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At least 145 records · Page 8Linked to original sources
PubMed2005

Antimicrobial peptides as microbicidal contraceptives: prophecies for prophylactics--a mini review.

The global increase in human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) and sexually transmitted infections (STIs) has led to the introduction of barrier methods, such as condoms. However, drawbacks associated with condoms, such as men being reluctant to use them and women being unable to negotiate their use, have led to the search for better and acceptable alternatives, namely the microbicides. These are gel formulations that, when used prior to sexual intercourse, protect against the transmission of HIV and other STIs. However, after observing the side-effects of nonoxynol-9, a component of the microbicidal formulations available on the market, the focus has shifted to natural available compounds demonstrating the preferred protective effects. Antimicrobial peptides (AMPs) are one such group of compounds present in a wide range of organisms from bacteria to humans. The existing 750 or so, low-molecular-weight, cationic charged peptides are classified into five major groups based on their three-dimensional structure obtained by nuclear magnetic resonance studies. The hypothesized mode of action seems to be the interaction of the positively charged peptides with the negatively charged phospholipids present on the surface of the cell membrane. Various studies have demonstrated the effect of several AMPs, namely, defensins, protegrins, cathelicidins, cecropins, polyphemusins, magainins and melittins, against various STI-causing pathogens and HIV/herpes simplex virus, both in vitro and in vivo. The contraceptive efficacies of magainin and nisin in vitro and in vivo are worth mentioning. We believe these peptides are suitable candidates in the development of newer mechanism-based microbicides in future.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Enzymology of the reduction of the novel fused pyrazine mono-n-oxide bioreductive drug, RB90740 roles for P450 reductase and cytochrome b5 reductase.

RB90740 is the lead compound in a series of fused pyrazine mono-N-oxide bioreductive drugs. Theses agents have potential application in cancer therapy, since they are more toxic to hypoxic than to aerobic cells as a consequence of their bioactivation by cellular reductase enzymes within the hypoxic regions of a tumour. In this study, mouse liver microsomes have been used to characterise the enzymology of the reductive activation of RB90740. Under hypoxic conditions, the reduction of RB90740 to its stable 2-electron reduced product RB92815 was supported by both NADH and NADPH, the former supporting a rate approximately 80% of the latter. Combining the two cofactors had no additive effect. Neither carbon monoxide nor metyrapone inhibited reduction of RB90740, indicating that P450 isozymes were not involved in the reduction of this compound. 2' AMP, and inhibitor of P450 reductase, did not inhibit formation of RB92815, whereas DPIC, another inhibitor but with a different mode of action, inhibited both the NADH, and NADPH-dependent reduction of RB90740. Similarly, two selective inhibitors of NADH: cytochrome b5 reductase, pHMB and PTU, completely inhibited both NADH and NADPH-dependent reduction of RB90740. Our findings implicate P450 reductase, cytochrome b5 reductase, and cytochrome b5 in the activation of the compound. However, there is no clear relationship between the intracellular levels of P450 reductase and cytochrome b5 reductase and the hypoxic toxicity of RB90740, which implies that other factors, in addition to drug activation, play a major role in controlling the toxicity of this particular bioreductive drug.

Animals↗
PubMed1994

Adenylyl cyclase mRNA expression does not reflect the predominant Ca2+/calmodulin-stimulated activity in the hypothalamus.

Only three (Types I, II, V) of the six currently-described subtypes of adenylyl cyclase are prominently expressed in the rat brain. These species are differently sensitive to Ca2+, beta gamma subunits of G-proteins and protein kinase C. A knowledge of the susceptibility of the cAMP-signalling system in particular brain regions to these diverse modes of regulation can shed light on the mechanism of action of the neurotransmitters that modify neuronal activity in such regions. Cyclic AMP is extensively involved in the physiological functions of the hypothalamus. We have used in situ hybridization histochemistry with synthetic oligonucleotides to examine the expression in the rat hypothalamus of the three major brain subtypes of adenylyl cyclase-Ca2+/calmodulin-stimulable (Type I), Ca(2+)-insensitive (Type II) and Ca(2+)-inhibitable (Type V). The hypothalamus expresses high levels only of Type II mRNA, particularly in the supraoptic and paraventricular nuclei. Curiously, the strong expression of the Ca(2+)-insensitive Type II mRNA and the lack of expression of the major brain specific Type I mRNA does not correlate with the adenylyl cyclase activity, which is largely Ca2+/calmodulin stimulable in plasma membranes prepared from the hypothalamus.

Adenylyl Cyclases↗
PubMed1990

Effects of protopine on blood platelet aggregation. II. Effect on metabolic system of adenosine 3',5'-cyclic monophosphate in platelets.

The mode of action of protopine on rabbit platelet aggregation was investigated in the metabolic system of adenosine 3',5'-cyclic monophosphate (cyclic AMP) in vitro experimental models. The inhibitory activity of protopine on adenosine 5'-diphosphate induced platelet aggregation was increased in the presence of prostaglandin I2 or papaverine in platelets. Protopine elevated content of the basal cyclic AMP accumulation in platelets and enhanced activity of crude adenylate cyclase prepared from platelets, but was ineffective on cyclic AMP phosphodiesterase. It is concluded that protopine has an inhibitory activity on platelet aggregation, activates adenylate cyclase and increases cyclic AMP content in platelets, in addition to other inhibitory actions in the metabolic system of cyclic AMP.

Alkaloids↗
PubMed2002

Inhibitory effect of the plant-extract osthole on L-type calcium current in NG108-15 neuronal cells.

The effects of osthole, a coumarin isolated from Cnidium monnieri (L.) Cusson, on ionic currents in a mouse neuroblastoma and rat glioma hybrid cell line, NG105-18, were investigated with the aid of the whole-cell voltage-clamp technique. Osthole (0.3-100 microM) caused an inhibition of voltage-dependent L-type Ca(2+) current (I(Ca,L)) in a concentration-dependent manner. Osthole produced no change in the overall shape of the current-voltage relationship of I(Ca,L). The IC(50) value of the osthole-induced inhibition of I(Ca,L) was 4 microM. The presence of osthole (3 microM) shifted the steady state inactivation curve of I(Ca,L) to a more negative potential by approximately -15mV. Osthole (3 microM) also produced a prolongation in the recovery of I(Ca,L) inactivation. Although osthole might suppress phosophodiesterases to increase intracellular adenosine-3',5'-cyclic monophosphate (cyclic AMP) or guanosine-3',5'-cyclic monophosphate (cyclic GMP), sp-cAMPS did not affect I(Ca,L) and 8-bromo-cyclic GMP slightly suppressed it. Thus, osthole-mediated inhibition of I(Ca,L) was not associated with intracellular cyclic AMP or GMP. However, no effect of osthole on voltage-dependent K(+) outward current was observed. Under a current-clamp mode, osthole could decrease the firing frequency of action potentials. Therefore, the channel-blocking properties of osthole may, at least in part, contribute to the underlying mechanisms by which it affects neuronal or neuroendocrine function.

Animals↗
PubMed1982

Effect of anti-allergic compounds on anaphylactic histamine secretion from rat peritoneal mast cells in the presence and absence of exogenous calcium.

The anti-allergic drugs theophylline, doxantrazole, quercetin, 8-bromo cyclic AMP, and disodium cromoglycate prevented anaphylactic histamine release from rat peritoneal mast cells in both the presence and absence of extracellular calcium. The activity of the test compounds under the latter conditions cannot be simply explained in terms of their postulated ability to block movement of the cation from the external environment into the cell. Alternative modes of action are thus considered.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1974

The effect of nickel on secretory systems. Studies on the release of amylase, insulin and growth hormone.

The effects of Ni(2+) on the release of amylase from rat parotids, insulin from mouse pancreatic islets and growth hormone from bovine pituitary slices were investigated. In all these secretory systems, Ni(2+) was shown to inhibit release evoked by a variety of stimuli both physiological and pharmacological. Measurements of rates of substrate oxidation and tissue concentrations of ATP and 3':5'-cyclic AMP suggest that this inhibitory action of Ni(2+) does not arise through an effect on energy metabolism or cyclic AMP metabolism. It is concluded that although some effects of Ni(2+) may involve antagonism between Ni(2+) and Ca(2+) in stimulus-secretion coupling, others appear to be independent of Ca(2+). It is suggested that Ni(2+) may block exocytosis by interfering with either secretory-granule migration or membrane fusion and microvillus formation. The possible mode of action of Ni(2+) and its potential use as a tool in the study of exocytosis are discussed.

Adenosine Triphosphate↗
PubMed1976

Neurobiological Considerations of the mode of action of lithium carbonate in the treatment of affective disorders?

The effects of lithium on membrane function and cellular processes are considered in relation to lithium's physiochemical properties. Several cellular regulatory functions, including cyclic AMP formation and metabolism and biogenic amine neurotransmitter metabolism, are examined as possible mechanisms whereby lithium might exert its mood stabilizing actions. The necessity for understanding lithium's interactions with "receptors" - the molecular sites affected by lithium - in considering its pre-and post-synapatic effects in stressed.

Affective Symptoms↗
PubMed1977

On the role of calcium as second messenger in liver for the hormonally induced activation of glycogen phosphorylase.

We have studied the mode of action of three hormones (angiotensin, vasopressin and phenylephrine, an alpha-adrenergic agent) which promote liver glycogenolysis in a cyclic AMP-independent way, in comparison with that of glucagon, which is known to act essentially via cyclic AMP. The following observations were made using isolated rat hepatocytes: (a) In the normal Krebs-Henseleit bicarbonate medium, the hormones activated glycogen phosphorylase (EC 2.4.1.1) to about the same degree. In contrast to glucagon, the cyclic AMP-independent hormones did not activate either protein kinase (EC 2.7.1.37) or phosphorylase b kinase (EC 2.7.1.38). (b) The absence of Ca2+ from the incubation medium prevented the activation of glycogen phosphorylase by the cyclic AMP-independent agents and slowed down that induced by glucagon. (c) The ionophore A 23187 produced the same degree of activation of glycogen phosphorylase, provided that Ca2+ was present in the incubation medium. (d) Glucagon, cyclic AMP and three cyclic AMP-dependent hormones caused an enhanced uptake of 45Ca; it was verified that concentrations of angiotensin and of vasopressin known to occur in haemorrhagic conditions were able to produce phosphorylase activation and stimulate 45Ca uptake. (e) Appropriate antagonists (i.e. phentolamine against phenylephrine and an angiotensin analogue against angiotensin) prevented both the enhanced 45Ca uptake and the phosphorylase activation. We interpret our data in favour of a role of calcium (1) as the second messenger in liver for the three cyclic AMP-independent glycogenolytic hormones and (2) as an additional messenger for glucagon which, via cyclic AMP, will make calcium available to the cytoplasm either from extracellular or from intracellular pools. The target enzyme for Ca2+ is most probably phosphorylase b kinase.

Angiotensin II↗
PubMed1987

Distinction between substrate- and enzyme-directed effects of modifiers of rabbit liver phosphorylase a phosphatases.

The natural substrate (phosphorylase a) and two alternative ones (phosphorylated histone and a tetradecapeptide consisting of residues 5-18 of rabbit skeletal muscle phosphorylase a) were used to distinguish the modes of action of some physiologically important effectors of four different molecular forms of rabbit liver phosphorlase a phosphatases. In general, glucose, caffeine, AMP, ADP, Pi, and glucose-1-P showed substrate-directed effects for the holophosphatase forms, since they usually did not affect the activity on histone phosphate and, with one slight exception (Pi), never affected the activity on the tetradecapeptide phosphate. ADP, Pi, and glucose-1-P did affect directly the relative mass (Mr) 35,000 phosphatase, in addition to an inhibition mediated via phosphorylase a. ATP exerted both substrate- and enzyme-directed effects for the Mr 35,000 phosphatase and phosphatases 1 and 2A2, but only a substrate-directed effect for phosphatase 2A1, suggesting that the gamma-subunit of the type 2 phosphatases may prevent ATP binding to the phosphatase. Mg2+ showed substrate-directed effects for phosphatases 1, 2A1, and 2A2, and an additional enzyme-directed effect for the Mr 35,000 phosphatase form. Furthermore, Mg2+ could not abolish ATP inhibition of the tetradecapeptide phosphatase activity, but significantly overcame ATP inhibition of the phosphorylase a phosphatase activity, thus suggesting that its ability to reverse the ATP effect is by a substrate-directed mechanism. The substrate-directed effects seen for the different ligands on the different phosphatase forms strongly indicate the significance of this form of control in the regulation of phosphorylase a phosphatase activities and may serve to narrow the otherwise broad substrate specificities of the major phosphorylase a phosphatase activities in mammalian tissues: phosphatases 1 and 2A.

Animals↗
PubMed1989

Intrinsic properties of nucleus reticularis thalami neurones of the rat studied in vitro.

1. Neurones of the nucleus reticularis thalami of the rat were studied by intracellular recordings from in vitro slices. The resting membrane potential was -56.28 +/- 5.86 mV (mean value +/- S.D.); input resistance was 43.09 +/- 9.74 M omega; the time constant tau was 16.51 +/- 3.99 ms. At the resting membrane potential tonic firing is present, while at membrane potentials more negative than -60 mV a burst firing mode gradually prevails. 2. Prolonged depolarizing current pulses superimposed on a steady hyperpolarization consistently activated sequences of burst-after-hyperpolarization complexes. The all-or-none burst response consisted of Na+-mediated, TTX-sensitive fast action potentials superimposed on a low threshold spike (LTS). The burst was followed by a stereotyped after-hyperpolarization lasting 100-120 ms (BAHP), with a maxima -85 mV. The BAHP was blocked by Cd2+ and apamine but not by 8-Br cyclic AMP. The early component of BAHP was significantly attenuated by TEA. The oscillatory rhythmic discharges were abolished by agents which blocked the BAHP. 3. The presence of strong after-hyperpolarizing potentials (SAHP and BAHP) in RTN neurones plays a significant role in determining two different functional states, defined as tonic and oscillatory burst firing modes, respectively.

Action Potentials↗
PubMed2006

Apidaecin-type peptides: biodiversity, structure-function relationships and mode of action.

Apidaecins (apidaecin-type peptides) refer to a series of small, proline-rich (Pro-rich), 18- to 20-residue peptides produced by insects. They are the largest group of Pro-rich antimicrobial peptides (AMPs) known to date. Structurally, apidaecins consist of two regions, the conserved (constant) region, responsible for the general antibacterial capacity, and the variable region, responsible for the antibacterial spectrum. The small, gene-encoded and unmodified apidaecins are predominantly active against many gram-negative bacteria by special antibacterial mechanisms. The mechanism of action by which apidaecins kill bacteria involves an initial non-specific binding of the peptides to an outer membrane (OM) component. This binding is followed by invasion of the periplasmic space, and by a specific and essentially irreversible combination with a receptor/docking molecule that may be a component of a permease-type transporter system on inner membrane (IM). In the final step, the peptide is translocated into the interior of the cell where it meets its ultimate target. Evidence that apidaecins are non-toxic for human and animal cells is a prerequisite for using them as novel antibiotic drugs. This review presents the biodiversity, structure-function relationships, and mechanism of action of apidaecins.

Amino Acid Sequence↗