Complementing ODE-Based System Analysis Using Boolean Networks Derived from an Euler-Like Transformation.

In this paper, we present a systematic transition scheme for a large class of ordinary differential equations (ODEs) into Boolean networks. Our transition scheme can be applied to any system of ODEs whose right hand sides can be written as sums and products of monotone functions. It performs an Euler-like step which uses the signs of the right hand sides to obtain the Boolean update functions for every variable of the corresponding discrete model. The discrete model can, on one hand, be considered as another representation of the biological system or, alternatively, it can be used to further the analysis of the original ODE model. Since the generic transformation method does not guarantee any property conservation, a subsequent validation step is required. Depending on the purpose of the model this step can be based on experimental data or ODE simulations and characteristics. Analysis of the resulting Boolean model, both on its own and in comparison with the ODE model, then allows to investigate system properties not accessible in a purely continuous setting. The method is exemplarily applied to a previously published model of the bovine estrous cycle, which leads to new insights regarding the regulation among the components, and also indicates strongly that the system is tailored to generate stable oscillations.

NaHS induces relaxation response in prostaglandin F(2α) precontracted bovine retinal arteries partially via K(v) and K(ir) channels.

Hydrogen sulphide (H2S) is known to be produced endogenously in ocular tissues with the highest levels in the retina and cornea. However, it is yet unclear whether it can modulate retinal arterial tone. Herein, we aimed to investigate the effectiveness and the mechanism of the action of H2S in the isolated bovine retinal arteries. For this purpose, the probable vasorelaxant and inhibitory effects of H2S on vascular reactivity were tested comparatively in the retinal arteries by using the donor, sodium hydrosulphide (NaHS). Thereafter, in relation to the mechanism of action of H2S, the role of nitric oxide (NO) and endothelial vasodilators of cyclooxygenase pathway as well as ATP-sensitive potassium channel (KATP), voltage-dependent potassium channel (Kv), calcium-activated potassium channel (KCa(++)), inwardly rectifying potassium channel (Kir), L-type voltage-dependent calcium channel and adenylate cyclase pathway were evaluated. NaHS (1µM-3mM) displayed prominent relaxations over the concentrations of 300 µM in both PGF2α and K(+) precontracted retinal arteries. Comparatively, in the presence of NaHS (3 mM) pretreatment, the maximum contractile responses and pEC50 values to PGF2α and K(+) were significantly reduced as well. Neither the presence of the known inhibitors of NO synthase, guanylate cyclase, cyclooxygenase, adenylate cyclase, KATP and KCa(++) type K(+) channels, and L-type voltage-dependent calcium channels nor the removal of endothelium, modified the relaxation response to NaHS in retinal arteries. However, a remarkable decrease was observed in the presence of the inhibitors of Kv or Kir type K(+) channels. In addition, administration of l-cysteine (1µM-3mM), the precursor of H2S, induced a modest relaxation response in PGF2α precontracted retinal arteries, which was significantly decreased in the presence of cystathionine-ß-synthase (CBS) inhibitor, aminooxyacetic acid, but was unmodified in the presence of the cystathionine-γ-lyase (CSE) inhibitor, dl-propargylglycine or the deendothelization of retinal arteries. Our findings suggested that H2S might play a substantial role in the regulation of retinal arterial tone possibly by acting on Kv and Kir channels.

Insulin/FOXO signaling regulates ovarian prostaglandins critical for reproduction.

Abnormalities in insulin/IGF-1 signaling are associated with infertility, but the molecular mechanisms are not well understood. Here we use liquid chromatography with electrospray ionization tandem mass spectrometry to show that the C. elegans insulin/FOXO pathway regulates the metabolism of locally acting lipid hormones called prostaglandins. C. elegans prostaglandins are synthesized without prostaglandin G/H synthase homologs, the targets of nonsteroidal anti-inflammatory drugs. Our results support the model that insulin signaling promotes the conversion of oocyte polyunsaturated fatty acids (PUFAs) into F-series prostaglandins that guide sperm to the fertilization site. Reduction in insulin signaling activates DAF-16/FOXO, which represses the transcription of germline and intestinal genes required to deliver PUFAs to oocytes in lipoprotein complexes. Nutritional and neuroendocrine cues target this mechanism to control prostaglandin metabolism and reproductive output. Prostaglandins may be conserved sperm guidance factors and widespread downstream effectors of insulin actions that influence both reproductive and nonreproductive processes.

F-series prostaglandin function as sex pheromones in the Korean salamander, Hynobius leechii.

In order to test whether prostaglandins (PGs) function as sex pheromones in Hynobius leechii, a salamander that externally fertilizes its eggs, we conducted electro-olfactogram (EOG) studies with 19 PGs, liquid chromatography tandem mass spectrometry (LC-MS/MS) analyses of female and male holding waters, and behavioral tests on selected PGs. Of the 19 PGs tested, only three induced strong EOG responses from both males and ovulated females: 15-epi-prostaglandin F2alpha (15(R)-PGF2alpha), 15-keto-prostaglandin F2alpha (15K-PGF2alpha), and 13,14-dihydro-15-keto-prostaglandin F2alpha (13,14-dh-15K-PGF2alpha). In the LC-MS/MS studies, samples of holding water from ovulated females contained higher concentrations of 15(R)-PGF2alpha, PGF2alpha, and 13,14-dh-15K-PGF2alpha than those from males or oviposited females. In the behavioral tests, only 15(R)-PGF2alpha and ovulated female holding water induced significant reproductive behavior from male salamanders. These results suggest that F-series prostaglandins function as sex pheromones in amphibians.

An investigation into the role of prostaglandins in zebrafish oocyte maturation and ovulation.

This study explored the potential for ovarian-derived prostaglandins (PGs) to be involved in the regulation of oocyte maturation and ovulation in zebrafish. It was demonstrated that cultured vitellogenic follicles have the capacity to produce prostaglandin E(2) (PGE(2)) and PGF(2alpha) in response to arachidonic acid (AA) in a concentration-dependent manner, and that AA stimulates the in vitro production of 17beta-estradiol (E(2)). The production of AA-stimulated PGF(2alpha) was significantly reduced by treatment with the non-selective cyclooxygenase (COX) inhibitor, indomethacin (INDO). Treatment of full-grown follicles with AA did not induce oocyte maturation as assessed by germinal vesicle breakdown, but INDO significantly decreased the rate of spontaneous maturation. Using Real-Time PCR, it was shown that follicles of different developmental size classes (primary growth and pre-vitellogenic, early-vitellogenic, and mid- to full-grown vitellogenic) express enzymes that release (cytosolic phospholipase A(2) (cPLA(2)); phospholipase Cgamma1) or metabolize (COX-1, COX-2, and prostaglandin synthase-2) AA to PG metabolites. The expression of cPLA(2) was found to be significantly greater in full-grown follicles compared to follicles of the pre- and early-vitellogenic stages. In vivo studies demonstrated that breeding groups of zebrafish exposed to 100 microg/L INDO exhibited reduced spawning rates and clutch sizes compared with control and 1 microg/L INDO exposed fish. In other studies, it was shown that naturally spawning groups of females exhibit increased ovarian levels of PGF(2alpha), E(2), and 17alpha,20beta-dihydroxy-4-pregnen-3-one (a maturation-inducing hormone in zebrafish) near the time of ovulation compared with non-breeding females. Collectively, these experiments indicate that the AA pathway in zebrafish ovaries is involved in the regulation of oocyte maturation and ovulation and a non-selective inhibitor of COX disrupts these processes.

[Comparative morpho-functional assessment of the impact produced by prolonged infusions of prostaglandins E and F on the course of genetically preconditioned arterial hypertension]. / Sravnitel'naia morfofunktsional'naia otsenka vliianiia prolongirovannykh infuzii prostaglandinov E i F na techenie geneticheski obuslovlennoi arterial'noi gipertonii.

The administration of prolonged intravenous infusions of prostaglandins is defined; the method provided for specifying a long-term impact produced by prostaglandins on a nature of the course of genetically preconditioned arterial hypertension (AHT) in rats. Infusions of PGE-2 bring about a prolonged and stable reduction of mean arterial presser (AP) by 10% versus its original value; they intensify 2-fold the depressor baroreflectory regulation and stimulate the urinary excretion of endogenous renal PGF-2 alpha; besides, they contribute to a better blood supply to organs, i.e. an increased perfusion of the cortical and medullary layers of the kidneys and of the brain substances; and dilatation of the intramural branches of the coronary arteries, due to which the AP becomes milder. Infusions of PGF-2 alpha contribute to a prolonged and stable elevation of mean AP by 12% versus the original value; they inhibit the depressor baroreflectory regulation and intensify the pressor baroreflectory regulation; they, additionally, induce the urinary excretion of endogenous renal PGF-2 alpha and correct the lesions in the blood supply to organs, i.e. pathological microcirculation, anemia and spasm of the renal parenchyma, ischemic foci in the myocardium, spastic contraction of small cerebral arteries, edema and destructive changes (of the local necrosis variation) in the cerebral substance microvessels concomitant with a commencing diapedetic hemorrhages. Finally, all above listed lesions are signs of the malignant AP course.

PGF(2alpha), a prostanoid released by endothelial cells activated by hypoxia, is a chemoattractant candidate for neutrophil recruitment.

Despite increasing evidence supporting the involvement of neutrophils in ischemic and postischemic damages, the mechanisms underlying the early recruitment of these cells are not completely understood. In this report, the effects of conditioned media from hypoxic endothelial cells on neutrophil chemotaxis were investigated by biochemical and morphological studies. We showed that conditioned media collected from several endothelial cell origins submitted to hypoxia as well as ischemic rat liver perfusion liquids have a chemotactic activity for neutrophils. The role of various chemoattractant molecules like HETEs, platelet-activating factor, and cytokines such as interleukin-8 and interleukin-1 was examined in the same model. Chemotactic peptide contribution was ruled out as boiled conditioned media still trigger chemotaxis. However, cell treatment with cyclooxygenase inhibitors, neutralization of PGF(2alpha) biological activity with polyclonal antibodies, and the neutrophil preincubation with a specific PGF(2alpha) antagonist, all dramatically inhibited neutrophil chemotaxis. A strong chemoattractant effect of pure exogenous PGF(2alpha) or of a synthetic analog was also observed. The major effect of PGF(2alpha) on neutrophil chemotaxis was confirmed ex vivo in a rat liver perfusion ischemic model. These results suggest that PGF(2alpha), a prostanoid abundantly released by the endothelium of hypoxic or ischemic tissues, is a chemoattractant molecule that might be involved in the early recruitment of neutrophils in ischemic organs.

The early fetal life of the equine conceptus.

This paper will discuss development of the equine conceptus, especially from the perspective of the maternal environment in which it develops and to which it has considerable influence.

Peptide growth factors in amphibian embryogenesis: intersection of modern molecular approaches with traditional inductive interaction paradigms.

Recent discoveries of the role peptide growth factors (PGFs) play in regulating embryonic patterning and differentiation have profoundly influenced research on the molecular biology of early amphibian embryogenesis. Several PGFs have been recognized to be present as endogenous components of amphibian eggs and early embryos, while other PGFs -- which are known from heterologous systems (e.g., Drosophila) -- exert remarkable effects when injected as either protein or mRNA into eggs/embryos or when added to cultured embryonic tissue. For a variety of reasons (reviewed herein) optimism abounds that an understanding in molecular terms of the classical Spemann and Nieuwkoop tissue interactions which are generally believed to drive embryonic patterning is within reach. A critical assessment of the interpretations of some of the contemporary data on PGFs (included herein) should, however, temper some of that optimism. Likely, multiple rather than single PGFs act in a combinatorial fashion to contribute to individual patterning events. As well, substantial redundancy in PGF regulatory circuits probably exists, so the heavy reliance on tissue culture assays and overexpression studies which characterize much recent research needs to be circumvented. Potential experimental approaches for "next generation" experiments are discussed.

Prostaglandin E2 and I2 regulate intercellular adhesion molecule-1 expression in interleukin-1 beta-stimulated human gingival fibroblasts.

The present study investigated the effect of prostaglandin (PG) E2 and PGI2 on intercellular adhesion molecule-1 (ICAM-1) expression in interleukin-1 beta (IL-1 beta)-stimulated human gingival fibroblasts (HGF). IL-1 beta potently induced ICAM-1 expression in HGF and indomethacin, a cyclooxygenase inhibitor, enhanced ICAM-1 expression in the cells. These data showed that endogenous PGs generated by HGF stimulated with IL-1 beta downregulated ICAM-1 expression. IL-1 beta significantly increased the levels of PGE2 and, to a lesser extent, those of 6-keto-PGF1 alpha (a stable metabolite of PGI2) in the culture media of HGF. Indomethacin completely inhibited the production of PGE2 and 6-keto-PGF1 alpha in IL-1 beta-stimulated HGF. Exogenous PGE2 and carbacyclin (a stable derivative of PGI2) in the presence of indomethacin dose-dependently suppressed ICAM-1 expression in IL-1 beta-challenged HGF. Since PGE2 and PGI2 are known to elevate intracellular cyclic AMP (cAMP) levels, we examined the effect of dibutyryl cAMP, a cAMP analogue, and isobutylmethylxanthine, a phosphodiesterase inhibitor, on ICAM-1 expression. Both agents downregulated ICAM-1 expression in IL-1 beta-stimulated HGF. These results suggest that PGE2 and PGI2 downregulate ICAM-1 expression in IL-1 beta-stimulated HGF through a cAMP-dependent mechanism and that intracellular cAMP elevation in HGF may control inflammatory and immune responses in periodontal disease.

Role of prostaglandins in acetylcholine-induced contraction of aorta from spontaneously hypertensive and Wistar-Kyoto rats.

Evidence in support of prostaglandin (PG) H2 as the endothelium-derived contracting factor released in response to acetylcholine in vessels from adult spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) is to a large degree indirect. Therefore, the purpose of the present study was to test the hypothesis that a prostaglandin or prostaglandins other than PGH2 may serve as the endothelium-derived contracting factor that mediates acetylcholine-induced contraction in these vessels. Acetylcholine-induced contraction of endothelium-intact aorta from 7- to 12-month-old SHR and WKY in the presence of the nitric oxide synthase inhibitor N omega-nitro-L-arginine was abolished by indomethacin and only partially decreased by the thromboxane (Tx) A2/PGH2 receptor antagonist SQ29548. Contraction induced by the TxA2/ PGH2 receptor agonist U46619 was abolished by SQ29548. These findings suggest that in endothelium-intact aorta from SHR and WKY, acetylcholine causes the release of a cyclooxygenase product other than PGH2 that induces contraction independently of TxA2/PGH2 receptor activation. To investigate which prostaglandin or prostaglandins could be responsible for the TxA2/PGH2 receptor-independent component, we challenged endothelium-denuded aorta from SHR and WKY with various prostaglandins in the presence of SQ29548. In SQ29548-treated aorta from 7- to 12-month-old rats, maximal contractions to PGF2 alpha, PGE2, and carbacyclin (a PGI2 analogue) were greater than the magnitude of acetylcholine-induced contraction. These findings suggest that PGF2 alpha, PGE2, and/or PGI2 could serve as mediators of the TxA2 receptor-independent component of the acetylcholine-induced contraction. However, in studies with SQ29548-treated aorta from 4- to 6-week-old SHR and WKY (an age at which acetylcholine-induced contraction is known to be absent), maximal contraction to PGF2 alpha and PGE2 was also greater or equivalent to that of SQ29548-treated aorta from 7- to 12-month-old rats, whereas carbacyclin induced negligible contraction. Thus, unlike PGE2 and PGF2 alpha, the age-dependent pattern of contraction induced by carbacyclin closely resembles the pattern induced by acetylcholine. We also measured the levels of PGI2 released in response to acetylcholine and found that they are sufficient to account for the TxA2 receptor-independent component of the acetylcholine-induced contraction. Thus, we propose that PGI2 released in response to acetylcholine may serve as the endothelium-derived contracting factor that elicits the TxA2/PGH2 receptor-independent and dependent components of the acetylcholine-induced contraction.

[Role of prostaglandins F and E in regulation of bronchial activity]. / Udzial prostaglandyn F i E w regulacji czynnosci oskrzeli.

Prostaglandins (PGs) belong to the family of eicosanoids. A main substrate in their biosynthesis is arachidonic acid. Involvement of PGs in regulation of bronchial activity is a complex process and far from being fully understood. In 1968 it was shown that prostaglandins E1 and E2 cause bronchodilation, while prostaglandin F2a constricts an isolated human smooth muscle. The recent studies which revealed protective effects of PGE2 on bronchial reaction induced in patients by ultrasonically nebulized distilled water, allergen, metabisulfite, or exercise, revitalized interest among clinicians. Reports that PGE2 inhibits airways response in bronchial provocation with lysine aspirin, allow to believe that PGE2 plays a role in pathogenesis of aspirin induced asthma.

Platelet-activating factor potentiates protamine-induced lung edema. Role of eicosanoids.

Platelet-activating factor (PAF) is a cell membrane-derived ether lipid that plays an important role in acute lung vascular injury. We recently reported that PAF potentiates protamine-induced lung edema by enhancing pulmonary venoconstriction. As PAF is known to stimulate lung eicosanoid synthesis, we investigated the role of peptidoleukotrienes and other eicosanoids in this priming effect of PAF. Addition of PAF (1.6 nM), followed 10 min later by protamine (50 micrograms/ml), to perfusate of salt solution-perfused rat lungs resulted in marked arterial and venous constrictions and severe lung edema. Lung tissue thromboxane B2, 6-ketoprostaglandin F1 alpha and leukotriene C4 (LTC4) were markedly elevated 20 min after PAF/protamine. Pretreatment of the lungs with AA-861, a specific 5-lipoxygenase inhibitor, blocked PAF/protamine-induced leukotriene synthesis, arterial and venous constrictions, and lung edema. In addition, injection of LTC4 (1 microgram) markedly potentiated protamine-induced arterial and venous constrictions and caused lung edema similar to PAF/protamine. Indomethacin, a specific cyclooxygenase inhibitor, also reduced the vasoconstrictive and edemagenic responses to PAF/protamine. However, the pulmonary edema after LTC4/protamine was not blocked by indomethacin. In separate experiments, infusion of this "priming" dose of PAF into isolated perfused lungs induced LTC4 synthesis and augmented lung thromboxane A2 synthesis after arachidonic acid infusion. We conclude that both cyclooxygenase and lipoxygenase products of arachidonic acid metabolism are involved in PAF-induced potentiation of protamine lung edema.

Pheromonal and reproductive function of F prostaglandins and their metabolites in teleost fish.

Although the function of prostaglandins in fish reproduction has not been well studied, it is becoming increasingly clear that prostaglandin F2 alpha or a compound closely resembling it serves three critical roles mediating reproductive activities in teleost fish. First, it appears to play a paracrine role in the ovary stimulating and/or modulating follicular rupture. Second, circulating levels of F prostaglandins rise at the time of ovulation and travel to the brain where they elicit female sexual behavior. Third, recent studies indicate that F prostaglandin is metabolized and released to the water where it functions as a sex pheromone stimulating male sexual behavior. Although these roles have been best characterized in the goldfish, ongoing studies indicate that metabolites of prostaglandin F2 alpha may commonly function as pheromones in many fish. Many questions remain about the identity(ies), origins, and species-specificity of the prostaglandin pheromone.

Evidence of organ damage after cardiopulmonary bypass. The role of elastase and vasoactive mediators.

In this study the causes of organ damage after cardiopulmonary bypass were multifactorial. The concentration of the proteolytic enzyme elastase, which was released from activated granulocytes in the milieu of significantly reduced levels of alpha 1-protease inhibitor (p less than 0.01), increased during cardiopulmonary bypass (p less than 0.01). In addition, bypass initiated platelet aggregation, which both altered the eicosanoid metabolism and caused the level of thromboxane A2 to increase and surpass the level of prostaglandin I2. Because thromboxane A2 dominance subsided immediately after cardiopulmonary bypass, the effect of thromboxane A2 (vasoconstriction) on the development of organ damage may have been influential only during bypass. Both during and after bypass, the increase in endothelin excretion (p less than 0.01 to 0.05) was believed to induce a further vasoconstriction in the microvasculature. On completion of the cardiopulmonary bypass, the elevation of the lysosomal enzyme beta-glucuronidase, which is a sensitive indicator of cellular damage, was influenced by the concentrations of elastase (r = 0.8) and endothelin (r = 0.52). As evidenced by leuko-sequestration in the lung after cardiopulmonary bypass, the increase in the alveolar-arterial oxygen tension difference correlated with the elastase concentration (r = 0.68). Renal damage, which was detected by an increase in renal tubular enzymes (N-acetyl-beta-D-glucosaminidase and gamma-glutamyltranspeptidase) was affected by the endothelin (r = 0.68, 0.56) and elastase levels (r = 0.58, 0.68), respectively, but not by the ratio of thromboxane B2 to prostaglandin F1 alpha. The elastase level influenced the pulmonary vascular resistance (r = 0.56). However, neither the cardiac index nor the systemic and pulmonary vascular resistances were influenced by the endothelin level and the ratio of thromboxane B2 to prostaglandin F1 alpha.

Endocrine correlates of mating-induced reductions in estrous behaviour in an induced ovulator, the ferret.

Experiments were conducted to assess the time course of behavioral and endocrine changes which occur in female ferrets as they switch from estrus to the pseudopregnant state. Significant reductions in females' acceptance of neck gripping by a stimulus male (receptivity) and in their latency to approach a stimulus male in an L-maze (proceptivity) were first observed 3 days after receipt of an intromission; no such changes occurred in other females which were only neck gripped by stimulus males during the initial test session. Corpora lutea were later found only in the ovaries of females which received intromissions, confirming that ovulation had occurred in these animals. Plasma concentrations of prostaglandin E1, prostaglandin F2 alpha, and the 13,14-dihydro 15-keto metabolite of prostaglandin F2 alpha (PGFM) were unchanged in female ferrets for 4-5 days after receipt of an intromission. By contrast, plasma concentrations of progesterone were significantly elevated beginning 5 days after, whereas plasma estradiol was significantly reduced beginning 4 days after receipt of an intromission. Daily sc administration of the progesterone receptor antagonist. RU 38486, significantly retarded the lengthening in females' approach latencies to a stimulus male, suggesting that postcoital elevations in circulating progesterone normally contribute to the expected decline in proceptive responsiveness. By contrast, postcoital reductions in acceptance quotients occurred at equivalent rates in females treated with RU 38486 versus vehicle, leading us to infer that postcoital reductions in estrogenic stimulation may cause this decline in ferrets' receptive responsiveness.

Endometrial electrogenic ion secretion in the rat is modulated by prostaglandins.

In the isolated rat uterus, maximal increases in endometrial electrogenic ion secretion produced by luminal prostaglandins (PGs) E1, E2 and F1, and measured as the short-circuit current (Isc), displayed bell-shaped dose-response curves. PGE1 was the most potent and PGF1 the least. The dose-response relationships for the decrease in resistance were curvilinear for PGE1 and PGF1 but bell shaped for PGE2. PGF1 was the most potent at inhibiting the increase in Isc induced by serosal adrenaline but not in inhibiting the fall in tissue resistance. The electrogenic ion secretion of rat endometrium is modulated by prostaglandins via a mechanism also influenced by adrenaline.

Prostaglandins--a role in adhesion formation. An experimental study.

The effect of intraperitoneal application of prostaglandins F2 alpha and E2 on adhesion formation was studied in the rat after traumatizing to the uterine serosa. Prostaglandins applied locally were found to increase intraperitoneal adhesion formation at the injury site, in comparison with controls. The effect of intraperitoneal application of prostaglandins F2 alpha and E2 on fibroblastic proliferation was examined in vitro, by fibroblastic cell culture of rat kidney, human kidney and human prepuce. No direct effect of prostaglandins on fibroblast proliferation could be demonstrated. It is concluded that prostaglandins play an important role in the process of adhesion formation. This effect is not related to fibroblast proliferation.