Incipient cholinesterase inhibition in volunteers ingesting monocrotophos or mevinphos for one month

Monocrotophos or mevinphos were administered daily for 1 month to groups of six and eight male subjects. Monocrotophos, 3.6 μg/kg, lowered plasma ChE by 15%, and 5.7 μg/kg lowered it by 24%. Compared with other organophosphorus pesticides studied in a similar experimental design, it appeared to be the most effective plasma ChE-inhibiting pesticide. It had no effect on red blood cell ChE. Mevinphos, 25 μg/kg, lowered plasma ChE by 13% and red blood cell ChE by 19%.     

Tissue cholinesterase inhibition by propranolol and related drugs

The effect of (+/-)-propranolol and some related drugs have been investigated on the cholinesterase (ChE) enzyme activity of heart and brain tissues of the rat. Brain homogenates hydrolysed more methacholine than benzoylcholine and the reverse was true for the heart tissue. In-vitro, (+/-)-, (+)- and (-)-propranolol, as well as its quaternary analogue, UM-272, all significantly inhibited heart and brain ChE. Timolol and sotalol, however, were less potent. In-vivo, (+/-)-propranolol (30 mumol kg-1) significantly inhibited brain ChE activity in rats when compared with saline controls. It is inferred that propranolol inhibits brain and heart ChE enzyme in a non-stereoselective manner and that this cholinomimetic action could be involved in the mediation of some of its therapeutic effects.     

Serum cholinesterase inhibition by omeprazole and lansoprazole

Omeprazole inhibited human and rat serum cholinesterase by approximately 5 to 60% over the 0.5 to 50 mg/L (1.4-140 microM) concentration range. In contrast lansoprazole only produced 20-30% inhibition at the highest concentration of 10 mg/L (29 microM). Thus omeprazole but not lansoprazole is likely to potentiate the effect of succinylcholine at human clinical concentrations by inhibiting its hydrolysis in vivo by serum cholinesterases.     

Regeneration of cholinesterase activities in humans and rats after inhibition by O,O-dimethyl-2,2-dichlorovinyl phosphate.

By applying rate constants determined in vitro for spontaneous reactivation and aging of O,O-dimethyl-2,2-dichlorovinyl phosphate (DDVP)-inhibited cholinesterases to enzyme activities measured in vivo after inhibition by DDVP, we evaluated whether regeneration in vivo is due to spontaneous reactivation of the inhibited enzyme or whether it must be attributed to enzyme synthesis. Regeneration in vivo of rat brain and plasma cholinesterase activities can be entirely attributed to spontaneous reactivation of the inhibited enzymes, with half-times of 2 and 2.5 hr for the brain and plasma enzyme, respectively. Regeneration in vivo of human erythrocyte and plasma cholinesterase activities is much slower than that predicted from spontaneous reactivation. It was therefore attributed to enzyme synthesis; the calculated half-times for the synthesis of erythrocyte and plasma cholinesterase are 15 and 6.7 days, respectively.     

Finding cholinesterase in endotheliocytes: cholinesterase inhibition by organophosphorus compounds leads to endotheliocyte deformation

Toxic action of some organophosphorus cholinesterase inhibitors (including phosphacol) on the state of microvessels was studied in rats. Cholinesterase was found in endotheliocytes and it was established that phosphacol inhibited this enzyme. This was one of the factors responsible for deformation of the luminal relief of the vessels and for violation of the blood microcirculation. The expression of these effects was different for various organophosphorus compounds.     

石杉碱类似物在体外对胆碱酯酶的抑制作用(英文)

用比色法测试表明,14个半合成类似物的抗AChE作用均弱于Hup-A,左旋二氢及四氢类似物的抗BuChE作用稍强于Hup-A,前者属混合型抑制剂,K_i值为0.12μmol·L~(-1)。后者属竞争型抑制剂,K_i值为0.56μmol·L~(-1)。二者不同于异氟磷,与AChE为可逆性结合。     

Stereoselectivity of cholinesterase inhibition by galanthamine and tolerance in humans

Summary The effect of galanthamine (GAL) and its 2 major metabolites on human cholinesterases has been explored. Epigalanthamine, a diastereomer of GAL, was 130-times less potent in vitro in its effect on acetylcholinesterase (AChE) in erythrocytes than the parent compound, and it did not differ significantly from the ketone galanthaminone. In vivo, the maximal 36–55% inhibition of AChE was approached 30 min after oral administration of 10 mg GAL. The duration of the catalytic inhibition corresponded to an elimination half-life of approximately 5–7 h. GAL was well tolerated in 8/8 healthy volunteers, and 3/4 Alzheimer patients tolerated the drug up to a daily dose of 40 mg.     

The characteristics of the inhibition of serum cholinesterase by metoclopramide

The inhibition of serum cholinesterase by metoclopramide has been previously characterised in vitro at high dilution of the enzyme. We examined the effect of varying enzyme dilution over a range of 1000 fold dilution, and assay temperature at 25°C and 37°C on the fractional inhibition of enzyme activity by metoclopramide. Neither enzyme concentration nor reaction temperature affected this fractional inhibition. Concentrations of metoclopramide producing 50% inhibition of enzyme activity were in the range 1.0–1.9×10^–6 M. Lineweaver-Burk analysis of the enzyme reaction suggests that the pattern of this inhibition is competitive.     

TASK1 (K(2P)3.1) K(+) channel inhibition by endothelin-1 is mediated through Rho kinase-dependent phosphorylation

BACKGROUND AND PURPOSE

TASK1 (K_2P3.1) two-pore-domain K⁺ channels contribute substantially to the resting membrane potential in human pulmonary artery smooth muscle cells (hPASMC), modulating vascular tone and diameter. The endothelin-1 (ET-1) pathway mediates vasoconstriction and is an established target of pulmonary arterial hypertension (PAH) therapy. ET-1-mediated inhibition of TASK1 currents in hPASMC is implicated in the pathophysiology of PAH. This study was designed to elucidate molecular mechanisms underlying inhibition of TASK1 channels by ET-1.

EXPERIMENTAL APPROACH

Two-electrode voltage clamp and whole-cell patch clamp electrophysiology was used to record TASK1 currents from hPASMC and Xenopus oocytes.

KEY RESULTS

ET-1 inhibited TASK1-mediated I_KN currents in hPASMC, an effect attenuated by Rho kinase inhibition with Y-27632. In Xenopus oocytes, TASK1 current reduction by ET-1 was mediated by endothelin receptors ET_A (IC₅₀= 0.08 nM) and ET_B (IC₅₀= 0.23 nM) via Rho kinase signalling. TASK1 channels contain two putative Rho kinase phosphorylation sites, Ser³³⁶ and Ser³⁹³. Mutation of Ser³⁹³ rendered TASK1 channels insensitive to ET_A- or ET_B-mediated current inhibition. In contrast, removal of Ser³³⁶ selectively attenuated ET_A-dependent TASK1 regulation without affecting the ET_B pathway.

CONCLUSIONS AND IMPLICATIONS

ET-1 regulated vascular TASK1 currents through ET_A and ET_B receptors mediated by downstream activation of Rho kinase and direct channel phosphorylation. The Rho kinase pathway in PASMC may provide a more specific therapeutic target in pulmonary arterial hypertension treatment.     

Ellagic acid prevents rat colon carcinogenesis induced by 1, 2 dimethyl hydrazine through inhibition of AKT-phosphoinositide-3 kinase pathway

Colon cancer is the third most malignant neoplasm in the world and chemoprevention through dietary intervention is an emerging option to reduce its mortality. Ellagic acid (EA) a major component of berries possesses attractive biological deeds. This study is aimed to investigate the effect of ellagic acid in fostering apoptosis in 1,2-dimethyl hydrazine (DMH) mediated experimental colon carcinogenesis model. Wistar male rats were segregated into four groups: group I-control rats, group II-rats received ellagic acid (60 mg/kg body weight p.o. every day), rats in group III-induced with DMH (20 mg/kg body weight, s.c.) for 15 weeks, DMH-induced group IV rats were initiated with ellagic acid treatment. The present study is designed to explore the significance of phosphoinositide-3-kinase (PI3K)/Akt molecular pathway as well as ellagic acid's chemopreventive effect in colon cancer. DMH-induced rats exhibited elevated expressions of PI3K and Akt as confirmed by immunofluorescence, immunoblot and confocal microscopic analysis. Mechanistically, ellagic acid was found to prevent PI3K/Akt activation that in turn, results in modulation of its downstream Bcl-2 family proteins. Bax expression and caspase-3 activation was noted after ellagic acid supplementation leading to elevation of cytochrome c (cyt c) levels and finally cell death. These observations were supported by the DNA fragmentation results, which showed the occurrence of apoptosis. This study reveals the involvement of PI3K-Akt signaling through which ellagic acid induces apoptosis and subsequently suppresses colon cancer during DMH-induced rat colon carcinogenesis. In conclusion, our findings demonstrate that ellagic acid begets apoptosis in DMH-induced colon carcinoma.     

Selective inhibition of 2 -adrenergic receptors by 1-(2,4-dimethylanilino)-3-isopropylamino-2-propanol

1-(2,4-Dimethylanilino)-3-isopropylamino-2-propanol (RB₂) was synthesized and evaluated for its selective β₂-receptor blocking property. RB₂ was found to antagonize selectively vasodepressor β₂-response.of isoprenaline without affecting the cardio accelerator β₂-response. As an antagonist of β₂-receptor, RB₂ was found to be equipotent to 1-(4′-nitrophenyl)-2-isopropylaminoethanol (INPEA), used as a standard β-receptor antagonist for comparison.     

Growth inhibition and induction of G(1) phase cell cycle arrest in neuroblastoma SH-SY5Y cell by tri-ortho-cresyl phosphate

It has been known that tri-ortho-cresyl phosphate (TOCP) can induce delayed neurotoxicity in humans and sensitive animal species; however, it also has influence on the developing central nervous system or differentiating neuronal cells. In this study, the effects of TOCP on cell proliferation and cell cycle regulation and the mechanisms that contribute to this effect were investigated by using human neuroblastoma SH-SY5Y cell line. Treatment of the cells with TOCP suppressed cell proliferation and reduced cell viability in a dose- and time-dependent manner. Analysis of cell cycle profile indicated that TOCP blocked cell cycle progression by arresting the cell cycle at G(1) phase. The data of determination of cell cycle regulated molecules at mRNA and protein levels showed that TOCP decreased cyclin D1 and increased p21 expression, while did not affect the p53 and p27 levels. Thus, these results indicated that TOCP might induce potential neurodevelopmental toxicity, and a possible mechanism of this toxicity might be the disturbance of cell proliferation by disrupting cell cycle regulatory proteins cyclin D1 and p21 expression.     

Differential inhibition of cyclooxygenase-1 (COX-1) and-2 (COX-2) by NSAIDS: Consequences on anti-inflammatory activity versus gastric and renal safety

The discovery of an inducible isoform of cyclooxygenase (COX-2) requires a refinement of the theory that inhibition of cyclooxygenase activity is responsible for both therapeutic and side-effects of nonsteroidal anti-inflammatory drugs (NSAIDs). Pharmacological results with developmental compounds suggest that COX-2 is the relevant target for the therapeutic (i.e. anti-inflammatory) effects of NSAIDs, whereas gastric and renal side-effects are related to inhibition of constitutive COX-1. However a role of COX-1 in inflammation cannot be excluded. Furthermore, more research effort is needed to investigate the functional relevance of COX-2 in normal tissue.     

Synthesis of 2-, 4- and 5-(2-alkylcarbamoyl-1-methylvinyl)-7-alkyloxybenzo[b]furans and their leukotriene B4 receptor antagonistic activity

Variable 7-carboxylpropoxy or (1-phenyl)ethoxybenzo[b]furan derivatives with (E)- and (Z)-2-alkylcarbamoyl-1-methylvinyl groups at the 2-, 4-, and 5-positions were prepared to find novel and selective leukotriene B(4) (LTB(4)) receptor antagonists. (E)-2-(2-Diethylcarbamoyl-1-methylvinyl)-7-(1-phenylethoxy)benzo[b]furan (4v) showed selective inhibition of the human BLT(2) receptor (hBLT(2)). On the other hand, (E)-2-acetyl-4-(2-diethylcarbamoyl-1-methylvinyl)-7-(1-phenylethoxy)benzo[b]furan (7c) inhibited both human BLT(1) receptor (hBLT(1)) and hBLT(2). The (E)-2-(2-diethylcarbamoyl-1-methylvinyl) group lay on approximately the same plane as the benzo[b]furan ring, whereas the (E)-4-(2-diethylcarbamoyl-1-methylvinyl) group had a torsion angle (45.7 degrees ) from the benzo[b]furan ring plane. However, the (Z)-(2-alkylcarbamoyl-1-methylvinyl)benzo[b]furans were inactive. The inhibitory activity depended on the conformation of the 2-alkylcarbamoyl-1-methylvinyl groups.