Triazene metabolism. II Transportability and enzyme inhibitory characteristics of metabolites of antitumor dimethyltriazenes

1981 ◽  
Vol 59 (12) ◽  
pp. 1239-1244 ◽  
Author(s):  
James R. P. Godin ◽  
Gerard Llanos ◽  
Keith Vaughan ◽  
Kenneth W. Renton
Keyword(s):  
Enzyme Activity ◽  
Enzyme Inhibition ◽  
Absorption Maximum ◽  
Ester Group ◽  
Significant Inhibition ◽  
Inhibitory Effects ◽  
Reversible Inhibition ◽  
Liver Esterase ◽  
Rate Of Hydrolysis

A series of dimethyltriazenes (Ar∙N=N∙NMe2), monomethyltriazenes (Ar∙N=N∙NH∙Me), and triazene carbinolamines (Ar∙N=N∙NMe∙CH2OH) have been studied for their inhibitory effects on the enzyme, hog liver esterase (EC 3.1.1.1). p-Nitrophenyl acetate was used as the model substrate and the rate of hydrolysis was followed spectrophotometrically at 400 nm, the absorption maximum of the p-nitrophenylate ion. Only triazenes with an ester group in the aryl moiety exhibited significant inhibition. Preincubation of the enzyme with the monomethyltriazene (MeO2C∙C6H4∙N=N∙NHMe) or the methyloltriazene (MeO2C∙C6H4∙N=N∙NMe∙CH2OH) gave enhanced inhibition, which was not observed when the dimethyltriazene (MeO2C∙C6H4∙N=N∙NMe2) was preincubated with the enzyme. Inhibition of enzyme activity by the monomethyltriazene was shown to be essentially irreversible, whereas the model substrates, methyl benzoate and methyl p-aminobenzoate, gave reversible inhibition in the same assay. The inhibition by the N-methyloltriazene was only partially reversible. The results are discussed with relevance to the role of the monomethyltriazenes and N-methyloltriazenes as possible transportable metabolites of the antitumour dimethyltriazenes.

Inhibition of gastric and pancreatic secretion in dogs by CGRP: role of somatostatin

1989 ◽  
Vol 256 (4) ◽  
pp. G715-G720 ◽  
Author(s):  
W. S. Helton ◽  
M. M. Mulholland ◽  
N. W. Bunnett ◽  
H. T. Debas
Keyword(s):  
Gastric Acid ◽  
Pancreatic Secretion ◽  
Inhibitory Action ◽  
Potential Role ◽  
Significant Inhibition ◽  
Inhibitory Effects ◽  
Exocrine Secretions ◽  
Calcitonin Gene ◽  
Somatostatin 14

The coexistence of calcitonin gene-related peptide (CGRP) and somatostatin (SS) within the stomach and pancreas and the potent inhibitory effects of both peptides on exocrine secretions from these organs suggest that they are functionally related. To assess the potential role of SS in the mediation of CGRP action, the effects of intravenous human CGRP (64, 132, and 264 pmol.kg-1.h-1) and somatostatin-14 (SS-14; 100, 400, and 800 pmol.kg-1.h-1) on plasma levels of SS immunoreactivity (SS-IR) and on pentagastrin-stimulated gastric and pancreatic secretion were compared in conscious dogs. CGRP caused significant inhibition of gastric acid (85-102%), pancreatic protein (63-86%), and pancreatic bicarbonate (74-89%) outputs and a simultaneous dose-related rise (40-102 fmol/ml) in plasma SS-IR. Cessation of CGRP infusion resulted in prompt return of plasma SS-IR to basal levels and an increase in gastric and pancreatic secretion. Although CGRP is a potent releasor of SS into the circulation, its inhibitory action on gastric acid secretion cannot be explained solely by a rise in plasma SS-IR. In the pancreas, in contrast to the stomach, inhibition appears to be more closely related to a rise in circulating level of SS-IR.

scholarly journals An MDM2 inhibitor achieves synergistic cytotoxic effects with adenoviruses lacking E1B55kDa gene on mesothelioma with the wild-type p53 through augmenting NFI expression

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Thao Thi Thanh Nguyen ◽  
Masato Shingyoji ◽  
Michiko Hanazono ◽  
Boya Zhong ◽  
Takao Morinaga ◽  
...  
Keyword(s):  
Wild Type ◽  
Inhibitory Effects ◽  
Cytotoxic Effects ◽  
P53 Expression ◽  
Nuclear Factor I ◽  
Infected Cells ◽  
Wild Type P53 ◽  
Mdm2 Inhibitor ◽  
P16 Expression

AbstractA majority of mesothelioma specimens were defective of p14 and p16 expression due to deletion of the INK4A/ARF region, and the p53 pathway was consequently inactivated by elevated MDM2 functions which facilitated p53 degradaton. We investigated a role of p53 elevation by MDM2 inhibitors, nutlin-3a and RG7112, in cytotoxicity of replication-competent adenoviruses (Ad) lacking the p53-binding E1B55kDa gene (Ad-delE1B). We found that a growth inhibition by p53-activating Ad-delE1B was irrelevant to p53 expression in the infected cells, but combination of Ad-delE1B and the MDM2 inhibitor produced synergistic inhibitory effects on mesothelioma with the wild-type but not mutated p53 genotype. The combination augmented p53 phosphorylation, activated apoptotic but not autophagic pathway, and enhanced DNA damage signals through ATM-Chk2 phosphorylation. The MDM2 inhibitors facilitated production of the Ad progenies through augmented expression of nuclear factor I (NFI), one of the transcriptional factors involved in Ad replications. Knocking down of p53 with siRNA did not increase the progeny production or the NFI expression. We also demonstrated anti-tumor effects by the combination of Ad-delE1B and the MDM2 inhibitors in an orthotopic animal model. These data collectively indicated that upregulation of wild-type p53 expression contributed to cytotoxicity by E1B55kDa-defective replicative Ad through NFI induction and suggested that replication-competent Ad together with augmented p53 levels was a therapeutic strategy for p53 wild-type mesothelioma.

scholarly journals Seed Gamma Irradiation of Arabidopsis thaliana ABA-Mutant Lines Alters Germination and Does Not Inhibit the Photosynthetic Efficiency of Juvenile Plants

Dose-Response ◽  
2020 ◽  
Vol 18 (4) ◽  
pp. 155932582097924
Author(s):  
Darya Babina ◽  
Marina Podobed ◽  
Ekaterina Bondarenko ◽  
Elizaveta Kazakova ◽  
Sofia Bitarishvili ◽  
...  
Keyword(s):  
Arabidopsis Thaliana ◽  
Growth Response ◽  
Dose Range ◽  
Fine Tuning ◽  
Plant Tolerance ◽  
Inhibitory Effects ◽  
Γ Irradiation ◽  
Photosynthetic Responses ◽  
Mutant Lines

Plant growth response to γ-irradiation includes stimulating or inhibitory effects depending on plant species, dose applied, stage of ontogeny and other factors. Previous studies showed that responses to irradiation could depend on ABA accumulation and signaling. To elucidate the role of ABA in growth and photosynthetic responses to irradiation, lines Col-8, abi3-8 and aba3 -1 of Arabidopsis thaliana were used. Seeds were γ-irradiated using 60Co in the dose range 50-150 Gy. It was revealed that the dose of 150 Gy affected germination parameters of aba3 -1 and Col-8 lines, while abi3-8 line was the most resistant to the studied doses and even showed faster germination at early hours after γ-irradiation at 50 Gy. These results suggest that susceptibility to ABA is probably more important for growth response to γ-irradiation than ABA synthesis. The photosynthetic functioning of 16-day-old plants mainly was not disturbed by γ-irradiation of seeds, and no indication of photosystem II photoinhibition was noticed, revealing the robustness of the photosynthetic system of A. thaliana. Glutathione peroxidase activity and ABA concentrations in plant tissues were not affected in the studied dose range. These results contribute to the understanding of germination and photosynthesis fine-tuning and of mechanisms of plant tolerance to ionizing radiation.

The zona incerta modulates spontaneous spike-wave discharges in the rat

2013 ◽  
Vol 109 (10) ◽  
pp. 2505-2516 ◽  
Author(s):  
Fu-Zen Shaw ◽  
Yi-Fang Liao ◽  
Ruei-Feng Chen ◽  
Yu-Hsing Huang ◽  
Rick C. S. Lin
Keyword(s):  
Functional Role ◽  
Significant Inhibition ◽  
Zona Incerta ◽  
Obvious Effect ◽  
Spike Wave Discharges ◽  
Long Evans ◽  
Oscillation Frequencies ◽  
Spike Wave ◽  
Stimulation Of

The contribution of the zona incerta (ZI) of the thalamus on spike-wave discharges (SWDs) was investigated. Chronic recordings of bilateral cortices, bilateral vibrissa muscle, and unilateral ZI were performed in Long-Evans rats to examine the functional role of SWDs. Rhythmic ZI activity appeared at the beginning of SWD and was accompanied by higher-oscillation frequencies and larger spike magnitudes. Bilateral lidocaine injections into the mystacial pads led to a decreased oscillation frequency of SWDs, but the phenomenon of ZI-related spike magnitude enhancement was preserved. Moreover, 800-Hz ZI microstimulation terminates most of the SWDs and whisker twitching (WT; >80%). In contrast, 200-Hz ZI microstimulation selectively stops WTs but not SWDs. Stimulation of the thalamic ventroposteriomedial nucleus showed no obvious effect on terminating SWDs. A unilateral ZI lesion resulted in a significant reduction of 7- to 12-Hz power of both the ipsilateral cortical and contralateral vibrissae muscle activities during SWDs. Intraincertal microinfusion of muscimol showed a significant inhibition on SWDs. Our present data suggest that the ZI actively modulates the SWD magnitude and WT behavior.

scholarly journals Amphetamine-Decreased Progesterone and Estradiol Release in Rat Granulosa Cells: The Regulatory Role of cAMP- and Ca2+-Mediated Signaling Pathways

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 493
Author(s):  
 Chung-Yu Chen ◽  
Chien-Rung Chen ◽  
Chiao-Nan Chen ◽  
Paulus S. Wang ◽  
Toby Mündel ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Prostaglandin F2α ◽  
Inhibitory Effect ◽  
Inhibitory Effects ◽  
Steroidogenic Enzyme ◽  
Estradiol Secretion ◽  
Basal Release ◽  
Ca2 Channels

The purpose of this study is to evaluate the amphetamine effects on progesterone and estradiol production in rat granulosa cells and the underlying cellular regulatory mechanisms. Freshly dispersed rat granulosa cells were cultured with various test drugs in the presence of amphetamine, and the estradiol/progesterone production and the cytosolic cAMP level were measured. Additionally, the cytosolic-free Ca2+ concentrations ([Ca2+]i) were measured to examine the role of Ca2+ influx in the presence of amphetamine. Amphetamine in vitro inhibited both basal and porcine follicle-stimulating hormone-stimulated estradiol/progesterone release, and amphetamine significantly decreased steroidogenic enzyme activities. Adding 8-Bromo-cAMP did not recover the inhibitory effects of amphetamine on progesterone and estradiol release. H89 significantly decreased progesterone and estradiol basal release but failed to enhance a further amphetamine inhibitory effect. Amphetamine was capable of further suppressing the release of estradiol release under the presence of nifedipine. Pretreatment with the amphetamine for 2 h decreased the basal [Ca2+]i and prostaglandin F2α-stimulated increase of [Ca2+]i. Amphetamine inhibits progesterone and estradiol secretion in rat granulosa cells through a mechanism involving decreased PKA-downstream steroidogenic enzyme activity and L-type Ca2+ channels. Our current findings show that it is necessary to study the possibility of amphetamine perturbing reproduction in females.

A possible role of arginase in the regulation of polyamine biosynthesis in the rat thyroid

1981 ◽  
Vol 98 (1) ◽  
pp. 57-61 ◽  
Author(s):  
Shigeru Matsuzaki ◽  
Mitsuo Suzuki ◽  
Koei Hamana
Keyword(s):  
Amino Acids ◽  
Enzyme Activity ◽  
Arginase Activity ◽  
Polyamine Biosynthesis ◽  
Rat Thyroid ◽  
Arginine Concentration

Abstract. Effect of chronic methylthiouracil (MTU) treatment on the thyroid arginase activity and thyroidal concentration of arginine, ornithine and other amino acids was studied in the rat. The activity of thyroid arginase increased significantly at 15 days of MTU treatment and the elevated enzyme activity was reduced to normal by l-thyroxine (T4) injection. The thyroidal concentration of polyamines was increased by MTU and decreased by T4 with the exception of spermine. The thyroidal concentration of arginine and lysine, a substrate and an inhibitor for arginase respectively decreased significantly, while that of ornithine remained unchanged after MTU treatment. T4 injected to MTU-pretreated rats restored the decreased arginine concentration to normal. These results suggest that ornithine supply for polyamine biosynthesis is regulated by the level of both arginase and lysine in the thyroid.

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