Inhibition of Recombinant Human Acetylcholinesterase Activity by Antipsychotics

Pharmacology ◽  
2019 ◽  
Vol 104 (1-2) ◽  
pp. 43-50 ◽  
Author(s):  
Keisuke Obara ◽  
Ayano Fujii ◽  
Chiaki Arie ◽  
Natsuki Harada ◽  
Fumiko Yamaki ◽  
...  
Keyword(s):  
Acetylcholinesterase Activity ◽  
Suppressive Effect ◽  
Blood Levels ◽  
Dependent Manner ◽  
Ache Inhibition ◽  
Inhibitory Effects ◽  
Concentration Dependent Manner ◽  
Nitrobenzoic Acid ◽  
Cholinergic Effects

Background/Aims: Extrapyramidal symptoms (EPS) are representative side effects of antipsychotics, caused by their inhibitory action on dopaminergic nerves in nigrostriatal pathways. EPS could be also caused by direct augmentation of cholinergic effects, for example, by acetylcholinesterase (AChE) inhibition. We investigated the potential inhibitory effects of 26 clinically available antipsychotics on the activity of recombinant human AChE (rhAChE) to predict the role of antipsychotic-induced AChE inhibition in EPS onset. Method: The degree of rhAChE activity inhibition was calculated using the 5,5′-dithio-bis-(2-nitrobenzoic acid) method. Results: At a concentration of 10–5 mol/L, haloperidol, bromperidol, timiperone, nemonapride, pimozide, risperidone, blonanserin, aripiprazole, and brexpiprazole inhibited rhAChE activity by >20%. Risperidone, aripiprazole, and brexpiprazole inhibited rhAChE activity in a concentration-dependent manner, and their effects were more potent than those of other antipsychotics. The inhibitory effects of these 3 drugs were evident from 10–6 mol/L, and their pIC50 values were 4.74 ± 0.04, 4.80 ± 0.04, and 4.93 ± 0.06, respectively. Notably, the concentration range in which aripiprazole inhibited rhAChE activity (≥10–6 mol/L) overlapped with its clinically achievable blood levels. Conclusion: Aripiprazole may cause EPS at clinical dosages by augmenting cholinergic effects via AChE inhibition, in addition to its suppressive effect on dopaminergic neurons.

The P-element-induced silencing effect of KP transposons is dose dependent in Drosophila melanogaster

Genome ◽  
2011 ◽  
Vol 54 (9) ◽  
pp. 752-762 ◽  
Author(s):  
Alireza Sameny ◽  
John Locke
Keyword(s):  
Drosophila Melanogaster ◽  
Critical Role ◽  
Mutagenic Effect ◽  
P Element ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
P Elements ◽  
Single Well ◽  
Dose Dependent

Transposable elements are found in the genomes of all eukaryotes and play a critical role in altering gene expression and genome organization. In Drosophila melanogaster, transposable P elements are responsible for the phenomenon of hybrid dysgenesis. KP elements, a deletion-derivative of the complete P element, can suppress this mutagenic effect. KP elements can also silence the expression of certain other P-element-mediated transgenes in a process called P-element-dependent silencing (PDS), which is thought to involve the recruitment of heterochromatin proteins. To explore the mechanism of this silencing, we have mobilized KP elements to create a series of strains that contain single, well-defined KP insertions that show PDS. To understand the quantitative role of KP elements in PDS, these single inserts were combined in a series of crosses to obtain genotypes with zero, one, or two KP elements, from which we could examine the effect of KP gene dose. The extent of PDS in these genotypes was shown to be dose dependent in a logarithmic rather than linear fashion. A logarithmic dose dependency is consistent with the KP products interacting with heterochromatic proteins in a concentration-dependent manner such that two molecules are needed to induce gene silencing.

Protein kinase C potentiates cAMP-stimulated mouse duodenal mucosal bicarbonate secretion in vitro

2004 ◽  
Vol 286 (5) ◽  
pp. G814-G821 ◽  
Author(s):  
Bi-Guang Tuo ◽  
Jimmy Y. C. Chow ◽  
Kim E. Barrett ◽  
Jon I. Isenberg
Keyword(s):  
Short Circuit ◽  
Short Circuit Current ◽  
Duodenal Mucosa ◽  
Bicarbonate Secretion ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Ussing Chambers ◽  
Duodenal Bicarbonate Secretion

PKC has been shown to regulate epithelial Cl- secretion in a variety of models. However, the role of PKC in duodenal mucosal bicarbonate secretion is less clear. We aimed to investigate the role of PKC in regulation of duodenal mucosal bicarbonate secretion. Bicarbonate secretion by murine duodenal mucosa was examined in vitro in Ussing chambers using a pH-stat technique. PKC isoform expression and activity were assessed by Western blotting and in vitro kinase assays, respectively. PMA (an activator of PKC) alone had no effect on duodenal bicarbonate secretion or short-circuit current ( Isc). When PMA and dibutyryl-cAMP (db-cAMP) were added simultaneously, PMA failed to alter db-cAMP-stimulated duodenal bicarbonate secretion or Isc ( P > 0.05). However, a 1-h preincubation with PMA potentiated db-cAMP-stimulated duodenal bicarbonate secretion and Isc in a concentration-dependent manner (from 10-8 to 10-5M) ( P < 0.05). PMA preincubation had no effects on carbachol- or heat-stable toxin-stimulated bicarbonate secretion. Western blot analysis revealed that PKCα, -γ, -ϵ, -θ, -μ, and -ι/λ were expressed in murine duodenal mucosa. Ro 31–8220 (an inhibitor active against PKCϵ, -α, -β, and -γ), but not Gö 6983 (an inhibitor active against PKCα, -γ, -β, and -δ), reversed the potentiating effect of PMA on db-cAMP-stimulated bicarbonate secretion. PMA also time- and concentration-dependently increased the activity of PKCϵ, an effect that was prevented by Ro 31–8220 but not Gö 6983. These results demonstrate that activation of PKC potentiates cAMP-stimulated duodenal bicarbonate secretion, whereas it does not modify basal secretion. The effect of PKC on cAMP-stimulated bicarbonate secretion is mediated by the PKCϵ isoform.

scholarly journals Sec1p directly stimulates SNARE-mediated membrane fusion in vitro

2004 ◽  
Vol 167 (1) ◽  
pp. 75-85 ◽  
Author(s):  
Brenton L. Scott ◽  
Jeffrey S. Van Komen ◽  
Hassan Irshad ◽  
Song Liu ◽  
Kirilee A. Wilson ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Membrane Fusion ◽  
Membrane Trafficking ◽  
Snare Complex ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Bud Neck ◽  
Precise Role

Sec1 proteins are critical players in membrane trafficking, yet their precise role remains unknown. We have examined the role of Sec1p in the regulation of post-Golgi secretion in Saccharomyces cerevisiae. Indirect immunofluorescence shows that endogenous Sec1p is found primarily at the bud neck in newly budded cells and in patches broadly distributed within the plasma membrane in unbudded cells. Recombinant Sec1p binds strongly to the t-SNARE complex (Sso1p/Sec9c) as well as to the fully assembled ternary SNARE complex (Sso1p/Sec9c;Snc2p), but also binds weakly to free Sso1p. We used recombinant Sec1p to test Sec1p function using a well-characterized SNARE-mediated membrane fusion assay. The addition of Sec1p to a traditional in vitro fusion assay moderately stimulates fusion; however, when Sec1p is allowed to bind to SNAREs before reconstitution, significantly more Sec1p binding is detected and fusion is stimulated in a concentration-dependent manner. These data strongly argue that Sec1p directly stimulates SNARE-mediated membrane fusion.

scholarly journals Role of some types of serotonin receptors in murine hypophyseal-testicular complex activation induced by the presence of a female

2003 ◽  
Vol 49 (6) ◽  
pp. 53-56
Author(s):  
T. G. Amstislavskaya ◽  
N. K. Popova
Keyword(s):  
Serotonin Receptors ◽  
Receptor Agonist ◽  
Serotonin Receptor ◽  
Receptive Female ◽  
Plasma Testosterone ◽  
Blood Levels ◽  
Inhibitory Effects ◽  
Sexual Activation ◽  
Different Types

Placement of a sexually receptive female mouse behind a partition that prevents physical contacts, but permits it to see and smell caused an increase in the blood levels of testosterone in male mice. The selective 5-HTIA-serotonin receptor agonist 08-OH- DPAT (0.1 mg/kg) and the mixed 5-HTIA/IB agonist eltoprazine, 3.0 and 10.0 mg/kg, blocked the activating effect of female exposure on the male pituitary-testicular system. The 5-HT/-receptor agonist p-MPPI (0.2 mg/kg) prevented the inhibitory effects of 8-OH-DPATand eltoprazine. The 5-HT/B-receptor agonist CGS- 12066A (1.0 and 2.0 mg/kg) exerted no effect while the mixed 5-HTIB/2C-receptor agonist TFMPP (5.2 mg/kg) inhibited a female-induced increase in the levels of male blood testosterone. The 5-HT/-receptor agonist keranserin (1.0 and 2.0 mg/kg) prevented a female-induced increase in the levels of testosterone. The 5-HT3-receptor agonist ondansetron (0.05 and 0.1 mg/kg) elevated the baseline level of plasma testosterone, but blocked receptive female-induced activation of the male hypothalamic-pituitary-testicular system (HPTS). It is concluded that 5-HTIA-receptors are involved in the control of male sexual activation. At the same time different types and even subtypes of the same type of 5-HT-receptors produce varying inhibitory and activating effects on the receptive female-induced activation of HPTS. Blocking of the female-induced activation of HPTS seems to be realized by involving 5-HTu- and 5-HT2C-receptors and its activation occurs with the participation of 5-HT^- and 5- HT3-receptors.

scholarly journals Effect of Palmitic Acid on Exosome-Mediated Secretion and Invasive Motility in Prostate Cancer Cells

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2722
Author(s):  
Ivan V. Maly ◽  
Wilma A. Hofmann
Keyword(s):  
Prostate Cancer ◽  
Palmitic Acid ◽  
Cancer Cells ◽  
Dependent Manner ◽  
Prostate Cancer Cells ◽  
Concentration Dependent Manner ◽  
Fat Consumption ◽  
Progression Markers

High fat consumption can enhance metastasis and decrease survival in prostate cancer, but the picture remains incomplete on the epidemiological and cell-biological level, impeding progress toward individualized recommendations in the clinic. Recent work has highlighted the role of exosomes secreted by prostate cancer cells in the progression of the disease, particularly in metastatic invasion, and also the utility of targeting these extracellular vesicles for diagnostics, as carriers of disease progression markers. Here, we investigated the question of a potential impact of the chief nutritional saturated fatty acid on the exosome secretion. Palmitic acid decreased the secretion of exosomes in human prostate cancer cells in vitro in a concentration-dependent manner. At the same time, the content of some prospective metastatic markers in the secreted exosomal fraction was also reduced, as was the ability of the cells to invade across extracellular matrix barriers. While by themselves our in vitro results imply that on the cell level, palmitic acid may be beneficial vis-à-vis the course of the disease, they also suggest that, by virtue of the decreased biomarker secretion, palmitic acid has the potential to cause unjustified deprioritization of treatment in obese and lipidemic men.

The Role Of Calcium In Platelet Microtubule Assembly- Disassembly

1981 ◽  
Author(s):  
M Kikuchi ◽  
Y Ikeda ◽  
M Handa ◽  
S Matsuda ◽  
H Muraki ◽  
...  
Keyword(s):  
Intracellular Calcium ◽  
Dynamic Equilibrium ◽  
Platelet Rich Plasma ◽  
Human Platelets ◽  
Microtubule Assembly ◽  
Base Line ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Transient Decrease

Microtubules exist in a dynamic equilibrium between polymerized and depolymerized forms in human platelets, playing a major role to maintain the discoid shape of platelets. It has been previously shown that the interaction of aggregating agents with platelets leads to a rapid but transient disassembly of microtubules. ( Steiner and Ikeda, J.Clin. Invest. 63:443,1979 ) In this paper, the role of calcium in the equilibrium between assembled and disassembled microtubules was investigated. The respective pools of soluble and polymerized tubulin were “frozen” by addition of a glycerol-dimethyl sulfoxide-containing medium to platelet rich plasma, preincubated with 2 µM A23187 for various time intervals. The two pools of tubulin were estimated by measuring the colchicine binding activities of total and polymerized tubulin according to the method of Wilson.Resting platelets were found to contain 56.2 ± 2.7 µg tubulin per 109 platelets, of which 56.7 % was in polymerized form. Addition of A23187 to platelet rich plasma produced a transient decrease in the pool of polymerized tubulin within 30 sec., followed by a return to base-line values within 2 min.. TMB-8, a known intracellular calcium antagonist, abolished this transient decrease in polymerized tubulin induced by A23187 in a concentration dependent manner, while indomethacin or acetylsalycylic acid did not.These findings may indicate the important role of intracellular calcium in microtubule assembly-disassembly.

Oxidation of ubiquinol by peroxynitrite: implications for protection of mitochondria against nitrosative damage

2000 ◽  
Vol 349 (1) ◽  
pp. 35-42 ◽  
Author(s):  
Francisco SCHÖPFER ◽  
Natalia RIOBÓ ◽  
María Cecilia CARRERAS ◽  
Beatriz ALVAREZ ◽  
Rafael RADI ◽  
...  
Keyword(s):  
Radical Scavenging ◽  
Redox Status ◽  
Experimental Models ◽  
Dependent Manner ◽  
Mitochondrial Membranes ◽  
Concentration Dependent Manner ◽  
Major Pathway ◽  
Membrane Bound ◽  
Spectroscopy Studies

A major pathway of nitric oxide utilization in mitochondria is its conversion to peroxynitrite, a species involved in biomolecule damage via oxidation, hydroxylation and nitration reactions. In the present study the potential role of mitochondrial ubiquinol in protecting against peroxynitrite-mediated damage is examined and the requirements of the mitochondrial redox status that support this function of ubiquinol are established. (1) Absorption and EPR spectroscopy studies revealed that the reactions involved in the ubiquinol/peroxynitrite interaction were first-order in peroxynitrite and zero-order in ubiquinol, in agreement with the rate-limiting formation of a reactive intermediate formed during the isomerization of peroxynitrite to nitrate. Ubiquinol oxidation occurred in one-electron transfer steps as indicated by the formation of ubisemiquinone. (2) Peroxynitrite promoted, in a concentration-dependent manner, the formation of superoxide anion by mitochondrial membranes. (3) Ubiquinol protected against peroxynitrite-mediated nitration of tyrosine residues in albumin and mitochondrial membranes, as suggested by experimental models, entailing either addition of ubiquinol or expansion of the mitochondrial ubiquinol pool caused by selective inhibitors of complexes III and IV. (4) Increase in membrane-bound ubiquinol partially prevented the loss of mitochondrial respiratory function induced by peroxynitrite. These findings are analysed in terms of the redox transitions of ubiquinone linked to both nitrogen-centred radical scavenging and oxygen-centred radical production. It may be concluded that the reaction of mitochondrial ubiquinol with peroxynitrite is part of a complex regulatory mechanism with implications for mitochondrial function and integrity.

scholarly journals Twenty Traditional Algerian Plants Used in Diabetes Therapy as Strong Inhibitors of α-Amylase Activity

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Ihcen Khacheba ◽  
Amar Djeridane ◽  
Mohamed Yousfi
Keyword(s):  
Amylase Activity ◽  
Aluminium Chloride ◽  
Total Phenolic ◽  
Dependent Manner ◽  
Inhibitory Effects ◽  
Concentration Dependent Manner ◽  
Diabetes Therapy ◽  
Methanolic Extracts ◽  
Phenolic Extract ◽  
Gallic Acid Equivalent

In the present work, we have studied the inhibitory effects of aqueous and alcoholic extracts of six Algerian medicinal plants known by their therapeutic virtues against diabetes. The total phenolic compounds content, assayed using Folin-Ciocalteu’s reagent, of the samples ranged from 0.183 mg/g to 43.088 mg/g and from 1.197 mg/g to 7.445 mg/g, expressed as gallic acid equivalent (GAE), for the, respectively, whereas the total flavonoids concentrations, detected using 2% of the aluminium chloride, ranged from 0.41 mg/g to 11.613 mg/g and from 0.0097 mg/g to 1.591 mg/g, expressed as rutin equivalents (RE), for the aqueous and methanolic extracts, respectively. The major plants were found to inhibit enzymatic activities of Aspergillus oryzae-amylase in a concentration dependent manner. The values of the inhibition constants (Ki) have been determined according to the Dixon and Lineweaver-Burk methods. The results showed that the Ki values were less than 55 ppm for the all extracts. A strong inhibition was found in the phenolic extract of Salvia officinalis with a Ki of 8 ppm.

Comparative Effects of Bupivacaine and Ropivacaine on Intracellular Calcium Transients and Tension in Ferret Ventricular Muscle

2004 ◽  
Vol 101 (4) ◽  
pp. 888-894 ◽  
Author(s):  
Yasushi Mio ◽  
Norio Fukuda ◽  
Yoichiro Kusakari ◽  
Yoshikiyo Amaki ◽  
Yasumasa Tanifuji ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Bay K 8644 ◽  
Clinical Settings ◽  
Ca Channel ◽  
Dependent Manner ◽  
Inhibitory Effects ◽  
Concentration Dependent Manner ◽  
Intracellular Ca ◽  
Slope Difference ◽  
The Relationship

Background Recent evidence suggests that ropivacaine exerts markedly less cardiotoxicity compared with bupivacaine; however, the mechanisms are not fully understood at the molecular level. Methods Isolated ferret ventricular papillary muscles were microinjected with the Ca-binding photoprotein aequorin, and intracellular Ca transients and tension were simultaneously measured during twitch in the absence and presence of bupivacaine or ropivacaine. Results Bupivacaine and ropivacaine (10, 30, and 100 microm) reduced peak systolic [Ca]i and tension in a concentration-dependent manner. The effects were significantly greater for bupivacaine, particularly on tension (approximately twofold). The percentage reduction of tension was linearly correlated with that of [Ca]i for both anesthetics, with the slope of the relationship being approximately equal to 1.0 for ropivacaine and approximately equal to 1.3 for bupivacaine (slope difference, P &lt; 0.05), suggesting that the cardiodepressant effect of ropivacaine results predominantly from inhibition of Ca transients, whereas bupivacaine suppresses Ca transients and the reaction beyond Ca transients, i.e., myofibrillar activation, as well. BAY K 8644, a Ca channel opener, abolished the inhibitory effects of ropivacaine on Ca transients and tension, whereas BAY K 8644 only partially inhibited the effects of bupivacaine, particularly the effects on tension. Conclusion The cardiodepressant effect of bupivacaine is approximately twofold greater than that of ropivacaine. Bupivacaine suppresses Ca transients more markedly than does ropivacaine and reduces myofibrillar activation, which may at least in part underlie the greater inhibitory effect of bupivacaine on cardiac contractions. These results suggest that ropivacaine has a more favorable profile as a local anesthetic in the clinical settings.

scholarly journals Mucin inhibitsPseudomonas aeruginosabiofilm formation by significantly enhancing twitching motility

2014 ◽  
Vol 60 (3) ◽  
pp. 155-166 ◽  
Author(s):  
Cecily L. Haley ◽  
Cassandra Kruczek ◽  
Uzma Qaisar ◽  
Jane A. Colmer-Hamood ◽  
Abdul N. Hamood
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Type Iv Pili ◽  
Dependent Manner ◽  
Twitching Motility ◽  
Strain Pao1 ◽  
Concentration Dependent Manner ◽  
Dependent Effect ◽  
Type Iv ◽  
Biofilm Development

In Pseudomonas aeruginosa, type IV pili (TFP)-dependent twitching motility is required for development of surface-attached biofilm (SABF), yet excessive twitching motility is detrimental once SABF is established. In this study, we show that mucin significantly enhanced twitching motility and decreased SABF formation in strain PAO1 and other P. aeruginosa strains in a concentration-dependent manner. Mucin also disrupted partially established SABF. Our analyses revealed that mucin increased the amount of surface pilin and enhanced transcription of the pilin structural gene pilA. Mucin failed to enhance twitching motility in P. aeruginosa mutants defective in genes within the pilin biogenesis operons pilGHI/pilJK-chpA-E. Furthermore, mucin did not enhance twitching motility nor reduce biofilm development by chelating iron. We also examined the role of the virulence factor regulator Vfr in the effect of mucin. In the presence or absence of mucin, PAOΔvfr produced a significantly reduced SABF. However, mucin partially complemented the twitching motility defect of PAOΔvfr. These results suggest that mucin interferes with SABF formation at specific concentrations by enhancing TFP synthesis and twitching motility, that this effect, which is iron-independent, requires functional Vfr, and only part of the Vfr-dependent effect of mucin on SABF development occurs through twitching motility.

Sign in / Sign up

Export Citation Format

Share Document