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PubMed1983

Caffeine inhibition of aflatoxin production: mode of action.

Evaluation of caffeine and a number of related methylxanthines indicated that the ability of the compound to inhibit growth and aflatoxin production by Aspergillus parasiticus is highly specific and does not involve an inhibition of cyclic AMP phosphodiesterase. Supplementation of the culture medium with purine bases, nucleosides, and nucleotides suggested that the inhibition of fungal growth could be partially overcome by adenine or guanine but that the purines had little effect on the inhibition of aflatoxin production. Likewise, increasing the levels of trace minerals did not overcome the inhibition of toxin production. Electron microscopic evaluation of caffeine-treated and -untreated cultures indicated that the compound produced observable changes in the ultrastructure of the fungus.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1983

Mechanisms of cyclic AMP phosphodiesterase regulation.

The mechanisms of regulation of cyclic AMP phosphodiesterases were studied using the cytoplasmic fraction of PC-12 cells sensitive to the action of nerve growth factor. The cells contain phosphodiesterases of two types. One of them possesses a high affinity for cyclic AMP (Km = 2.46 mM), whereas the other has the affinity by an order worse (Km = 37.1 mM). PC-12 cell differentiation under the action of nerve growth factor is connected with the cyclic nucleotide elevation; however, activities of both phosphodiesterases remain unchanged. This indicates that the regulation of activity of these enzymes in PC-12 cells is mediated by second messenger effects. The main object of cell regulation is phosphodiesterase with low affinity for the substrate. Its activity is modulated by the calmodulin-Ca2+ complex, cyclic GMP and NAD+ at micromolar concentrations. The effect on the phosphodiesterase system of both a "quick" messenger, Ca2+ and "slow" messengers, cyclic GMP and NAD+, has the same consequences: the turnover number of the enzymic reaction increases that is accompanied by a proportional decrease in the enzyme affinity for cyclic AMP so that the ratio Vmax/Km remains constant. A possible explanation of functional significance of such an activity modulation may be the necessity to maintain the conditions for phosphodiesterase functioning when Km much greater than [cyclic AMP] and the reaction rate are directly proportional to the substrate concentration: v = Vmax/Km [cyclic AMP]. Then the cells are transferred into such a mode when autoregulation of the cyclic nucleotide level takes place. Besides the transient effects causing changes in phosphodiesterase activity, studies of PC-12 cells revealed a chronic effect of phosphodiesterase activity change under the action of staphylococcal enterotoxin A. This protein which induces differentiation of PC-12 cells and possesses a NAD+-glycohydrolase activity is translocated into cytoplasm of cells in the presence of NAD+ and accomplishes ADP-ribosylation of phosphodiesterase. As a result, the enzyme activity falls, cyclic AMP level increases and cell differentiation starts. The activity of soluble phosphodiesterase of PC-12 cells also decreases under the effect of two neurotoxins from bee venom, melittin and tertiapin. Both the toxins at concentration of 10 microM completely block calcium regulation of the enzyme. The mechanism of tertiapin action was investigated on a model system of calmodulin-bovine brain phosphodiesterase. It appeared that inhibition of Ca2+ action is achieved as the result of binding of two toxin molecules with Kd = 2 mM to the activated calmodulin molecule.(ABSTRACT TRUNCATED AT 400 WORDS)

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1994

Prostaglandins E2 and E1 inhibit cytokine-induced metalloprotease expression in human synovial fibroblasts. Mediation by cyclic-AMP signalling pathway.

BACKGROUND: Cytokine modulated matrix metalloprotease (MMP, i.e., collagenase and stromelysin) synthesis may be associated etiologically with osteoarthritic diseases. The aim of this study was to investigate the mode of action by which interleukin-1 beta (IL-1 beta) induced collagenase and stromelysin mRNA expression and synthesis in normal human synoviocytes and to explore mechanisms of suppression of these proteolytic enzymes by prostaglandins (PG). EXPERIMENTAL DESIGN: Collagenase and stromelysin expression and synthesis were induced in cultured human synoviocytes with rhIL-1 beta in the absence or presence of either chemical inhibitors of protein kinase (PK) A and C, PGE2 or PGE1, or cAMP mimetics. We used enzyme immunoassays to determine MMP antigen levels in spent culture medium and Northern hybridization to measure steady-state MMP mRNA expression. RESULTS: Dose-response experiments revealed that 10 pg/ml of interleukin-1 beta was an effective sub-saturating concentration for the induction of collagenase and stromelysin expression in normal human synovial fibroblasts. The rate of collagenase synthesis and expression peaked at 18 to 24 hours after rhIL-1 beta stimulation, whereas stromelysin output increased steadily within the experimental time frame (72 hours). Protein kinase C inhibitors, H-7 and staurosporine, prevented the rhIL-1 beta induction of MMP mRNA expression and protein synthesis. Pretreatment of synoviocytes with phorbol myristate acetate for 18 hours abrogated the ability of rhIL-1 beta to induce MMP synthesis. Prostaglandins E2 and E1 potently inhibited in a dose-dependent fashion rhIL-1 beta induced MMP synthesis: PGE2, IC50, collagenase, 2.3 ng/ml; stromelysin, 21.2 ng/ml; PGE1, IC50, collagenase, 2.5 ng/ml; stromelysin, 13.4 ng/ml. MMP mRNA steady-state levels were suppressed in a fashion similar to that of the protein synthesis. Forskolin, dibutyryl cAMP, and 3-isobutyl-1-methyl xanthine mimicked the effects of the prostaglandins (PGs). [N-(2-methyl-amino)-5-isoquinoline-sulfonamide dihydrochloride] (H-8), an inhibitor of PKA activity, could reverse to a large extent, the suppressive effects of the PGs as did cycloheximide when preincubated with PGE2 before rhIL-1 beta activation of synoviocytes. CONCLUSIONS: We conclude that IL-1 beta stimulates MMP synthesis by activating PKC but not PKA, and that the synthesis of collagenase and stromelysin is discoordinate on a temporal and quantitative basis. PGs inhibit rhIL-1 beta-induced MMP expression and synthesis by virtue of their ability to increase cAMP intracellular levels and subsequent activation of signal transduction mechanisms involving PKA. Homeostasis may be maintained in acute episodes of joint inflammation through feedback processes involving locally produced eicosanoids.

Alprostadil↗
PubMed2004

Novel mode of action of tylophorine analogs as antitumor compounds.

Tylophorine and its analogs are phenanthroindolizidine alkaloids, several of which have been isolated from the Tylophora genus of plants. Evaluation of (+)-S-tylophorine [DCB-3500 (NSC-717335)] and its analog DCB-3503 (NSC-716802) in the National Cancer Institute tumor screen showed a fairly uniform and potent inhibition of cell growth in all 60 cell lines (GI(50) approximately 10(-8) M). To further evaluate the antitumor potential of these compounds, we synthesized four tylophorine analogs, designated DCB-3500, DCB-3501, DCB-3502, and DCB-3503. All four tylophorine analogs exerted potent growth-inhibitory effects against HepG2, a human hepatocellular carcinoma cell line, and KB, a human nasopharyngeal carcinoma cell line. HepG2 cells were more sensitive than KB in terms of loss of clonogenicity. KB variants, which are resistant to etoposide, hydroxyurea, or camptothecin, have similar sensitivities to the tylophorine analogs, as do the parental KB cells. Treatment of nude mice bearing HepG2 tumor xenografts by i.p. injections of DCB-3503 at 6 mg/kg every 8 h on days 0 and 3 resulted in significant tumor growth suppression (P < 0.0001). Unlike conventional antitumor drugs, 3 micro M DCB-3503 did not cause DNA breaks or apoptosis in HepG2 cells. Tylophorine analogs induced albumin expression and decreased alpha-fetoprotein expression in HepG2 cells, which suggests that tylophorine analogs could induce HepG2 differentiation. Tylophorine analogs had an inhibitory effect on cyclic AMP response elements, activator protein-1 sites, or nuclear factor-kappaB binding site-mediated transcriptions. In summary, these tylophorine analogs are a unique class of antitumor compounds that have a mode of action different from known antitumor drugs.

Alkaloids↗
PubMed1982

Prostacyclin: effects on cyclic AMP in bone cells.

Prostacyclin (PGI2) increased cyclic AMP in specific rat bone cell populations obtained by sequential collagenase digestion of calvariae. An osteoclastic population, characterized by high acid phosphatase levels and the ability to resorb bone in vitro, was more sensitive as reflected by responses to lower doses of PGI2 (2.3 x 10(-8)M) as well as greater responses to higher doses (3.5 x 10(-4)) of PGI2 than the other populations isolated. The osteoblastic populations, characterized by high alkaline phosphatase levels and the inability to resorb devitalized bone did not respond significantly to PGI2 at doses less than 10(-4)M and increases in cAMP were smaller. Then results suggest a differential effect of PGI2 on osteoclasts and osteoblasts which may be involved in the mode of action of endogenously produced PGI2 in bone.

Animals↗
PubMed1987

Dual activation by thyrotropin of the phospholipase C and cyclic AMP cascades in human thyroid.

In human thyroid slices prelabeled with myo-[2-3H]inositol, thyrotropin (TSH, 3-30 mU/ml) stimulated IP3, IP2 and IP1 generation over a prolonged time course. The cAMP response was much more sensitive to TSH, peaking between 1 and 5 mU/ml. Forskolin (10(-5) M) and isoproterenol had no effect on basal IP levels, while carbamylcholine (10(-5) M, 10(-4) M) also increased IP accumulation. These data suggest that in the human thyroid, TSH activates a phospholipase C generating IP3 and diacylglycerol independently of the well-known adenylate cyclase stimulation. They validate in the human model a dual mode of action of the hormone previously proposed on the basis of indirect observations.

Cyclic AMP↗
PubMed1987

Ganglioside inhibition of attachment and differentiation of cultured rat granulosa cells: interactions with fibronectin.

The involvement of fibronectin in the attachment and differentiation of rat granulosa cells, cultured in a chemically defined medium, was investigated using the inhibitory properties of mixed brain gangliosides (MBGs) and highly purified disialoganglioside, GD1a. MBGs inhibited cell attachment to plastic culture surfaces in a concentration-dependent manner, with 0.1 mmol l-1 causing significantly decreased attachment between 0.5 and 24 h of incubation. Inhibition of attachment to a fibronectin-coated substratum was even greater. The inhibitory effect of MBGs was not caused by binding to the cell surface, but instead the inhibitory factor(s) were adsorbed on a surface of immobilized human plasma fibronectin, thereby preventing cell attachment to this surface. The inhibitory action of MBGs was also neutralized by the addition of soluble fibronectin. Furthermore, at least one component of MBGs, detected chemically following thin-layer chromatography, was directly shown to bind to human fibronectin. MBGs inhibited to varying degrees the follicle-stimulating hormone(FSH)-dependent responses: augmentation of cellular protein content, production of adenosine 3',5'-cyclic monophosphate (cyclic AMP) and progestins (progesterone + 20 alpha-hydroxypregn-4-en-3-one + pregnenolone), and induction of aromatase activity. These inhibitory activities of MBGs could not be eliminated by adsorption on immobilized fibronectin or reversed by addition of soluble fibronectin, thus distinguishing these actions from the early inhibition of cell attachment. FSH-dependent responses were also inhibited by GD1a, while responses to stimulation by dibutyryl cyclic AMP plus 3-isobutyl-1-methyl xanthine were less affected by this ganglioside. These results suggest that gangliosides inhibit attachment of granulosa cells in culture by binding to fibronectin, whereas the inhibition of FSH-dependent differentiation occurs by other modes of action that are unrelated to the effects on cell adhesion.

Animals↗
PubMed1988

Effect of mono-(2-ethylhexyl)phthalate on follicle-stimulating hormone responsiveness of cultured rat Sertoli cells.

Mono-(2-ethylhexyl)phthalate (MEHP) is one of a number of phthalate esters known to damage the rat testis with the Sertoli cell as its target. These effects can be modeled using primary testicular cell cultures. Stimulation of rat Sertoli cells by follicle-stimulating hormone (FSH) results in an increase in release of cAMP into the culture medium. However, cultures pretreated with MEHP (10(-7)-10(-4) M) showed a dose-related reduction in FSH-stimulated cAMP production (maximally greater than 50%), suggesting that MEHP is interfering with the FSH receptor-adenyl cyclase system. Detailed investigations of the system were conducted utilizing forskolin and choleratoxin, which both stimulate adenyl cyclase but bypass the FSH receptor to produce an increase in cAMP secretion. Cultures pretreated with MEHP (10(-9)-10(-5)M) showed no reduction in either forskolin- or choleratoxin-stimulated cAMP production. However, at low doses (10(-8)-10(-6)M) MEHP produced a potentiation (up to three times) of both forskolin- and choleratoxin-stimulated cAMP secretion, but gave slight inhibition at 5 X 10(-5) and 10(-4) M. These data indicate that MEHP produces a perturbation at the level of the FSH receptor, causing an inhibition of FSH action. This finding may be related to the age-dependent toxicity of the compound, since FSH is critical for the initiation of spermatogenesis in young animals, but is not necessary for the maintenance of spermatogenesis in adults. Thus an effect on FSH responsiveness in vitro may provide an indication of the mode of action of MEHP in vivo.

Animals↗
PubMed2001

Regulation of gonadotropin subunit genes in tilapia.

A steroidogenic tilapia gonadotropin (taGtH=LH) was purified from pituitaries of hybrid tilapia (Oreochromis niloticus x O. aureus) and a homologous RIA was established. This RIA enabled the study of the endocrine regulation of GtH release, the transduction pathways involved in its secretion and its profile during the spawning cycle. Discrepancies between steroid and taGtH peaks during the cycle led to the conclusion that an additional gonadotropin similar to salmonid FSH operates early in the cycle. In order to identify this hormone and to study the endocrine control of synthesis of all gonadotropin (GtH) subunits, a molecular approach was taken. The cDNA sequences and the entire gene sequences encoding the FSHbeta and LHbeta subunits, as well as an incomplete sequence of the glycoprotein hormone alpha subunit (GPalpha), were cloned. Salmon gonadotropin-releasing hormone (sGnRH) elevated mRNA steady-state levels of all three GtH subunits in cultured pituitary cells. Pituitary adenylate cyclase-activating polypeptide (PACAP) and neuropeptide Y (NPY) also stimulated the expression of these subunits and potentiated the effect of GnRH, except that NPY did not affect FSHbeta. The GnRH and NPY effects were found to be mediated mainly through protein kinase C (PKC), while protein kinase A (PKA) cascade was involved to a lesser extent. Mitogen-activated protein kinase (MAPK) cascade takes part in mediating GnRH effects, possibly via PKC. Testosterone (T) and estradiol (E2), but not 11-ketotestosterone (KT), are able to elevate GPalpha and LHbeta mRNAs in pituitary cells of early maturing or regressing males. Low levels of T exposure are associated with elevated FSHbeta mRNA in cells of mature fish, while higher levels suppress it, but elevate LHbeta mRNA. In vivo observations also showed the association of low T levels with increased FSHbeta mRNA and high T levels with elevated LHbeta mRNA. In accordance with these findings, analysis of LHbeta and FSHbeta 5' gene-flanking regions revealed on both gene promoters a GtH-specific element (GSE), half site estrogen response elements (ERE), cAMP response element (CRE) and AP1. In vitro experiments showed that recombinant human activin-A leads to higher levels of GPalpha, FSHbeta and LHbeta mRNAs in pituitary cell culture. Porcine inhibin marginally decreased the mRNA levels of GPalpha and FSHbeta, but at a low level (1 ng/ml) it stimulated that of LHbeta. These results shed some light on certain hypothalamic and gonadal hormones regulating the expression of GtH subunit genes in tilapia. In addition, they provide evidence for their differential regulation, and insight into their mode of action.

Activins↗
PubMed1988

In vitro investigations on a new positive inotropic and vasodilating agent (BM 14.478) that increases myocardial cyclic AMP content and myofibrillar calcium sensitivity.

BM 14.478 (7,7-dimethyl-2-(4-pyridyl)-6,7-dihydro-3H,5H pyrrolo[2,3-f]benz-imidazol-6-one) was investigated in several in vitro experiments to elucidate its positive inotropic and vasodilating efficacy and its mode of action. A direct positive inotropic action was achieved in papillary muscles (10(-6) to 5 X 10(-4) M) and electrically driven atria (10(-8) to 5 X 10(-4) M) from guinea pig hearts. The effect was not affected by propranolol, cimetidine, or tetrodotoxin, but diminished by carbachol. The effect of isoprenaline was amplified by threshold concentrations of BM 14.478 (10(-6) M). There was only a slight intrinsic chronotropic activity in spontaneously beating guinea pig atria. Atrial cyclic AMP (cAMP) was increased from 1.46 +/- 0.06 to 1.97 +/- 0.03 pmol/mg wet wt, at 3 X 10(-6) M. This might be due to an inhibition of cardiac phosphodiesterase(s) (PDE). IC50 of bovine PDE was 7.2 X 10(-5) M (5.4 X 10(-5) M to 9.7 X 10(-5) M). BM 14.478 shortened the duration of transmembrane action potential (90% repol.) by 8% and increased the Vmax of slow action potentials by 32% at 3 X 10(-4) M. In skinned porcine heart muscle fibers an increase in calcium-activated force up to 43 +/- 7% was observed (10(-7) to 10(-4) M). Rat aortas were relaxed by about 75% maximally (10(-7) to 10(-4) M). It is concluded that BM 14.478 is a potent inotropic drug which acts via an increase in myocardial cAMP content and in calcium sensitivity of contractile proteins.

Animals↗