Antiulcerogenic and antisecretory effects of a novel diphenylmethane derivative and antiestrogen binding site ligand

1988 ◽  
Vol 66 (8) ◽  
pp. 1139-1143 ◽  
Author(s):  
Gary B. Glavin ◽  
Lorne J. Brandes
Keyword(s):  
Binding Site ◽  
Gastric Acid ◽  
Stress Ulcer ◽  
Acid Output ◽  
Corticosterone Level ◽  
Plasma Corticosterone ◽  
Gastric Ulcers ◽  
Ulcer Formation

N,N-Diethyl-2-[4-(phenylmethyl)-phenoxy]-ethanamine hydrochloride (DPPE) is a para-diphenylmethane derivative that binds selectively and with high affinity to the microsomal antiestrogen binding site (AEBS). Recent studies with DPPE indicate that AEBS is closely related to a lower affinity non-H1, non-H2 histamine site that may be associated with calcium channels; the DPPE–AEBS site is different from that which verapamil binds, however. DPPE, but not verapamil, demonstrates antiproliferative effects in vitro and is antiestrogenic in vivo. We now show that DPPE profoundly inhibits restraint and cold stress and ethanol-induced gastric ulcer formation, accelerates ulcer healing, attenuates the stress-induced rise in plasma corticosterone level, and significantly reduces basal and H2 agonist (dimaprit)-stimulated and, to a lesser extent, bethanechol-stimulated gastric acid output in conscious rats. A nonulcerogenic but prostaglandin-depleting dose of indomethacin completely blocks the inhibitory effects of DPPE on stress ulcer formation. Conversely, verapamil only slightly attenuates dimaprit-stimulated gastric acid secretion and exacerbates ethanol-induced gastric ulcers; its anti-stress ulcer effects are only partially attenuated by indomethacin. These findings support the likelihood that the site of action of DPPE is different from that of verapamil, and that an effect on prostaglandins may, at least in part, contribute to its antiulcer and apparent cytoprotective effects.

Relationship between maternal milk PGE2 and gastric acid secretion in newborn rats

1990 ◽  
Vol 259 (5) ◽  
pp. G702-G708
Author(s):  
A. Wirbel ◽  
R. Ducroc ◽  
B. Garzon ◽  
C. Merlet-Benichou ◽  
J. P. Geloso
Keyword(s):  
Acid Secretion ◽  
Gastric Acid Secretion ◽  
Gastric Acid ◽  
Acid Output ◽  
Sesame Oil ◽  
Newborn Rats ◽  
Maternal Milk ◽  
Infant Rats

We previously demonstrated that in rats gastric acid secretion declines after birth and drops steeply on day 12 of life. In the present study, we investigated the part played in this decline by prostaglandin E2 (PGE2) from maternal milk. PGE2 content was first measured in the milk of untreated dams 0, 1, 5, 10, 12, 15, and 18 days after parturition. PGE2 levels were high during the first 5 days (123.5-200.5 pg/ml), declined significantly between days 10 and 15 (56.6-85.4 pg/ml; P less than 0.05), and dropped to 18.4 pg/ml on day 18. We also found that depleting milk of PGE2 prevented drop of acid secretion in 12-day-old suckling rats. Injecting lactating dams with indomethacin significantly reduced milk PGE2 content by 65% vs. milk of untreated dams. Surprisingly, administration of sesame oil, the indomethacin vehicle to the dams, increased milk PGE2 content by 182%. In the pups of the indomethacin-treated dams, acid secretion did not drop. On the contrary, in vivo basal and histamine-induced acid output rose markedly by 40 and 50%, respectively, and in vitro the net movements of 36Cl and 22Na measured in the isolated stomach indicated that active Cl- secretion had resumed. Mucosal PGE2 did not appear to be significantly involved in early development of acid secretion because administration of indomethacin to pups from untreated dams did not significantly modify the secretion measured on day 12. Data indicate that maternal milk depletion of PGE2 prevents the drop of gastric acid secretion previously observed in 12-day-old pups and suggest that in infant rats maternal PGE2 plays a physiological part in regulating acid secretion.

Changes in characteristics of rat adrenal glomerulosa cells under acute and chronic treatment with ACTH

1983 ◽  
Vol 61 (7) ◽  
pp. 538-546 ◽  
Author(s):  
François Legros ◽  
Jean-Guy Lehoux
Keyword(s):  
Corticosterone Level ◽  
Plasma Corticosterone ◽  
High Plasma ◽  
Zona Glomerulosa ◽  
Cell Suspensions ◽  
Duration Of Treatment ◽  
Glomerulosa Cells ◽  
Cessation Of Treatment

Groups of Long Evans rats were treated with 15 IU ACTH/day for 1–9 days and sacrificed at different intervals during and after treatment. Aldosterone and corticosterone plasma levels were increased above control values for the entire duration of treatment and were decreased to control values as early as 3 days posttreatment. The uptake of [125I]angiotensin II ([125I]AII) by adrenocortical glomerulosa cell suspensions was diminished by 71% at day 9 of treatment and this [125I]AII-uptake capacity slowly returned to control values after cessation of treatment (66.0% of control at day +19). The association constants at equilibrium (Ka) for AII receptors were similar in both treated (0.19 × 109 M−1 at day 9) and control (0.12 × 109 M−1) rats, whereas the number of AII-binding sites was lowered in the glomerulosa cells of treated (Nmax = 6 fmol/50 000 cells) compared with control (29 fmol) animals. In vitro cell suspensions from treated rats had, compared with controls, a lowered basal aldosterone and an increased corticosterone output. Addition of ACTH (10−8 M) to these cell suspensions showed no effect on the aldosterone or corticosterone output, whereas a significant stimulation was observed for cells obtained from control animals. Studies on rats treated 9 days and sacrificed 19 days after cessation of treatment demonstrated that the basal aldosterone and corticosterone output from zona glomerulosa cell suspensions was comparable with that of control rats; the steroid output of these cells could be further stimulated in vitro by addition of ACTH. It is concluded that the chronic ACTH treatment produced (i) a loss of AII receptor of adrenal zona glomerulosa cells, a phenomenon that was reversible 3–4 weeks posttreatment; (ii) a decreased capacity of glomerulosa cells to further respond to ACTH stimuli in vitro, suggesting either a loss of ACTH receptor by these cells or a decrease in activity of enzymes responsible for steroidogenesis, or a lack of endogenous precursor; (iii) a diminution of the thickness of the zona glomerulosa accompanied by an enlargement of the zonae fasciculate–reticularis, resulting in high circulating plasma corticosterone. This high plasma corticosterone level might well be the source of the precursor used in vivo by the zona glomerulosa to maintain the observed high plasma aldosterone level, despite the lowered overall steroidogenic capacities of these cells demonstrated by our in vitro studies.

Tonic suppression of gastric acid secretion by endogenous peptides in neonatal rats

1995 ◽  
Vol 269 (5) ◽  
pp. G721-G728
Author(s):  
R. K. Rao ◽  
S. Pepperl ◽  
F. Porreca
Keyword(s):  
Acid Secretion ◽  
Gastric Acid Secretion ◽  
Gastric Acid ◽  
Acid Output ◽  
Neonatal Rats ◽  
In Vitro Techniques ◽  
Basal Acid ◽  
Old Rats

Stimulation of gastric acid secretion by secretagogues was measured in developing rats by in vivo and in vitro techniques. Basal acid outputs in vivo were very low in 8- and 14-day-old rats compared with those in 20- and 30-day-old rats. In 20-day-old rats, all secretagogues increased acid output in vivo, whereas only carbachol, pentagastrin, and sulfated cholecystokinin octapeptide (CCK-8S) were active in 14-day-old rats. In contrast, basal acid output in vitro and stimulation by secretagogues did not differ significantly with age. CCK-8S-stimulated acid output in vitro in 14-day-old rats was blocked by L-365,260, L-364,718, tetrodotoxin, and atropine, but not by hexamethonium, whereas gastrin-stimulated acid output was blocked only by L-365,260. Furthermore, acid output in vivo was elevated three- to fourfold by subcutaneous naloxone-methiodide or L-364,718, but not by L-365,260, in 14-day-old rats; none of these antagonists produced an effect in 20-day-old rats. These studies show that low basal gastric acid output in neonatal rats is caused by tonic inhibitory regulation by endogenous regulatory peptides.

PITUITARY AND ADRENAL RESPONSIVENESS IN RATS AFTER PROLONGED TREATMENT WITH ACTH

1963 ◽  
Vol 41 (1) ◽  
pp. 1771-1777
Author(s):  
E. Stark ◽  
J. Fachet ◽  
Katherine Mihály
Keyword(s):  
Prolonged Exposure ◽  
Corticosterone Level ◽  
Plasma Corticosterone ◽  
Prolonged Treatment ◽  
Plasma Corticosterone Level ◽  
Operative Trauma ◽  
Corticosterone Secretion ◽  
Adrenal Corticosterone

Prolonged exposure to ACTH considerably increased adrenal responsiveness in the rat both in vivo and in vitro. The last of 5 and 14 daily injections each produced a significantly higher blood corticosterone level than did a single injection. In the presence of ACTH added in vitro, adrenal corticosterone production in animals subjected to prolonged treatment with ACTH significantly exceeded the production per unit of weight and unit of time measured in saline-treated animals. Reduced adrenal responsiveness in the stage of resistance, elicited by formalin as a non-specific stress, cannot be invoked as an explanation for the absence of an increase in corticosterone secretion. The conclusion is that after prolonged exposure to non-specific stress there is no longer any ACTH hypersecretion.Twenty-four hours after the last injection of prolonged ACTH treatment there was inhibition of endogenous ACTH release by the pituitary gland, formalin produced no rise in the corticosterone level of the peripheral blood, and operative trauma caused substantially less ascorbic acid depletion than it did in saline-treated controls, although the plasma corticosterone level was normal or below normal.

PITUITARY AND ADRENAL RESPONSIVENESS IN RATS AFTER PROLONGED TREATMENT WITH ACTH

1963 ◽  
Vol 41 (8) ◽  
pp. 1771-1777 ◽  
Author(s):  
E. Stark ◽  
J. Fachet ◽  
Katherine Mihály
Keyword(s):  
Prolonged Exposure ◽  
Corticosterone Level ◽  
Plasma Corticosterone ◽  
Prolonged Treatment ◽  
Plasma Corticosterone Level ◽  
Operative Trauma ◽  
Corticosterone Secretion ◽  
Adrenal Corticosterone

Prolonged exposure to ACTH considerably increased adrenal responsiveness in the rat both in vivo and in vitro. The last of 5 and 14 daily injections each produced a significantly higher blood corticosterone level than did a single injection. In the presence of ACTH added in vitro, adrenal corticosterone production in animals subjected to prolonged treatment with ACTH significantly exceeded the production per unit of weight and unit of time measured in saline-treated animals. Reduced adrenal responsiveness in the stage of resistance, elicited by formalin as a non-specific stress, cannot be invoked as an explanation for the absence of an increase in corticosterone secretion. The conclusion is that after prolonged exposure to non-specific stress there is no longer any ACTH hypersecretion.Twenty-four hours after the last injection of prolonged ACTH treatment there was inhibition of endogenous ACTH release by the pituitary gland, formalin produced no rise in the corticosterone level of the peripheral blood, and operative trauma caused substantially less ascorbic acid depletion than it did in saline-treated controls, although the plasma corticosterone level was normal or below normal.

scholarly journals Development of Physiologically Based Pharmacokinetic Model for Orally Administered Fexuprazan in Humans

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 813
Author(s):  
Yoo-Seong Jeong ◽  
Min-Soo Kim ◽  
Nora Lee ◽  
Areum Lee ◽  
Yoon-Jee Chae ◽  
...  
Keyword(s):  
Gastric Acid ◽  
Pbpk Model ◽  
Pbpk Modeling ◽  
Drug Candidate ◽  
Metabolite Formation ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

Fexuprazan is a new drug candidate in the potassium-competitive acid blocker (P-CAB) family. As proton pump inhibitors (PPIs), P-CABs inhibit gastric acid secretion and can be used to treat gastric acid-related disorders such as gastroesophageal reflux disease (GERD). Physiologically based pharmacokinetic (PBPK) models predict drug interactions as pharmacokinetic profiles in biological matrices can be mechanistically simulated. Here, we propose an optimized and validated PBPK model for fexuprazan by integrating in vitro, in vivo, and in silico data. The extent of fexuprazan tissue distribution in humans was predicted using tissue-to-plasma partition coefficients in rats and the allometric relationships of fexuprazan distribution volumes (VSS) among preclinical species. Urinary fexuprazan excretion was minimal (0.29–2.02%), and this drug was eliminated primarily by the liver and metabolite formation. The fraction absorbed (Fa) of 0.761, estimated from the PBPK modeling, was consistent with the physicochemical properties of fexuprazan, including its in vitro solubility and permeability. The predicted oral bioavailability of fexuprazan (38.4–38.6%) was within the range of the preclinical datasets. The Cmax, AUClast, and time-concentration profiles predicted by the PBPK model established by the learning set were accurately predicted for the validation sets.

scholarly journals Transcription of alpha-specific genes in Saccharomyces cerevisiae: DNA sequence requirements for activity of the coregulator alpha 1.

1993 ◽  
Vol 13 (11) ◽  
pp. 6866-6875 ◽  
Author(s):  
D C Hagen ◽  
L Bruhn ◽  
C A Westby ◽  
G F Sprague
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Binding Site ◽  
Dna Sequences ◽  
Point Mutations ◽  
Transcription Activation ◽  
Specific Gene ◽  
Binding Assays ◽  
Weak Binding

Transcription activation of alpha-specific genes in Saccharomyces cerevisiae is regulated by two proteins, MCM1 and alpha 1, which bind to DNA sequences, called P'Q elements, found upstream of alpha-specific genes. Neither MCM1 nor alpha 1 alone binds efficiently to P'Q elements. Together, however, they bind cooperatively in a manner that requires both the P' sequence, which is a weak binding site for MCM1, and the Q sequence, which has been postulated to be the binding site for alpha 1. We analyzed a collection of point mutations in the P'Q element of the STE3 gene to determine the importance of individual base pairs for alpha-specific gene transcription. Within the 10-bp conserved Q sequence, mutations at only three positions strongly affected transcription activation in vivo. These same mutations did not affect the weak binding to P'Q displayed by MCM1 alone. In vitro DNA binding assays showed a direct correlation between the ability of the mutant sequences to form ternary P'Q-MCM1-alpha 1 complexes and the degree to which transcription was activated in vivo. Thus, the ability of alpha 1 and MCM1 to bind cooperatively to P'Q elements is critical for activation of alpha-specific genes. In all natural alpha-specific genes the Q sequence is adjacent to the degenerate side of P'. To test the significance of this geometry, we created several novel juxtapositions of P, P', and Q sequences. When the Q sequence was opposite the degenerate side, the composite QP' element was inactive as a promoter element in vivo and unable to form stable ternary QP'-MCM1-alpha 1 complexes in vitro. We also found that addition of a Q sequence to a strong MCM1 binding site allows the addition of alpha 1 to the complex. This finding, together with the observation that Q-element point mutations affected ternary complex formation but not the weak binding of MCM1 alone, supports the idea that the Q sequence serves as a binding site for alpha 1.

scholarly journals A nucleosome-positioning sequence is required for GCN4 to activate transcription in the absence of a TATA element.

1990 ◽  
Vol 10 (8) ◽  
pp. 4256-4265 ◽  
Author(s):  
C J Brandl ◽  
K Struhl
Keyword(s):  
Binding Site ◽  
Transcriptional Activation ◽  
Nucleosome Positioning ◽  
Alternative Mechanism ◽  
Tata Element ◽  
Binding Factor ◽  
Positioning Analysis ◽  
Binding Sequence

In the gal-his3 hybrid promoter his3-GG1, the yeast upstream activator protein GCN4 stimulates transcription when bound at the position normally occupied by the TATA element. This TATA-independent activation by GCN4 requires two additional elements in the gal enhancer region that are distinct from those involved in normal galactose induction. Both additional elements appear to be functionally distinct from a classical TATA element because they cannot be replaced by the TFIID-binding sequence TATAAA. One of these elements, termed Q, is essential for GCN4-activated transcription and contains the sequence GTCAC CCG, which overlaps (but is distinct from) a GAL4 binding site. Surprisingly, relatively small increases in the distance between Q and the GCN4 binding site significantly reduce the level of transcription. The Q element specifically interacts with a yeast protein (Q-binding protein [QBP]) that may be equivalent to Y, a protein that binds at a sequence that forms a constraint to nucleosome positioning. Analysis of various deletion mutants indicates that the sequence requirements for binding by QBP in vitro are indistinguishable from those necessary for Q activity in vivo, strongly suggesting that QBP is required for the function of this TATA-independent promoter. These results support the view that transcriptional activation can occur by an alternative mechanism in which the TATA-binding factor TFIID either is not required or is not directly bound to DNA. In addition, they suggest a potential role of nucleosome positioning for the activity of a promoter.

scholarly journals Negative-feedback regulation of FGF signalling by DUSP6/MKP-3 is driven by ERK1/2 and mediated by Ets factor binding to a conserved site within the DUSP6/MKP-3 gene promoter

2008 ◽  
Vol 412 (2) ◽  
pp. 287-298 ◽  
Author(s):  
Maria Ekerot ◽  
Marios P. Stavridis ◽  
Laurent Delavaine ◽  
Michael P. Mitchell ◽  
Christopher Staples ◽  
...  
Keyword(s):  
Binding Site ◽  
Negative Feedback ◽  
Fluorescent Protein ◽  
Gene Promoter ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Negative Feedback Regulation ◽  
Fgf Signalling

DUSP6 (dual-specificity phosphatase 6), also known as MKP-3 [MAPK (mitogen-activated protein kinase) phosphatase-3] specifically inactivates ERK1/2 (extracellular-signal-regulated kinase 1/2) in vitro and in vivo. DUSP6/MKP-3 is inducible by FGF (fibroblast growth factor) signalling and acts as a negative regulator of ERK activity in key and discrete signalling centres that direct outgrowth and patterning in early vertebrate embryos. However, the molecular mechanism by which FGFs induce DUSP6/MKP-3 expression and hence help to set ERK1/2 signalling levels is unknown. In the present study, we demonstrate, using pharmacological inhibitors and analysis of the murine DUSP6/MKP-3 gene promoter, that the ERK pathway is critical for FGF-induced DUSP6/MKP-3 transcription. Furthermore, we show that this response is mediated by a conserved binding site for the Ets (E twenty-six) family of transcriptional regulators and that the Ets2 protein, a known target of ERK signalling, binds to the endogenous DUSP6/MKP-3 promoter. Finally, the murine DUSP6/MKP-3 promoter coupled to EGFP (enhanced green fluorescent protein) recapitulates the specific pattern of endogenous DUSP6/MKP-3 mRNA expression in the chicken neural plate, where its activity depends on FGFR (FGF receptor) and MAPK signalling and an intact Ets-binding site. These findings identify a conserved Ets-factor-dependent mechanism by which ERK signalling activates DUSP6/MKP-3 transcription to deliver ERK1/2-specific negative-feedback control of FGF signalling.

UHF-1, a factor required for maximal transcription of early and late sea urchin histone H4 genes: analysis of promoter-binding sites

1991 ◽  
Vol 11 (2) ◽  
pp. 1048-1061
Author(s):  
I J Lee ◽  
L Tung ◽  
D A Bumcrot ◽  
E S Weinberg
Keyword(s):  
Binding Site ◽  
Sea Urchin ◽  
Transcriptional Start Site ◽  
Sodium Dodecyl ◽  
Nuclear Extract ◽  
Dnase I ◽  
Histone H4 ◽  
Band Shift

A protein, denoted UHF-1, was found to bind upstream of the transcriptional start site of both the early and late H4 (EH4 and LH4) histone genes of the sea urchin Strongylocentrotus purpuratus. A nuclear extract from hatching blastulae contained proteins that bind to EH4 and LH4 promoter fragments in a band shift assay and produced sharp DNase I footprints upstream of the EH4 gene (from -133 to -106) and the LH4 gene (from -94 to -66). DNase I footprinting performed in the presence of EH4 and LH4 promoter competitor DNAs indicated that UHF-1 binds more strongly to the EH4 site. A sequence match of 11 of 13 nucleotides was found within the two footprinted regions: [sequence: see text]. Methylation interference and footprinting experiments showed that UHF-1 bound to the two sites somewhat differently. DNA-protein UV cross-linking studies indicated that UHF-1 has an electrophoretic mobility on sodium dodecyl sulfate-acrylamide gels of approximately 85 kDa and suggested that additional proteins, specific to each promoter, bind to each site. In vitro and in vivo assays were used to demonstrate that the UHF-1-binding site is essential for maximal transcription of the H4 genes. Deletion of the EH4 footprinted region resulted in a 3-fold decrease in transcription in a nuclear extract and a 2.6-fold decrease in expression in morulae from templates that had been injected into eggs. In the latter case, deletion of the binding site did not grossly disrupt the temporal program of expression from the injected EH4 genes. LH4 templates containing a 10-bp deletion in the consensus region or base substitutions in the footprinted region were transcribed at 14 to 58% of the level of the wild-type LH4 template. UHF-1 is therefore essential for maximal expression of the early and late H4 genes.

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