ABSTRACT
BACKGROUND: NY-ESO-1 antibodies are specifically observed in patients with NY-ESO-1-expressing tumours. We analysed whether the NY-ESO-1 humoral immune response is a useful tumour marker of gastric cancer. METHODS: Sera from 363 gastric cancer patients were screened by enzyme-linked immunosorbent assay (ELISA) to detect NY-ESO-1 antibodies. Serial serum samples were obtained from 25 NY-ESO-1 antibody-positive patients, including 16 patients with curative resection and 9 patients who received chemotherapy alone. RESULTS: NY-ESO-1 antibodies were detected in 3.4% of stage I, 4.4% of stage II, 25.3% of stage III, and 20.0% of stage IV patients. The frequency of antibody positivity increased with disease progression. When the NY-ESO-1 antibody was used in combination with carcinoembryonic antigen and CA19-9 to detect gastric cancer, information gains of 11.2% in stages III and IV, and 5.8% in all patients were observed. The NY-ESO-1 immune response levels of the patients without recurrence fell below the cutoff level after surgery. Two of the patients with recurrence displayed incomplete decreases. The nine patients who received chemotherapy alone continued to display NY-ESO-1 immune responses. CONCLUSION: When combined with conventional tumour markers, the NY-ESO-1 humoral immune response could be a useful tumour marker for detecting advanced gastric cancer and inferring the post-treatment tumour load in seropositive patients.
Subject(s)
Antibodies, Neoplasm/blood , Antigens, Neoplasm/immunology , Biomarkers, Tumor/blood , Membrane Proteins/immunology , Stomach Neoplasms/immunology , Aged , Antigens, Tumor-Associated, Carbohydrate/analysis , Carcinoembryonic Antigen/analysis , Disease Progression , Female , Humans , Immunity, Humoral , Male , Middle Aged , Prognosis , Stomach Neoplasms/diagnosis , Stomach Neoplasms/pathology , Tumor BurdenABSTRACT
Mutations in the STA gene at the Xq28 locus have been found in patients with X-linked Emery-Dreifuss muscular dystrophy (EDMD). This gene encodes a hitherto unknown protein named 'emerin'. To elucidate the subcellular localization of emerin, we raised two antisera against synthetic peptide fragments predicted from emerin cDNA. Using both antisera, we found positive nuclear membrane staining in skeletal, cardiac and smooth muscles in the normal controls and in patients with neuromuscular diseases other than EDMD. In contrast, a deficiency in immunofluorescent staining of skeletal and cardiac muscle from EDMD patients was observed. A 34 kD protein is immunoreactive with the antisera--the protein is equivalent to that predicted for emerin. Together, our findings suggest the specific deficiency of emerin in the nuclear membrane of muscle cells in patients with EDMD.
Subject(s)
Membrane Proteins/deficiency , Muscular Dystrophies/metabolism , Nuclear Envelope/metabolism , Thymopoietins/deficiency , Adolescent , Adult , Amino Acid Sequence , Base Sequence , DNA , Fluorescent Antibody Technique, Indirect , Humans , Immunoblotting , Male , Molecular Sequence Data , Muscles/cytology , Muscles/metabolism , Muscular Dystrophy, Emery-Dreifuss , Mutation , Nuclear Proteins , Subcellular FractionsABSTRACT
OBJECTIVE: Cytomegalovirus (CMV) is the most common cause of congenital infection and can cause neurodevelopmental disabilities, although a majority of patients are asymptomatic. Biomarkers associated with disease severity would be desirable to distinguish asymptomatic from mildly symptomatic patients who may benefit from antiviral treatment. MicroRNAs (miRNAs) are noncoding RNAs that may have the potential to serve as biomarkers. STUDY DESIGN: Thirteen infants with congenital CMV infection were enrolled, and plasma levels of 11 human- and 3 CMV-encoded miRNAs were quantitated by real-time PCR. Plasma levels of miRNAs and their associations with clinical features were evaluated. RESULTS: The levels of miR-183-5p and miR-210-3p were significantly higher in patients with congenital CMV infection than in control infants, whereas no significant associations between levels of miRNAs and clinical features of congenital CMV infection were observed. CONCLUSION: Plasma miRNAs could be associated with the pathogenesis of congenital CMV infection and could be used as disease biomarkers.
Subject(s)
Cytomegalovirus Infections/congenital , Cytomegalovirus/genetics , MicroRNAs/blood , Antiviral Agents , Biomarkers/blood , Cytomegalovirus Infections/blood , DNA, Viral/urine , Female , Humans , Infant , Infant, Newborn , Male , Real-Time Polymerase Chain ReactionABSTRACT
The nonmetabolizable glucose analogue 3-O-methyl-glucose is known to protect pancreatic B-cells against streptozocin (STZ) when injected with or just before STZ. If 3-O-methyl-glucose and the sugar moiety of STZ compete for a glucose recognition site on B-cells, it seemed likely that 3-O-methyl-2-deoxy-2-( [(methylnitrosoamino)carbonyl]amino)-D-glucopyranose, an analogue of STZ with a 3-O-methyl-glucosyl residue, would cause experimental diabetes. This possibility was tested by synthesis of this analogue (alpha-anomer) and comparison of its diabetogenic activity in Wistar rats with that of STZ. Results showed that the compound was diabetogenic and as potent as STZ. This new analogue is the first of the various STZ derivatives reported to show diabetogenic activity. Its activity supports the idea that 3-O-methyl-glucose and STZ bind competitively with a glucose recognition site on pancreatic B-cells.
Subject(s)
Diabetes Mellitus, Experimental/chemically induced , Glucose/metabolism , Islets of Langerhans/metabolism , Streptozocin/analogs & derivatives , 3-O-Methylglucose , Acetylglucosamine/pharmacology , Animals , Blood Glucose/analysis , Deoxyglucose/pharmacology , Hyperglycemia/chemically induced , Islets of Langerhans/drug effects , Male , Methylglucosides/pharmacology , Rats , Rats, Inbred Strains , Streptozocin/pharmacologyABSTRACT
The interaction between thyroglobulin liposomes, as a model of colloid droplets, and thyroidal lysosomes was studied in an in vitro system. On sucrose density gradient centrifugation analysis, particulate lysosomes were distributed in a high density region and were apparently clearly separated from the liposomal peak. However, when the liposomes and lysosomes were incubated together and then analyzed, the liposomes were found to migrate with the lysosomal peak. The extent of this translocation of liposomes depended on the incubation temperature: after incubations at 37 C and 0 C, 56% and 35%, respectively, of the radioactivity of liposomes was found in the lysosomal peak. This phenomenon was inhibited by 50% in the presence of 10(-3)M chlorpromazine. Matrix-labeled liposomes [125I]thyroglobulin liposomes), and membrane labeled lipolomes ([14C]-cholesterol-labeled thyroglobulin liposomes) showed similar distribution patterns in the lysosomal peak on gradient centrifugation. The liposomal thyroglobulin was hydrolyzed in a time-dependent manner in the fraction showing both radioactivity and acid phosphatase activity. These results provide direct evidence of liposome-lysosome fusion, or formation of phagolysosomes.
Subject(s)
Liposomes/metabolism , Lysosomes/metabolism , Thyroglobulin/metabolism , Thyroid Gland/metabolism , Animals , Centrifugation, Density Gradient , Hydrolysis , In Vitro Techniques , Rats , Thyroid Hormones/metabolismABSTRACT
The interaction between [131I]-thyroglobulin liposomes and thyroidal lysosomes was used as an in vitro model system for analyzing the relation of colloid droplets to lysosomes in follicular cells. The rates of hydrolysis of [131I]-thyroglobulin in a liposome-lysosome system (Lipo-Lyso system) and a thyroglobulin-lysosome system (TG-Lyso system) were compared. Hydrolysis of thyroglobulin in the Lipo-Lyso system increased hyperbolically and was greater than that in the TG-Lyso system for about 10 h. Liposomal thyroglobulin was not degraded by the 20,000 X g supernatant obtained on disruption of the lysosomal fraction. On varying the pH of the incubation medium, the highest activity was observed under acidic conditions in both systems. Under neutral or weakly alkaline conditions, the Lipo-Lyso system still showed 50% of the maximal hydrolytic activity, while the TG-Lyso system showed no activity. ATP and anaerobic conditions had no effect on either system. Cysteine (5 X 10-2M) and p-chloromercuribenzene sulfonic acid (PCMBS, 10-3 M) had not influence on hydrolysis in the Lipo-Lyso system, but in the TG-Lyso system cysteine greatly increased, and PCMBS significantly reduced the rate of hydrolysis. Dibutyryl cyclic AMP had no effect. Chlorpromazine (Cpz) decreased liposomal thyroglobulin hydrolysis in a concentration-dependent manner. In the TG-Lyso system, concentrations of 10-4M Cpz had no effect. These results strongly suggest that liposomes rapidly fused with lysosomes, providing optimal conditions for hydrolysis of thyroglobulin.
Subject(s)
Liposomes/metabolism , Lysosomes/metabolism , Models, Biological , Thyroglobulin/metabolism , Thyroid Hormones/metabolism , Adenosine Triphosphate/pharmacology , Anaerobiosis , Animals , Bucladesine/pharmacology , Chloromercuribenzoates/pharmacology , Chlorpromazine , Cysteine/pharmacology , Hydrogen-Ion Concentration , Hydrolysis , In Vitro Techniques , Rats , Thyroid Gland/ultrastructure , Time FactorsABSTRACT
Spin-trapping techniques and electron spin resonance (ESR) spectroscopy were used to study the relationship between the effect of streptozotocin (STZ) on pancreatic beta-cells and free radical formation by these cells. Results showed that STZ enhanced generation of the DMPO-OH radical adduct, which is a degradation product of the superoxide anion (O2-) in the presence of cellular components, in a hypoxanthine-xanthine oxidase (XOD) system with a homogenate of beta-cells. This enhancing effect was also observed in a system without cellular components; STZ increased the signal height due to the O2- radical in a concentration-dependent manner and caused a maximum of 150% enhancement at a concentration of 1.5 mM. Thus, STZ seemed to enhance the generation of the O2- radical in the XOD system, probably by some mechanism of its interaction with XOD. Pancreatic beta-cells exhibited a high XOD activity and a very low superoxide dismutase activity. Therefore, the present result supports the possibility that the cytotoxic effect of STZ is closely related to free radical generation in pancreatic beta-cells.
Subject(s)
Islets of Langerhans/enzymology , Streptozocin/pharmacology , Superoxides/metabolism , Xanthine Oxidase/metabolism , Animals , Animals, Newborn , Electron Spin Resonance Spectroscopy , Free Radicals , Kinetics , Rats , Rats, Inbred Strains , Streptozocin/analogs & derivativesABSTRACT
We studied the changes of frontal and parietal somatosensory evoked potentials (SEPs) in the awake state versus different stages of sleep in 10 normal adult subjects. Frontal and parietal SEP components were affected differentially as sleep stages progressed. In general, the amplitudes of frontal components, notably P22, were increased in sleep, whereas the amplitudes of parietal components were decreased in sleep. A sensitive waveform change from the awake state to sleep was present in the frontal response, where a subtle notched negativity, termed "N40," was present only in the awake state and quickly dissipated in all stages of sleep, including stage 1. The amplitude changes from the awake state to stage 3/4 sleep were neither linear nor parallel among SEP components. The most discordant changes occurred in stage 3/4. The amplitudes for the frontal N18-P22-N30 complex and parietal N20-P26-N32 complex increased from stage 2 to stage 3/4, while those for frontal N30-fP40 and parietal N32-pP40 decreased. In contrast to these divergent amplitude changes, the latencies of all components except P14 and frontal N18 showed progressive prolongation from the awake state to slow-wave sleep. The SEP waveforms and latencies in REM sleep approximated those in the awake state, although amplitudes for frontal peaks still remained slightly higher and amplitudes for parietal peaks slightly lower. We postulate that interactions of excitatory and inhibitory phenomena are responsible for the component-dependent and sleep-stage-dependent amplitude enhancement or depression in sleep.
Subject(s)
Evoked Potentials, Somatosensory , Frontal Lobe/physiology , Parietal Lobe/physiology , Sleep Stages/physiology , Adult , Electroencephalography , Humans , Male , Middle Aged , Reference Values , Sleep, REM/physiology , Wakefulness/physiologyABSTRACT
This study was designed to characterize the interaction of CH3HgCl or HgCl2 with thyroid peroxidase (TPO). Two types of experiments were performed. First, the thyroids from rats that were given 5.6 mg/kg/day of either CH3HgCl or HgCl2 for 2 weeks by intubation were subjected to histochemical treatment and then to electron microscopy. TPO activities in all cell compartments were inhibited by HgCl2 but not by CH3HgCl. Morphological observation showed that taller epithelia were induced by HgCl2, whereas flattened epithelia forming large follicles were induced by CH3HgCl. The serum thyrotropin level was substantially lowered by CH3HgCl but was unchanged by HgCl2. Second, the guaiacol oxidation by TPO in isolated and ruptured pig thyroid cells was spectrophotometrically monitored in the presence of either CH3HgCl or HgCl2. The TPO was not inhibited by CH3HgCl but was inhibited by HgCl2. These results indicated that CH3HgCl induced a hypothyroid state without affecting TPO, whereas HgCl2 inhibited TPO and induced a hypertropic state owing to compensation for loss of enzyme activity, and that the lack of inhibitory activity of CH3HgCl was not due to the inability to penetrate the cells. Therefore, there appeared to be a differential interaction of organic and inorganic forms of mercurials with the thyroid.
Subject(s)
Mercuric Chloride/pharmacology , Methylmercury Compounds/pharmacology , Peroxidases/metabolism , Thyroid Gland/enzymology , 3,3'-Diaminobenzidine/metabolism , Animals , Cell Separation , Epithelium/metabolism , Epithelium/ultrastructure , Guaiacol/metabolism , Histocytochemistry , Male , Microscopy, Electron , Oxidation-Reduction , Rats , Rats, Inbred Strains , Swine , Thyroid Gland/cytology , Thyroid Gland/ultrastructureABSTRACT
The effects of streptozotocin (STZ) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) on monolayer cultures of rat pancreatic beta cells were compared. The intracellular NAD concentration was markedly decreased by both 2 mmol STZ/l and 13.6 mumol MNNG/l, but insulin secretion was decreased significantly only by STZ. The intracellular ATP level decreased rapidly and in a time-dependent manner with STZ, but decreased less on treatment with MNNG: 80% decrease with STZ but only 35% decrease with MNNG in 12 h in the cells exposed to the chemicals for 1 h and then washed thoroughly. STZ decreased oxygen consumption of rat liver mitochondria in a time- and dose-dependent manner and enhanced the generation of hydroxyl radicals (DMPO-adducts). This enhancement was doubled on the addition of succinate as a substrate. Mitochondrial ATP production was also decreased significantly by STZ, but not by MNNG. Thus the marked depletion of intracellular ATP in beta cells by STZ seems to be due mainly to a direct effect on mitochondrial production. From these results, we suggest that the cytotoxic effect of STZ in pancreatic beta cells is due to a reduction in the intracellular level of ATP, rather than of NAD.
Subject(s)
Adenosine Triphosphate/analysis , Islets of Langerhans/metabolism , Streptozocin/toxicity , Animals , Animals, Newborn , Cells, Cultured , Insulin/analysis , Islets of Langerhans/drug effects , Methylnitronitrosoguanidine/toxicity , Mitochondria, Liver/drug effects , Mitochondria, Liver/metabolism , NAD/analysis , Oxygen Consumption/drug effects , Rats , Rats, Inbred StrainsABSTRACT
Exposure of rat pancreatic beta cells in monolayer culture to 2 mmol streptozotocin (STZ)/l for 1 h followed by thorough washing inhibited their uptake of [14C]nicotinamide and [3H]2-deoxyglucose [( 3H]2-DG) to about 50% and also reduced the intracellular ATP concentration to 50% of that in control cells. These changes were not due to a lethal cytotoxic effect of STZ, because cell viability, as estimated by succinic dehydrogenase activity, was 90% of that of control cells. Oligomycin and carbonylcyanide-m-chlorophenylhydrazone (CCCP), an uncoupler of oxidative phosphorylation, caused a dose-dependent decrease in intracellular ATP concentration while maintaining high cell viability. These ATP-depleted cells showed a decrease in insulin release and an inhibition of the uptake of [14C]nicotinamide and [3H]2-DG in a dose-dependent manner. Therefore oligomycin and CCCP reproduced the same effects as those found in beta cells treated with STZ. These results suggest that the uptake of nicotinamide and 2-DG by beta cells might be regulated by their intracellular ATP concentration. The decreased uptake of nicotinamide in ATP-depleted beta cells caused by STZ might explain the lack of protective effect of nicotinamide against STZ cytotoxicity when administered after the latter. Furthermore, the radiotracer experiments demonstrated that the transport of nicotinamide by intact beta cells was inhibited in a dose-dependent manner by 2-DG and vice versa, i.e. the transport of 2-DG was inhibited by nicotinamide. These findings suggest the existence of a common transport mechanism in beta cells responsible for the uptake of nicotinamide and 2-DG, the transport of which is known to occur by facilitated diffusion.
Subject(s)
Islets of Langerhans/metabolism , Niacinamide/metabolism , Streptozocin/pharmacology , Adenosine Triphosphate/metabolism , Animals , Carbon Radioisotopes , Carbonyl Cyanide m-Chlorophenyl Hydrazone/pharmacology , Cells, Cultured , Deoxyglucose/metabolism , Depression, Chemical , Dose-Response Relationship, Drug , Insulin/biosynthesis , Intracellular Fluid/metabolism , Islets of Langerhans/drug effects , Oligomycins/pharmacology , Rats , Rats, Inbred Strains , TritiumABSTRACT
The role of xanthine oxidase in thyroid function was studied in the rat in vivo by different approaches. Allopurinol, an inhibitor of xanthine oxidase, was administered by mixing it with a powdered diet (16 mg/100 g body wt per day for 10 days). This treatment significantly reduced the total uptake of iodide and inhibited the organification of iodide in the rat thyroid gland. Thyroid xanthine oxidase and dehydrogenase were almost completely inactivated by tungstate, which was given to rats (100 p.p.m./animal per day in drinking water for 10 days) maintained on a purified diet containing low levels of molybdenum. Under these conditions, no inhibitory effect was observed on synthesis of thyroid hormones. It therefore seemed reasonable to assume that the suppressive effect of allopurinol on the biosynthesis of thyroid hormones is not mediated by xanthine oxidase.
Subject(s)
Iodine/metabolism , Thyroid Gland/metabolism , Tungsten Compounds , Xanthine Oxidase/metabolism , Allopurinol/pharmacology , Animals , Male , Rats , Rats, Inbred Strains , Thyroid Gland/drug effects , Thyroid Gland/enzymology , Tungsten/pharmacology , Xanthine Dehydrogenase/metabolismABSTRACT
Recent studies have indicated that the blood glucose level of rats with streptozotocin (STZ)-induced diabetes (type 1) is normalized without an increase in the plasma insulin level by administration of sodium orthovanadate in the drinking water. The mechanism of this insulin-like effect of vanadate is unknown. In this study, we investigated whether vanadyl ion, which is less toxic than vanadate to rats, also has an insulin-like effect in rats with STZ-induced diabetes. When rats with STZ-induced diabetes were given a daily i.p. injection of vanadyl sulphate (9.3 and 4.6 mg vanadium/kg body weight), their blood glucose level decreased from about 22.2 to about 7.2 mmol glucose/l within 2 days and remained low for at least 12 weeks. This treatment did not affect their low plasma insulin level. Quantitative electron spin resonance (ESR) spectrometry showed that most of the vanadium (about 90%) in their tissues was present as a vanadyl form (VO2+). ESR analysis also showed that the vanadyl ion in tissues was bound endogenously with four oxygen ligands from either water or oxyamino acid residues in proteins. Vanadyl sulphate accelerated glucose incorporation into adipocytes of rats, suggesting that the action of vanadyl ion is peripheral. Interestingly, vanadyl sulphate at a high concentration (about 10 mmol/l) was more effective than insulin in enhancing glucose uptake. This study demonstrated that: (1) vanadyl sulphate (+4 oxidation state), like vanadate ion, normalizes the blood glucose levels of rats with STZ-induced diabetes; (2) the action of vanadyl ion is peripheral; and (3) the active form of vanadium for an insulin-like effect may be a vanadyl form, not vanadate.
Subject(s)
Blood Glucose/metabolism , Diabetes Mellitus, Experimental/metabolism , Vanadium Compounds , Vanadium/pharmacology , Adipose Tissue/metabolism , Animals , Diabetes Mellitus, Experimental/blood , Electron Spin Resonance Spectroscopy , Glucose/metabolism , Insulin/blood , Male , Rats , Rats, Inbred Strains , Vanadium/metabolismABSTRACT
Ethylidene glucose (4,6-O-ethylidene glucose; EG) is known to bind the outer surface of the glucose transporter in the membranes of human erythrocytes and other mammalian cells. If a glucose transport system is present on pancreatic beta cells and recognizes the glucose moiety of streptozotocin (STZ), EG should protect beta cells from the cytotoxicity of STZ when it is administered with STZ. This possibility was examined in in-vivo experiments in rats. When EG and STZ were injected into rats together the animals did not become diabetic, as judged by their blood glucose levels, response in a glucose-tolerance test, and insulin secretion in response to feeding. These results suggest that there is a glucose transporter present in beta cells and also the transport of streptozotocin into beta cells through this system.
Subject(s)
Diabetes Mellitus, Experimental/prevention & control , Glucose/analogs & derivatives , Islets of Langerhans/drug effects , Streptozocin/antagonists & inhibitors , Animals , Biological Transport , Blood Glucose/metabolism , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/metabolism , Dose-Response Relationship, Drug , Glucose/pharmacology , Glucose Tolerance Test , Insulin/metabolism , Insulin Secretion , Male , Rats , Rats, Inbred StrainsABSTRACT
4,6-O-Ethylidene glucose (ethylidene glucose), a specific inhibitor at the outer surface of a glucose transporter in the cell membranes, substituted analogue of streptozotocin was newly synthesized. This compound did not induce diabetes in rats and also did not show cytotoxic effect on pancreatic beta cells of neonatal rats in a monolayer culture system. The reasons why such a molecule was designed and why it showed no biological effects are discussed on the basis of a structure-activity relationship. Our results afford positive evidence for the presence of a glucose transport system or a glucose transporter on pancreatic beta cells and its involvement in the action of streptozotocin on beta cells.
Subject(s)
Diabetes Mellitus, Experimental/chemically induced , Glucose/analogs & derivatives , Streptozocin/analogs & derivatives , Animals , Autoradiography , Blood Glucose/metabolism , Carbon Radioisotopes , Glucose/pharmacokinetics , In Vitro Techniques , Insulin/metabolism , Islets of Langerhans/drug effects , Islets of Langerhans/metabolism , Male , Monosaccharide Transport Proteins/metabolism , NAD/metabolism , Rats , Rats, Inbred Strains , Streptozocin/chemical synthesis , Streptozocin/pharmacokinetics , Streptozocin/toxicityABSTRACT
We describe an electro-oculographic study of upbeat nystagmus in 4 patients, with neuropathological correlation in one. All patients had lesions in the pontine tegmentum. The electro-oculographic data may be explained by imbalanced vertical vestibular or smooth pursuit eye movement control. The nystagmus stopped or reversed direction during convergence or in supine head positions. We propose that changes in the intensity or direction of upbeat nystagmus that are induced by convergence or changes in head position, are caused by vertical imbalance in the otolithic-ocular reflex, when superimposed on an imbalanced vestibulo-ocular reflex (VOR). Imbalance of the otolithic-ocular reflex and the vertical VOR are caused by damage in the pontomedullary tegmentum.
Subject(s)
Medulla Oblongata/pathology , Nystagmus, Pathologic/physiopathology , Pons/pathology , Adult , Aged , Aged, 80 and over , Darkness , Electrooculography , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Nystagmus, Pathologic/pathology , Posture , Reflex, Vestibulo-Ocular , SaccadesABSTRACT
Electrolyte-induced myelinolysis was produced in rats to evaluate electrophysiological derangement in the brainstem. Auditory brainstem responses (ABRs) were used to assess the brainstem function. Rats treated with hypertonic saline for 2 days had normal interpeak latencies in ABRs. Rats treated with vasopressin-induced hyponatremia alone and those with hypertonic saline after 3 days of hyponatremia had significantly prolonged interpeak latencies between waves II-III and III-IV in ABRs. These prolongations indicate electrophysiological derangement of the upper pons and mesencephalon in hyponatremic rats as well as in rats with hyponatremia followed by hypernatremic myelinolysis. In view of these data, hyponatremia may be a prerequisite for electrolyte-induced myelinolysis and electrolyte derangements such as hyponatremia, and rapidly correcting hypernatremia may be the cause of electrolyte-induced myelinolysis in rats.
Subject(s)
Auditory Pathways/physiopathology , Brain Stem/physiopathology , Demyelinating Diseases/physiopathology , Hypernatremia/physiopathology , Hyponatremia/physiopathology , Animals , Demyelinating Diseases/chemically induced , Electrophysiology , Mesencephalon/physiopathology , Pons/physiopathology , Rats , Rats, Inbred Strains , Saline Solution, Hypertonic , Vasopressins/pharmacologyABSTRACT
A new microcrystalline boehmite (tentatively named PT-A) was synthesized as an efficient phosphate adsorbent to replace aluminum hydroxide gel. The characteristic structure of PT-A was examined by nitrogen adsorption/desorption, X-ray diffraction, deviation microscopy, and scanning electron microscopy to establish a pore structural model of PT-A. With this model structure, the details of the mechanism of interaction between PT-A and phosphate in the presence of bovine serum albumin (BSA) are discussed. PT-A is a spherical particle with a diameter of approximately 100 microns and a porous surface structure, and its inside is packed with boehmite microcrystals (crystallite size, 2 nm). PT-A has three types of pores in its structure: a micropore with a narrow size-distribution, a mesopore with a broad size-distribution, and a macropore (radii of pores are 0.7, 1-20, and approximately 300 nm, respectively). When phosphate was incubated with PT-A in human gastric and intestinal juices or in an aqueous solution containing BSA, the amounts of phosphate adsorbed by PT-A were not affected by the presence of proteins. The nitrogen adsorption/desorption isotherms and energy dispersive X-ray analyses demonstrated that phosphate could diffuse to the smaller tunnels freely even if the external surface of PT-A was covered with BSA. It was also demonstrated that the main site of adsorption for phosphate was in micropores of PT-A, whereas BSA was adsorbed only to the external surface and none entered inside smaller tunnels consisting of micro- and mesopores.
Subject(s)
Aluminum Hydroxide/chemistry , Aluminum Oxide/chemistry , Phosphates/chemistry , Adsorption , Gastric Juice/chemistry , Humans , Ligands , Microscopy, Electron, Scanning , Nitrogen/chemistry , Particle Size , Porosity , Serum Albumin, Bovine , Thermodynamics , X-Ray DiffractionABSTRACT
Aluminum hydroxide gel (ALG) has been effective for ameliorating acidosis associated with phosphatemia caused by hemodialysis. However, aluminum accumulation in the body causes severe side effects. As substitute for ALG, a new type of aluminum oxide hydroxide (tentatively named PT-A) was prepared with the hope of future clinical use. PT-A has a microcrystalline structure with a high resistance to pH change and has more phosphate-binding efficacy than ALG. It was tested for possible interaction with protein by adsorption test, zeta-potential analysis, X-ray diffraction, and scanning electron microscopy. Bovine serum albumin (BSA) was chosen as a model protein. The interaction of BSA with PT-A depended on the amount of adsorbent. Protein adsorption occurred rapidly and reached the maximal level at near neutral pHs. Phosphate adsorption was not affected by the presence of BSA, but the interaction of BSA with PT-A was significantly reduced by the presence of phosphate. Zeta-potential changes on the surface of PT-A indicated that the positively charged surface of PT-A was covered with negatively charged phosphate ions that repelled negatively charged BSA molecules. X-ray diffraction patterns indicated no observable structural alteration caused by adsorption of BSA or phosphate, and scanning electron microscopy revealed that BSA covered the outer surface of PT-A but did not cover small pores, where phosphate can freely penetrate.
Subject(s)
Aluminum Hydroxide/chemistry , Aluminum Oxide/chemistry , Serum Albumin, Bovine/pharmacokinetics , Adsorption , Aluminum Hydroxide/pharmacology , Aluminum Oxide/pharmacology , Animals , Cattle , Drug Interactions , Hydrogen-Ion Concentration , Phosphates/chemistry , Phosphates/pharmacokinetics , Proteins/chemistry , Proteins/pharmacokinetics , Serum Albumin, Bovine/chemistry , Surface PropertiesABSTRACT
We propose new hypotheses for the mechanisms of streptozotocin (STZ) and alloxan inducing experimental diabetes in animals. STZ is transported into pancreatic beta cells through glucose transporter in the cell membranes and attacks mitochondria. Mitochondrial ATP generation is inhibited and the resulting high concentration of intracellular ADP causes its degradation providing hypoxanthine, a substrate of xanthine oxidase (XOD) whose activity is intrinsically very high in beta cells. Then, XOD-catalyzing reaction is proceeded as proved by increased formation of uric acid and O2- radicals are produced, but beta cells are inefficient to scavenge these radicals because of their extremely low activity of superoxide dismutase. On the other hand, STZ directly activates XOD and enhances O2- generation. Consequently, pancreatic beta cells are dually suffered from O2- radicals or probably hydroxyl radicals derived from the former when exposed to STZ. Allopurinol, an inhibitor of XOD, can protect animals from the diabetogenic effect of STZ. In pancreatic beta cells, alloxan anion radicals are generated from alloxan probably mediated by the action of microsomal cytochrome P-450 system. These radicals have long half-life and directly damage DNA in vitro. The widely accepted hypothesis that the cause of alloxan-induced diabetes is attributable to O2- radicals formed from alloxan is excluded, because alloxan itself shows a very potent scavenging effect to O2- radicals. Therefore alloxan anion radicals seem to be directly related to the incidence of diabetes by alloxan.