The window that is opened by optical isomers.
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Anesthetics↗
Biomedical subjects
I Ueda
Publications and source records attributed to I Ueda.
The effects of temperature and pressure on the thermodynamic activity of anesthetics.
Anesthetic potency is often expressed by volume percent or partial pressure in the gas phase, concentrations in the aqueous phase, etc. However. these values do not represent the anesthetic activity at the action sites. Because the activity at the action sites is difficult to obtain. Ferguson (Ferguson, J., 1939. Proc. R. Soc. Lond. B 127 387-404) defined the thermodynamic activity, which is the ratio between the anesthetizing partial pressure and the vapor pressure of the pure anesthetic at the same temperature. This paper discusses the effects of temperature and pressure on the thermodynamic activity of anesthetics. It also discusses the limitations of the Meyer-Overton rule.
Anesthetics↗
Do anesthetics act by competitive binding to specific receptors? Phase transition of firefly luciferase.
1. Firefly luciferase (FFL) emits a flash of light when mixed with ATP and luciferin in the presence of molecular oxygen. 2. Halothane inhibited FFL at 0.22 mM, while myristic acid inhibited it at 0.68 microM. Under steady-state conditions, myristic acid competed with luciferin. The Lineweaver-Burk plots of anesthetics were nonlinear. 3. The Hill numbers for anesthetics were above 1, while that of myristic acid was below 1 (0.89). Anesthetics interact with FFL cooperatively at multiple sites. The binding site of myristic acid is limited. 4. FFL undergoes a phase transition at 37-40 degrees C. Anesthetics decreased, while myristic acid increased the transition temperature. 5. The contrasting effects of anesthetics and myristic acid are discussed according to Koshland's transition-state model for myristic acid, which involves specific receptors, and Eyring's unfolded-state model for anesthetics, which involves nonspecific conformational change. Fatty acids are receptor-binders and structure-maker of FFL. Anesthetics are non-specific binders and structure-breaker of FFL.
Acylation↗
Irreversible phase transition of firefly luciferase: contrasting effects of volatile anesthetics and myristic acid.
Firefly luciferase (FFL) has been used as a lipid-free protein model to study direct interaction of anesthetics with proteins. FFL emits a burst of light when luciferin and ATP are added in the presence of oxygen. Volatile anesthetics inhibited FFL at mM ranges, while myristic acid inhibited it at microM range. Despite the large difference, octanol/water partition coefficients of both myristic acid and halothane are 199. Differential scanning calorimetry (DSC) showed that thermal transition occurred at 38.5 degreesC with excess enthalpy of denaturation of 91.9 kcal mol-1. The transition, however, was irreversible. According to the irreversible transition kinetics, the anesthetic effects were evaluated by the temperature where the irreversible transition is half completed (T1/2). Volatile anesthetics decreased T1/2 at mM ranges, while myristic acid and oxyluciferyladenylate (luciferin competitor) increased it at microM ranges. Luciferin is a heterocyclic carboxylate and acylates AMP. Carboxyl group of myristic acid appears to make a high affinity contact to the luciferin-recognition sites. The induced-fit theory states that binding of substrates induces the enzyme into high-energy transition state. Myristic acid stabilized FFL at the transition state, which resisted thermal denaturation. Anesthetics destabilized FFL by reversibly unfolding the protein into less active intermediate states and promoted irreversible transition when the temperature is elevated.
Anesthetics, Inhalation↗
Is there a specific receptor for anesthetics? Contrary effects of alcohols and fatty acids on phase transition and bioluminescence of firefly luciferase.
Firefly luciferase emits a burst of light when mixed with ATP and luciferin (L) in the presence of oxygen. This study compared the effects of long-chain n-alcohols (1-decanol to 1-octadecanol) and fatty acids (decanoic to octadecanoic acids) on firefly luciferase. Fatty acids were stronger inhibitors of firefly luciferase than n-alcohols. Myristyl alcohol inhibited the light intensity by 50% (IC50) at 13.6 microM, whereas the IC50 of myristic acid was 0.68 microM. According to the Meyer-Overton rule, fatty acids are approximately 12,000-fold stronger inhibitors than corresponding alcohols. The Lineweaver-Burk plot showed that myristic acid inhibited firefly luciferase in competition with luciferin, whereas myristyl alcohol inhibited it noncompetitively. The differential scanning calorimetry (DSC) showed that an irreversible thermal transition occurred at approximately 39 degrees C with a transition DeltaHcal of 1.57 cal g-1. The ligand effects on the transition were evaluated by the temperature where the irreversible change is half completed. Alcohols decreased whereas fatty acids increased the thermal transition temperature of firefly luciferase. Koshland's transition-state theory (Science. 1963. 142:1533-1541) states that ligands that bind to the substrate-recognition sites induce the enzyme at a transition state, which is more stabilized than the native state against thermal perturbation. The long-chain fatty acids bound to the luciferin recognition site and stabilized the protein conformation at the transition state, which resisted thermal denaturation. Eyring's unfolding theory (Science. 1966. 154:1609-1613) postulates that anesthetics and alcohols bind nonspecifically to interfacial areas of proteins and reversibly unfold the conformation. The present results showed that alcohols do not compete with luciferin and inhibit firefly luciferase nonspecifically by unfolding the protein. Fatty acids are receptor binders and stabilize the protein conformation at the transition state.
Alcohols↗
Donor lymphocyte infusion at unstable mixed chimerism in an allogeneic BMT recipient for chronic granulomatous disease.
We report a 14-year-old boy who had successfully received allogeneic BMT for chronic granulomatous disease and 3 years later was treated with donor lymphocyte infusion (DLI, 3.3 x 10(8) cells/kg) at unstable mixed chimerism in association with reduced neutrophil function. Following DLI, the patient developed transient acute hepatic GVHD, which was confirmed by liver biopsy and was manageable with cyclosporin A and prednisolone. The patient eventually attained complete chimerism with improved neutrophil function. At the time of writing (2.5 years from the DLI), the patient is doing well, free from infectious episodes and chronic GVHD. Our experience suggests that DLI could be a safe and effective strategy for dissolution of unstable mixed chimerism in BMT recipients for inherited disorders.
Adolescent↗
Negative entropy of halothane binding to protein: 19F-NMR with a novel cell.
An obvious difficulty of the study of binding of volatile anesthetics to proteins is to prevent loss of the ligand during the procedure. A novel NMR tube was designed that consists of concentric double cylinders which slide each other under sealed condition. A gas space is left in the tube to measure the free anesthetic concentration in the gas phase, which is in equilibrium with the solution. The enthalpy change of anesthetic transfer from water to BSA, deltaH(w-->r) was -40 kJ x mol(-1). The Gibbs free energy deltaG(w-->r) was -14.0 kJ x mol(-1) at 283 K (K(D) = 2.6 mM) and increased to -11.6 kJ x mol(-1) at 310 K (K(D) = 10.9 mM). The maximum binding site (Bmax) was 19.3 at 10 degrees C and increased to 34.5 at 37 degrees C. The entropy change, deltaS(w-->r) was -92 J x mol(-1) x K(-1) and was almost constant in the temperature range 10 approximately 37 degrees C. Contrary to the general consensus that hydrophobic interaction is entropy-driven, the binding of halothane to BSA was enthalpy-driven, compensating the opposing effect of deltaS with negative deltaH at the biologically meaningful temperature range. Possible cause of the negative deltaS relating to the conformational change of BSA is discussed.
Entropy↗
Titration calorimetry of anesthetic-protein interaction: negative enthalpy of binding and anesthetic potency.
Anesthetic potency increases at lower temperatures. In contrast, the transfer enthalpy of volatile anesthetics from water to macromolecules is usually positive. The transfer decreases at lower temperature. It was proposed that a few selective proteins bind volatile anesthetics with negative delta H, and these proteins are involved in signal transduction. There has been no report on direct estimation of binding delta H of anesthetics to proteins. This study used isothermal titration calorimetry to analyze chloroform binding to bovine serum albumin. The calorimetrically measured delta H cal was -10.37 kJ.mol-1. Thus the negative delta H of anesthetic binding is not limited to signal transduction proteins. The binding was saturable following Fermi-Dirac statistics and is characterized by the Langmuir adsorption isotherms, which is interfacial. The high-affinity association constant, K, was 2150 +/- 132 M-1 (KD = 0.47 mM) with the maximum binding number, Bmax = 3.7 +/- 0.2. The low-affinity K was 189 +/- 3.8 M-1 (KD = 5.29 mM), with a Bmax of 13.2 +/- 0.3. Anesthetic potency is a function of the activity of anesthetic molecules, not the concentration. Because the sign of delta H determines the temperature dependence of distribution of anesthetic molecules, it is irrelevant to the temperature dependence of anesthetic potency.
Anesthetics↗
Levels of Porphyromonas gingivalis Fimbriae and inflammatory cytokines in gingival crevicular fluid from adult human subjects.
The Porphyromonas gingivalis fimbriae level was examined in the gingival crevicular fluid (GCF) from adult human subjects using an immunoblot assay with a monoclonal antibody. The cytokines, interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-6 and tumor necrosis factor-alpha (TNF-alpha) levels in the GCF were quantified by enzyme-linked immunosorbent assay (ELISA). The reactivity of the GCF samples with the monoclonal antibody against P. gingivalis fimbriae was related to the IL-2 beta, IL-6 and TNF-alpha levels. Moreover, the fimbriae content was associated with the gingival index (GI). In contrast, no significant correlation was seen between the fimbriae content and IL-1 alpha level. These results suggest that there are possible associations between P. gingivalis fimbriae and IL-1 beta, IL-6 and TNF-alpha in the gingival crevicular fluid.
Adult↗
Thermodynamic aspects of hydrophobicity and the blood-brain barrier permeability studied with a gel filtration chromatography.
It has been said that the selective permeability across the blood--brain barrier depends on several physicochemical properties of drugs such as hydrophobicity, molecular weight, and hydrogen-bonding potential. In order to investigate quantitatively the relationship between the blood--brain barrier permeability and the hydrophobicity of drugs, we have measured the micelle/water partition properties (Pmic) by the MLC (micellar liquid chromatography) method using a gel filtration version and compared with the blood--brain barrier permeability. The thermodynamic aspects of partition were derived by separating the micelle/water partition coefficient (log Pmic) into the enthalpy term PH and the entropy term PS. It was found that the PH shows a good correlation to the permeability, although log Pmic fails to do so. The result means that PH, which is easily obtained from the in vitro experiment, can be used as an excellent standard in discussing the transport phenomena through the blood--brain barrier.
Blood-Brain Barrier↗
Cuff bulk of tracheal tubes in adolescence.
PURPOSE: To investigate cuff types for potential use in late childhood and early adolescence for appropriate fit. METHOD: Formulae suggest the use of a tracheal tube having a 6.5 mm internal diameter at ages 8 to 10 years, so a model system was used to test the passage of cuffed and uncuffed tracheal tubes of 6.5 mm internal diameter through calibrated holes 8.1-16.6 mm diameter, in plastic plates. RESULTS: Uncuffed tracheal tubes passed through 9.0 mm diameter holes. "High pressure" cuffed tubes passed through 10.5 to 11.3 mm holes. "Low pressure" cuffed tubes passed through 12.3 to 16.4 mm. CONCLUSION: Patients aged 8 to 10 yr have a limiting internal diameter at the cricoid of 8 to 10 mm. Their unstretched tracheal diameter below the cricoid is only about 11 mm. The actual outside diameters of "low pressure" cuffs chosen by commonly used formulae considerably exceed the limiting diameters of eight to ten year old patients, even considering recommended compensation factors. Analysis of background data indicates that these problems are especially aggravated at this age by non-linear growth of the cricoid.
Child↗
Adhesion of Porphyromonas gingivalis fimbriae to human gingival cell line Ca9-22.
In this study, we examined the effects of selected environmental factors on the adhesion of Porphyromonas gingivalis fimbriae, an important structure involved in attachment of the bacteria to human gingival cells. The human gingival carcinoma cell line Ca9-22 was grown in microculture plates, and adherence was detected by use of 125I-labeled fimbriae. Adhesion was increased by changes in pH from 7.0-8.0, but was decreased by increase in the sodium chloride concentration above 0.15 M. Trypsin treatment of Ca9-22 cells also augmented adhesion of the fimbriae to the cells. These results indicate that fimbrial adhesion to gingival cells is controlled by various environmental factors, and the data on trypsin treatment suggest that elevated levels of protease in the gingival sulcus, such as can occur with poor oral hygiene and gingivitis, may expose adhesion molecules on the gingival cell surface, thereby promoting the attachment of P. gingivalis fimbriae.
Bacterial Adhesion↗
Inductive effect of Porphyromonas gingivalis fimbriae on differentiation of human monocytic tumor cell line U937.
This study used the human monocytic tumor cell line U937 to examine whether Porphyromonas gingivalis fimbriae induce differentiation of monocyte/macrophage progenitors. When the progenitor cells were incubated with P. gingivalis fimbriae, the incubation resulted in increased Fc rosette formation and increased CD11b production by the cells. The presence of a protein kinase C inhibitor, H7 or calphostin C, in the medium eliminated the stimulatory effects of P. gingivalis fimbriae on Fc rosette formation. Furthermore, CD11b expression was inhibited by calphostin C. In contrast, HA1004 , an inhibitor of cyclic nucleotide-dependent protein kinase, had no effect on P. gingivalis fimbriae-induced Fc rosette formation or CD11b expression. These results demonstrate that P. gingivalis fimbriae are a potent inducer of the differentiation of the monocyte/macrophage tumor cell line U937, most probably via cyclic nucleotide-independent protein kinase C.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
The requirement of heat shock cognate 70 protein for mitochondrial import varies among precursor proteins and depends on precursor length.
The cytosolic heat shock cognate 70-kDa protein (hsc70) is required for efficient import of ornithine transcarbamylase precursor (pOTC) into rat liver mitochondria (K. Terada, K. Ohtsuka, N. Imamoto, Y. Yoneda, and M. Mori, Mol. Cell. Biol. 15:3708-3713, 1995). The requirement of hsc70 for mitochondrial import of various precursor proteins and truncated pOTCs was studied by using an in vitro translation import system in which hsc70 was completely depleted. hsc70-dependent import of pOTC was about 60% of the total import, while import of the aspartate aminotransferase precursor, the serine:pyruvate aminotransferase precursor, and 3-oxoacyl coenzyme A thiolase was about 50, 30, and 0%, respectively. The subunit sizes of these four precursor proteins were 40 to 47 kDa. When pOTC was serially truncated from the COOH terminal, the hsc70 requirement decreased gradually and was not evident for the shortest truncated pOTCs of 90 and 72 residues. These truncated pOTCs were imported and proteolytically processed rapidly in 0.5 to 2 min at 25 degrees C, and the processed mature portions and the presequence portion were rapidly degraded. Sucrose gradient centrifugation analysis followed by import assay showed that pOTC synthesized in rabbit reticulocyte lysate forms an import-competent complex of about 11S in an hsc70-dependent manner. S values of import-competent forms of aspartate aminotransferase precursor, serine:pyruvate aminotransferase precursor, and 3-oxoacyl coenzyme A thiolase were 9S, 9S, and 4S, respectively. Thus, the S value decreased as the hsc70 dependency decreased. Precursor proteins were coimmunoprecipitated from the reticulocyte lysate containing the newly synthesized precursor proteins with an hsc70 antibody. The amount of coimmunoprecipitated proteins was much larger in the absence of ATP than in its presence. Among the four precursor proteins, the amount of coimmunoprecipitated protein decreased as the hsc70 dependency decreased.
Acetyl-CoA C-Acyltransferase↗
[Anesthesia mechanisms: nerve excitation and temperature].
Depolarization of a nerve membrane produces heat while repolarization absorbs heat. This is equivalent to the phase transition of water where freezing of water produces heat and melting of ice absorbs heat. In this context, high temperature (as in water) supports resting potential and low temperature (as in ice) supports action potential. When assessed by the equilibrium between the two phases, anesthetized state is the high temperature state. Nevertheless, low temperature supports anesthesia. The two opposing facts confuse the understanding of anesthesia mechanisms. The inconsistency arises from the two effects of heat on nerve excitation. One is one the equilibrium between the resting and active states of the excitation machinery, and the other is on the reaction rate process. This review annotŁatsz why low temperature facilitates anesthesia while high temperature supports the resting state of nerves.
Action Potentials↗
Observation of cosmic-ray antiprotons at energies below 500 MeV.
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Journal Article↗
From ice crystals to fruit flies.
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Anesthetics↗
Micelle/water partition properties of phenols determined by liquid chromatographic method. Proposal for versatile measure of hydrophobicity.
Partition properties have been determined for 28 monosubstituted phenols in the sodium dodecylsulfate (SDS)/water system by micellar liquid chromatography (MLC), offering a useful and versatile method to estimate the hydrophobicity of compounds. The enthalpy and entropy terms of partition have also been determined from variable temperature experiments on MLC and are interpreted by such factors as molecular size and hydrogen-bond ability of the solute. The pi constants (pi, pi H and pi S) are determined from the experimental partition properties and applied to quantitative structure-activity relationships (QSAR) analysis, and their versatility supported.
Chemical Phenomena↗