[Treatment of hypertension associated with diabetes mellitus].
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Antihypertensive Agents↗
Biomedical subjects
K Negishi
Publications and source records attributed to K Negishi.
Preparation of DNA-chitosan columns and their applications: binding of carcinogens to the column.
DNA, either native or denatured, can be immobilized by complexing with chitosan. The DNA-chitosan, which is insoluble in aqueous media, contains DNA at about 50% in weight. The DNA in the complex is accessible by enzymes and reagents. Carcinogenic heterocyclic amines, having affinity to DNA, can be adsorbed to the DNA-chitosan. The DNA-chitosan complex can be homogeneously dispersed in celite powder, and the resultant DNA-chitosan-celite is a material suitable to construct an immobilized DNA-column. The column was shown to be effective in concentrating heterocyclic amines.
Adsorption↗
Yeast oligonucleotide transformation: its mechanism and application to analysis of mutations induced by defined DNA lesions.
We have studied mutagenic specificity of an abasic site by the yeast-transformation procedure using an oligonucleotide containing a single furan-type abasic site. The recipient yeast used was deficient in the major AP endonuclease (apn1). Sequence analysis of the transformants suggested that dATP was incorporated most frequently opposite the abasic site, while dGTP seemed to be incorporated opposite the abasic site in the recipient proficient in apn1. To explore the mechanism of this oligonucleotide transformation, we have also analyzed the transformation with phosphorothioate oligonucleotides with mismatched 3'-end. The results are discussed.
Carbon-Oxygen Lyases↗
Mutational analysis of the CitA citrate transporter from Salmonella typhimurium: altered substrate specificity.
The CitA citrate transporter in Salmonella typhimurium is encoded by the citA gene and consists of 434 amino acid residues that probably include 12 membrane-spanning segments [Shimamoto. T., et al. (1991) J. Biochem. 110, 22-28]. CitA mutants with altered substrate specificities were isolated by in vitro mutagenesis using nitrous acid. The mutants could grow on isocitrate as a sole carbon source which normally cannot be transported well by the CitA transporter of S. typhimurium. The mutation sites in the citA gene of the nine mutants were determined to involve single residues at seven sites (one mutation per mutant). The original amino acid residues at these sites (Arg-19, Ala-38, Glu-51, Gly-132, Ala-169, Pro-262 and Leu-271) were identified to be responsible for the altered substrate specificity. All these amino acid residues were conserved in four other homologous citrate transporters from Escherichia coli, Citrobacter amalonaticus and Klebsiella pneumoniae and are suggested to be involved in substrate recognition by the CitA transporter.
Amino Acid Sequence↗
Effects of glutamic acid and related agents on horizontal cells in a marine teleost retina.
Excitatory amino acids (EAAs) such as glutamic and aspartic acids, considered as the most likely neurotransmitters at the photoreceptor-horizontal cell synapse of teleost retinas, as well as agonists such as kainic acid and several of their antagonists, were applied to isolated and superfused retinas of the teleost Eugerres plumieri. Intracellular recordings from horizontal cells reveal that EAA receptors are of the kainate-quisqualate type. There is competitive inhibition between the agonist and antagonist agents used, and under their combined effect, the synapse under study remains operational, in a functional state, able to modulate the horizontal cell membrane potential upon retinal illumination.
Animals↗
A higher proinsulin response to glucose loading predicts deteriorating fasting plasma glucose and worsening to diabetes in subjects with impaired glucose tolerance.
To evaluate the clinical significance of proinsulin determination, we measured glucose, insulin, C-peptide and proinsulin during 75-g oral glucose loading in 59 patients. In a 2.5-year follow-up study of 37 subjects with impaired glucose tolerance (IGT) at the initial test, 11 patients changed from IGT to a normal state and 5 patients showed worsening to overt Type 2 diabetes with elevation of fasting plasma glucose; 21 patients remained unchanged. Although our data showed that both fasting (IGT: p = 0.4523) and 120-min plasma glucose (IGT: p = 0.8168) values at the initial test were not significantly correlated with increased fasting plasma glucose levels in a 2.5-year follow-up study, subjects with a higher 120-min proinsulin response to glucose during the initial OGTT showed a significant correlation (IGT: p < 0.0001) with increased fasting plasma glucose levels after follow-up period and developed Type 2 diabetes. The present findings suggest that the proinsulin response to glucose loading might be a useful indicator for predicting worsening to diabetes in subjects with impaired glucose tolerance.
Administration, Oral↗
HAM1, the gene controlling 6-N-hydroxylaminopurine sensitivity and mutagenesis in the yeast Saccharomyces cerevisiae.
The ham1 mutant of yeast Saccharomyces cerevisiae is sensitive to the mutagenic and lethal effects of the base analog, 6-N-hydroxylaminopurine (HAP). We have isolated a clone from a centromere-plasmid-based genomic library complementing HAP sensitivity of the ham1 strain. After subcloning, a 3.4 kb functional fragment was sequenced. It contained three open reading frames (ORFs) corresponding to proteins 353, 197 and 184 amino acids long. LEU2+ disruptions of the promoter and N-terminal part of the gene coding 197 amino acids long protein led to moderate and strong sensitivity to HAP, respectively, and were allelic to the original ham1-1 mutation. Thus this ORF represents the HAM1 gene. The deduced amino acid sequence of HAM1 protein was not similar to any protein sequence of the SwissProt database. The HAM1 gene was localized on the right arm of chromosome X between cdc8 and cdc11. Spontaneous mutagenesis was not affected by the ham1::LEU2 disruption mutation.
Adenine↗
Elevated erythrocyte sodium-lithium counter-transport in hypertensive patients with non-insulin-dependent diabetes mellitus.
Increased erythrocyte (RBC) sodium-lithium (Na-Li) counter transport (CT) has been reported to be a genetic marker for essential hypertension (EHT). In addition, increased RBC Na-Li CT has been demonstrated in insulin-dependent diabetic (IDDM) patients with nephropathy, indicating that a predisposition to hypertension may cause renal damage and impaired renal function. Therefore, the present study was designed to determine RBC Na-Li CT in subjects with essential hypertension (EHT) and non-insulin-dependent diabetics (NIDDM) with or without hypertension (NIDDMHT or NIDDMNT), using the method of Canessa et al. with a slight modification by flame photometry and expressed as nmol Li/5 x 10(6) RBC/h. Na-Li CT in patients with EHT (0.159 +/- 0.051 (S.D.), n = 26) or NIDDMHT (0.168 +/0 0.083, n = 42) was higher than that in NIDDMNT patients (0.127 +/- 0.059, n = 27, P < 0.05). Among the NIDDMHT patients, those with clinical nephropathy had the same levels of Na-Li CT as those without nephropathy. When the NIDDM patients were divided into two groups with or without insulin treatment, the Na-Li CT in hypertensives was higher than that in normotensives, irrespective of whether or not they were on insulin therapy. Addition of insulin to RBCs in vitro did not augment the Na-Li CT activity. These results suggest that an increase of Na-Li CT may not be due to the stimulatory effect of endogenous or exogenous insulin, and reflect a genetic predisposition for hypertension, and hence diabetic nephropathy, not only in IDDM but also NIDDM patients.
Antiporters↗
[Density distribution of dopaminergic neurons in the retina of a marine teleost, Thamnoconus (Navodon) modestus].
By means of tyrosine hydroxylase immnocytochemical detection, regional densities of dopaminergic (DAergic) neurons were measured in 6 whole-mounted retinas of a marine teleost, Thamnoconus (Navodon) modestus. Isodensity lines of DAergic cells in the right retina were drawn to make a contour map. Depending upon the range of cell densities, the retinal field was divided into 3 regions: zone A, containing more than 300 per mm square; zone B, from 200 to 299; and zone C, below 200. Zone A was located in the small temporal (A1) and nasal (A2) areas as well as in the peripheral margin (A3). Zone B formed a horizontal streak-like band between regions A1 and A2. Low density areas (C) were located dorsally or ventrally to zone B. Where the densities were higher, soma sizes appeared to be smaller. DAergic neurons in the peripheral zone A3 were bipolar and the dendrites ran parallel to the retinal margin, while DAergic neurons in the other zones were multipolar and the dendrites ran in various directions. The presence of the small temporal (A1) and nasal areas (A2) with high densities of DAergic neurons, as well as the streak-like area (B) with a relatively high density, may correspond to similar areas in the isodensity contour map of ganglion cells.
Animals↗
Metformin decreases blood pressure and obesity in OLETF rats via improvement of insulin resistance.
To determine whether improvement of insulin resistance decreases blood pressure as well as obesity, metformin (100 mg/kg/d) or vehicle was administered for 20 weeks to 12-week-old male Otsuka Long-Evans Tokushima Fatty (OLETF) rats (n = 10 each), a newly developed animal model of non-insulin-dependent diabetes mellitus (NIDDM) with mild obesity, hyperinsulinemia, and hypertriglyceridemia. Oral administration of metformin ameliorated glucose intolerance and attenuated the insulin response to glucose loading (2 g/kg, i.p.), as evidenced by a decrease in the area under the curve for glucose and insulin at 24 weeks by 19% and 37%, respectively. At 21 weeks, systolic blood pressure was significantly lower in the metformin group than in controls (130 +/- 1.9 vs. 143 +/- 2.7 mmHg, p < 0.01), despite no difference in body weight. Subsequently, blood pressure tended to be slightly but insignificantly lower in the metformin group, and body weight was significantly lower in the metformin group (532 +/- 9.8 vs. 587 +/- 10.3 g at 31 weeks, p < 0.01). Metformin treatment also lowered the level of serum triglycerides (9.4 +/- 0.6 vs. 13.2 +/- 0.5 mmol/l, p < 0.01) and the plasma norepinephrine concentration (4,222 +/- 373 vs. 7,548 +/- 1,058 pg/ml, p < 0.01). These results suggest that metformin-induced improvement of insulin resistance in obese rats with NIDDM may lower blood pressure, as well as decrease sympathetic activity and reduce body weight.
Aging↗
Differentiation of photoreceptors, glia, and neurons in the retina of the cichlid fish Aequidens pulcher; an immunocytochemical study.
Light-microscopic immunocytochemistry was carried out to investigate the developmental dynamics of several neurochemical markers in the retina of blue acara (Aequidens pulcher). As a rule, double-label experiments were performed in order to determine the absolute and relative timing of the appearance of these markers. The diameter of eye-ball (from 0.6 to 1.2 mm) and the body length (from 4.6 to 9.4 mm) enlarged in parallel during the observation period of 2 to 9 days after spawning (day 2-9); hatching took place usually on day 2. Immunoreactive proliferating cell nuclear antigen (ir-PCNA) was present in all neuroblasts (the embryonic homogeneous cell stage; day 1.0-2.0), but was lost progressively in a center-to-periphery and apparent proximal-to-distal sequence as the cells and layers differentiated. In late larvae and juveniles, ir-PCNA was confined to a ring of dividing neuroblasts at the retinal margin and to a population of scattered rod precursors in the outer nuclear layer. Immunoreactive structures of representative antigens progressively appeared after ir-PCNA had decayed. Around hatching, at the synaptic separation stage (day 2.0-2.5), luteinizing hormone-releasing hormone-ir centrifugal fibers, visinin-ir cones, glial fibrillary acidic protein-ir structures and gamma-aminobutyric acid-ir cell bodies appeared, which were followed by the emergence of rhodopsin-ir rods and tyrosine hydroxylase-ir interplexiform cells (on day 2.5-3.0) and serotonin-, neuropeptide Y- and substance P-ir amacrine cells (on day 3.0-4.0). The results indicate that photoreceptor cells, and especially rods start to differentiate at an earlier stage of retinogenesis than has previously been proposed. In addition, an extraretinal tissue in the brain identified as the prospective pineal organ was found to be visinin- and rhodopsin-immunoreactive on day 1.5-2.0 before these photoreceptor-specific antigens became positive in the retina.
Animals↗
Effect of troglitazone (CS-045) and bezafibrate on glucose tolerance, liver glycogen synthase activity, and beta-oxidation in fructose-fed rats.
To clarify the relationship between lipid and glucose metabolism abnormalities in fructose-fed rats, we examined whether an improvement of insulin sensitivity by troglitazone (CS-045) or a decrease in plasma lipids by bezafibrate affects the relationship between serum levels of lipid and glucose. In addition, we also examined changes in liver glycogen metabolism and beta-oxidation in fructose-fed rats. Troglitazone ameliorated fasting hyperlipidemia, hyperglycemia, and hyperinsulinemia. In addition, it augmented glycogen synthase activity by 53%, and decreased the mitochondrial palmitic acid beta-oxidation rate and ketone body production rate by 27% and 55%, respectively. However, hyperglycemia and liver glycogen synthase activity were not improved by bezafibrate treatment despite a marked reduction of serum triglyceride (TG) levels resulting from a 1.76-fold increase in mitochondrial oxidation and a 2.04-fold increase in hepatic ketone body production. These results suggest that abnormalities in glucose and lipid metabolism in fructose-fed rats, which are ameliorated by troglitazone, may be closely linked to reduced glycogen synthase activity in the liver.
Animals↗
Spectra of superoxide-induced mutations in the lacI gene of a wild-type and a mutM strain of Escherichia coli K-12.
We have analyzed the spectra of superoxide-induced mutations in the chromosomal lacI gene of a wild-type and a mutM strain of Escherichia coli K-12. The mutM strain is known to be deficient in removing 8-hydroxyguanine from DNA. An intracellular superoxide-generating agent, menadione, was used to cause the mutation. Analysis of the mutated DNA showed marked differences between the mutants from the wild type and those from the mutM strain. In the mutants from the wild type, all possible base-pair substitutions were present and their proportions were similar to each other, whereas in those from the mutM bacteria there was a 90% bias in favor of transversion. Furthermore, in the mutM strain GC-to-CG transversion rather than GC-to-TA was predominantly induced. 64% of the GC-to-CG transversions in the mutM strain occurred at the site of (CT/GC)GGC (mutated base underlined). The favorable mutation site, CTGGC, was the same as that of the UV- and sunlight-induced mutations previously reported: the mutations observed there were also G-to-C transversions. We speculate from these results that the superoxide in the cells may lead to production of a modified guanine that can pair with guanine and is subject to removal by the MutM protein.
Base Sequence↗
Patterns of rod proliferation in deep-sea fish retinae.
In a sample of 37 species of deep-sea fish species from the sea floor of the Porcupine Seabight and the Gobal spur (North Atlantic) we investigated the overall structure of the retina with special respect for the organization of rods, their length and their arrangement in multiple banks. Using an immunocytochemical marker for cell proliferation (PCNA) we studied the mechanisms of rod proliferation, and, by means of serial section reconstruction followed their integration into the existing population of rods. Furthermore, in three different species we have observed growth related changes in retinal thickness, rod density and proliferation activity. We found evidence for two different principles for the organization of rods in these deep-sea fish retinae. In the first group of species represented by Nematonurus armatus and Coryphaenoides guentheri we found rods to be rather short (20-30 microns) and arranged in three and more banks. In these species rod proliferation occurred in a single band of cells immediately vitread of the external limiting membrane, thus showing a high degree of spatial and temporal order. In these species, young rods are inserted just sclerad of the external limiting membrane and the older outer segments pushed away from the incoming light towards the back of the eye. This may be linked to a progressive loss of function of the older rods and might represent an alternative mechanism to the disk shedding in other vertebrates. In the second population (e.g. Conocara macroptera, Alepocephalus agassizii) we observed considerably longer rod outer segments (60-80 microns) forming no more than two layers. These retinae had rod precursors arranged in disseminated clusters throughout the outer nuclear layer indicating the lack of clear spatio-temporal order in mitotic activity along with a more statistical pattern of integration of the newly formed outer segments. In our sample of species both populations were of about equal size suggesting that the two mechanisms are equally effective and may have arisen independently.
Animals↗
Induction of DNA recombination by activated 3-amino-1-methyl-5H-pyrido[4,3-b]indole.
To investigate the genotoxic properties of a food-derived carcinogen, 3-amino-1-methyl-5H-pyrido-[4,3-b]indole (Trp-P-2), we have tested whether Trp-P-2 and its metabolically transformed products can induce DNA recombinations. Trp-P-2 is a strong mutagen and its activated form, the N-hydroxylated derivative, Trp-P-2(NHOH), is known to form DNA adducts and cause DNA chain cleavage. Using a system in which phage lambda undergoes recombination inside host Escherichia coli, we have found that Trp-P-2(NHOH), but not Trp-P-2 itself, can induce recombination. A nitroso derivative of Trp-P-2, Trp-P-2(NO), which can be reduced intracellularly to form Trp-P-2(NHOH), also induced recombination. Active oxygens are implicated in this recombinogenic action, since Trp-P-2(NHOH) is known to undergo spontaneous oxidative degradation, generating active oxygen radicals which can cause DNA chain cleavages. 4-Hydroxyaminoquinoline N-oxide and phenyl-hydroxylamine also showed recombinogenic actions in this assay system; hence, it is suspected that aromatic amine-type carcinogens have this property in common.
Bacteriophage lambda↗
[Mechanisms of nucleoside-analog mutagenesis].
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Base Sequence↗
Growth factors influence contractility and alpha-smooth muscle actin expression in bovine lens epithelial cells.
PURPOSE: To determine whether basic fibroblast growth factor (bFGF) and transforming growth factor-beta 2 (TGF-beta 2) influence the contractile activity and the expression of alpha-smooth muscle actin (alpha-SMA) in bovine lens epithelial cells (LECs). To examine whether modulation of contractile activity by these growth factors depends on changes of alpha-SMA expression. METHODS: Bovine LECs were cultured in collagen gel in MED 5 medium (F-12 nutrient mixture supplemented with 5% fetal bovine serum) with or without bFGF (1 to 100 ng/ml) or TGF-beta 2 (0.01 to 10 ng/ml). To evaluate collagen gel contraction, the longest and shortest diameters of the gels were measured daily for 7 days, and the area was determined. Detection of alpha-SMA in the gels was performed immunohistochemically using a mouse monoclonal antibody against alpha-SMA. The percentage of alpha-SMA-positive cells to the total number of cells was determined. RESULTS: Control gels cultured with MED 5 medium alone contracted to 15.8% +/- 3.4% of their original area after 7 days. TGF-beta 2 significantly increased this contraction in a dose-dependent manner, whereas bFGF significantly decreased it. Approximately 30% of cells in the control gels were alpha-SMA positive. TGF-beta 2 significantly increased the alpha-SMA positivity dose dependently, whereas bFGF significantly decreased it. The percent positivity for alpha-SMA and the gel area showed a significant negative correlation. CONCLUSIONS: TGF-beta 2 increased collagen gel contraction and alpha-SMA expression in bovine LECs, whereas bFGF decreased these parameters. Because collagen gel contraction was correlated with alpha-SMA expression, the modulation of LEC contractile activity by growth factors may be related to an effect on alpha-SMA.
Actins↗
[Intermittent mini-dose vancomycin intravenous administration and closed continuous irrigation technique applied to mediastinitis caused by MRSA following mitral valve replacement].
Mediastinitis caused by MRSA (Methicillin-Resistant Staphylococcus aureus) remains an intractable infection producing high mortality even in these days of advanced chemotherapy. The authors report a case of mediastinitis due to MRSA complicated with acute renal failure following mitral valve replacement. The patient's mediastinum had been thoroughly cleaned with physiological saline solution with 0.2% povidone iodine, and underwent a chemotherapy regimen of mini-dose vancomycin. The patient made favorable progress and recovered completely. Our patient's progress confirmed that when chemotherapy using vancomycin is administered in a patient whose condition is complicated with acute renal failure, closely monitoring the vancomycin serum concentration is essential. Intermittent mini-dose intravenous administration is sufficient to maintain an effective vancomycin serum concentration. In our case, vancomycin serum concentration measured before and at completion of dialysis revealed no appreciable decline.
Acute Kidney Injury↗