lysine synthesis neutrophil

UNLABELLED: Lysine (K)-specific demethylase 6A (KDM6A) is a frequently mutated tumor suppressor gene in pancreatic ductal adenocarcinoma (PDAC). However, the impact of KDM6A loss on the PDAC tumor immune microenvironment is not known. This study used a genetically engineered, pancreas-specific Kdm6a knockout (KO) PDAC mouse model and human PDAC tissue samples to demonstrate that KDM6A loss correlates with increased tumor-associated neutrophils and neutrophil extracellular traps (NET) formation, which are known to contribute to PDAC progression...

The diabetic wound is easily to develop into a chronic wound because of the extremely serious and complex inflammatory microenvironment including biofilm formation, over-expressed reactive oxygen species (ROS), hypoxia and insufficiency of nitric oxide (NO) synthesis. In this work, a multifunctional hydrogel was designed and prepared by crosslinking hydrophilic poly(PEGMA-co-GMA-co-AAm) (PPGA) polymers with hyperbranched poly-L-lysine (HBPL)-modified manganese dioxide (MnO2 ) nanozymes. Pravastatin sodium, which is supposed to participate in the synthesis of NO, was further loaded to obtain the HMP hydrogel...

Peripheral neutrophils in HIV-infected individuals are characterized by impairment of chemotaxis, phagocytosis, bactericidal activity, and oxidative burst ability regardless of whether patients are receiving antiretroviral therapy or not. Neutrophil dysfunction leads not only to increased susceptibility to opportunistic infections but also to tissue damage through the release of reactive oxygen species (ROS), proteases, and other potentially harmful effector molecules contributing to AIDS progression. In this study, we demonstrated high levels of histone H3 lysine K4 trimethylated (H3K4me3) and dysregulation of DNA transcription in circulating neutrophils of HIV-infected subjects...

Myocardial fibrosis is the result of excessive fibrillar collagen synthesis and deposition without reciprocally balanced degradation. It causes cardiac dysfunction, arrhythmias, and ischaemia, and thereby determines the clinical course and outcome of cardiac patients even when adequately treated. Therefore, further research is needed to identify and better understand the factors that trigger and maintain the myocardial fibrotic response against different injuries in a variety of cardiac diseases. Here, we will focus on the following major areas of research: molecules that stimulate the differentiation of fibroblasts into myofibroblasts and subsequently alter collagen turnover (e...

Glycogen synthase kinase 3 (GSK-3) is associated with several cellular systems, including immune response. Lithium, a widely used pharmacological treatment for bipolar disorder, is a GSK-3 inhibitor. GSK-3α is the predominant isoform in human neutrophils. In this study, we examined the effect of GSK-3 inhibition on the production of TNF-α by neutrophils. In the murine air pouch model of inflammation, lithium chloride (LiCl) amplified TNF-α release. In lipopolysaccharide-stimulated human neutrophils, GSK-3 inhibitors mimicked the effect of LiCl, each potentiating TNF-α release after 4 h, in a concentration-dependent fashion, by up to a 3-fold increase (ED50 of 1 mM for lithium)...

Listeria monocytogenes is an intracellular, foodborne gastrointestinal pathogen that is primarily responsible for causing listeriosis or food poisoning in otherwise healthy individuals. Infections that arise during pregnancy or within immune compromised individuals are much more serious resulting in the risk of fetal termination or fetal fatality postpartum in the former and septicemia or meningitis with a 20% fatality rate in the latter. While the roles of internalin proteins and listeriolysin-O in the infection process are well characterized, the specific roles of lysine-modified phospholipids in the membrane of L...

Further studies are reported on the utilization of the versatile reaction between chiral sulfinimines and alkyldiphenylsilyl lithium reagents with the goal of preparing a wide range of silanediol-based protease inhibitors. In particular, focus has been placed to demonstrate how a number of genetically encoded amino acid side chains such as serine, threonine, tyrosine, lysine, proline, arginine, aspartate and asparagine might be incorporated into the overall approach. Efforts to apply this synthetic methodology for accessing biologically relevant silanediol dipeptide mimics are also described...

UNLABELLED: The synthesis and validation of a new, highly potent (64)Cu-labeled peptide, cFLFLFK-PEG-(64)Cu, that targets the formyl peptide receptor (FPR) on leukocytes is described. The peptide ligand is an antagonist of the FPR, designed not to elicit a chemotactic response resulting in neutropenia. Evidence for the selective binding of this synthesized ligand to neutrophils is provided. PET properties of the compound were evaluated in a mouse model of lung inflammation. METHODS: The FPR-specific peptide, cinnamoyl-F-(D)L-F-(D)L-FK (cFLFLF), was sequentially conjugated with a bifunctional polyethylene glycol moiety (PEG, 3...

During inhalational anthrax, Bacillus anthracis survives and replicates in alveolar macrophages, followed by rapid invasion into the host's bloodstream, where it multiplies to cause heavy bacteremia. B. anthracis must therefore defend itself from host immune functions encountered during both the intracellular and the extracellular stages of anthrax infection. In both of these niches, cationic antimicrobial peptides are an essential component of the host's innate immune response that targets B. anthracis. However, the genetic determinants of B...

The evolution of bacterial pathogens from commensal organisms involves virulence gene acquisition followed by pathoadaptation to the new host, including inactivation of antivirulence loci (AVL). AVL are core ancestral genes whose expression is incompatible with the pathogenic lifestyle. Previous studies identified cadA (encoding lysine decarboxylase) as an AVL of Shigella spp. In this study, AVL of Shigella were identified by examining a phenotypic difference from its non-pathogenic ancestor, Escherichia coli...

In intestinal inflammation, mucosal injury is often exacerbated by the reaction of NO with neutrophil-derived superoxide to form the potent oxidant peroxynitrite. Peroxynitrite also has antimicrobial properties that aid in the killing mechanism of macrophages and neutrophils. Cryptosporidium parvum parasitizes intestinal epithelium, resulting in loss of epithelial cells and mucosal inflammation. Synthesis of NO is significantly increased and arises from the induced expression of inducible nitric oxide synthase (iNOS) by the infected epithelium...

Oxidative modification of low density lipoprotein (LDL) is involved in the pathogenesis of atherosclerosis and coronary heart disease, which are low in the Mediterranean area possibly due to a high dietary proportion of plant foods. Ethanolic extracts were prepared from more than 120 Mediterranean edible plants collected in remote areas (which maintain their traditional diet) and their antioxidant potential was studied. Extracts derived from Agaricus campestris, Cynara cardunculus, Thymus pulegioides, and Vicia faba were subjected to further analysis in this study...

Cytochrome c (cyt c)-derived protein radicals, radical adduct aggregates, and protein tyrosine nitration have been implicated in the pro-apoptotic event connecting inflammation to the development of diseases. During inflammation, one of the reactive oxygen species metabolized via neutrophil activation is hypochlorite (HOCl); destruction of the mitochondrial electron transport chain by hypochlorite is considered to be a damaging factor. Previous study has shown that HOCl induces the site-specific oxidation of cyt c at met-80...

The aqueous solubility and/or dispersibility of synthetic carotenoid analogs can be improved by varying the chemical structure(s) of the esterified moieties. In the current study, a highly water-dispersible astaxanthin (3,3'-dihydroxy-beta,beta-carotene-4,4'-dione) derivative was synthesized by esterification to the amino acid L-lysine, and subsequently converted to the tetrahydrochloride salt. Deep violet, evenly colored aqueous suspensions were obtained with addition of the novel derivative to USP purified water up to a maximum of 181...

Increased levels of proinflammatory cytokines are present in bronchoalveolar lavage fluid in various lung diseases. Redox-sensitive transcription factors such as NF-kappaB regulate gene transcription for these cytokines. We therefore studied the effect of a new thiol antioxidant compound, Nacystelyn (NAL), on IL-8 regulation in a human macrophage-derived cell line (THP-1). LPS (10 microg/ml) increased IL-8 release compared with control levels. This LPS activation was inhibited by coincubation with NAL (1 and 5 mM)...

In order to explore the properties of chemotactic N-formylpeptides containing isopeptide bonds within their backbones, a group of lysine-containing analogs of the prototypical chemotactic tripeptide N-formylmethionyl-leucyl-phenylalanine (fMLF) was synthesized. The new analogs were designed by adding to the HCO-Met or Boc-Met residue a dipeptide fragment made up of Lys and Phe residues joined through Lys N alpha or N epsilon bonds, in all possible combinations. Thus, the following six pairs of tripeptides were synthesized and examined for their bioactivity: RCO-Met-Lys(Z)-Phe-OMe (2a, b), RCO-Met-Lys(Z-Phe)-OMe (3a, b), Z-Lys(RCO-Met)-Phe-OMe (4a, b), Z-Phe-Lys(RCO-Met)-OMe (5a, b), RCO-Met-Phe-Lys(Z)-OMe (6a, b) and Z-Lys(RCO-Met-Phe)-OMe (7a, b), with R=OC(CH3)(3 )and R=H for compounds a and b, respectively...

Nitric oxide is a crucial mediator of several forms of glomerulonephritis. We examined the effects of NO on the mRNA expression pattern in glomerular mesangial cells by using a low-stringency reverse transcriptase-polymerase chain reaction method and detected a cDNA fragment that was induced by interleukin 1b (IL-1b) and further up-regulated by the NO donor diethylenetriamine-nitric oxide (DETA-NO). Each respective cDNA fragment was found to match with the cDNAs of rat macrophage inflammatory protein 2 (MIP-2) and GRO/cytokine-induced neutrophil chemoattractant 2b (CINC-2b)...

Cyanate spontaneously transformed from urea increases as renal function decreased. Acting as a potential toxin, the active form of cyanate, isocyanic acid, carbamoylates amino acids, proteins, and other molecules, changing their structure, charge, and function. The resulting in vivo carbamoylation can modify the molecular activity of enzymes, cofactors, hormones, low-density lipoproteins, antibodies, receptors, and transport proteins. Antibodies specific for epsilon-amino-carbamoyl-lysine (homocitrulline) located carbamoylated proteins in situ in neutrophils, monocytes, and erythrocytes...

Isolated cell systems of human neutrophils (PMNs) and monocyte-derived macrophages (MDMs) were used to compare the destructive potential of these cells during the acute and chronic phases of inflammation, respectively. The contrast in the damage to poly(urethane)s (PUs) was monitored by measuring radiolabel release elicited from a (14)C-polyester-urea-urethane (PEUU) during incubation with both cell types. Human PMN were seeded onto polymer-coated glass slips and both radiolabel release as well as serine protease activity [assayed with N-benzyloxycarbonyl lysine thiobenzyl ester (BLT)] were measured 18 h later...

Increased NO synthesis, due to inducible NO synthase (iNOS) activity, is found in macrophage-associated glomerulonephritis. Little is known about NO in neutrophil-dependent immune complex inflammation, and its role remains controversial. We therefore studied early phase heterologous nephrotoxic nephritis (HNTN) induced in rats by nephrotoxic globulin and the effects of selective iNOS inhibition of this model. At 2 h of the model iNOS mRNA was induced and nitrite (NO-2) was generated in glomeruli incubated ex vivo (5...