Interferons and indoleamine 2,3-dioxygenase: Role in antimicrobial and antitumor effects

Summary Indoleamine 2,3-dioxygenase (IDO) is an interferon (IFN)-induced protein that initiates the metabolism of tryptophan along the kynurenine pathway. Although IDO can be induced by IFN- in many cell types, only mononuclear phagocytes have been shown to be induced to decyclize tryptophan by all three IFN classes. Since tryptophan is an essential amino acid necessary for a variety of metabolic processes, depletion of available tryptophan may be an important mechanism for control of rapidly-dividing microbial pathogens and tumors. The purpose of this review is to present evidence that documents the effects of IFN-induced IDO on prokaryotic and eukaryotic pathogens, as well as on a variety of tumor cell lines.     

Lipid complexes with cationic peptides and OAKs; their role in antimicrobial action and in the delivery of antimicrobial agents

Antimicrobial agents are toxic to bacteria by a variety of mechanisms. One mechanism that is very dependent on the lipid composition of the bacterial membrane is the clustering of anionic lipid by cationic antimicrobial agents. Certain species of oligo-acyl-lysine (OAK) antimicrobial agents are particularly effective in clustering anionic lipids in mixtures mimicking the composition of bacterial membranes. The clustering of anionic lipids by certain cationic antimicrobial agents contributes to the anti-bacterial action of these agents. Bacterial membrane lipids are a determining factor, resulting in some species of bacteria being more susceptible than others. In addition, lipids can be used to increase the effectiveness of antimicrobial agents when administered in vivo. Therefore, we review some of the structures in which lipid mixtures can assemble, to more effectively be utilized as antimicrobial delivery systems. We describe in more detail the complexes formed between mixtures of lipids mimicking bacterial membranes and an OAK and their usefulness in synergizing with antibiotics to overcome bacterial multidrug resistance.     

The role of 2,3-Diphosphoglyceric acid in the potassium transport of human erythrocytes

Zusammenfassung Der 2,3-Diphosphoglyzerat-Stoffwechsel menschlicher roter Blutkörperchen bedingt die Geschwindigkeit des infolge von ATP-Mangels auftretenden K⁺-Austritts. Der rasche K⁺-Austritt der Erythrocyten kann dann auftreten, wenn die Zellen kein 2,3-Diphosphoglyzerat mehr enthalten.

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The excellent technical assistance of Miss E.Mészáros is gratefully acknowledged.     

The role of mammalian antimicrobial peptides and proteins in awakening of innate host defenses and adaptive immunity

Since we live in a dirty environment, we have developed many host defenses to contend with microorganisms. The epithelial lining of our skin, gastrointestinal tract and bronchial tree produces a number of antibacterial peptides, and our phagocytic neutrophils rapidly ingest and enzymatically degrade invading organisms, as well as produce peptides and enzymes with antimicrobial activities. Some of these antimicrobial moieties also appear to alert host cells involved in both innate host defense and adaptive immune responses. The epithelial cells are a source of constitutively produced beta defensin (HBD1) and proinflammatory cytokine-inducible beta defensins (HBD2 and -3) and cathelicidin (LL37). The neutrophils-derived antimicrobial peptides are released on demand from their cytoplasmic granules. They include the enzymes cathepsin G and chymase, azurocidin, a defensins and cathelicidin. In contrast, C5a and C3b are produced by activation of the serum complement cascade. The antimicrobial moieties direct the migration and activate target cells by interacting with selected G-protein-coupled seven-transmembrane receptors (GPCRs) on cell surfaces. The beta defensins interact with the CCR6 chemokine GPCRs, whereas cathelicidins interact with the low-affinity FPRL-1 receptors. The neutrophil-derived cathepsin G acts on the high-affinity FMLP receptor (GPCR) known as FPR, while the receptors for chymase and azurocidin have not been identified as yet. The serum-derived C5a uses a GPCR known as C5aR to mediate its chemotactic and cell-activating effects. Consequently, all these ligand-receptor interactions in addition to mediating chemotaxis also activate receptor-expressing cells to produce other mediators of inflammation.     

The effects of ethanol on embryonic actin: a possible role in teratogenesis

When the neural crest is cultured in the long or short term presence of ethanol, monoclonal anti-actin reveals the development of a disorganized actin cytoskeleton. In the long term, many cells fail to differentiate morphologically, whereas in the short term already differentiated cells rapidly alter their shape and their cell-to-cell contacts.     

The effects of ethanol on embryonic actin: A possible role in teratogenesis

Summary When the neural crest is cultured in the long or short term presence of ethanol, monoclonal anti-actin reveals the development of a disorganized actin cytoskeleton. In the long term, many cells fail to differentiate morphologically, whereas in the short term already differentiated cells rapidly alter their shape and their cell-to-cell contacts.     

Beyond natural antimicrobial peptides: multimeric peptides and other peptidomimetic approaches

Naturally occurring antimicrobial peptides (AMPs) present several drawbacks that strongly limit their development into therapeutically valuable antibiotics. These include susceptibility to protease degradation and high costs of manufacture. To overcome these problems, researchers have tried to develop mimics or peptidomimetics endowed with better properties, while retaining the basic features of membrane-active natural AMPs such as cationic charge and amphipathic design. Protein epitope mimetics, multimeric (dendrimeric) peptides, oligoacyllysines, ceragenins, synthetic lipidated peptides, peptoids and other foldamers are some of the routes explored so far. The synthetic approach has led to compounds that have already entered clinical evaluation for the treatment of specific conditions, such as Staphylococcus (MRSA) infections. Should these trials be successful, an important proof-of-concept would be established, showing that synthetic oligomers rather than naturally occurring molecules could bring peptide-based antibiotics to clinical practice and the drug market for local and systemic treatment of medical conditions associated with multi-drug resistant pathogens.     

Critical role of extracellular vesicles in modulating the cellular effects of cytokines

Under physiological and pathological conditions, extracellular vesicles (EVs) are present in the extracellular compartment simultaneously with soluble mediators. We hypothesized that cytokine effects may be modulated by EVs, the recently recognized conveyors of intercellular messages. In order to test this hypothesis, human monocyte cells were incubated with CCRF acute lymphoblastic leukemia cell line-derived EVs with or without the addition of recombinant human TNF, and global gene expression changes were analyzed. EVs alone regulated the expression of numerous genes related to inflammation and signaling. In combination, the effects of EVs and TNF were additive, antagonistic, or independent. The differential effects of EVs and TNF or their simultaneous presence were also validated by Taqman assays and ELISA, and by testing different populations of purified EVs. In the case of the paramount chemokine IL-8, we were able to demonstrate a synergistic upregulation by purified EVs and TNF. Our data suggest that neglecting the modulating role of EVs on the effects of soluble mediators may skew experimental results. On the other hand, considering the combined effects of cytokines and EVs may prove therapeutically useful by targeting both compartments at the same time.     

Levels of erythrocyte 2,3 DPG and ATP in heavy hashish smokers

Summary The variations in concentration of ATP and 2,3 DPG, and in lactic acid production as a function of time, were measured in the erythrocytes of heavy hashish smokers. Results indicate that the most remarkable reduction in concentration of the compounds examined occurred at 30 and 45 min after hashish smoking. The findings are discussed in connection with the possible influence of hashish components, especially ⁹-THC, on the erythrocyte glycolytic pathway.     

Phytotoxic effects of cadmium in leaf segments ofAvena sativa L., and the protective role of calcium

Cellular and Molecular Life Sciences - It is shown that ethylene production can be stimulated in peeled oat leaf segments in the dark by cadmiun at concentrations below 0.01 mM, and that...     

Short native antimicrobial peptides and engineered ultrashort lipopeptides: similarities and differences in cell specificities and modes of action

Due to the rapid emergence of resistant microbes to the currently available antibiotics, cationic antimicrobial peptides have attracted considerable interest as a possible new generation of anti-infective compounds. However, low cost development for therapeutic or industrial purposes requires, among other properties, that the peptides will be small and with simple structure. Therefore, considerable research has been devoted to optimizing peptide length combined with a simple design. This review focuses on the similarities and differences in the mode of action and target cell specificity of two families of small peptides: the naturally occurring temporins from the skin of amphibia and the engineered ultrashort lipopeptides. We will also discuss the finding that acylation of cationic peptides results in molecules with a more potent spectrum of activity and a higher resistance to proteolytic degradation. Conjugation of fatty acids to linear native peptide sequences is a powerful strategy to engineer novel successful anti-infective drugs.     

Continued in vitro and in vivo release of an antitumor drug from albumin microspheres

Heated albumin microspheres with an average diameter of 45 +/- 8 microns and containing mitomycin C, released, in vitro, about 20% of this antibiotic over a 3-day period. VX-2 tumors were implanted into the hind leg of rabbits and the drug-containing microspheres were injected into the femoral artery of these animals. High levels of the drug were maintained for several hours in the tumor and growth of the tumor was inhibited considerably, compared to findings in control rabbits given the conventional mitomycin C. Half the number of the rabbits treated with our new method are alive with no evidence of tumor.     

Does increased gastric mucus play a role in the ulcer-protecting effects of zinc sulphate?

Summary Zinc sulphate pretreatment i.p. produces dose-related reductions in stress ulcer incidence in pylorus-occluded rats. The associated increases in gastric wall mucus, in stressed and nonstressed animals, suggest that a similar effect may contribute to its ulcer-reducing ability in man.     

Biochemical polymorphism and the 2,3-diphosphoglycerate in the sheep red blood cells

Summary There was no significant difference in the level of 2,3-DPG in the red blood cells of sheep of different haemoglobin types (Hb A and Hb B) or potassium types (HK and LK). However, low glutathione (GSH^L) sheep had significantly higher (p<0.01) level of 2,3-DPG in their red blood cells than high glutathione (GSH^H) sheep. There was also significant effect of interactions between glutathione, haemoglobin and potassium types (p<0.05) and glutathione and haemoglobin types (p<0.01) on red cell 2,3-DPG levels.     

On the role of carbonic anhydrase in the anticonvulsant effects of triethyltin (TET)

Summary Triethyltin (TET) and acetazolamide (ACTZ) both produce marked anticonvulsant effects as evaluated by the maximal electroshock seizure test. However, the mechanism responsible for the anticonvulsant effect of TET and ACTZ is probably not the same since TET does not inhibit the activity of carbonic anhydrase isozyme C in vitro.This study was supported by NIEHS Toxicology Training grant No. ES07 090, NIOSH grant No. OH07085 and a University of Texas Biomedical Research grant. We wish to thank Rebecca Crenshaw for her excellent technical assistance.     

Brown adipose tissue in young mice: Activity and role in thermoregulation

Zusammenfassung Gewicht und die Bernsteinsäuredehydrogenase-Aktivität des braunen interskapularen Fettgewebes wurden bei Foeten und jungen Mäusen gemessen. Beide Variabeln zeigen ein Maximum bei der Geburt und ein Minimum im Alter von 5 Tagen. Die Temperaturmessungen des Gehirns und des braunen Fettgewebes zeigen, dass bei neugeborenen Mäusen bei 26°C die Temperatur des Gehirns höher ist als diejenige des braunen Fettgewebes, während im Alter von 12 Tagen das braune Fettgewebe wärmer ist.