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PubMed1986

[Proton beam therapy].

Proton beam therapy has been developed for about the last ten years as one of the most reasonable treatment techniques in cancer therapy, based upon the beneficial features of proton beams. Because of the favorable clinical results obtained further progress in this form of treatment is expected. The fundamental and clinical features of this technique and also the future plans being studied at the moment are discussed here, based on the clinical results obtained mainly at the Particle Radiation Medical Science Center of Tsukuba University. The fundamental features of a proton beam are the possibility of selective irradiation of the tumor lesion and minimal irradiation of the surrounding normal tissues due to its fine dose distribution and favorable biological response which is similar to that of 60Co gamma rays. Due to these beneficial features of proton beams, tumor lesions have been successfully irradiated with sufficiently large doses, avoiding irradiation of important organs close to the lesions. Treatment results revealed sufficient control of lesions resistant to conventional radiotherapy, such as locally advanced lesions, lesions with large volume or those with low sensitivity. These results suggested that proton beam therapy could be applied to radical treatment of lesions over a much wider indication range, especially in deep-seated organs, compared with conventional radiotherapy. Investigations of proton beam treatment are to be further continued with the development of techniques to delives precisely controlled irradiation to lesions in moving organs and of a treatment unit installable in cancer hospitals.

Carcinoma, Squamous Cell↗
PubMed1987

[Results of treatment of Itsenko-Cushing disease using proton irradiation of the hypophysis].

The application of protons (heavy charged particles) for irradiation of the pituitary body has some essential advantages over other types of teletherapy: insignificant destruction of surrounding tissues, a possibility of a single therapeutic session as well as the absence of post-radiation effects. Proton beam therapy was given to 98 patients with Icenko-Cushing disease aged 15 to 40. Mild cases were treated by proton beam irradiation only while severe cases were managed using proton beam therapy combined with unilateral adrenalectomy or oral administration of ortho-para-DDD. Catamnesis duration varied from 3 to 5 years. In most cases the exposure dose was 80-90 Gy (50-110 Gy). The procedure was well tolerated by all the patients. A dynamic multipolar converting method with 15-20 entrance poles in the left temporal area was employed (with the beam energy of 200 MeV). Stabilization of the course of disease and some clinical improvement were observed in most of the patients 3-4 months after proton beam therapy. In 6-36 months after irradiation 90% of the patients showed normal biochemical indices and the absence of any clinical signs of the disease. Three-five years after treatment, 94% of the patients were in steady remission. A 24-hour ACTH and cortisol normalization pattern was observed in all the patients in parallel with an increase in GH and gonadotropin secretion and a decrease in the prolactin level. Sex function renewal appeared to be the first clinical sign of remission. Young patients aged 15 to 20 with a short duration of disease reached remission faster than patients of the other age groups. Thus the results of proton beam therapy of 98 patients with Icenko-Cushing disease after a follow-up of 3-5 years showed a high efficacy of this type of treatment. The method can be used alone or in combination with unilateral adrenalectomy as well as with oral administration of ortho-para-DDD.

Adolescent↗
PubMedDate not supplied

[Demonstration of three protonated forms of poly(A): potentiometric and conductometric study of isoionic solutions].

It is shown that there are three parts on the potentiometric titration curves of isoionic solutions of poly(A) ascribed to the three protonated structures. Double-helical protonated structures are especially stable in isoionic solution. These parts on potentiometric curves are attributed to the single-stranded poly(A), to the completely protonated double-stranded poly(A+).poly(A+), and to the semiprotonated poly(A+).poly(A) structures: D, A, B forms of poly(A), respectively. pK0 values of these forms are calculated. The D form portion is found to be about 18% in isoionic solution, 40% in KCl solution (from 0.01 to 1.0 M), 40% in solution, containing 1.2 X 10(-3) M MgCl2 and 70% in 8 X 10(-4) M MgCl2 solution. The increase of MgCl2 concentration up to 8 X 10(-4) M leads to complete degradation of the double-helical structure. Only single-stranded D form exists in 5 X 10(-3) M MgCl2 solution. About 5-7% of all protons become inaccessible for titration in all solutions containing KCl and in the presence of small amounts of MgCl2. This phenomenon can not be explained by aggregation of poly(A), because all protons become accessible for titration in more concentrated MgCl2 solution when aggregation of poly(A) is significant and accompanied by the precipitation of sediment insoluble in NaOH. The supposition is made, that unprotonated double-stranded poly(A) can exist in salt-free solution at neutral pH. It is this form that is protonated with decrease of pH.

Chemical Phenomena↗
PubMed1984

Energy-linked nicotinamide nucleotide transhydrogenase. Properties of proton-translocating mitochondrial transhydrogenase from beef heart purified by fast protein liquid chromatography.

Mitochondrial nicotinamide nucleotide transhydrogenase from beef heart was purified by a novel procedure involving fast protein liquid chromatography and characterized with respect to molecular and catalytic properties. The method is reproducible, gives highly pure transhydrogenase as judged by silver staining, and can be modified to produce large amounts of pure transhydrogenase protein suitable for e.g. sequencing and other protein chemical studies. Transhydrogenase purified by fast protein liquid chromatography is reconstitutively active and pumps protons as indicated by an extensive quenching of 9-aminoacridine fluorescence. Under conditions which generate a proton gradient in the absence of a membrane potential the activity of reconstituted transhydrogenase is close to zero indicating a complete and proper incorporation in the membrane and a preferential regulation of the enzyme by a proton gradient rather than a membrane potential. Treatment of reconstituted transhydrogenase with N,N-dicyclohexylcarbodiimide results in an inhibition of proton pump activity without an effect on uncoupled catalytic activity, suggesting that proton translocation and catalytic activities are not obligatory linked or that this agent separates proton pumping from the catalytic activity.

Aminacrine↗
PubMed1983

Proton nuclear magnetic resonance of neutral and acidic glycosphingolipids.

A number of intact neutral glycosphingolipids (globo, asialoganglio, neolacto, and gala series), gangliosides, and sulfatide were analyzed by proton nuclear magnetic resonance (NMR) using dimethyl-d6 sulfoxide as a solvent at different conditions of measurement. The chemical shifts of amide proton of ceramide, N-acetylhexosamine and sialic acid moieties were positioned with regularity, thus providing their molar composition. The chemical shifts of amide proton in ceramide moiety differed with respect to constituent fatty acids; delta 7.45 to 7.52 ppm at 25 degrees C for the nonhydroxy acids and 7.32 to 7.42 ppm for the hydroxy acids. The chemical shifts of methyl proton in N-acetyl group were distinguished between N-acetylhexosamine and N-acetylneuraminic acid, and those in N-acetylgalactosamine were discriminated between neutral glycolipids and gangliosides. In the presence or absence of D2O in dimethyl sulfoxide at 110 degrees C, the anomeric protons resonated with regularity characteristic of respective monosaccharide linkages, and the anomeric protons of N-acetylgalactosamine in neutral glycolipids and gangliosides were clearly distinguished. The present study thus demonstrates the general applicability of NMR procedure to glycosphingolipids, providing the determination of chemical composition of both the lipophilic and carbohydrate moieties and the structural elucidation.

Glycosphingolipids↗
PubMed1981

[Proton translocation coefficient for H+-ATPase of rat liver mitochondria].

Some features of H+-ATPase function in intact mitochondria of rat liver were studied. Simultaneously the activities of ATPase and proton translocase were measured, using a previously described technique. The proton translocation coefficient of H+-ATPase has been found to be equal to 3.6. The protonophore 3.5-di-tert-butyl-4-hydroxybenzylidenemalononitrile diminishes the proton translocation coefficient. It was concluded that when considering the mechanism of proton translocation by H+-ATPase, it is necessary to assume the possibility of transport of 3 or 4 protons per every hydrolyzed molecule of ATP allowing a changeable efficiency of the process. The decrease of the translocase coefficient in the presence of the protonophore appears to result from the ability of this uncoupler to return the transferred protons to the mitochondrial matrix.

Adenosine Triphosphatases↗
PubMed1995

[Membrane fusion between Ehrlich ascites of mastocarcinoma cells and liposome induced by proton translocation of transplasma membrane NADH-ferricyanide redox enzymes].

By using resonance energy transfer assay (RET) and fluorescence microscopy we show experimental evidence that membrane fusion of Ehrlich ascites of mastocarcinoma cells with liposomes could be induced by the proton translocation activity associated with NADH-ferricyanide redox enzyme of transplasma membrane of cancer cells. The iodoacetate, an inhibitor of glycolysis, was found to be able to depress the proton translocation activity and also to inhibit the membrane fusion. It is suggested that NADH produced mainly by glycolysis is utilized as the substrate (electron donor) for transmembrane ferricyanide reduction, and the proton pumping activity in the cancer cells is coupled to the transmembrane NADH-ferricyanide redox enzyme system. Experiments also show that membrane fusion extent of cancer cells with liposomes is proportional to the amount of H+ pumped out by the cells and membrane fusion process also exhibits a H+ consuming mode just as in fusion process of mitochondria with liposomes by redox enzyme proton pumps of respiratory chain. All of the results presented in this paper consists with recent reports of this laboratory, which indicated that various types of proton pumping system from different membrane system of cell have a new function in membrane fusion. Therefore, the proton pumping induced membrane fusion may have a more general physiological importance in triggering and modulating fusion process of native membrane in vivo.

Animals↗
PubMed1996

[Ulcer drugs: profile of side effects of proton-pump blockers in comparison to H2 blockers in the spontaneous reporting system].

Inhibition of gastric acid secretion by drugs remains the most important rational approach to the treatment of acid related diseases. Histamine H2-antagonists and more recently the proton pump blockers have become the first line treatment for acid peptic diseases. Proton pump blockers bind specifically to the proton pump of the parietal cells and thus inhibit the final acid secretion independently from the activating stimuli. Because of this specific mechanism fewer adverse effects on other systems in the body are expected with proton pump blockers than with histamine antagonists. An analysis of the spontaneous reports which the Swiss Drug Monitoring Center (SANZ) received from 1981 to 1995 showed striking differences in the adverse drug reaction profile: hypersensitivity reactions with fever and anaphylactic reactions, liver disorders such as cholestatic hepatitis, most with severe progression and requiring hospitalization, as well as endocrine disorders were reported more frequently with histamine antagonists, skin reactions and joint disorders, however, were reported more often with proton pump blockers. Our data also support the conclusion that adverse drug reactions to proton pump blockers and histamine antagonists are rare in the spontaneous reporting scheme (reporting rate < 1%). There was a somewhat higher rate of serious reports with histamine antagonists. These data do not allow conclusions concerning long-term effects or effects with larger than recommended dosages.

Anti-Ulcer Agents↗
PubMed1998

Proton-controlled electron transfer in cytochrome c oxidase: functional role of the pathways through Glu 286 and Lys 362.

We have used a combination of site-directed mutagenesis and spectroscopic techniques to investigate electron-transfer reactions between hemes a and a3 in cytochrome c oxidase. A state of the enzyme was prepared in which heme a/CuA are oxidized and heme a3/CuB are reduced with CO bound to heme a3, which stabilizes the reduced state of the binuclear center. In addition, in this state the pKs of protonatable groups in the vicinity of the binuclear center, interacting electrostatically with heme a3, are larger than with oxidized heme a3. Upon flash photolysis of CO from the two-electron reduced enzyme electrons at heme a3 equilibrate rapidly with heme a. In the R. sphaeroides enzyme the electron-transfer rates from heme a to a3 and from heme a3 to a were, deconvoluted and were found to be approximately 1.5.10(5) s-1 and approximately 1.4.10(5) s-1, respectively. After this rapid electron equilibration between hemes a and a3, protons are released from groups interacting electrostatically with heme a3, which is associated with additional electron transfer from heme a3 to heme a. The proton-coupled electron transfer displays a pH dependent extent and rate. In addition, it displays a deuterium-isotope effect of a factor of about three. The reaction sequence is compatible with the three-dimensional cytochrome c oxidase structure, which shows that more protonatable groups are found around heme a3 than around heme a and supports the involvement of the binuclear center in proton pumping. Proton uptake/release upon reduction/oxidation of heme a3 takes place through a proton pathway including residues Thr(I-359) and Lys(I-362) (K-pathway), but not through the pathway including residues Asp(I-132) and Glu(I-286) (D-pathway). During reaction of the reduced enzyme with O2, both substrate and pumped protons are taken up through the D-pathway.

Amino Acid Sequence↗
PubMed2001

Coupling of proton flow to ATP synthesis in Rhodobacter capsulatus: F(0)F(1)-ATP synthase is absent from about half of chromatophores.

F(0)F(1)-ATP synthase (H(+)-ATP synthase, F(0)F(1)) utilizes the transmembrane protonmotive force to catalyze the formation of ATP from ADP and inorganic phosphate (P(i)). Structurally the enzyme consists of a membrane-embedded proton-translocating F(0) portion and a protruding hydrophilic F(1) part that catalyzes the synthesis of ATP. In photosynthetic purple bacteria a single turnover of the photosynthetic reaction centers (driven by a short saturating flash of light) generates protonmotive force that is sufficiently large to drive ATP synthesis. Using isolated chromatophore vesicles of Rhodobacter capsulatus, we monitored the flash induced ATP synthesis (by chemoluminescence of luciferin/luciferase) in parallel to the transmembrane charge transfer through F(0)F(1) (by following the decay of electrochromic bandshifts of intrinsic carotenoids). With the help of specific inhibitors of F(1) (efrapeptin) and of F(0) (venturicidin), we decomposed the kinetics of the total proton flow through F(0)F(1) into (i) those coupled to the ATP synthesis and (ii) the de-coupled proton escape through F(0). Taking the coupled proton flow, we calculated the H(+)/ATP ratio; it was found to be 3.3+/-0.6 at a large driving force (after one saturating flash of light) but to increase up to 5.1+/-0.9 at a smaller driving force (after a half-saturating flash). From the results obtained, we conclude that our routine chromatophore preparations contained three subsets of chromatophore vesicles. Chromatophores with coupled F(0)F(1) dominated in fresh material. Freezing/thawing or pre-illumination in the absence of ADP and P(i) led to an increase in the fraction of chromatophores with at least one de-coupled F(0)(F(1)). The disclosed fraction of chromatophores that lacked proton-conducting F(0)(F(1)) (approx. 40% of the total amount) remained constant upon these treatments.

Adenosine Diphosphate↗
PubMed1992

Effects of inducing expression of cloned genes for the F0 proton channel of the Escherichia coli F1F0 ATPase.

To evaluate whether expression of cloned genes for the F0 proton channel of the Escherichia coli F1F0 ATPase is sufficient to cause membrane proton permeability, plasmids carrying different combinations of the uncB, E, and F genes, encoding the a, c, and b subunits of the F0 sector, cloned behind the inducible lac promoter in pUC9 or pUC18, were constructed. The effects of inducing F0 synthesis in an unc deletion strain were monitored by measuring cell growth rate, quantitating F0 subunits by immunoblotting, and measuring the ability of membranes to maintain a respiration-induced proton gradient and to bind F1 and carry out energy-coupling reactions. The levels of functional reconstitutable F0 in membranes could be increased four- to sixfold with no change in cellular growth rate or membrane proton permeability (assayed by fluorescence quenching). These results were obtained in uninduced cultures, so the F0 genes were presumably being transcribed from some promoter besides lac. Induction of transcription of all three F0 genes produced increased amounts of F0 subunits in membranes as determined by immunoblot and F1-binding assays, but, when reconstituted with F1, the F0 in membranes isolated from induced cultures was significantly less functional than the F0 in membranes isolated from uninduced cultures. Such induction did result in growth inhibition, but there was no correlation between growth inhibition and either increased membrane proton permeability or the presence of functional, reconstitutable F0.

Adenosine Triphosphate↗
PubMed1995

Mechanisms of proximal proton secretion in BBM of herbivorous, omnivorous, and carnivorous species.

The mechanisms of proton secretion by the proximal brush-border membrane (BBM) were compared in carnivorous (dog), omnivorous (human, pig, rat), and herbivorous (rabbit, hamster) species. The activity of the proton pump (V-type bafilomycin-sensitive H(+)-adenosinetriphosphatase) and of the Na+/H+ exchanger (amiloride-sensitive quenching of acridine orange fluorescence), the two major proton secretion mechanisms, was measured. The enzymatic activity of the H(+)-adenosinetriphosphatase activity was measured in intact (endosomes) and solubilized (0.1% deoxycholate or Triton X-100) BBM vesicles isolated by conventional Mg2+ precipitation techniques. In all species, but not in humans, the fraction of the ATP turnover energizing the proton pump (bafilomycin-sensitive respiration) was also measured in isolated proximal tubules. Significant differences in acid transport mechanisms were noted between species, with the proton pump predominating in the BBM of carnivorous species and the Na+/H+ exchanger predominating in the BBM of herbivorous species. The fraction of respiration suppressible by bafilomycin in proximal tubules was also different in all the species considered. This may indicate a different organization of proximal H+ transport related to the species-specific menace to acid-base balance.

Animals↗
PubMed1992

The membrane sector of vacuolar H(+)-ATPase by itself is impermeable to protons.

The sensitivity for vanadate of proton uptake activities of isolated chromaffin granules and yeast vacuoles was investigated. About 0.5 mM vanadate caused 50% inhibition of ATP-dependent proton uptake activity in both membranes. The proton conductivity across chromaffin granule membranes and yeast vacuoles was assayed in the presence and absence of the catalytic sectors of their respective V-ATPases. Removal of the catalytic sectors by cold treatment in the presence of MgATP did not change the proton conductivity of the membranes. Similar results were obtained with yeast vacuoles of mutants that did not assemble the catalytic sector of the enzyme. These results are in contrast to the effect of removing the catalytic sectors of F-ATPases from various sources. The mechanistic and biological significance of the difference in the behavior of the two families of proton pumps is discussed.

Animals↗
PubMed1999

A dual-tuned resonator for proton-decoupled phosphorus-31 chemical shift imaging of the brain.

A fully quadrature dome-shaped resonator is presented that has been dual-tuned for proton and phosphorus operation at 1.5 T. The resonator is 16.5 cm in length and 23 cm in diameter. Phantom studies were performed to demonstrate the utility of the resonator for proton imaging, shimming, and proton-decoupled phosphorus spectroscopy. In human subjects, proton-decoupled phosphorus chemical shift imaging spectra of the brain were acquired at 27 cm3 resolution in 34 min. Volunteer studies demonstrated improved resolution of phosphomonoesters, phosphodiesters, and nucleoside triphosphates due to proton decoupling. Sensitive coverage of the brain extended from the most superior cerebral cortex to the cerebellum. Acquisition of good quality 31P spectra over this volume is due to the dome structure as well as quadrature operation at both proton and phosphorus frequencies.

Brain↗
PubMed2005

Cooperativity and proton transfer in hydrogen-bonded triads.

Ab initio MP2/6-311+G(3df,2pd) and MP2/aug-cc-pVTZ calculations have been carried out to investigate the structures and properties of AHXHYH(3) (A=F, Cl; X=F, Cl; Y=N, P) hydrogen-bonded complexes. Significant cooperative effects are observed in the XHYH3 dyads in the triads due to the presence of the polar near-neighbor AH. These effects are greater when the polar partner is HF, which is a better proton donor than HCl. Structural changes, red shifts of proton-donor stretching frequencies, nonadditive interaction energies, and electron density redistributions unambiguously demonstrate that the X--HY hydrogen bond (HB) is stronger in the triads than in the corresponding dyads, while the X--H bond of the proton donor becomes weaker. Even more pronounced cooperative effects are observed in the AHXH dyads due to the presence of the YH3 partner. These effects are weaker in complexes having PH3 rather than NH3 as the proton acceptor, since NH3 is a stronger base. Cooperativity also enhances the proton-donating ability of the YH3 moiety, with the result that all complexes except FHFHPH3 are cyclic. Cooperativity, together with the ease of breaking the Cl--H bond in ClHClHNH3 and FHClHNH3, leads to proton transfer (PT), so that these two complexes are better described as approaching hydrogen-bonded ClHCl- x +HNH3 and FHCl- x +HNH3 ion pairs.

Journal Article↗
PubMed2001

Proton MR spectroscopy of the lumbar spine in patients with glycogen storage disease type Ib.

Glycogen storage disease type Ib is an autosomal recessive inherited metabolic disorder resulting from deficiency of the microsomal glucose-6-phosphatase enzyme system. Six patients (three of which were treated with granulocyte colony stimulating factor) suffering from this disease were examined using image guided localized proton magnetic resonance (MR) spectroscopy. The relative signal intensities of water and lipid protons of the lumbar spine were determined. Comparison was made with iliac crest biopsies in the glycogen storage disease type Ib patients and localized proton MR spectroscopic values of the lumbar spine obtained by thirteen healthy volunteers. The data demonstrate for the first time that hypercellularity and myeloid hyperplasia in subjects with glycogen storage disease type Ib due to functionally impaired leucocytes results in a strongly increased water proton signal with a very low or absent lipid signal in localized proton MR spectroscopy. Upon granulocyte colony stimulating factor treatment, the water proton signal in the lumbar spine is not further augmented.

Adolescent↗
PubMed2005

Protonation of trimipramine salts of maleate, mesylate and hydrochloride observed by 1H, 13C and 15N NMR spectroscopy.

Protonation of the tricyclic antidepressant drug trimipramine with maleic acid, methanesulfonic acid and hydrochloric acid was studied using 1H, 13C and 15N NMR spectroscopy at natural abundance. The effect of counter ions on the protonation was compared under identical conditions of solvent, concentration and temperature using homonuclear and heteronuclear one- and two-dimensional experiments. Differential protonation of the terminal tertiary amine nitrogen is determined from the indirect spin-spin couplings, chemical shifts, 13C relaxation data and variable-temperature experiments. In the maleate salt, only one of the acidic protons is involved in protonation, the other being associated with the anion moiety. 15N chemical shifts of the protonated nitrogens are nearly linearly related to the pK(a) of the constituent acid.

Antidepressive Agents, Tricyclic↗
PubMed2006

Evaluating the quality of NMR structures by local density of protons.

Evaluating the quality of experimentally determined protein structural models is an essential step toward identifying potential errors and guiding further structural refinement. Herein, we report the use of proton local density as a sensitive measure to assess the quality of nuclear magnetic resonance (NMR) structures. Using 256 high-resolution crystal structures with protons added and optimized, we show that the local density of different proton types display distinct distributions. These distributions can be characterized by statistical moments and are used to establish local density Z-scores for evaluating both global and local packing for individual protons. Analysis of 546 crystal structures at various resolutions shows that the local density Z-scores increase as the structural resolution decreases and correlate well with the ClashScore (Word et al. J Mol Biol 1999;285(4):1711-1733) generated by all atom contact analysis. Local density Z-scores for NMR structures exhibit a significantly wider range of values than for X-ray structures and demonstrate a combination of potentially problematic inflation and compression. Water-refined NMR structures show improved packing quality. Our analysis of a high-quality structural ensemble of ubiquitin refined against order parameters shows proton density distributions that correlate nearly perfectly with our standards derived from crystal structures, further validating our approach. We present an automated analysis and visualization tool for proton packing to evaluate the quality of NMR structures.

Crystallography, X-Ray↗