Showing papers in "General Pharmacology-the Vascular System in 1996"

Pharmacological and biochemical actions of simple coumarins : Natural products with therapeutic potential

Abstract: 1. 1. More than 1300 coumarins have been identified from natural sources, especially green plants. The pharmacological and biochemical properties and therapeutic applications of simple coumarins depend upon the pattern of substitution. More complex related compounds based on the coumarin nucleus include the dicoumarol/warfarin anticoagulants, aflatoxins and the psoralens (photosensitizing agents). 2. 2. Coumarin itself (1,2-benzopyrone) has long-established efficacy in slow-onset long-term reduction of lymphoedema in man, as confirmed in recent double-blind trials against elephantiasis and postmastectomy swelling of the arm. The mechanism of action is uncertain, but may involve macrophage-induced proteolysis of oedema protein. However, coumarin has low absolute bioavailability in man (<5%), due to extensive first-pass hepatic conversion to 7-hydroxycoumarin followed by glucuronida. tion. It may, therefore, be a prodrug. 3. 3. Scoparone (6,7-dimethoxycoumarin) has been purified from the hypolipidaemic Chinese herb Artemisia scoparia and shown to reduce the proliferative responses of human peripheral mononuclear cells, to relax smooth muscle, to reduce total cholesterol and triglycerides and to retard the characteristic pathomorphological changes in hypercholesterolaemic diabetic rabbits. Various properties of scoparone were suggested to account for these findings, including ability to scavenge reactive oxygen species, inhibition of tyrosine kinases and potentiation of prostaglandin generation. 4. 4. Osthole (7-methoxy-8-[3-methylpent-2-enyl]coumarin) from Angelica pubescens, used also in Chinese medicine, causes hypotension in vivo, and inhibits platelet aggregation and smooth muscle contraction in vitro. It may interfere with calcium influx and with cyclic nucleotide phosphodiesterases. 5. 5. Cloricromene, a synthetic coumarin derivative, also possesses antithrombotic antiplatelet actions, inhibits PMN neutrophil function and causes vasodilatation. Some of these properties of cloricromene have been ascribed to inhibition of arachidonate release from membrane phospholipids. 6. 6. Simple coumarins possessing ortho-dihydroxy functions, such as fraxetin and 4-methyldaphnetin, are potent inhibitors (low micromolar) of lipid peroxidation and scavengers of superoxide anion radicals and of aqueous alkylperoxyl radicals, but may be pro-oxidant (enhancing generation of hydroxyl radicals) in the presence of free iron ions. These coumarins also inhibit the proinflammatory 5-lipoxygenase enzyme at micromolar concentrations. Another related coumarin, 5, 7-dihydroxy-4-methylcoumarin, is of special interest as it inhibits lipid peroxidation, and scavenges alkylperoxyl and superoxide radicals. Unlike most other simple coumarins studied, 5,7-dihydroxy-4-methylcoumarin also scavenges hypochlorous acid, and is a potent inhibitor of cyclo-oxygenase, but is not pro-oxidant. 7. 7. 5,7- and 6,7-dihydroxy-4-methylcoumarin both reduced the duration of ventricular fibrillation in postischaemic reperfused isolated perfused rat hearts (in which oxygen-derived free radicals are implicated), showing that these antioxidant coumarins possess beneficial properties in this pathophysiological model. 8. 8. In view of the established low toxicity, relative cheapness, presence in the diet and occurrence in various herbal remedies of coumarins, it appears prudent to evaluate their properties and applications further.

Pharmacology of methylglyoxal: formation, modification of proteins and nucleic acids, and enzymatic detoxification--a role in pathogenesis and antiproliferative chemotherapy.

Abstract: 1. Methylglyoxal is a reactive alpha-oxoaldehyde and physiological metabolite formed by the fragmentation of triose-phosphates, and by the metabolism of acetone and aminoacetone. 2. Methylglyoxal modifies guanylate residues to form 6,7-dihydro-6,7-dihydroxy-6-methyl-imidazo[2,3-b]purine-9(8)one and N2-(1-carboxyethyl)guanylate residues and induces apoptosis. 3. Methylglyoxal modifies arginine residues in proteins to form N(delta)-(4,5-dihydroxy-4-methylimidazolidin-2-yl) ornithine, N(delta)-(5-hydro-5-methylimidazol-4-on-2-yl)ornithine and N(delta)-(5)methylimidazol-4-on-2-yl)ornithine residues. 4. Methylglyoxal-modified proteins undergo receptor-mediated endocytosis and lysosomal degradation in monocytes and macrophages, and induce cytokine synthesis and secretion. 5. Methylglyoxal is detoxified by the glyoxalase system. Decreased detoxification of methylglyoxal may be induced pharmacologically by glyoxalase I inhibitors which have anti-tumor and anti-malarial activities. 6. The modification of nucleic acids and protein by methylglyoxal is a signal for their degradation and may have a role in the development of diabetic complications, atherosclerosis, the immune response in starvation, aging and oxidative stress.

Vasorelaxing activity of resveratrol and quercetin in isolated rat aorta

Abstract: 1. Both resveratrol and quercetin dose-dependently inhibited the contractile response to noradrenaline (NA) in isolated endothelium-intact rat aorta. This inhibitory effect on vascular contraction was blocked by pretreatment of the blood vessel with the nitric oxide (NO) synthase inhibitor, L-NNA (1 microM). 2. Quercetin at a concentration > 1 x 10(-5) M, and resveratrol at > 3 x 10(-5) M, caused relaxation of the phenylephrine (PE) precontracted endothelium-intact aorta, and L-NNA, at 1 x 10(-6) M, reversed the relaxation. 3. At higher concentrations, > 6 x 10(-5) M, resveratrol and quercetin also relaxed the endothelium-denuded aortic rings. However, this effect could not be reversed by the NO inhibitor. 4. It is concluded that resveratrol and quercetin exert both indirect and direct vasodilator effects on the blood vessel by nitric oxide-mediated and non-NO-mediated mechanisms, respectively.

The P-glycoprotein multidrug transporter.

Abstract: 1. P-glycoprotein (P-gp) is a transmembrane protein involved in ATP-dependent efflux of various structurally unrelated anticancer drugs. Its overexpression in cancer cells decreases intracellular drug concentrations and, thus, confers a multidrug resistance phenotype. 2. P-gp is encoded by MDR genes, which constitute a small gene family comprising two genes in humans and three genes in rodents. Only the MDR1 gene in humans and mdr1 and mdr3 genes in rodents have been demonstrated to be involved in drug resistance. 3. P-gp encoded by the human MDR1 gene is a phosphorylated and glycosylated protein 1289 amino acids long, and consists of 2 halves that share a high degree of similarity. 4. A wide variety of cancers have been shown to express P-gp, including solid tumors and hematological malignancies. This P-gp positivity can be evidenced at the time of diagnosis prior to chemotherapy or at relapse after treatment, and has been correlated with treatment failure and poor prognosis in several types of cancer. In addition, P-gp is also expressed by some normal tissues, such as liver and kidney. 5. P-gp expression is regulated by various factors, including xenobiotics and hormones. 6. P-gp-mediated multidrug resistance can be reversed by various unrelated compounds called chemosensitizers or reversing agents. These drugs act through inhibition of P-gp function and have entered clinical trials.

Bleomycin: revival of an old drug.

Abstract: 1. Bleomycin (BLM) is a cytotoxic drug currently used in anticancer chemotherapy. We present here a summary of the well established "old" knowledge concerning BLM structure, properties and activity at the molecular level, as well as its current clinical uses. 2. Then, we introduce "new" recent facts concerning BLM interaction with animal cells, that demonstrate the peculiar characteristics of that drug and its potentialities. Indeed, BLM has an high intrinsic cytotoxicity (i.e. it is a very potent drug once inside the cell). However, BLM cytotoxicity is limited because BLM is unable to diffuse through the plasma membrane. The very low amounts of BLM that can reach the cell interior enter the cells by a mechanism that requires BLM interaction with a plasma membrane protein. 3. Finally, we present and discuss a new possible use of BLM in an antitumor approach that we term electrochemotherapy. This new treatment, still under development, is based on the increased BLM delivery into tumor cells after cell permeabilization by electric pulses administered locally at the solid tumor site. This results in a huge local potentiation of BLM activity, in the absence of systemic adverse effects. Clinical trials are in progress.

Gliotoxin and related epipolythiodioxopiperazines

Abstract: 1. Gliotoxin belongs to the epipolythiodioxopiperazine class of secondary metabolites. These compounds show a diverse range of biological activity including antimicrobial, antifungal and antiviral properties. They also display potent in vitro and in vivo immunomodulating activity. 2. Their properties resulted in a number of early studies designed to exploit their possible chemotherapeutic value, although the general toxicity of most members of this class has precluded clinical use. 3. Most recently, their selective immunosuppressive properties have led to the possibility of ex vivo treatment of tissue to selectively remove immune cells responsible for tissue rejection. The mode of action of gliotoxin appears to be via covalent interaction to proteins through mixed disulphide formation and gliotoxin has been shown to inhibit a number of thiol requiring enzymes. 4. Gliotoxin is also a potent inducer of apoptotic cell death in a number of cells. Gliotoxin and other members of this class of toxins may be produced in vivo during the course of fungal infections and contribute to the aetiology of the disease.

Salivary mucins in oral mucosal defense

Abstract: 1. Salivary mucins are well recognized as an important factor in the preservation of the health of the oral cavity. These large glycoproteins play a major role in the formation of protective coatings covering tooth enamel and oral mucosa, which act as a dynamic functional barrier capable of modulating the untoward effects of oral environment, and are of significance to the processes occurring within the epithelial perimeter of mucosal defense. 2. Based on macromolecular characteristics, the mucins in saliva fall into high (> 1000 kDa) and low (200-300 kDa) molecular weight forms. The two forms, although differ with respect to bacterial clearance ability, display virtually identical carbohydrate chain make-up, ranging in size from 3 to 16 sugar units. 3. Of the two mucin forms, the low molecular weight form more efficient in bacterial aggregation, predominates in saliva and oral mucosal mucus coat of caries-resistant individuals, while the level of the high molecular weight form is higher in caries-susceptible subjects. The saliva of caries-resistant individuals also exhibits greater activity of protease capable of conversion of the high molecular weight mucin to the low molecular weight form. 4. The bacterial aggregating activity of salivary mucins appears to be associated with sulfomucins rather than sialomucins. While the removal of sialic acid causes only partial loss in mucin aggregating capacity, a complete loss in the bacterial aggregating activity occurs following mucin desulfation. 5. The mucins in oral mucosal mucus coat interact with the epithelial surfaces through specific membrane receptors. This interaction apparently involves the carbohydrate moiety of mucin molecule and may be rendered vulnerable to disruption by opportunistic bacteria colonizing the oral mucosa. 6. Salivary sulfo- and sialomucins actively participate in the modulation of the oral mucosal calcium channel activity through the inhibition of EGF-stimulated channel protein tyrosine phosphorylation. This function of salivary mucins is of paramount importance to mucosal calcium homeostasis.

Volume-activated Cl− channels

Abstract: 1. An increase in cell volume activates, in most mammalian cells, a Cl- current, ICl,vol. This current is involved in a variety of cellular functions, such as the maintenance of a constant cell volume, pH regulation, and control of membrane potential. It might also play a role in the regulation of cell proliferation and in the processes that control transition from proliferation to differentiation. This review focuses on various aspects of this current, including its biophysical characterisation and its functional role for various cell processes. 2. Volume-activated Cl- channels show all outward rectification. Iodide is more permeable than chloride. In some cell types, ICl,vol inactivates at positive potentials. Single channel conductance can be divided mainly into two groups: small (< 5 pS) and medium conductance channels (around 50 pS). 3. The pharmacology and modulation of these channels are reviewed in detail, and suggest the existence of an heterogeneous family of multiple volume-activated Cl- channels. 4. Molecular candidates for this channel (i.e. ClC-2, a member of the ClC-family of voltage-dependent Cl- channels, the mdr-1 encoded P-glycoprotein, the nucleotide-sensitive pICln protein and phospholemman) will be discussed.

Cellular resistance to anthracyclines

Abstract: The antracyclines induce multiple intracellular effects; however, inhibition of the nuclear enzyme topoisomerase II (TOPO II) is the main mechanism of action. Resistance to anthracyclines in tumor cells is multifactorial. The main mechanisms are: (1) the classic multidrug resistance (MDR) phenotype, which is due to the presence of P-glycoprotein (PGP) in plasma membrane, that is, a “pump” that can extrude a wide range of anticancer drugs. Membrane-active drugs (e.g., verapamil) have been found in vitro to reverse this phenotype. Most clinical studies including chemosensitizers have, however, been disappointing. (2) Non-PGP-mediated MDR: this phenotype is characterized by expression of other proteins in the plasma membrane which are also able to extrude anticancer drugs. (3) Changes in the intracellular distribution of drug: this mechanism has been demonstrated in several cell lines, most often in combination with PGP or Non-PGP-mediated resistance. (4) Glutathione transferases (GST) and detoxification mechanisms: these represent a multigene family of enzymes that conjugate glutathione to chemically reactive groups. Direct evidence for a causative role of GST in anthracycline resistance is missing. (5) Alterations in TOPO II (at-MDR): DNA topoisomerases are involved in several aspects of DNA metabolism, in particular genetic recombination, DNA transcription, and chromosome segregation. Low levels of expression or alterations in TOPO II are associated in vitro with resistance. (6) Increased DNA repair: in several cell lines, an increase in the efficacy of DNA repair has been associated with resistance to doxorubicin (DOX). So far, only classic MDR has been shown to contribute to resistance in clinical conditions, whereas evidence for the other mechanisms of resistance is still missing.

Platelet-derived growth factor (PDGF): actions and mechanisms in vascular smooth muscle.

Abstract: 1. 1. PDGF is a highly hydrophilic cationic glycoprotein (Mr 28-35kDa) produced by platelets, monocyte/macrophages, endothelial cells and vascular smooth muscle cells under some conditions. 2. 2. Since its original description, PDGF has attracted much attention and it is currently believed to play a role in atherosclerosis and other vascular pathologies. 3. 3. This review describes the vascular biology of PDGF. It particularly focuses on recent findings regarding the intracellular signals activated by PDGF in the context of vascular smooth muscle cell proliferation, migration and contraction.

Effects of flavonoids on rat aortic smooth muscle contractility: structure-activity relationships.

Abstract: 1. Flavonoids produced a concentration-dependent relaxation of the contractile responses induced by noradrenaline, KCl, or phorbol 12-myristate-13-acetate in rat aortic rings. Only the flavonoid with three contiguous hydroxyls in B rings (myricetin), at low concentrations, potentiates the contractions evoked by these agonists. 2. The relaxant effects of flavanone on the noradrenaline-induced contractions were potentiated by isoprenaline and those of morin, chrysin, flavanone, and naringenin by sodium nitroprusside. 3. Several mechanisms are implicated in the vasodilatory effects of flavonoids: inhibition of protein kinase C; inhibition of cyclic nucleotide phosphodiesterases; and/or decreased Ca2+ uptake.

The use of caffeine as a metabolic probe for human drug metabolizing enzymes

Abstract: 1. Caffeine (CA) is metabolized extensively and at least 17 metabolites arising from primary and secondary biotransformation pathways are found in urine following CA ingestion. The enzymes responsible for the formation of most of the metabolites derived from CA have been identified. 2. Given the near ubiquitous consumption of CA, this compound potentially constitutes a useful substrate probe for assessment of certain xenobiotic metabolizing enzyme activities in vivo. Indeed, various ratios of CA metabolites excreted in urine (urinary metabolic ratios; MRs) are now utilized widely for the population screening of enzyme activities. 3. Excretion of the acetylated secondary metabolite 5-actylamino-6-formylamino-3-methyluracil (AFMU) is dependent on the activity of the polymorphic N-acetyltransferase (NAT2), and certain MRs incorporating AFMU may be used for NAT2 phenotyping. 4. The conversion of 1-methylxanthine (1-MX), another secondary metabolite of CA, to 1-methyluric acid (1-MU) is catalyzed by xanthine oxidase (XO), and the urinary 1-MU to 1MX ratio reflects XO activity. 5. N3-demethylation to form paraxanthine (PX), a reaction mediated by cytochrome P4501A2 (CYP1A2), is the dominant primary metabolic pathway of CA. CA N3-demethylation activity may be used as a measure of human hepatic CYP1A2 in vitro. 6. Plasma CA clearance is considered to reflect CYP1A2 activity in vivo. Although a number of MRs are based on the excretion of PX metabolites (PX derived from CA is employed for the assessment of CYP1A2 activity in vivo), factors other than enzyme activity may affect these ratios.

Calcitonin gene-related peptide: vasoactive effects and potential therapeutic role.

Abstract: 1. 1. The cardiovascular biology of calcitonin gene-related peptide (CGRP) and the structurally related peptides amylin and adrenomedullin are briefly reviewed. 2. 2. CGRP is a potent and long-lasting vasodilator; its possible role in disease, and the therapeutic potential of CGRP receptor agonists and antagonists is discussed.

G-protein-coupled receptors in HL-60 human leukemia cells.

Abstract: 1. 1. HL-60 human leukemia cells are a widely employed model system for the analysis of signal transduction processes mediated via regulatory heterotrimeric guanine nucleotide-binding proteins (G-proteins). HL-60 promyelocytes are pluripotent and can be differentiated into neutrophilic or monocytic cells. 2. 2. HL-60 cells express formyl peptide-, complement C5a-, leukotriene B4 (LTB4)- and platelet-activating factor receptors, receptors for purine and pyrimidine nucleotides, histamine H1- and H2-receptors, β2-adrenoceptors and prostaglandin receptors. 3. 3. The major G-proteins in HL-60 cells are pertussis toxin (PTX)-sensitive Gi-proteins (Gi2 > Gi3). Gs-proteins and G-proteins of the Gq-family (e.g., G16) are expressed, too. 4. 4. G-protein-regulated effector systems in HL-60 cells are adenylyl cyclase and phospholipase C-β2 (PLC-β2) and, possibly, phospholipase D (PLD), nonselective cation (NSC) channels and NADPH oxidase. 5. 5. The expression of signal transduction pathways in HL-60 cells strongly depends on the differentiation state of cells. 6. 6. Formyl peptides, via Gi-proteins, mediate activation of PLC, PLD, NSC channels, NADPH oxidase and azurophilic granule release and are referred to as full secretagogues. In dibutyryl cAMP (Bt2cAMP)-differentiated HL-60 cells, C5a and LTB4 are partial and incomplete secretagogues, respectively. There are substantial differences in the Gi-protein activations induced by formyl peptides, C5a and LTB4. 7. 7. In HL-60 promyelocytes, purine and pyrimidine nucleotides mediate activation of PLC and NSC channels largely via PTX-insensitive G-proteins and induce functional differentiation. In Bt2cAMP-differentiated HL-60 cells, they additionally activate PLD, NADPH oxidase and granule release via PTX-sensitive and -insensitive pathways. ATP and UTP are partial secretagogues. Multiple types of receptors (i.e., P2Y- and P2U-receptors and pyrimidinocyeptors) may mediate the effects of nucleotides in HL-60 cells. 8. 8. Bt2cAMP- and 1α,25-dihydroxycholecalciferol-differentiated HL-60 cells express Hl-receptors coupled to Gi-proteins and PTX-insensitive G-proteins. In the former cells, histamine mediates activation of PLC and NSC channels, and in the latter, activation of NSC channels. Histamine is an incomplete secretagogue in these cells. 9. 9. HL-60 promyelocytes express H2-receptors coupled to adenylyl cyclase, PLC, and NSC channels. There are substantial differences in the agonist/antagonist profiles of H2-receptor-mediated cAMP formation and rises in cytosolic Ca2+ concentration, indicative of the involvement of different H2-receptor subtypes. H2-receptors mediate functional differentiation of HL-60 cells. 10. 10. Certain cationic-amphiphilic histamine receptor ligands (i.e., 2-substituted histamines, lipophilic guanidines, and a histamine trifluoromethyl-toluidide derivative) show stimulatory effects in HL-60 cells that are attributable to receptor-independent activation of Gi-proteins.

Role of endothelium in the vasodilating effect of progestins and androgens on the rat thoracic aorta.

Abstract: 1. 1. In the rat thoracic aorta, contractions induced by noradrenaline were inhibited by the steroids progesterone, pregnanolone, testosterone and 5α- and 5β-dihydrotestosterone. 2. 2. Removal of endothelium did not prevent relaxation to the steroids, suggesting that the vasodilating effect of steroids occurred on the smooth muscle cells. 3. 3. γ-Aminobutyric acid (GABA) did not modify noradrenaline-induced contraction. Thus, the vasodilation elicited by steroids is not apparently mediated by GABA receptors. 4. 4. On the basis that noradrenaline opens receptor-operated calcium channels to induce contraction, we suggest that relaxation by steroids involves a blockade of this type of channels.

Hypochlorous acid and its pharmacological antagonism: An update picture

Abstract: 1. 1. Some biochemical and pathophysiological aspects of hypochlorous acid (a major oxidant species produced by activated white blood cells) are discussed. 2. 2. Moreover, we have discussed the problem of the pharmacological scavenging of hypochlorous acid, focusing attention on the biochemical tests able to study therapeutically relevant scavenging properties of various drugs against hypochlorous acid itself.

A2 adenosine receptors: their presence and neuromodulatory role in the central nervous system

Abstract: 1. 1. Adenosine is an endogenous neuromodulator that exerts its depressant effect on neurons by acting on the A 1 adenosine receptor subtype. Excitatory actions of adenosine, mediated by the activation of the A 2 adenosine receptor subtype, have also been shown in the central nervous system. 2. 2. Adenosine A 2a receptors are highly localized in the striatum, as demonstrated by the binding assay of the A 2a selective agonist, CGS2680, and by analysis of the A 2 receptor mRNA localization with in situ hybridization histochemistry. However, adenosine A 2a receptors, albeit at lower levels, are also localized in other brain regions, such as the cortex and the hippocampus. 3. 3. In the striatum, adenosine A 2a receptors are implicated in the control of motor activity. Evidences exists of an antagonistic interaction between adenosine A 2a and dopamine D 2 receptors. 4. 4. Utilizing selective agonists and antagonists for adenosine A 2a receptors, their role in the modulation of the release of several neurotransmitters (acetylcholine, dopamine, glutamate, GABA) has been extensively studied in the brain (striatum, cortex, hippocampus). Controversial results have been obtained and, because the overall effect of endogenous adenosine in the brain is that of an inhibitory tonus, the physiological meaning of the excitatory A 2 receptor remains to be clarified.

Possible mechanism of antihyperglycemic effect of Azadirachta indica leaf extract. Part IV

Abstract: 1. Effect of epinephrine on the increment index calculated from intravenous glucose tolerance tests and on hepatic glycogen before and after A. indica leaf extract treatment was studied in normal and streptozotocin-induced diabetic rabbits. 2. A. indica leaf extract, in itself, was found to have no action on peripheral utilization of glucose or on hepatic glycogen. 3. The reduction in peripheral utilization of glucose and glycogenolytic effect due to epinephrine action was blocked by A. indica leaf extract, however, almost completely in diabetic rabbits and to a certain extent in normal ones. 4. The results are discussed.

The dermorphin peptide family.

Abstract: 1. 1. In 1980, the skin of certain frogs belonging to the genus Phyllomedusinae was found to contain two new peptides that proved to be selective μ-opioid agonists. Given the name dermorphins, these were the first members of a peptide family that in the past 15 years has grown to reach a total of seven naturally occurring peptides and nearly 30 synthetic analogs. 2. 2. Dermorphin peptides are potent analgesics in rodents and primates, including man. Some dermorphins can enter the blood-brain barrier and produce central antinociception after peripheral administration. 3. 3. The dermorphin family also includes μ1-opioid receptor selective agonists that produce intense opioid analgesia, but stimulate pulmonary ventilation. 4. 4. Experiments in rats and mice chronically exposed to dermorphins have shown that not only do they have higher antinociceptive efficacy and potency than morphine, but they are also less likely than morphine to produce tolerance, dependence and opiate side effects.

The mode of action of the antimalarial artemisinin and its derivatives

Abstract: 1. 1. Artemisinin (qinghaosu) is a sesquiterpene endoperoxide derived from a plant which was used in Chinese herbal medicine for thousands of years. 2. 2. Artemisinin and its derivatives have potent antimalarial activity, and are now being used clinically in much of the world. 3. 3. The artemisinin derivatives have an unusual mode of action involving the iron-catalyzed generation of a carbon-centered free radical followed by the alkylation of malaria-specific proteins.

The role of cyclic nucleotides in neutrophil migration.

Abstract: 1. 1. The literature concerning the effects of cAMP and especially cGMP on neutrophil migration is reviewed. 2. 2. Experiments with agents that enhance cGMP level, and with electroporated neutrophils in which cGMP was introduced, show that the nucleotide has different effects. There is a maximal stimulation at a specific concentration while higher concentrations are less effective or even inhibitory. 3. 3. Some physiologically active peptides such as granulocyte-macrophage colony-stimulating factor (GM-CSF), atrial natriuretic factor, and endothelin appear to modify neutrophil migration via a cGMP-dependent mechanism. 4. 4. Dependent on concentration and conditions (random migration vs. fMLP-activated migration, using nitric oxide (NO), NO donors, and inhibitors of NO synthase), NO has stimulatory or inhibitory effects on neutrophil migration. 5. 5. The differential effects of cGMP and cAMP on neutrophil migration are discussed with regard to intracellular actions, metabolism, interaction with calcium, and relation to structural changes required for cell movement.

Basis of the antiseizure action of phenytoin.

Abstract: 1. Phenytoin has been used with much clinical success against all types of epileptiform seizures, except petit mal epilepsy, for over 50 years. Its mechanism of action, however, is still open to interpretation. 2. Several potential targets for phenytoin action have been identified within the central nervous system. These include the Na-K-ATPase, the GABAA receptor complex, ionotropic glutamate receptors, calcium channels and sigma binding sites. 3. To date, though, the best evidence hinges on the inhibition of voltage-sensitive Na+ channels in the plasma membrane of neurons undergoing seizure activity. Quieter nerve cells are far less affected. Moreover, the fact that phenytoin also has important cardiac antiarrhythymic effects and can inhibit Na+ influx into cardiac cells supports the idea that the primary target of phenytoin is, indeed, the Na+ channel.

Examination of coumarins, flavonoids and polysaccharopeptide for antibacterial activity.

Abstract: 1. Coumarins, flavonoids and polysaccharopeptide were tested for antibacterial activity. 2. The bacteria used for this study included clinical isolates of Staphylococcus aureus, Shigella flexneri, Salmonella typhi, Escherichia coli and Pseudomonas aeruginosa. 3. Most of the coumarins tested failed to inhibit the bacteria at 25 mg/l. Edultin at 128 mg/l inhibited 4 of the 8 P. aeruginosa strains and 1 of the S. aureus strains tested. O-acetylcolumbianetin and imperatorin did not inhibit any isolate, even at 128 mg/l. 4. When tested at the dose of 128 mg/l, the flavonoids (rutin, naringin and baicalin) inhibited 25% or less of P. aeruginosa and only baicalin was active against S. aureus. 5. Arbutin and 4-(beta-D-glucopyranosyloxyl)-benzaldehyde inhibited 3 of the 8 P. aeruginosa strains when tested at 128 mg/l. 6. Polysaccharopeptide from the fungus Coriolus versicolor failed to inhibit any P. aeruginosa or S. aureus strain at 128 mg/l.

Hypothermia as an indicator of the acute effects of lipopolysaccharides : Comparison with serum levels of IL1β, IL6 and TNFα

Abstract: 1. 1. Hypothermia was investigated as a parameter indicating the severity of the acute effects of lipopolysaccharides (LPS) in BALB/c mice, and was compared with the induction of serum levels of IL1β, TNFα and IL6. 2. 2. Hypothermia induced by low doses of LPS (10–50 μg/mouse IP LPS E. coli 0111:B4) peaked at 2 hr after LPS and then either plateaued (50 μg) or declined. LPS, 100 and 300 μ, induced greater degrees of hypothermia that plateaued or continued to increase with time for 8 hr. Higher doses of LPS induced similar levels of hypothermia until 4 hr but then continued to increase markedly until 8 hr. 3. 3. TNFα levels peaked early (1–2 hr) and declined rapidly, IL6 levels peaked at 3 hr and then declined slowly, and IL1β levels peaked at 4 hr, declined at lower doses of LPS, plateaued at higher doses and continued to slowly increase at highest doses. 4. 4. The peak levels of the cytokines (IL1β up to 4 hr) and hypothermia (4 hr) increased in relation to the dose of LPS and maximum responses were apparently achieved in all cases at 300–1000 μg LPS. 5. 5. A similar parallel between hypothermia and induction of cytokines was observed in C5 7BL6 and OF1 mice, which were good and poor responders to LPS, respectively, and with the more potent Shigella dysenteria LPS in BALB/c mice. 6. 6. In conclusion, hypothermia is a useful parameter for indicating the strength of the acute effects of LPS. Further studies are necessary to determine whether or not the cytokines studied here play a causative role in hypothermia.

Immunomodulation and antitumor activity of polysaccharide-protein complex from the culture filtrates of a local edible mushroom, Tricholoma lobayense

Abstract: 1. 1. The polysaccharide-protein complex(PSPC) isolated from the culture filtrate of Tricholoma lobayense showed antitumor activity in mice. 2. 2. PSPC had the ability to restore the phagocytic function of peritoneal exudate cells (PEC) and T-cell mitogenic activity of tumor-bearing mice. 3. 3. An increase in the production of reactive nitrogen intermediates and tumor necrosis factor (TNF) was determined in PEC of mice that had received PSPC. 4. 4. The present study showed that PSPC both induced the various immune responses in vivo and exhibited cytotoxicity against tumor cell lines in the presence of PSPC at doses of 30 and 60 μ/ml in vitro .

The eosinophil and its role in asthma

Abstract: 1. 1. The eosinophil is part of the host defence mechanism to parasitic infection, but is also a key cell in many inflammatory disorders. 2. 2. Eosinophils synthesise a range of pro-inflammatory and cytotoxic mediators, such as basic proteins, hydrolytic enzymes, lipid mediators, cytokines, oxygen metabolites and neuropeptides. 3. 3. Eosinophils are recruited to the lung during episodes of asthma. They migrate from the blood vessels into the tissue via a series of interactions between their surface adhesion molecules and endothelial cells or the extracellular matrix. 4. 4. Activation and prolonged survival of eosinophils occurs upon exposure to mediators released from other tissue resident leukocytes, including eosinophils themselves, and from respiratory tract epithelial cells. Release of eosinophilic mediators causes tissue damage and persistent inflammation of the lung. 5. 5. Currently the most effective therapy for asthma lies with anti-inflammatory drugs, of which the main choices are inhaled corticosteroids or cromolyn sodium and nedocromil sodium.

Effect of the milk extract of Semecarpus anacardium nut on adjuvant arthritis--a dose-dependent study in Wistar albino rats.

Abstract: 1. Adjuvant-induced arthritis in rats is used as a pathologic model for chronic inflammatory disease to evaluate the efficacy of therapeutic agents. 2. In the present work, attempts have been made to study the potency of a milk extract of Semecarpus anacardium (Serankottai Nei), a Siddha preparation from Semecarpus anacardium nut, which has been shown to have antiarthritic effects. 3. Experimental arthritis induces a significant modification in lysosomal enzyme release and total carbohydrate components of glycoprotein. 4. Milk extract was administered at the dose level of 50, 100, 150, 200, and 250 mg/kg body weight in olive oil orally (volume 0.5 ml) after 14 days from the day of adjuvant injection. 5. After administration of the extract the lysosomal enzyme activity and protein-bound carbohydrate component levels were significantly normalized. 6. The data obtained clearly indicate that the Semecarpus anacardium is effective at the dose level of 150 mg/kg body weight in adjuvant-induced arthritis in albino Wistar rats.

The antiparasite effects of cyclosporin A: possible drug targets and clinical applications

Abstract: 1. The immunosuppressive drug cyclosporin A, and some of its nonimmunosuppressive derivatives, are potent inhibitors of a range of parasites of humans. 2. Cyclosporin A and the structurally unrelated immunosuppressant FK506 are known to act on T-lymphocytes as complexes with their binding proteins, cyclophilins and FKBPs, respectively. 3. Cyclophilins and FKBPs have been structurally identified in a number of parasites and, in some instances, are believed to play roles in the antiparasitic actions of these drugs. 4. Nonimmunosuppressive cyclosporins and FK506 derivatives may have clinical potential in certain parasitic diseases, especially malaria and schistosomiasis, and identification of the targets of these drugs in parasites may lead to development of novel chemotherapeutic agents.

Immunomodulatory effect of a polysaccharide-enriched preparation of Codonopsis pilosula roots

Abstract: 1. A polysaccharide-enriched fraction (CPPS) was prepared from Codonopsis pilosula root extract utilizing a procedure that entailed extraction with aqueous buffer and precipitation with ethanol. 2. After administration of CPPS in drinking water to C57BL/6 mice at a dosage of 10 mg/L for 4 weeks, the splenocytes exhibited lowered mitogenic responses to Concanavalin A (ConA) and lipopolysaccharide (LPS). The in vitro production of reactive nitrogen intermediates was inhibited. 3. However, when oral administration of CPPS was prolonged to 8 weeks, there was a potentiation of ConA-stimulated and LPS-stimulated mitogenic responses. 4. When tested under in vitro conditions, CPPS augmented the mitogenic response of splenocytes to ConA. However, there was no effect on the pinocytic activity of mouse macrophages, nor was there any proliferative activity on mouse melanoma B16 cells.

Selective protective effect of an extract from Fumaria parviflora on paracetamol-induced hepatotoxicity

Abstract: 1. The hepatoprotective activity of an aqueous-methanolic extract of Fumaria parviflora was investigated against paracetamol- and CCI4-induced hepatic damage. 2. Paracetamol (1 g/kg; orally) produced 100% mortality in mice; pretreatment of animals with the plant extract (500 mg/kg; orally) reduced the death rate to 50%. 3. Pretreatment of rats with plant extract (500 mg/kg, orally twice daily for 2 days) prevented (P 0.05) the CCI4-induced rise in serum enzyme levels. 4. Posttreatment with 3 successive doses of the extract (500 mg/kg, 6 hourly) also restricted the paracetamol-induced hepatic damage. 5. The plant extract (500 mg/kg; orally) caused significant prolongation in pentobarbital (75 mg/ kg)-induced sleep as well as increased strychnine-induced lethality in mice (P < 0.05), suggestive of an inhibitory effect on microsomal drug metabolizing enzymes (MDME). 6. It is conceivable therefore, that Fumaria parviflora extract exhibits a selective protective effect against paracetamol-induced hepatotoxicity, probably mediated through MDME inhibition.