ATP and Formyl Peptides Facilitate Chemoattractant Leukotriene-B4 Synthesis and Drive Calcium Fluxes, Which May Contribute to Neutrophil Swarming at Sites of Cell Damage and Pathogens Invasion.

Here, we demonstrate that human neutrophil interaction with the bacterium fuels leukotriene B4 synthesis induced by the chemoattractant fMLP. In this work, we found that extracellular ATP (eATP), the amount of which increases sharply during tissue damage, can effectively regulate fMLP-induced leukotriene B4 synthesis. The vector of influence strongly depends on the particular stage of sequential stimulation of neutrophils by bacteria and on the stage at which fMLP purinergic signaling occurs.

Redox processes are major regulators of leukotriene synthesis in neutrophils exposed to bacteria ; the way to manipulate neutrophil swarming.

Neutrophils play a primary role in protecting our body from pathogens. When confronted with invading bacteria, neutrophils begin to produce leukotriene B4, a potent chemoattractant that, in cooperation with the primary bacterial chemoattractant fMLP, stimulates the formation of swarms of neutrophils surrounding pathogens. Here we describe a complex redox regulation that either stimulates or inhibits fMLP-induced leukotriene synthesis in an experimental model of neutrophils interacting with .

Unapproved clinical trials in Russia: exception or norm?

Background: In modern Russia, any clinical investigation of a pharmaceutical for use in humans is subject to prior evaluation and approval by the Ministry of Health and its Central Ethics Committee. Despite this, some researchers and trial sponsors fail to comply, this is particularly true in case of the studies initiated by domestic sponsors or sponsor-investigators and published in Russian language medical journals. This exploratory research aims to discover whether it is a sporadic non-compliance with regulations or a common practice.

Magic Peptide: Unique Properties of the LRR11 Peptide in the Activation of Leukotriene Synthesis in Human Neutrophils.

Neutrophil-mediated innate host defense mechanisms include pathogen elimination through bacterial phagocytosis, which activates the 5-lipoxygenase (5-LOX) product synthesis. Here, we studied the effect of synthetic oligodeoxyribonucleotides (ODNs), which mimic the receptor-recognized sites of bacterial (CpG-ODNs) and genomic (G-rich ODNs) DNAs released from the inflammatory area, on the neutrophil functions after cell stimulation with . A possible mechanism for ODN recognition by Toll-like receptor 9 (TLR9) and RAGE receptor has been proposed.

The Potential of Telomeric G-quadruplexes Containing Modified Oligoguanosine Overhangs in Activation of Bacterial Phagocytosis and Leukotriene Synthesis in Human Neutrophils.

Human neutrophils are the first line of defense against bacterial and viral infections. They eliminate pathogens through phagocytosis, which activate the 5-lipoxygenase (5-LOX) pathway resulting in synthesis of leukotrienes. Using HPLC analysis, flow cytometry, and other biochemical methods, we studied the effect of synthetic oligodeoxyribonucleotides (ODNs) able to fold into G-quadruplex structures on the main functions of neutrophils.

PBAF lacking PHD domains maintains transcription in human neutrophils.

The myeloid precursor cell differentiation requires an extensive chromatin remodeling. We show that the level of the PBAF chromatin remodeling complex decreases following the start of differentiation of myeloid precursors, becoming very low in the terminally differentiated peripheral blood (PB) neutrophils where it co-localizes with Pol II on the transcriptionally active chromatin. Previously, we have shown that the PHF10 subunit of the PBAF signature module has four isoforms, two of them (PHF10-P) contain a tandem of C-terminal PHD domains.

Synthetic CpG oligonucleotides as potential modulators of neutrophil survival in PAMP-associated inhibition of apoptosis.

We studied the effects of a synthetic CpG oligonucleotide (CpG ODN2006) on polymorphonuclear leukocyte (PMNL, neutrophil) survival and oxidant status. CpG ODN2006 showed a dose-dependent effect on the apoptosis of resting neutrophils. Without affecting the viability of resting cells, low concentrations of CpG ODN2006 interfered with Salmonella typhimurium-mediated viability prolongation and increased neutrophil apoptosis to control levels.

Nitric Oxide in Life and Death of Neutrophils.

Background: Nitric Oxide (NO) is a key signalling molecule that has an important role in inflammation. It can be secreted by endothelial cells, neutrophils, and other cells, and once in circulation, NO plays important roles in regulating various neutrophil cellular activities and fate.

Objective: To describe neutrophil cellular responses influenced by NO and its concomitant compound peroxynitrite and signalling mechanisms for neutrophil apoptosis.

G-quadruplex-forming oligodeoxyribonucleotides activate leukotriene synthesis in human neutrophils.

Human polymorphonuclear leukocytes (PMNLs, neutrophils) play a major role in the immune response to bacterial and fungal infections and eliminate pathogens through phagocytosis. During phagocytosis of microorganisms, the 5-lipoxygenase (5-LOX) pathway is activated resulting in generation of leukotrienes, which mediate host defense. In this study, a library of oligodeoxyribonucleotides (ODNs) with varying numbers of human telomeric repeats (d(TTAGGG)) and their analogues with phosphorothioate internucleotide linkages and single-nucleotide substitutions was designed.

Fine Regulation of Neutrophil Oxidative Status and Apoptosis by Ceruloplasmin and Its Derivatives.

Timely neutrophil apoptosis is an essential part of the resolution phase of acute inflammation. Ceruloplasmin, an acute-phase protein, which is the predominant copper-carrying protein in the blood, has been suggested to have a marked effect on neutrophil life span. The present work is a comparative study on the effects of intact holo-ceruloplasmin, its copper-free (apo-) and partially proteolyzed forms, and synthetic free peptides RPYLKVFNPR (883-892) and RRPYLKVFNPRR (882-893) on polymorphonuclear leukocyte (PMNL, neutrophil) oxidant status and apoptosis.

Ceruloplasmin-derived peptide is the strongest regulator of oxidative stress and leukotriene synthesis in neutrophils.

Ceruloplasmin, an acute-phase protein, can affect the activity of leukocytes through its various enzymatic activities and protein-protein interactions (with lactoferrin, myeloperoxidase, eosinophil peroxidase, serprocidins, and 5-lipoxygenase (5-LOX), among others). However, the molecular mechanisms of ceruloplasmin activity are not clearly understood. In this study, we tested the ability of two synthetic peptides, RPYLKVFNPR (883-892) (P1) and RRPYLKVFNPRR (882-893) (P2), corresponding to the indicated fragments of the ceruloplasmin sequence, to affect neutrophil activation.

Effects of phosphodiester and phosphorothioate ODN2216 on leukotriene synthesis in human neutrophils and neutrophil apoptosis.

Polymorphonuclear leukocytes (PMNLs, neutrophils) play a major role in the initiation and resolution of the inflammatory response, and neutrophil apoptosis is a critical step in resolving inflammation. We examined the effects of oligodeoxynucleotide (ODN) species with different numbers of phosphodiester and phosphorothioate bonds on leukotriene synthesis in PMNLs and on neutrophil apoptosis. Our modifications were based on the well-known ODN2216 molecule (Krug et al.

Polymorphonuclear leukocyte apoptosis is accelerated by sulfatides or sulfatides-treated Salmonella Typhimurium bacteria.

Neutrophils die by apoptosis following activation and uptake of microbes or enter apoptosis spontaneously at the end of their lifespan if they do not encounter a pathogen. Here we report that sulfatides or sulfatides-treated Salmonella Typhimurium bacteria accelerated human neutrophil apoptosis. Neutrophil apoptosis was examined by flow cytometry.

Regulation of 5-oxo-ETE synthesis by nitric oxide in human polymorphonuclear leucocytes upon their interaction with zymosan and Salmonella typhimurium.

In the present study we have presented data on the regulation of LT (leukotriene) and 5-oxo-ETE (5-oxo-6,8,11,14-eicosatetraenoic acid) syntheses in human neutrophils upon interaction with OZ (opsonized zymosan) or Salmonella typhimurium. Priming of neutrophils with PMA (phorbol 12-myristate 13-acetate) and LPS (lipopolysaccharide) elicits 5-oxo-ETE formation in neutrophils exposed to OZ, and the addition of AA (arachidonic acid) significantly increases 5-oxo-ETE synthesis. We found that NO (nitric oxide)-releasing compounds induce 5-oxo-ETE synthesis in neutrophils treated with OZ or S.