Stimulatory Effect Of Low Doses Research Articles

Hormetic Effects of Carbendazim on Mycelial Growth and Aggressiveness of Magnaporthe oryzae.

Rice blast caused by Magnaporthe oryzae is one of the most destructive fungal diseases of rice worldwide. Stimulatory effects of low doses of fungicides on pathogens are closely relevant to disease management. In the present study, in potato dextrose agar (PDA) amended with carbendazim at a dose range from 0.003 to 0.3 μg/mL, stimulatory effects on the mycelial growth of three isolates sensitive to carbendazim were tested. Carbendazim at concentrations from 0.003 to 0.1 µg/mL showed stimulatory effects on mycelial growth of isolates Guy11 and H08-1a, while carbendazim at concentrations from 0.003 to 0.03 µg/mL stimulated the growth of isolate P131. The maximum stimulation magnitudes were 11.84% for the three isolates tested. Mycelial colonies grown on PDA amended with different concentrations of carbendazim were incubated at 28 °C in darkness for 7 days as the pretreatment. Pretreatment mycelia were inoculated on fresh fungicide-free PDA and subsequent mycelia growth stimulations were still observed, and the maximum stimulation magnitudes were 9.15% for the three isolates tested. Pretreatment mycelia did not significantly change the tolerance to H2O2 and NaCl, except that the tolerance to H2O2 was increased significantly (p < 0.05) when the carbendazim was at 0.3 µg/mL. After five generations of mycelial transference on fungicide-free PDA, the transgenerational hormesis of mycelial were exhibited when transferred onto PDA supplemented with carbendazim at 0.3 µg/mL, and the maximum percent stimulation was 51.28%. The time course of infection indicated that the visible initial necrotic symptoms could be detected at 2 DPI on leaves treated with carbendazim at 0.03 µg/mL, whereas no necrotic symptom could be discerned for the control. Statistical results of lesion area and lesion type at 7 DPI showed that there was a significant stimulation (p < 0.05) on aggressiveness of M. oryzae isolate Guy11 on detached rice leaves at 0.03 µg/mL carbendazim. These results will advance our understanding of hormetic effects of fungicides and provide valuable information for judicious application of fungicides.

Hormesis in Plants: The Role of Oxidative Stress, Auxins and Photosynthesis in Corn Treated with Cd or Pb.

Hormesis, which describes the stimulatory effect of low doses of toxic substances on growth, is a well-known phenomenon in the plant and animal kingdoms. However, the mechanisms that are involved in this phenomenon are still poorly understood. We performed preliminary studies on corn coleoptile sections, which showed a positive correlation between the stimulation of growth by Cd or Pb and an increase in the auxin and H2O2 content in the coleoptile sections. Subsequently, we grew corn seedlings in hydroponic culture and tested a wide range of Cd or Pb concentrations in order to determine hormetic growth stimulation. In these seedlings the gas exchange and the chlorophyll a fluorescence, as well as the content of chlorophyll, flavonol, auxin and hydrogen peroxide, were measured. We found that during the hormetic stimulation of growth, the response of the photosynthetic apparatus to Cd and Pb differed significantly. While the application of Cd mostly caused a decrease in various photosynthetic parameters, the application of Pb stimulated some of them. Nevertheless, we discovered that the common features of the hormetic stimulation of shoot growth by heavy metals are an increase in the auxin and flavonol content and the maintenance of hydrogen peroxide at the same level as the control plants.

Stimulatory Effects of Sublethal Doses of Carbendazim on the Virulence and Sclerotial Production of Botrytis cinerea.

Stimulatory effects of low doses of fungicides on the virulence of phytopathogens have profound implications for applications of fungicides. The present study demonstrated that carbendazim sprayed at 0.001 to 0.03 μg/ml had stimulatory effects on the virulence of mycelia of Botrytis cinerea, and the maximum percent stimulations were 15.5 and 21.4% for isolates HB459 and HB536, respectively. Potato dextrose agar (PDA) amended with carbendazim at 0.01, 0.02, and 0.05 μg/ml inhibited mycelial growth of isolate HB536 by 0.8, 10.0, and 30.6%, respectively. However, after the inhibited mycelia were inoculated on cucumber leaves, virulence increased by 10.1, 12.9, and 10.8%, respectively. With respect to sclerotial production, carbendazim at 0.005 and 0.02 μg/ml in PDA significantly (P < 0.05) increased, while at 0.1 μg/ml significantly (P < 0.05) reduced the sclerotial number and weight of both isolates compared with nontreated controls. Conidia germination percentages slightly yet statistically significantly (P < 0.05) increased after being inoculated on PDA amended with carbendazim at 0.001 and 0.005 μg/ml. Carbendazim at 0.001∼0.02 μg/ml, either sprayed on cucumber leaves or cosuspended with conidia, exerted significantly (P < 0.05) stimulatory effects on the virulence of B. cinerea conidia. Mechanism studies showed that sublethal doses of carbendazim did not increase the expression levels of pathogenicity-related pectin methylesterase gene Bcpme1, endopolygalacturonase gene Bcpg2, cutinase gene CutA, xylanase gene Xyn11A, or NADPH oxidase gene BcnoxA.

Age-related declines in thirst and salt appetite responses in male Fischer 344 × Brown Norway rats

The F344×BN strain is the first generational cross between Fischer 344 (F344) and Brown Norway (BN) rats. The F344×BN strain is widely used in aging studies as it is regarded as a model of “healthy” aging (Sprott, 1991). In the present work, male F344×BN rats aged 4mo (young, n=6) and 20mo (old, n=9) received a series of experimental challenges to body fluid homeostasis to determine their thirst and salt appetite responses. Corresponding urinary responses were measured in some of the studies. Following sodium depletion, old rats ingested less saline solution (0.3M NaCl) than young rats on a body weight basis, but both ages drank enough saline solution to completely repair the accrued sodium deficits. Following intracellular dehydration, old rats drank less water than young rats, again on a body weight basis, and were less able than young rats to drink amounts of water proportionate to the osmotic challenge. Compared with young rats, old rats drank less of both water and saline solution after combined food and fluid restriction, and also were refractory to the stimulatory effects of low doses of captopril on water drinking and sodium ingestion. Age differences in urinary water and sodium excretion could not account for the age differences in accumulated water and sodium balances. These results extend observations of diminished behavioral responses of aging animals to the F344×BN rat strain and support the idea that impairments in behavior contribute more to the waning ability of aging animals to respond to body fluid challenges than do declines in kidney function. In addition, the results suggest that behavioral defense of sodium homeostasis is less diminished with age in the F344×BN strain compared to other strains so far studied.

Locomotor activity changes in female adolescent and adult rats during repeated treatment with a cannabinoid or club drug

Adolescents and young adults of both sexes are the primary consumers of “club” drugs; yet, most of the mechanistic preclinical research in this area has been performed in adult male rodents. The purpose of this study was to evaluate the acute and repeated effects of drugs that are commonly abused by adolescents in female adolescent and adult rats in a rodent model of behavioral sensitization. During two five-day periods separated by a two-day break, rats were injected daily with saline or with one of the following drugs: cocaine (7 or 15mg/kg), ketamine (3 or 10mg/kg), 3,4-methylenedioxymethamphetamine (MDMA) (3, 10, or 30mg/kg), or Δ9-tetrahydrocannabinol (THC) (0.03, 0.1, 0.3 or 1mg/kg) and their locomotor activity was measured. Cocaine increased activity across days in both age groups. Whereas ketamine produced progressive increases in activity with repeated administration in rats of both ages, MDMA increased, and then decreased, activity in the chronic dosing regimen in female adolescents only. Tolerance to the initial stimulatory effects of low doses of THC was observed at both ages. The results with THC are similar to those obtained for male rats tested under identical conditions in a previous study; however, in contrast with the present results in females, male adolescent rats in the previous study failed to develop behavioral sensitization to ketamine. Together, these results suggest that age and sex strongly influence the progressive adaptive changes that occur with repeated administration of some, but not all, of these commonly abused substances.

Ethanol‐Induced Social Facilitation in Adolescent Rats: Role of Endogenous Activity at Mu Opioid Receptors

Ethanol consumption is considerably elevated during adolescence. Attractiveness of alcohol for humans during the adolescent developmental period is based, in part, on its ability to induce social facilitation--a facilitation of social interactions not only evident in human adolescents but also in adolescent rats. Endogenous opioid systems are among the multiple neural systems implicated in the behavioral and reinforcing effects of ethanol and may play a substantial role in modulating stimulatory effects of low doses of ethanol on social behavior during adolescence. This possibility was explored in the present study through the use of an animal model of peer-directed social behavior. Sprague-Dawley rats were challenged early in adolescence with saline or ethanol intraperitoneally (i.p.), placed into an individual holding cage for 30 minutes, and then tested in a familiar situation with a nonmanipulated partner of the same age and sex. In Experiment 1, each test subject was injected subcutaneously with one of the three doses of a nonselective opioid antagonist naloxone (0, 0.05, and 0.1 mg/kg), 5 minutes prior to the social interaction test and 25 minutes following challenge with saline or ethanol (0.5 g/kg), whereas in Experiment 2 animals were challenged with one of the six doses of ethanol (0, 0.25, 0.5, 0.75, 1.0, and 1.25 g/kg) prior to injection of either saline or naloxone (0.05 mg/kg). In Experiment 3, animals were pretreated i.p. with the selective mu-opioid antagonist CTOP (0, 0.01, 0.025, 0.05, and 0.1 mg/kg) 30 minutes prior to challenge with saline or ethanol (0.5 g/kg). Low doses of ethanol (0.5 and 0.75 g/kg) produced social facilitation, as indexed by significant increases in play fighting and social investigation. Both doses of naloxone and the three highest doses of CTOP blocked the stimulatory effects of ethanol on play fighting but not on social investigation. These effects were not associated with alterations in ethanol pharmacokinetic properties or with shifts in the biphasic ethanol dose-response curve. Ethanol-induced facilitation of social play behavior seen in adolescent animals is mediated in part through ethanol-induced release of endogenous ligands for the mu-opioid receptor or an ethanol-associated enhancement of sensitivity of these receptors for their endogenous ligands.

PRECLINICAL STUDY: Age‐dependent differences in sensitivity and sensitization to cannabinoids and ‘club drugs’ in male adolescent and adult rats

Lifelong substance abuse is often initiated during adolescence; yet, most pre-clinical research in this area has been conducted in adult animals. Substantial evidence exists that the brain development that continues throughout adolescence may result in pharmacological responses that differ in a crucial manner from those of adults. The goal of this study was to evaluate age differences in motor activity following acute and repeated administration of drugs that are commonly abused by adolescents, including cocaine, Delta(9)-tetrahydrocannabinol (Delta(9)-THC), and the club drugs, ketamine and 3,4-methylenedioxymethamphetamine (MDMA). Adolescent and adult male rats were injected once daily with saline or with a dose of one of the test drugs for two 5-day dosing periods, separated by a 2-day drug holiday during which they remained in their home cages. Following each injection, rats were placed in a locomotor chamber for a 20-minute session. The potencies of cocaine, ketamine and MDMA for producing motor stimulation were less in male adolescents than in male adults. Furthermore, sensitization to the club drug, ketamine, developed after repeated dosing in adults, but not adolescents. In contrast, adolescents were initially more sensitive to the stimulatory effects of low doses of Delta(9)-THC than were adults, although rapid tolerance occurred. These results suggest that adolescents are less sensitive to the acute and repeated stimulant effects of some, but not all, of the drugs that are preferentially abused by this age group. This differential sensitivity may contribute to the different patterns of use that have been noted in adolescent versus adult drug abusers.

Effects of bile acids on pancreatic ductal bicarbonate secretion in guinea pig

Background and aims:Acute pancreatitis is associated with significant morbidity and mortality. Bile reflux into the pancreas is a common cause of acute pancreatitis and, although the bile can reach both...

DIFERENTIAL EFFECTS OF BILE ACIDS ON PANCREATIC DUCTAL BICARBONATE SECRETION

Background & Aims: Acute pancreatitis is a serious disease which is associated with significant morbidity and mortality. Bile reflux into the pancreas is one of the commonest causes of acute pancreatitis. Although the bile can reach both acinar and ductal cells during biliary pancreatitis, much more research has been done on acinar cells. Our aim was to characterize the effects of bile acids on HCO3- secretion from ductal epithelia. Methods: Isolated guinea pig intra/interlobular pancreatic ducts were microperfused from the luminal and/or basolateral membranes. The effects of chenodeoxycholate (CDC) and glycochenodeoxycholate (GCDC) on intracellular calcium concentration and pH were measured using fluorescent dyes by microfluorometry. Changes of intracellular pH were measured to estimate the HCO3- and H+ transport across the membrane. Results: Luminal administration of a low dose (0.1mM) of CDC stimulated HCO3- secretion which could be blocked by luminal administration of H2DIDS. In contrast, either luminal or basolateral administration of high dose (1mM) of CDC strongly inhibited ductal HCO3- secretion. Both CDC and GCDC elevated intracellular calcium concentration and this effect was blocked by BAPTA-AM and caffeine. BAPTA-AM inhibited the stimulatory effect of low doses of CDC on HCO3- secretion, but did not modulate the inhibitory effect of high does of CDC. Conclusions: We conclude that the stimulated HCO3- and fluid secretion by low concentrations of bile acids protect the pancreas against the toxic bile, whereas inhibition of secretion by high concentrations of bile acid s may contribute to the progression of acute pancreatitis.

Combination of adenosine A1 and A2A receptor blocking agents induces caffeine-like locomotor stimulation in mice

The spontaneous locomotor activity of C57BL/6J mice was examined, using an automated detection system based on infra-red beams, after administration of caffeine (3–30 mg/kg, i.p.), the adenosine A2A receptor selective antagonist SCH 58261 (0.312–2.5 mg/kg, i.p.) and the A1 selective antagonist DPCPX (1.25–5 mg/kg, i.p.). SCH 58261 failed to influence motor activity in mice habituated to the test environment. DPCPX produced a small increase in motility and locomotion (significant at the dose of 5.0 mg/kg), much weaker than that produced by caffeine. Combined administration of DPCPX (1.2 mg/kg, i.p.) and SCH 58261 (1.2 mg/kg, i.p.) produced stimulation of motility and locomotion comparable with the effect of caffeine (15 mg/kg, i.p.). In contrast to motility and locomotion, rearing counts were not significantly influenced by DPCPX, SCH 58261, their combination, or by caffeine. Caffeine (15 mg/kg, i.p.) caused an increase in NGFI-A mRNA (an immediate early gene was chosen as an index of neuronal activation) in the piriform cortex 4 h after injection. This effect was reproduced by the combination of A1 and A2A receptor antagonist. It is hypothesised that the stimulatory effect of low doses of caffeine in C57BL/6J mice is due to concomitant blockade of both A1 and A2A adenosine receptors.

The adenosine A 1 receptor contributes to the stimulatory, but not the inhibitory effect of caffeine on locomotion: a study in mice lacking adenosine A 1 and/or A 2A receptors

Caffeine has biphasic effects on locomotion, and blockade of the adenosine A 2A receptor (A2AR) is necessary for the stimulatory effect of low doses of caffeine, but not for the locomotor depressant effect observed at high doses. We wanted to elucidate the role of the adenosine A 1 receptor (A1R) in mediating the locomotor effects of increasing doses of caffeine using wild-type mice (A1R WT), mice heterozygous for (A1R HET), and mice lacking the adenosine A 1 receptor (A1R KO). Caffeine had the typical biphasic dose–effect relationship in all three genotypes, but the stimulatory action of caffeine was facilitated in the A1R KO mice. In order to investigate the interaction between blockade of A1Rs and A2ARs, mice lacking both receptors (A1R KO/A2AR KO) were tested. Regardless of A1R genotype, animals lacking A2AR were not stimulated by caffeine, whereas animals heterozygous for A2AR were. As expected, the A1R is not crucial for the stimulatory effect of caffeine, but seems to modulate the effect of caffeine exerted via A2AR blockade. Furthermore, these results suggest that the inhibitory effect of high doses of caffeine is due neither to blockade of the A1R, nor of the A2AR, and an effect independent of these adenosine receptors is likely.

Protein Kinase A Is a Negative Regulator of Renal Branching Morphogenesis and Modulates Inhibitory and Stimulatory Bone Morphogenetic Proteins

Protein kinase A (PKA) regulates morphogenetic responses to bone morphogenetic proteins (BMPs) during embryogenesis. However, the mechanisms by which PKA regulates BMP function are unknown. During kidney development, BMP-2 and high doses of BMP-7 inhibit branching morphogenesis, whereas low doses of BMP-7 are stimulatory (Piscione, T. D., Yager, T. D., Gupta, I. R., Grinfeld, B., Pei, Y., Attisano, L., Wrana, J. L., and Rosenblum, N. D. (1997) Am. J. Physiol. 273, F961-F975). We examined the interactions between PKA and these BMPs in embryonic kidney explants and in the mouse inner medullary collecting duct-3 model of collecting duct morphogenesis. H-89, an inhibitor of PKA, stimulated branching morphogenesis and enhanced the stimulatory effect of low doses of BMP-7 on tubule formation. Furthermore, H-89 rescued the inhibition of tubulogenesis by BMP-2 (or high doses of BMP-7) by attenuating BMP-2-induced collecting duct apoptosis. In contrast, 8-bromo-cAMP, an activator of PKA, inhibited tubule formation and attenuated the stimulatory effects of low doses of BMP-7. To determine mechanisms underlying the interdependence of BMP signaling and PKA activity, we examined the effect of PKA on the known signaling events in the BMP-2-dependent Smad1 signaling pathway and the effect of BMP-2 on PKA activity. PKA did not induce endogenous Smad1 phosphorylation, Smad1-Smad4 complex formation, or Smad1 nuclear translocation. In contrast, BMP-2 increased endogenous PKA activity and induced phosphorylation of the PKA effector, cAMP-response element-binding protein, in a PKA-dependent manner. We conclude that BMP-2 induces activation of PKA and that PKA regulates the effects of BMPs on collecting duct morphogenesis without activating the known signaling events in the BMP-2-dependent Smad1 signaling pathway.

Ritanserin potentiates the stimulatory effects of raclopride on neuronal activity and dopamine release selectivity in the mesolimbic dopaminergic system.

The atypical profile of clozapine and some other new antipsychotic drugs has been attributed to a relatively selective effect on the mesolimbic dopaminergic system, as well as to their potent serotonin 5-HT2 receptor antagonism and high ratio of 5-HT2 to dopamine D2 receptor affinities. It is unclear, however, how concurrent 5-HT2 and D2 receptor antagonism specifically affects the mesoaccumbens and the mesocortical dopaminergic systems. The present study examined the effect of pretreatment with the 5-HT2 receptor antagonist, ritanserin, on changes in midbrain dopamine neuronal activity as well as in forebrain, extracellular concentrations of dopamine, induced by relatively low doses of the D2 receptor antagonist raclopride, utilizing in vivo extracellular single cell recording techniques and voltammetry in anesthetized rats, as well as microdialysis in freely moving rats. Raclopride alone (10-2560 microgram/kg, i.v.) induced a dose-dependent increase in three parameters of neuronal activity, i.e. burst firing, firing rate and variation coefficient, of midbrain DA neurons. This effect of raclopride was more pronounced in cells of the ventral tegmental area than in cells of the substantia nigra-zona compacta. Ritanserin alone (1.0 mg/kg, i.v.) also increased all three parameters of neuronal activity in dopamine cells of the ventral tegmental area, but only firing rate in the cells of the substantia nigra. Ritanserin pretreatment (30 min) significantly enhanced the stimulatory effects of low doses of raclopride (10-20 micrograms/kg, s.c.) increased extracellular concentrations of dopamine in the medial prefrontal cortex and the dorsolateral striatum by 75 and 110%, respectively, as measured by microdialysis. Ritanserin alone (1.5 mg/kg, s.c.) did not significantly affect cortical and striatal extracellular dopamine concentrations; however, pretreatment (40 min) with ritanserin elevated the raclopride-induced increase of dopamine concentrations in the medial prefrontal cortex of about 250%, but failed to affect the action of raclopride on striatal dopamine levels. Raclopride alone (10 and 320 micrograms/kg, i.v.) dose-dependently increased extracellular concentrations of dopamine in the nucleus accumbens and the dorsolateral striatum to about 500%, as determined by voltammetry. Ritanserin alone (1.0 mg/kg, i.v.) did not significantly affect the voltammetric dopamine signal in the nucleus accumbens or the dorsolateral striatum; however, ritanserin pretreatment (30 min) enhanced the raclopride-induced increase in accumbal but not striatal dopamine concentrations to about 1600%. The stimulatory effect of the combined ritanserin plus raclopride treatment on neuronal activity and DA release was more pronounced in the mesolimbic than the nigrostriatal dopaminergic system. The present data indicate that concurrent 5-HT2 and D2 receptor antagonism selectively affects the activity of the mesolimbic dopaminergic system. These findings provide an experimental basis for the notion that combined 5-HT2 and D2 receptor antagonism may underlie the limbic mode of action of at least some atypical antipsychotic drugs and consequently contribute to their unique therapeutic effects.

Effect of low-dose gamma radiation on nuclear RNA-polymerase activity and protein synthesis in liver cells of different-age chicks

The effect of low-dose (0.05 Gy) gamma irradiation of chicks in the preincubation period on subsequent liver cell RNA-polymerase activity and protein synthesis is studied at different ages. It is shown that irradiated chicks demonstrate an increased level of RNA-polymerase and increased incorporation of labeled amino acids into cytoplasmic proteins. Apparently, low-dose ionizing radiation induces activation of the liver cell genome, this being one of the main mechanisms of the general stimulatory effect of low doses.

A Turnover Study of Hypothalamic Monoamine Oxidase (MAO) and Effects of MAO Inhibition on Gonadotropin Secretion in the Female Catfish, Heteropneustes fossilis

In the present study, the rate constants of degradation ( k) and synthesis (S) and half-life of hypothalamic monoamine oxidase were determined to explain annual variations and biphasic effects of the enzyme to low and high doses of estradiol-17β (E 2) in 3-week ovariectomized Heteropneustes fossilis . In the preparatory phase, the half-life ( t 1/2) of the enzyme was the longest (21.16 days) with low k (0.03275 days -1) and S (0.000845 Units/day) values, suggesting a low turnover of the enzyme. In the prespawning phase the t 1/2 was the shortest (11.65 days) with high k (0.0595 days -1) and S (0.011 Units/day) values. The low and high turnovers of the enzyme, respectively, in these two seasons could be correlated to low and high profiles of plasma E 2 levels. In the resting phase, the values were in between ( t 1/2 = 18.83 days, k = 0.0368 days -1, S = 0.00211 Units/day) but the plasma E 2 level was undetectable. Three weeks of ovariectomy increased the t 1/2 (19.04 days) compared to that of the control (11.61 days) with decreases in both k and S values. The administration of a low dose of E 2 (0.1 μg/g BW) further increased the t 1/2 (19.63 days) over that of the ovariectomized fish with a significant rise in the S value. However, a high dose of E 2 (1.0 μg/g BW) decreased it (13.33 days) by reducing the S and elevating the k values. These results suggest that the stimulatory effect of low doses of E 2 on the enzyme activity is produced by elevating its synthesis rate and the inhibitory effect of high doses of E 2 by simultaneously decreasing the synthesis and increasing the degradation rates of the enzyme. The administration of a single dose (75 mg/kg BW) of pargyline has elevated plasma gonadotropin (GTH) level after 3 and 6 hr and 7 days in the sham-ovariectomized (control), ovariectomized, and ovariectomized low-E 2-dose groups; the peak increase was found at 6 hr. On the contrary, in the ovariectomized high-E 2 group the GTH level was inhibited at 3 and 6 hr postinjection. These changes in the GTH level could be correlated with changes in the profiles of hypothalamic monoamines. The data show that E 2 exerts its feedback regulation of GTH by modifying monoaminergic activity at the level of oxidative deamination.

All-Trans Retinoic Acid Directly Inhibits Granulocyte Colony-Stimulating Factor-Induced Proliferation of CD34+ Human Hematopoietic Progenitor Cells

In this study we examine the effects of retinoids on purified CD34+ human hematopoietic progenitor cells. All-trans retinoic acid inhibited granulocyte colony-stimulating factor (G-CSF)-induced proliferation of CD34+ cells in short-term liquid cultures in a dose-dependent fashion with maximal inhibition of 72% at a concentration of retinoic acid of 1 mumol/L. Although no significant effects were observed on granulocyte-macrophage CSF (GM-CSF)--interleukin-3--or stem cell factor (SCF)-induced proliferation, the combinations of G-CSF and each of these cytokines were all inhibited. Moreover, retinol (3 mumol/L) and chylomicron remnant retinyl esters (0.1 mumol/L) in concentrations normally found in human plasma also had inhibitory effects. Single-cell experiments showed that the effects of retinoic acid were directly mediated. Retinoids also significantly inhibited G-CSF-induced colony formation in semisolid medium, with 88% inhibition observed at a concentration of retinoic acid of 1 mumol/L. However, we did not observe any effects of retinoic acid on G-CSF-induced differentiation as assessed by morphology and flowcytometry. Similar to previous findings using total bone marrow mononuclear cells, we observed a stimulation of GM-CSF-induced colony formation after 14 days. We also observed a stimulatory effect of low doses of retinoic acid (30 nmol/L) on blast-cell colony formation on stromal cell layers. Taken together, the data indicate that vitamin A present in human plasma has inhibitory as well as stimulatory effects on myelopoiesis.

All-trans retinoic acid directly inhibits granulocyte colony- stimulating factor-induced proliferation of CD34+ human hematopoietic progenitor cells

In this study we examine the effects of retinoids on purified CD34+ human hematopoietic progenitor cells. All-trans retinoic acid inhibited granulocyte colony-stimulating factor (G-CSF)-induced proliferation of CD34+ cells in short-term liquid cultures in a dose-dependent fashion with maximal inhibition of 72% at a concentration of retinoic acid of 1 mumol/L. Although no significant effects were observed on granulocyte- macrophage CSF (GM-CSF)--interleukin-3--or stem cell factor (SCF)- induced proliferation, the combinations of G-CSF and each of these cytokines were all inhibited. Moreover, retinol (3 mumol/L) and chylomicron remnant retinyl esters (0.1 mumol/L) in concentrations normally found in human plasma also had inhibitory effects. Single-cell experiments showed that the effects of retinoic acid were directly mediated. Retinoids also significantly inhibited G-CSF-induced colony formation in semisolid medium, with 88% inhibition observed at a concentration of retinoic acid of 1 mumol/L. However, we did not observe any effects of retinoic acid on G-CSF-induced differentiation as assessed by morphology and flowcytometry. Similar to previous findings using total bone marrow mononuclear cells, we observed a stimulation of GM-CSF-induced colony formation after 14 days. We also observed a stimulatory effect of low doses of retinoic acid (30 nmol/L) on blast-cell colony formation on stromal cell layers. Taken together, the data indicate that vitamin A present in human plasma has inhibitory as well as stimulatory effects on myelopoiesis.

Modulation of amnionic adenylate cyclase and cAMP phosphodiesterase by prostaglandins E1 and F2 alpha.

The action of prostaglandins E1 and F2 alpha on adenylate cyclase and cAMP phosphodiesterase was assayed in cell membrane fractions of amnion obtained before and after labor from term physiological pregnancies. Both prostaglandins stimulate the activity of adenylate cyclase in a dose-dependent manner. After spontaneous delivery both prostaglandins stimulate the activity of phosphodiesterase at lower doses and inhibit it at higher ones while the stimulatory effect of low doses is missing before labor. Such a behavior could represent a mechanism for the preservation of the cAMP-mediated processes throughout the entire event of delivery.

Neuromodulatory roles of purines

AbstractIn the present overview we focus on two aspects: (a) the role of adenosine as an endogenous cerebroprotective agent and (b) the possible significance of adenosine‐dopamine interactions. Adenosine is a normal constituent of the brain extracellular environment. Its levels greatly increase upon neuronal excitation or as a consequence of decreased supply of metabolic substrates. Via its receptors it tends to limit its own formation in several ways. By increasing blood flow and glucose uptake it increases substrate supply. By decreasing the release of excitatory neurotransmitters and by causing hyperpolarization it decreases energy demand. This suggests a role as an endogenous cerebroprotective agent, something which is supported by several lines of pharmacological evidence.The adenosine A2a receptor is enriched in dopamine rich‐areas of the brain and it has been found to be colocalized with dopamine D2 receptors on medium‐sized spiny neurons in the striatum. Recent evidence shows that A2 agonists decrease agonist binding to dopamine D2 receptors. Furthermore, adenosine receptor antagonists have been shown to produce behavioural effects that are due to enhanced dopaminergic neurotransmission. It is suggested that the A2‐ D2‐receptor interactions may explain some of the stimulatory effects of low doses of caffeine. © 1993 Wiley‐Liss, Inc.

Regulation of murine T-lymphocyte function by spleen cell-derived and exogenous serotonin.

The modulatory effects of serotonin on T-cell activity were investigated. T-cell blastogenesis of normal spleen cells was slightly stimulated by the addition of low doses (1 and 10 ng/ml) of the inducer of serotonin release, fenfluramine. In contrast to the stimulatory effects of low doses of fenfluramine, high doses of fenfluramine (1 and 10 ug/ml) or of exogenously added serotonin (> or = 0.1 ug/ml) inhibited T-cell activation. Both the stimulation by low dose fenfluramine and the inhibition by high dose fenfluramine were accentuated by pretreating mice with tryptophan to heighten intracellular stores of serotonin and then inducing serotonin release. Pretreatment of mice with the serotonin inhibitor p-chlorophenylalanine (PCPA) abolished the fenfluramine inhibition of T-cell activation indicating that the fenfluramine inhibitory effect was mediated via endogenous spleen cell-derived serotonin. However, the PCPA treatment diminished T-cell activation. These results suggest that endogenous serotonin causes a biphasic dose-response effect on T-cell activity with serotonin being required for optimal T-cell function, low doses being immune stimulatory and higher doses being suppressive.