A novel plant-derived inhibitor of cAMP-mediated fluid and chloride secretion

1999 ◽  
Vol 276 (1) ◽  
pp. G58-G63 ◽  
Author(s):  
S. E. Gabriel ◽  
S. E. Davenport ◽  
R. J. Steagall ◽  
V. Vimal ◽  
T. Carlson ◽  
...  
Keyword(s):  
Cholera Toxin ◽  
Ussing Chamber ◽  
Fluid Secretion ◽  
Chloride Secretion ◽  
Inhibitory Effect ◽  
Adult Mice ◽  
Dependent Inhibition ◽  
Chamber Studies

We have identified an agent (SP-303) that shows efficacy against in vivo cholera toxin-induced fluid secretion and in vitro cAMP-mediated Cl−secretion. Administration of cholera toxin to adult mice results in an increase in fluid accumulation (FA) in the small intestine (FA ratio = 0.63 vs. 1.86 in control vs. cholera toxin-treated animals, respectively). This elevation in FA induced by cholera toxin was significantly reduced (FA ratio = 0.70) in animals treated with a 100 mg/kg dose of SP-303 at the same time as the cholera treatment. Moreover, when SP-303 was administered 3 h after cholera toxin, a dose-dependent inhibition of FA levels was observed with a half-maximal inhibitory dose of 10 mg/kg. In Ussing chamber studies of Caco-2 or T84 monolayer preparations, SP-303 had a significant effect on both basal current and forskolin-stimulated Cl−current. SP-303 also induced an increase in resistance that paralleled the observed decrease in current. These data suggest that SP-303 has an inhibitory effect on cAMP-mediated Cl−and fluid secretion. Thus SP-303 may prove to be a useful broad-spectrum antidiarrheal agent.

scholarly journals Rotavirus Infection Is Not Associated with Small Intestinal Fluid Secretion in the Adult Mouse

2006 ◽  
Vol 80 (22) ◽  
pp. 11355-11361 ◽  
Author(s):  
Shirin Kordasti ◽  
Claudia Istrate ◽  
Mahanez Banasaz ◽  
Martin Rottenberg ◽  
Henrik Sjövall ◽  
...  
Keyword(s):  
Fluid Secretion ◽  
Chloride Secretion ◽  
Potential Difference ◽  
Pathophysiological Mechanism ◽  
Rotavirus Infection ◽  
In Vivo Experiments ◽  
Adult Mice ◽  
Small Intestines

ABSTRACT In contrast to humans, adult but not infant small animals are resistant to rotavirus diarrhea. The pathophysiological mechanism behind this age-restricted diarrhea is currently unresolved, and this question was investigated by studying the secretory state of the small intestines of adult mice infected with rotavirus. Immunohistochemistry and histological examinations revealed that rotavirus (strain EDIM) infects all parts of the small intestines of adult mice, with significant numbers of infected cells in the ilea at 2 and 4 days postinfection. Furthermore, quantitative PCR revealed that 100-fold more viral RNA was produced in the ilea than in the jejuna or duodena of adult mice. In vitro perfusion experiments of the small intestine did not reveal any significant changes in net fluid secretion among mice infected for 3 days or 4 days or in those that were noninfected (37 ± 9 μl · h−1 · cm−1, 22 ± 13 μl · h−1 · cm−1, and 33 ± 6 μl · h−1 · cm−1, respectively) or in transmucosal potential difference (4.0 ± 0.3 mV versus 3.9 ± 0.4 mV), a marker for active chloride secretion, between control and rotavirus-infected mice. In vivo experiments also did not show any differences in potential difference between uninfected and infected small intestines. Furthermore, no significant differences in weight between infected and uninfected small intestines were found, nor were any differences in fecal output observed between infected and control mice. Altogether, these data suggest that rotavirus infection is not sufficient to stimulate chloride and water secretion from the small intestines of adult mice.

scholarly journals LC478, a Novel Di-Substituted Adamantyl Derivative, Enhances the Oral Bioavailability of Docetaxel in Rats

Pharmaceutics ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 135 ◽  
Author(s):  
Seung Han ◽  
Qili Lu ◽  
Kyeong Lee ◽  
Young Choi
Keyword(s):  
Oral Bioavailability ◽  
Oral Absorption ◽  
Ussing Chamber ◽  
Absolute Bioavailability ◽  
Time Curve ◽  
Glycoprotein P ◽  
Dose Concentration ◽  
Chamber Studies

P-glycoprotein (P-gp)-mediated efflux of docetaxel in the gastrointestinal tract mainly impedes its oral chemotherapy. Recently, LC478, a novel di-substituted adamantyl derivative, was identified as a non-cytotoxic P-gp inhibitor in vitro. Here, we assessed whether LC478 enhances the oral bioavailability of docetaxel in vitro and in vivo. LC478 inhibited P-gp mediated efflux of docetaxel in Caco-2 cells. In addition, 100 mg/kg of LC478 increased intestinal absorption of docetaxel, which led to an increase in area under plasma concentration-time curve (AUC) and absolute bioavailability of docetaxel in rats. According to U.S. FDA criteria (I, an inhibitor concentration in vivo tissue)/(IC50, inhibitory constant in vitro) >10 determines P-gp inhibition between in vitro and in vivo. The values 15.6–20.5, from (LC478 concentration in intestine, 9.37–12.3 μM)/(IC50 of LC478 on P-gp inhibition in Caco-2 cell, 0.601 μM) suggested that 100 mg/kg of LC478 sufficiently inhibited P-gp to enhance oral absorption of docetaxel. Moreover, LC478 inhibited P-gp mediated efflux of docetaxel in the ussing chamber studies using rat small intestines. Our study demonstrated that the feasibility of LC478 as an ideal enhancer of docetaxel bioavailability by P-gp inhibition in dose (concentration)-dependent manners.

scholarly journals A Potential Role of Progestin-Induced Laminin-5/α6-Integrin Signaling in the Formation of Side Branches in the Mammary Gland

Endocrinology ◽  
2012 ◽  
Vol 153 (10) ◽  
pp. 4990-5001 ◽  
Author(s):  
Gabriele Meyer ◽  
Jeffrey Leipprandt ◽  
Jianwei Xie ◽  
Mark D. Aupperlee ◽  
Sandra Z. Haslam
Keyword(s):  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Nuclear Factor Κb ◽  
Inhibitory Effect ◽  
Collagen Gels ◽  
Paracrine Factor ◽  
Laminin 5 ◽  
Adult Mice

Abstract Mammary organoids from adult mice produce tubules, analogous to mammary ducts in vivo, in response to hepatocyte growth factor (HGF) when cultured in collagen gels. The combination of HGF plus progestin (R5020) causes reduced tubule number and length. We hypothesized that the inhibitory effect on tubulogenesis was due to progestin-mediated alteration of HGF/c-Met signaling. Using molecular inhibitors and short hairpin RNA, it was determined that HGF activation of Ras-related C3 botulinum toxin substrate (Rac1) was required for the formation of cytoplasmic extensions, the first step of tubulogenesis, and that Rac1 activity was Src kinase (Src) and focal adhesion kinase (FAK) dependent. The highly novel finding was that R5020 reduced tubulogenesis by up-regulating and increasing extracellular laminin and α6-integrin ligation to reduce activation of the Src, focal adhesion kinase, and Rac1 pathway. Receptor activator of nuclear factor-κB ligand, another progesterone-induced paracrine factor, did not replicate this effect of R5020. The inhibitory effect of R5020 on tubulogenesis was likely mediated through progesterone receptor (PR) isoform A (PRA), because PRA is the predominant PR isoform expressed in the organoids, and the progestin-induced effect was prevented by the PR antagonist RU486. These results provide a plausible mechanism that explains progestin/PRA-mediated blunting of HGF-induced tubulogenesis in vitro and is proposed to be relevant to progesterone/PRA-induced side-branching in vivo during pregnancy.

Possible Mode of Action of Ticlopidine: A Novel Inhibitor of Platelet Aggregation

1979 ◽  
Author(s):  
H. Johnson ◽  
J. B. Heywood
Keyword(s):  
Platelet Aggregation ◽  
Mode Of Action ◽  
Potent Inhibitor ◽  
Platelet Reactivity ◽  
Inhibitory Effect ◽  
Thromboxane Synthetase ◽  
Sustained Effect ◽  
Dependent Inhibition

Ticlopidine (T) is weakly active in vitro, but is a potent inhibitor of platelet aggregation induced by ADP, collagen, thrombin, adrenaline, arachidonic acid, prostaglandin (PG) endoperoxide and thromboxane A2 with a sustained effect, when administered to a variety of animal species, including man. Platelets from treated animals were normal in ultrastructure and 14C-ADP binding was not modified by T. Basal PG synthesis was unaffected, whereas aspirin (A) had a marked inhibitory effect. Platelet cyclo-oxygenase and thromboxane synthetase activities were 90.6±12.9 and 96.1±5.3% of control following T treatment. In contrast to A, T had no effect on vascularprostacyclin (PGI2) synthesis, this being 1.4±0.1, 0.5±0.1 and 1.3±0. 3ng/mg wet weight aorta in T and A-treated and control animals respectively. Platelets from T-treated rats were significantly more responsive to inhibition by exogenous PGI2 (0.2-4 ng/ml) and PGE1 (4- 20 ng/ml). when compared with controls. T administration (30-300 mg/kg) resulted in a dose-dependent inhibition of ADP-induced platelet aggregation (26.0- 87. 5%) and enhancement of platelet reactivity to PGI2 (37.0-159.8%). There was a good correlation between these parameters (r=+0.994). T is a potent inhibitor of platelet aggregati on with a novel mode of action. It is not aspirin-like, but may act to potentiate endogenous PGI2 in vivo, possibly through an effect on platelet adenylate cyclase.

Lu 23051, A New Potent Inhibitor Of Platelet Aggregation

1981 ◽  
Author(s):  
H D Lehmann ◽  
J Gries ◽  
D Lenke
Keyword(s):  
Platelet Aggregation ◽  
Ex Vivo ◽  
Platelet Rich Plasma ◽  
Coronary Vessels ◽  
Inhibitory Effect ◽  
Spontaneously Hypertensive ◽  
Dependent Inhibition ◽  
Induced Aggregation

6- [p-(2-(Chiorpropionylamino)phenyl] -4.5-dihydro-5-methyl-3(2H)-pyridazinone, LU 23051, is primarily characterized by its strong inhibition of platelet aggregation under in vitro and in vivo conditions. In vitro there is a concentration-dependent inhibition of ADP and collagen induced aggregation in platelet rich plasma of man, rat and dog. The inhibitory concentration EC 33 % is 0.0010-0.030 mg/1 (man: ADP-0.030, col 1.-0.013 mg/l) depending on species and type of aggregation. When administered orally in ex vivo experiments on rats and dogs the substance is found to have a dose-dependent antiaggregatory effect in the range from 0.1-3.16 mg/kg. The ED 33 % is 0.27-0.63 mg/kg.-In addition after oral administration the substance has a good inhibitory effect in models being based on intravascular platelet aggregation. Thus, a dose of 1 mg/kg inhibits laser-induced aggregation in mesenteric venules of rats. Mortality after i.v. injection of collagen in mice is reduced by 50 % after a dose of 0.02 mg/kg. A dose of 0.039 mg/kg prolongs the bleeding time of rats by 50 %. The aggregation-inhibiting action is of long duration (0.1 mg/kg p.o.∼24 h). The substance does not interfere with clotting.Besides its effect on platelet aggregation LU 23051 acts as vasodilatator as well. Dilatation of coronary vessels by 100 % is seen in isolated guinea-pig hearts at a concentration of 0.1 mg/l. In spontaneously hypertensive rats the substance has an anti hypertensive effect. The ED 20 % is 0.36 mg/kg p.o.The combination of antiaggregatory and vasodilatatory effects opens up interesting aspects with respect to the pharmacotherapeutic use of the new substance

scholarly journals Inhibitory roles of the mammalian GnIH ortholog RFRP3 in testicular activities in adult mice

2014 ◽  
Vol 223 (1) ◽  
pp. 79-91 ◽  
Author(s):  
Shabana Anjum ◽  
Amitabh Krishna ◽  
Kazuyoshi Tsutsui
Keyword(s):  
Cell Proliferation ◽  
Germ Cell ◽  
Inhibitory Effect ◽  
The Body ◽  
Adult Mice ◽  
Gonadotropin Inhibitory Hormone ◽  
Different Doses ◽  
Germ Cell Proliferation

The aim of this study was to evaluate the effects ofin vivoandin vitrotreatments with RFamide-related peptide 3 (RFRP3), a mammalian gonadotropin-inhibitory hormone ortholog, on testicular activities, i.e. spermatogenesis and steroidogenesis, in mice. Mice were treatedin vivowith different doses of RFRP3 (control: 0.02 μg, 0.2 μg, and 2.0 μg/day) for 8 days. Forin vitrostudy, the testes of mice were evaluated with different doses of RFRP3 (control: 1 and 10 ng/ml) with or without LH (control: 10 and 100 ng/ml) for 24 h at 37 °C. RFRP3 treatment produced significant changes in the body mass, circulating steroid level, and testicular activity in mice. RFRP3 treatment also caused dose-dependent histological changes in spermatogenesis, such as decline in germ cell proliferation and survival markers and increase in apoptotic markers in testis. Bothin vivoandin vitrostudies showed the inhibitory effect of RFRP3 on testosterone synthesis in the testis. RFRP3 inhibited the expression of the receptor for LH (LHCGR), STAR protein, cytochrome P450 side-chain cleavage (CYP11A1) and 3β-hydroxysteroid dehydrogenase in the testis, and testosterone secretion dose dependently. This study also suggested that the inhibitory effect of RFRP3 in the testis may be mediated through local production of GnRH. Thus, RFRP3 inhibits testicular steroidogenesis and spermatogenesis either indirectly through GnRH or by directly influencing germ cell proliferation, survival, and apoptosis.

scholarly journals Opposing roles for Egalitarian and Staufen in transport, anchoring and localization of oskar mRNA in the Drosophila oocyte

PLoS Genetics ◽  
2021 ◽  
Vol 17 (4) ◽  
pp. e1009500
Author(s):  
Sabine Mohr ◽  
Andrew Kenny ◽  
Simon T. Y. Lam ◽  
Miles B. Morgan ◽  
Craig A. Smibert ◽  
...  
Keyword(s):  
Binding Sites ◽  
Inhibitory Effect ◽  
Multiple Roles ◽  
Rna Transport ◽  
Nurse Cells ◽  
Stem Loop ◽  
Stem Loop Structure ◽  
Dependent Inhibition

Localization of oskar mRNA includes two distinct phases: transport from nurse cells to the oocyte, a process typically accompanied by cortical anchoring in the oocyte, followed by posterior localization within the oocyte. Signals within the oskar 3’ UTR directing transport are individually weak, a feature previously hypothesized to facilitate exchange between the different localization machineries. We show that alteration of the SL2a stem-loop structure containing the oskar transport and anchoring signal (TAS) removes an inhibitory effect such that in vitro binding by the RNA transport factor, Egalitarian, is elevated as is in vivo transport from the nurse cells into the oocyte. Cortical anchoring within the oocyte is also enhanced, interfering with posterior localization. We also show that mutation of Staufen recognized structures (SRSs), predicted binding sites for Staufen, disrupts posterior localization of oskar mRNA just as in staufen mutants. Two SRSs in SL2a, one overlapping the Egalitarian binding site, are inferred to mediate Staufen-dependent inhibition of TAS anchoring activity, thereby promoting posterior localization. The other three SRSs in the oskar 3’ UTR are also required for posterior localization, including two located distant from any known transport signal. Staufen, thus, plays multiple roles in localization of oskar mRNA.

Leptin inhibits basal but not gonadotrophin-stimulated testosterone production in the immature mouse and sheep testis

2008 ◽  
Vol 20 (4) ◽  
pp. 519 ◽  
Author(s):  
Muren Herrid ◽  
Yin Xia ◽  
Tim O'Shea ◽  
James R. McFarlane
Keyword(s):  
Leydig Cell ◽  
Developmental Stages ◽  
Physiological State ◽  
Inhibitory Effect ◽  
Slice Culture ◽  
Testosterone Production ◽  
Adult Mice ◽  
High Concentrations

The mechanisms whereby leptin regulates testosterone secretion are complex and are likely to involve actions at different levels of the hypothalamus–pituitary–gonadal axis. In the present study, the effect of leptin on testicular steroidogenesis at different developmental stages in mice and sheep was investigated. Testosterone data from testicular slice and Leydig cells of immature and adult mice testes demonstrated that the action of leptin in the regulation of steroidogenesis appears to be dependent on the developmental stage of the testis. Leptin biphasically modulates basal testosterone production in immature testicular slice cultures: at relatively low concentrations (6.25–12.5 ng mL–1) leptin exerts a significant inhibitory effect, but has less of an effect at very low (1.25 ng mL–1) or high concentrations (25 ng mL–1). However, leptin failed to modulate basal testosterone levels in Leydig cell preparations. In contrast with immature testes, leptin was unable to regulate either basal or human chorionic gonadotrophin (10 IU mL–1)-stimulated testosterone production in adult testicular slices or Leydig cell cultures. The age- and concentration-dependent regulation pattern was confirmed using sheep testicular slice culture. Leptin (1.56–25 ng mL–1) significantly inhibited basal testosterone production in the testis from birth to Day 21, but had no effect on Day 27 or older testes. However, the plasma and testicular concentrations of leptin and testosterone data in the ram indicate that such a regulatory effect of leptin on testis steroidogenesis in vitro is unable to efficiently influence testosterone concentrations in vivo. This does not exclude the possibility of a non-competitive mechanism of interaction between leptin and luteinising hormone to regulate testosterone production. Thus, we hypothesise that leptin is not an important independent regulator of testosterone concentration in the normal physiological state. The physiological significance and mechanism of leptin regulation of basal testosterone production are not known; further studies are required to elucidate these important issues.

The Effect of Barbituric Acid Derivatives on Platelet Function in Vitro and in Vivo

1973 ◽  
Vol 30 (02) ◽  
pp. 315-326
Author(s):  
J. Heinz Joist ◽  
Jean-Pierre Cazenave ◽  
J. Fraser Mustard
Keyword(s):  
Platelet Aggregation ◽  
Platelet Function ◽  
Barbituric Acid ◽  
Platelet Rich Plasma ◽  
Inhibitory Effect ◽  
Primary Response ◽  
Sodium Pentobarbital ◽  
Barbituric Acid Derivatives

SummarySodium pentobarbital (SPB) and three other barbituric acid derivatives were found to inhibit platelet function in vitro. SPB had no effect on the primary response to ADP of platelets in platelet-rich plasma (PRP) or washed platelets but inhibited secondary aggregation induced by ADP in human PRP. The drug inhibited both phases of aggregation induced by epinephrine. SPB suppressed aggregation and the release reaction induced by collagen or low concentrations of thrombin, and platelet adherence to collagen-coated glass tubes. The inhibition by SPB of platelet aggregation was readily reversible and isotopically labeled SPB did not become firmly bound to platelets. No inhibitory effect on platelet aggregation induced by ADP, collagen, or thrombin could be detected in PRP obtained from rabbits after induction of SPB-anesthesia.

Inhibition of Human and Animal Platelet Adhesiveness to Glass Bead Columns by Adenosine, Dipyridamole, Chlorpromazine and Acetylsalicylic Acid

1976 ◽  
Vol 36 (02) ◽  
pp. 401-410 ◽  
Author(s):  
Buichi Fujttani ◽  
Toshimichi Tsuboi ◽  
Kazuko Takeno ◽  
Kouichi Yoshida ◽  
Masanao Shimizu
Keyword(s):  
Guinea Pig ◽  
Acetylsalicylic Acid ◽  
Guinea Pigs ◽  
Glass Bead ◽  
Animal Species ◽  
Inhibitory Effect ◽  
Rabbit Platelet ◽  
Platelet Adhesiveness

SummaryThe differences among human, rabbit and guinea-pig platelet adhesiveness as for inhibitions by adenosine, dipyridamole, chlorpromazine and acetylsalicylic acid are described, and the influence of measurement conditions on platelet adhesiveness is also reported. Platelet adhesiveness of human and animal species decreased with an increase of heparin concentrations and an increase of flow rate of blood passing through a glass bead column. Human and rabbit platelet adhesiveness was inhibited in vitro by adenosine, dipyridamole and chlorpromazine, but not by acetylsalicylic acid. On the other hand, guinea-pig platelet adhesiveness was inhibited by the four drugs including acetylsalicylic acid. In in vivo study, adenosine, dipyridamole and chlorpromazine inhibited platelet adhesiveness in rabbits and guinea-pigs. Acetylsalicylic acid showed the inhibitory effect in guinea-pigs, but not in rabbits.

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