Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Presentation of drugs most worthy of interest in autumn 1995. Among these, the ACE inhibitors, the HMGCOA inhibitors, the Proton Pump inhibitors, the serotoninergics used against depression and migraine, the endobronchial corticoids and finally the ASA. Review of their successes, failures and uncertainties.
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PMID:[Leading drugs in 1995: success, failures and uncertainties]. 748 Dec 49

Escherichia coli 30 S ribosomal subunits undergo a reversible change under low monovalent or divalent cation concentration and become inactive in tRNA binding and 50 S subunit association. In the inactive form, 16 S rRNA base-pairs (921-922).(1395-1396) and (923-925).(1391-1393), which are part of region 28, are unstable and an alternate arrangement, (921-923).(1532-1534), is detected by psoralen photochemical crosslinking. Site-directed mutagenesis has been used to investigate whether changes in base-paired region 28 or the alternate secondary structure is responsible for the inactivity of the subunit. 30 S subunits with the substitution C1533A or with deletion of nucleotides 1534 to 1542 can still be inactivated like the wild-type 30 S subunit. On the other hand, 30 S subunits that contain sequence changes in the 920 to 926 region show moderate to severe decreases in tRNA binding even under activating conditions. When 30 S subunits containing these mutations were subjected to chemical probing, they failed to show the normal hyper-reactivity of nucleotide G926 and, instead, reactivity was shifted to G925 or to G928, and G929. Two mutations in the 920 region result in structures in which A1394 is base-paired rather than being unpaired as normal; deletion but not substitution of A1394 resulted in loss of tRNA binding activity and depression of the reactivity of G926. Mutations were made to insert or delete a nucleotide at position 920. The deletion mutant but not the insertion mutant has decreased tRNA binding activity and also low reactivity of G926. We conclude that structural changes in region 28 account for the active/inactive difference in tRNA binding. Molecular models of region 28 were made using the program MC-SYM. Models that include a hydrogen bond interaction between A1394 and G1392 account for the G926 reactivity in the wild-type sequence and account for the effects of most of the mutations in changing the G926 reactivity.
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PMID:Structural changes in base-paired region 28 in 16 S rRNA close to the decoding region of the 30 S ribosomal subunit are correlated to changes in tRNA binding. 754 48

The effects of hydrogen cyanide (HCN) on the neural mechanisms controlling breathing were studied. Two in vitro experimental models were utilized; the brain stem-spinal cord and the medullary slice preparations isolated from neonatal rats. Cyanide, at concentrations deemed lethal in vivo (50 microM), caused a modest (< 15%) depression of the frequency and amplitude of inspiratory rhythmic discharge when added to the bathing media. Moreover, the neuronal network underlying respiratory rhythmogenesis continued to function for hours in the presence of very high concentrations of cyanide (600 microM). We hypothesize that the rapid suppression of breathing caused by cyanide in vivo is due to changes in neuronal excitability in respiratory modulating populations in the CNS rather than due to perturbations of cellular oxidative metabolism or neurons within respiratory rhythm generating centres.
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PMID:Effects of cyanide on the neural mechanisms controlling breathing in the neonatal rat in vitro. 756 81

The present study was undertaken to investigate the role of endogenous hydrogen peroxide (H2O2) in cardiac depression and cytotoxicity during hemorrhagic shock and reinfusion. To achieve this objective, the changes in the cardiac function and contractility, plasma creatine kinase (CK) and CK-MB activity and lactate concentration, oxyradical-producing activity of polymorphonuclear leukocytes (PMNL-CL), and cardiac malondialdehyde (MDA) concentration in anesthetized dogs were determined before and during shock and reinfusion in the presence of absence of catalase (a metabolizer of H2O2). The dogs were divided into three groups randomly. Group I: sham, four hour duration; group II: two hours of shock followed by two hours of reinfusion; group III: same as group II but pretreated with catalase. Hemorrhage shock was produced in the dogs by lowering the mean arterial pressure to 50 +/- 5 mm Hg by bleeding into standard blood bank bags containing 63 mL of citrate, phosphate, dextrose, and adenine (CPDA) anticoagulant for 450 mL of blood. The shock was maintained for two hours by bleeding or reinfusing the shed blood as needed. Cardiac function and contractility were depressed while plasma CK, CK-MB, and lactate increased during shock. Reinfusion after two hours of shock tended to return hemodynamic parameters and plasma lactate levels toward control values. Plasma CK and CK-MB and PMNL-CL increased further. Cardiac MDA content also increased after shock and reinfusion, suggesting oxidative damage. Pretreatment with catalase attenuated the deleterious effects of shock and reinfusion on the cardiovascular function and contractility, and the rise in plasma CK, CK-MB, and lactate, PMNL-CL, and cardiac MDA. However, the protection with catalase was not complete. These results suggest that hydrogen peroxide (H2O2) may partly be involved in the deterioration of cardiovascular function and cellular injury during hemorrhagic shock and reinfusion.
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PMID:Beneficial effects of antioxidants in hemorrhagic shock. 772 48

Considerable phospholipase D (PLD) activity is localized in myocardial sarcoplasmic reticular (SR) membranes, where it may take part in the regulation of Ca2+ movements. In this study, we examined thiol group dependence as a possible regulatory mechanism for SR PLD. SR membranes isolated from rat heart were exposed to four types of thiol group modifiers, which all induced a decrease in SR PLD activity that was prevented by dithiothreitol. Furthermore, since abnormalities in thiol status and Ca2+ homeostasis are characteristic for the myocardial cell damage induced by oxidative stress, we also studied the effects of oxidants on the SR PLD activity. The enzyme was not affected by xanthine-xanthine oxidase, but was depressed by hydrogen peroxide and by hypochlorous acid. These inhibitory effects were prevented by catalase as well as by methionine and dithiothreitol, respectively. Furthermore, reduced glutathione protected against the hydrogen peroxide-induced depression, whereas oxidized glutathione inhibited SR PLD. The results indicate that SR PLD activity is inhibited by nonradical oxidants, hydrogen peroxide and hypochlorous acid, through reversible modification of associated thiol groups. Thus, the enzyme may be controlled by the glutathione redox status of the cardiac cell.
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PMID:Involvement of thiol groups in the impairment of cardiac sarcoplasmic reticular phospholipase D activity by oxidants. 778 Jun 80

The toxicity of aminoglycosides is related to their concentrative uptake by proximal tubular cells and their capacity to interact with critical intracellular targets. Concentrative uptake is mediated by adsorptive endocytosis across the apical membrane followed by sequestration within lysosomes. The fundamental mechanism underlying the toxicity of these organic polycations is their capacity to interact electrostatically with and disrupt the metabolism of anionic phospholipids, especially the phosphoinositides. Polyaspartic acid, a polyanionic peptide, protects against aminoglycoside nephrotoxicity by forming electrostatic complexes with these drugs and inhibiting their interaction with critical intracellular targets. The selective toxicity of beta-lactams towards renal proximal tubular cells is related to their concentrative uptake via the organic anion transport system. Lipid peroxidation appears to play a major role in the toxicity of cephaloridine. Depressed mitochondrial respiration secondary to acylation of the mitochondrial transporter for succinate has been implicated in the pathogenesis of toxicity caused by other cephalosporins and carbapenems. The predilection of the kidney for amphotericin B toxicity is unclear as little drug is excreted by the kidneys. Toxicity is manifested by increased renal vascular resistance, depression of RBF and GFR, and altered tubular function that reflects the capacity of this drug to interact with cholesterol-containing membranes and increase membrane permeability to ions including potassium, hydrogen, calcium, and magnesium.
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PMID:Antibiotic-related nephrotoxicity. 780 Feb 46

A previously reported depression of glutamate responses by angiotensin II was investigated to define the nature of this neuromodulatory effect. Studies were carried out in an vitro brain slice preparation containing the locus coeruleus, using intracellular recordings, and iontophoretic, micropressure and bath perfusion methods for application of drugs. The angiotensin action was found to be blocked by a non-peptide antagonist specific for the angiotensin type 2 receptor, and not by an antagonist selective for the type 1 receptor. Excitatory postsynaptic potentials mediated primarily by excitatory amino acids were also depressed by angiotensin II. The angiotensin II depressions of glutamate were shown to be strong and highly specific. The low effectiveness of bath-applied compared with iontophoretically or micropressure-applied angiotensin II was found to be at least partly explained by a rapid degradation by peptidases. Ammonium ions and hydrogen ions were also able to depress glutamate responses, but these effects were not specific for locus coeruleus neurons and were mediated independently of the angiotensin actions. Strong depression by angiotensin II of excitatory postsynaptic potentials as well as exogenously applied glutamate strengthens the strong possibility of a physiological role for this neuromodulatory mechanism. The identification of the type 2 angiotensin receptor subtype as the mediator of this effect indicates a novel functional role for this receptor, since previously recognized functions of angiotensin II in the brain, such as vascular and body fluid regulation, have been associated with the type 1 receptor.
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PMID:Angiotensin II depresses glutamate depolarizations and excitatory postsynaptic potentials in locus coeruleus through angiotensin II subtype 2 receptors. 781 98

The effect of high concentrations of proline on the diffusion coefficient of water has been examined to assess the extent to which the resulting thermodynamic nonideality could be explained on the statistical-mechanical basis of excluded volume. In fact, such a space-filling role not only accounts for the proline concentration-dependence of the diffusion coefficient of water but it also accounts for the nonideality of proline in freezing point depression and isopiestic measurements. These findings refute the conclusion (Schobert, B. and Tschesche, H. (1978) Biochim. Biophys. Acta 541, 270-277) that the stabilization of enzyme structure by high concentrations of proline stems from self-association of the imino acid via intermolecular hydrogen bonding; and thereby support the concept that the protective effect of proline on enzyme stability must reside mainly in its action as an inert, space-filling solute.
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PMID:Elimination of self-association as the source of the thermodynamic nonideality in aqueous proline solutions. 791 80

Ultraviolet thermal denaturation studies substantiate our earlier hypothesis that substitution of a L-nucleotide residue for a D-nucleotide within a DNA duplex permits a stable structure in which all bases are paired through Watson-Crick hydrogen bonds (Damha, M. J., Giannaris, P. A., Marfey, P., & Reid, L. S. (1991) Tetrahedron Lett. 32, 2573-2576). This conclusion is also evident from the NMR work of Blommers et al. [Blommers, M. J. J., et al. (1994) Biochemistry (following paper in this issue)]. Our thermal denaturation studies indicate that, while weakening the interaction with target DNA and RNA, these substitutions allow for excellent cooperative binding. When the target is single-stranded DNA, the melting temperature of the complex is lowered by 4-5 degrees C per L-dU incorporation and by 0.4-2.6 degrees C when an internal D-dC is replaced by L-dC (1 M NaCl). When the target is RNA, the depression of Tm is also greater for L-dU substitutions (5-8 degrees C) than for L-dC substitutions (2-4 degrees C). The depressions of Tm caused by introducing A/C and G/T mismatches at the same positions were significantly greater. L/D-DNA chimeras were found to activate RNase H cleavage when hybridized to RNA. Furthermore, the stability of chimeric L/D-DNA against degradation by various commercial phosphodiesterases was found to be significant, as was their stability against digestion in human serum. These experiments establish that L/D-DNA chimeras serve as excellent models of antisense oligonucleotides.
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PMID:Antisense L/D-oligodeoxynucleotide chimeras: nuclease stability, base-pairing properties, and activity at directing ribonuclease H. 801 50

The noncompetitive N-methyl-D-aspartate antagonist (5R,10S)-(+)-5-methyl- 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801) and three dopamine agonists [(+/-)6-chloro-7,8-dihydroxy-2,3,4,5-tetrahydro-1-phenyl-1H-3-benzazepin e hydrobromide (SKF-81297), (+/-)6,chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5- tetrahydro-1H-3-benzazepine hydrobromide (SKF-82958) selective for D1 and (-)-2-[N-propyl-N-(2-thienyl)ethyl-amino-5- hydroxytetralin] hydrochloride (N-0923) selective for D2 receptors] were studied in seven adult female hemiparkinsonian Macaca nemestrina monkeys. Video recordings of free circling behavior showed that both SKF-82958 and N-0923 produced dose-related mean increases in contraversive rotations during the 120-min period after i.m. injection. SKF-81297 (21.1, 67.8 and 210.7 micrograms/kg) was relatively inactive compared to SKF-82958 (24.8, 74.8 and 234 micrograms/kg). The selective D2 agonist N-0923 (3.2, 10 and 32 micrograms/kg, i.m.) was the most potent in producing contraversive circling behavior. The noncompetitive N-methyl-D-aspartate antagonist dizocilpine (MK-801), in doses of 10 and 32 micrograms/kg i.m., produced a very slight increase in contraversive circling in contrast to the selective dopamine agonist SKF-82958. A large dose (100 micrograms/kg, i.m.) of MK-801 produced marked central nervous system depression. In combination with the dopamine agonists N-0923 and SKF-82958, MK-801 depressed contraversive circling in all doses studied. This study using hemiparkinsonian monkeys does not support the suggestion that a noncompetitive N-methyl-D-aspartate antagonist such as MK-801 would be useful in adjunctive therapy of human Parkinson's disease.
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PMID:N-methyl-D-aspartate receptor antagonist and dopamine D1 and D2 agonist interactions in 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine-induced hemiparkinsonian monkeys. 809 26


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