bronchial cross-sectional area (BCA) in vivo with a superfine fibreoptic bronchoscope (SFB). Employing this method, we evaluated in vivo spasmolytic effect of K and adrenaline (A). METHODS: Twenty-one mongrel dogs were anaesthetized with pentobarbitone (30 mg.kg-1) and paralyzed with pancuronium (200 micrograms.kg-1.h-1). The trachea was intubated with an endotracheal tube that has a second lumen for insertion of a SFB (OD: 2.2 mm) to measure the BCA continuously. The tip of the SFB was placed between the 2nd and 3rd bronchial bifurcation of the right lung. A videoprinter printed the BCA, which was then measured with NIH Image. Bronchoconstriction was produced with histamine (H: 10 micrograms.kg-1 + 500 micrograms.kg-1.h-1) which was administered until the end of the experiment. The BCA was assessed before and 30 min after the start of H infusion. The dogs were randomly allocated to 3 groups of 7 dogs each. In group K, K (0-10 mg.kg-1) was given i.v., and the BCA was measured 5 min after each K dose. In group A, A (0-0.4 microgram.kg-1) was given i.v., and the BCA was measured 1 min after each A dose. In group A + K, K (1 mg.kg-1 i.v. + 1 mg.kg-1.h-1 i.v.) was given followed, 30 min after, by A i.v. in the same doses as in group A. The BCA was assessed 30 min after the start of K and again 1 min after each A dose. RESULTS: K 10 mg.kg-1 reversed H-induced bronchoconstriction. A subthreshold dose of K significantly potentiated the effect of A, reversing the decrease in BCA by H. CONCLUSION: We have found that K could reverse the H-induced bronchoconstriction and potentiate the A-induced bronchial relaxation.
Animals↗
Inhibited hypothalamic histamine metabolism during isoflurane and sevoflurane anesthesia in rats.
BACKGROUND: Histamine is most densely distributed in the hypothalamus and has an important effect on consciousness or wakefulness. It has been little considered whether general anesthetics could exert their effects on hypothalamic histamine metabolism. The present study was conducted to investigate the effects of isoflurane and sevoflurane anesthesia on hypothalamic histamine metabolism. METHODS: Sixty male Wistar rats were divided equally into isoflurane and sevoflurane anesthesia groups. Each group was divided into three equal sub-groups: the control, anesthesia and recovery groups. The rats of the anesthesia and recovery groups were exposed to either 2% isoflurane or 3% sevoflurane for 30 min. The recovery group was kept in air for 30 min after anesthesia. The rats were decapitated to dissect out hypothalamus which was divided into the fore and rear portion. The contents of histamine and 1-methylhistamine, which is a main histamine metabolite, were determined by high-performance liquid chromatography. The obtained data were analyzed by one-way analysis of variance followed by Bonferoni's test. RESULTS: Histamine contents of the anterior and posterior hypothalamus in both isoflurane and sevoflurane groups increased significantly during the anesthesia and 1-methylhistamine contents of the anterior and posterior hypothalamus in sevoflurane group increased remarkably after anesthesia. The increases of histamine contents supposedly reflected inhibited histamine metabolism and the increases of 1-methylhistamine would be caused by acceleration of histamine degradation. CONCLUSIONS: Histamine metabolism was inhibited during both isoflurane and sevoflurane anesthesia and accelerated only in the posterior hypothalamus during the emergence from these anesthetics.
Analysis of Variance↗
Fosfomycin reduces CD15s-related antigen expression of Streptococcus pyogenes.
We have previously shown the immunological mimicry of human sialyl-Lewis(x) (CD15s) by a surface antigen of Streptococcus pyogenes. This mimicking surface antigen may act as a ligand to the selectin family and may induce antibody production against CD15s on host cells, suggesting a possible role in the pathogenesis of S. pyogenes. In this study, the effects of antibiotics on the CD15s-related antigen expression of S. pyogenes were examined at a concentration below the MIC (sub-MIC). The amounts of CD15s on the surfaces of S. pyogenes cells and on the surfaces of S. pyogenes biofilms were determined by a whole-cell enzyme-linked immunosorbent assay and by laser scanning fluorescence microscopy, respectively, by using an anti-CD15s monoclonal antibody. At the sub-MICs, fosfomycin (1R,2S-1,2-epoxypropyl phosphonic acid), its enantiomer (1S,2R-1,2-epoxypropyl phosphonic acid), and benzylpenicillin significantly inhibited the CD15s expression of all strains studied. The effects of fosfomycin and its enantiomer on biofilms were also observed by scanning electron microscopy. Incubation of S. pyogenes with the sub-MIC of fosfomycin or its enantiomer, which has no antibacterial activity, reduced the amount of CD15s on the biofilm surface and made it smooth. These results suggest that fosfomycin or its enantiomer might be useful for preventing S. pyogenes adherence to human CD15s receptors and the resulting immunological pathogenicity.
Anti-Bacterial Agents↗
Use of a gastric juice-based PCR assay to detect Helicobacter pylori infection in culture-negative patients.
A gastric juice-based PCR assay was compared with culture, microscopy, and a rapid urease test with specimens from 114 subjects. The PCR and conventional tests were positive for 76 and 62% of the subjects, respectively. The prevalence of gastroduodenal disease and seropositivity for anti-Helicobacter pylori immunoglobulin G were similarly high among conventional-test-positive and PCR-only-positive subjects compared to all-negative ones. The PCR assay is recommended to confirm the H. pylori status of culture-negative peptic-ulcer patients.
Adult↗
Sporadic cases of dentatorubral-pallidoluysian atrophy associated with maternal transmission.
We report siblings, a 21-year-old woman (proband) and her 26-year-old brother, with dentatorubral-pallidoluysian atrophy (DRPLA). There was no family history of DRPLA and no clinical abnormalities in their parents, who were both above the age of 50. Analysis of the DRPLA gene of leukocytes showed CAG repeat sizes to be 64/17 in the proband, 58/20 in her brother, and 56/8 in their mother. Sporadic cases of DRPLA can occur with maternal as well as paternal transmission.
Adult↗
Syntheses of taxuspine C derivatives as functional inhibitors of P-glycoprotein, an ATP-associated cell-membrane transporter.
UV-Irradiation of taxinine and related compounds in acetonitrile induced a smooth transannulation between the C-3 and C-11 positions without any influence from the C-2, C-9 and C-10 substituents to give tetracyclic taxuspine C derivatives in almost quantitative yields. Photochemical transannular reaction of taxoids possessing a cinnamoyl group in the side-chain was accompanied by an E,Z-isomerization of the cinnamoyl moiety. Cellular accumulation of vincristine, a useful drug for cancer chemotherapy, in multidrug-resistant ovarian cancer cells was found to increase most effectively in the case of 5-O-benzoylated 5-O-decinnamoyltaxuspine C. This indicates that the 5-O-benzoylated taxuspine C derivative may be a promising functional inhibitor of P-glycoprotein, which acts as an ATP-associated efflux pump for cancer chemotherapeutic agents.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Molecular variation of the human angiotensinogen core promoter element located between the TATA box and transcription initiation site affects its transcriptional activity.
Recent genetic studies indicate that several molecular variants discovered in angiotensinogen (AG), the precursor of vasoactive octapeptide angiotensin II, could potentially be responsible for inherited predisposition to human blood pressure variation. We have previously shown that a ubiquitously expressed nuclear factor, AGCF1, bound to AGCE1 (AG core promoter element 1 including the core nucleotides, CTCGTG, CTC-type) located between the TATA box and transcription initiation site (positions -25 to -1) is an authentic regulator of human AG transcription. In the present study, we showed that AGCF1 has biologically and immunologically similar properties to those of a helix-loop-helix nuclear factor USF1 and examined the effects of two other naturally occurring molecular variants (ATCGTG, ATC-type and ATTGTG, ATT-type) found in the AGCE1 position on the human AG transcriptional activity. Competitive gel-shift and transfection experiments demonstrated that the transcriptional activity for the CTC- and ATC-type promoters was 2.5 times higher than that for the ATT-type through the alteration of AGCF1-binding affinity. These results suggest the possible involvement of USF1 as a component in AGCF1 formation and the potential importance of AGCE1 variation in blood pressure regulation through human AG expression.
Angiotensinogen↗
Etomidate inhibits [3H]noradrenaline release from SH-SY5Y human neuroblastoma cells.
We have examined the effects of the intravenous anaesthetic induction agent etomidate on K+ and carbachol evoked [3H]noradrenaline ([3H]NA) release and the associated increase in [Ca2+]i in SH-SY5Y human neuroblastoma cells in a attempt to study potential anaesthetic target site(s). Preincubation with etomidate produced a dose-dependent inhibition of both K+ and carbachol evoked [3H]NA release with estimated IC50 values of 88 and 69 microM, respectively. Only K+ stimulated increase in [Ca2+]i was inhibited by etomidate preincubation with an IC50 of 146 microM. Acute addition of etomidate after K+ challenge also inhibited the increase in [Ca2+]i with an IC50 of 99 microM. In addition etomidate displaced the binding of [3H]PN200-110 to L-type voltage sensitive Ca2+ channels with a Ki of 48 microM. As K+ but not carbachol evoked [3H]NA release is extracellular Ca2+ dependent and was inhibited by etomidate these data coupled with the PN200-110 displacement studies suggest that etomidate may interact with L-type voltage sensitive Ca2+ channels. The inhibition of carbachol evoked release without affecting the associated increase in [Ca2+]i suggests that etomidate may exert additional effects at either the muscarinic receptor or the secretory machinery in these cells.
Calcium↗
Mitosis specific serine phosphorylation and downregulation of one of the focal adhesion protein, paxillin.
Mitotic cells typically lack well-formed focal adhesions. As an approach to explore the dynamic process regulating the focal adhesion assembly, we examined states of focal adhesion proteins during mitosis of the cell cycle. We found that the amount of paxillin was significantly reduced during mitosis of the cell cycle, whereas other focal adhesion proteins including talin, vinculin and Focal Adhesion Kinase did not. Proteolytic degradation appeared to be involved in the mitotic reduction, but transcriptional and/or translational controls of the mRNA were not essential for this downregulation. Moreover, concurrent with the decreased protein level, phosphorylation status of paxillin altered during mitosis; mitotic paxillin was phosphorylated primarily on serine and dephosphorylated on tyrosine while interphase one was phosphorylated both on serine and tyrosine. We found that mitotic phosphorylation created an electrophoretically slow-migrating population of paxillin which was barely detected in interphase cells. This mitotic specific modification occurred with both alpha and beta isoforms of paxillin. We also examined the fate of paxillin protein by changing its protein amount. We found that majority of paxillin overexpressed was subjected to the specific modification but not to the downregulation in the mitotic arrested cells. On the other hand, paxillin exogenously expressed at a moderate level was subjected to both the mitotic modification and downregulation. Collectively, we concluded that paxillin's specific serine phosphorylation together with the proteolytic downregulation of a limited fraction of paxillin is taken place during the mitosis of the cell cycle.
Animals↗
Coupling of the cloned rat kappa-opioid receptor to adenylyl cyclase is dependent on receptor expression.
This study describes the coupling of the recombinant rat kappa-opioid receptor expressed in Chinese hamster ovary (CHO) cells to adenylyl cyclase and the effects of receptor density. The binding of [3H]diprenorphine ([3H]DPN) was dose dependent and saturable in membranes prepared from cells of early (p4-7) and late (p14-17) passage after transfection. As passage increased the receptor numbers (Bmax) declined from 231 +/- 24 (early) to 31 +/- 2 fmol/mg protein (late) but the equilibrium dissociation constant (Kd) did not change. Spiradoline dose dependently displaced [3H]DPN from membranes prepared from early and late cells revealing both high (Ki[H]) and low (Ki[L]) affinity binding sites. There were no significant differences in the proportion of these sites (approximately 50% Ki(L):50% Ki[H]), and whilst spiradoline was generally less potent in late cells the differences were small and failed to reach statistical significance. In contrast, spiradoline produced a dose dependent inhibition of forskolin stimulated cAMP formation in whole cells with pIC50 of 8.62 and 8.00 in early compared with late cells. In addition, the maximum inhibition was dramatically reduced from 47 to 22%. Etorphine, (+/-)bremazocine, ICI-204,448 and (+/-)trans-U-50488 methanesulfonate (1 microM), compounds with activity at kappa-receptors, produced a greater inhibition of cAMP formation in early (42.2, 45.8, 50.2 and 50.5%, respectively) than late (12.9, 11.8, 13.5 and 7.8%, respectively) cells, indicating that expression dependent inhibition of cAMP formation was not kappa-agonist specific. Collectively, these data suggest that in CHO cells, kappa-opioid receptor coupling to adenylyl cyclase is dependent on receptor expression levels.
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
Redox regulation of the DNA binding activity in transcription factor PEBP2. The roles of two conserved cysteine residues.
Transcription factor PEBP2/CBF consists of a DNA binding subunit, alpha, and a regulatory subunit, beta. The alpha subunit has an evolutionarily conserved 128-amino acid region termed "Runt domain" that is responsible for both DNA binding and heterodimerization with the beta subunit. The Runt domain in all mammalian submembers of the alpha subunit contains two conserved cysteine residues, and its DNA binding activity undergoes redox regulation. To investigate the mechanism of this redox regulation, we performed site-directed mutagenesis of the two conserved cysteines in the Runt domain of the mouse PEBP2alphaA homolog. Substitution of Cys-115 to serine resulted in a partially impaired DNA binding, which remained highly sensitive to a thiol-oxidizing reagent, diamide. Conversely, the corresponding substitution of Cys-124 caused an increased DNA binding concomitant with an increased resistance to diamide. In contrast, substitution of either cysteine to aspartate was destructive to DNA binding to marked extents. These results have revealed that both Cys-115 and Cys-124 are responsible for the redox regulation in their own ways with low and high oxidizabilities, respectively. We have also found that two cellular thiol-reactive proteins, thioredoxin and Ref-1, work effectively and synergistically for activation of the Runt domain. Interestingly, the beta subunit further enhanced the activation by these proteins and reciprocally prevented the oxidative inactivation by diamide. These findings collectively suggest the possibility that the Runt domain's function in vivo could be dynamically regulated by the redox mechanism with Trx, Ref-1, and the beta subunit as key modulators.
Amino Acid Sequence↗
AP-1 transcriptional activity is regulated by a direct association between thioredoxin and Ref-1.
Thioredoxin (TRX) is a pleiotropic cellular factor that has thiol-mediated redox activity and is important in regulation of cellular processes, including proliferation, apoptosis, and gene expression. The activity of several transcription factors is posttranslationally altered by redox modification(s) of specific cysteine residue(s). One such factor is nuclear factor (NF)-kappa B, whose DNA-binding activity is markedly augmented by TRX treatment in vitro. Similarly, the DNA-binding activity of activator protein 1 (AP-1) is modified by a DNA repair enzyme, redox factor 1 (Ref-1), which is identical to a DNA repair enzyme, AP endonuclease. Ref-1 activity is in turn modulated by various redox-active compounds, including TRX. We here report the molecular cascade of redox regulation of AP-1 mediated by TRX and Ref-1. Phorbol 12-myristate 13 acetate efficiently translocated TRX into the HeLa cell nucleus where Ref-1 preexists. This process seems to be essential for AP-1 activation by redox modification because co-overexpression of TRX and Ref-1 in COS-7 cells potentiated AP-1 activity only after TRX was transported into the nucleus by phorbol 12-myristate 13 acetate treatment. To prove the direct active site-mediated association between TRX and Ref-1, we generated a series of substitution-mutant cysteine residues of TRX. In both an in vitro diamide-induced cross-linking study and an in vivo mammalian two-hybrid assay we proved that TRX can associate directly with Ref-1 in the nucleus; also, we demonstrated the requirement of cysteine residues in the TRX catalytic center for the potentiation of AP-1 activity. This report presents an example of a cascade in cellular redox regulation.
Animals↗
Adult T cell leukemia (ATL)-derived factor/human thioredoxin prevents apoptosis of lymphoid cells induced by L-cystine and glutathione depletion: possible involvement of thiol-mediated redox regulation in apoptosis caused by pro-oxidant state.
Thiol compounds, such as L-cysteine and glutathione (GSH), play crucial roles in the regulation of lymphocyte proliferation. In this study, we analyzed the effect of L-cystine and GSH depletion on lymphocyte survival and investigated the regulatory roles of adult T cell leukemia (ATL)-derived factor (ADF)/human thioredoxin (hTRX) in relation to these low m.w. thiols. MT-1, MT-2, and Jurkat cells underwent apoptosis when cultured in the L-cystine- and GSH-free medium within 18 to 24 h. Dichlorofluorescin oxidation assay indicated that the apoptosis in MT-1 and MT-2 cells was preceded by an increase in the level of intracellular hydrogen peroxide (H2O2). The addition of catalase and recombinant ADF/hTRX (rADF) partially blocked the apoptosis in a dose-dependent manner. rADF has been also shown to enhance the internalization of L-cystine into MT-2 cells in a dose-dependent manner, whereas oxidized rADF or mutated rADF that has no insulin-reducing activity failed to do so. Furthermore, culture in the L-cystine- and GSH-free medium lowered the cellular GSH content of PHA blasts, which was restored dose-dependently by rADF. These data suggest that the inability to neutralize oxidative stress results in the apoptosis of lymphoid cells under L-cystine- and GSH-depleted conditions. The protective effects of rADF may be explained by direct scavenging action on H2O2 (catalase-like activity) or by indirect neutralizing effects on the pro-oxidant status through enhancing the L-cystine internalization and elevating the intracellular GSH content.
Apoptosis↗