Highly Selective MIF Ketonase Inhibitor KRP-6 Diminishes M1 Macrophage Polarization and Metabolic Reprogramming.

Macrophage polarization is highly involved in autoimmunity. M1 polarized macrophages drive inflammation and undergo metabolic reprogramming, involving downregulation of mitochondrial energy production and acceleration of glycolysis. Macrophage migration inhibitory factor (MIF), an enigmatic tautomerase (ketonase and enolase), was discovered to regulate M1 polarization.

Synthesis and evaluation of a new class of MIF-inhibitors in activated macrophage cells and in experimental septic shock in mice.

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with enzymatic activities. Anti-inflammatory effects of MIF enzyme inhibitors indicate a link between its cytokine- and catalytic activities. Herein the synthesis, docking, and bioactivity of substituted benzylidene-1-indanone and -1-tetralone derivatives as MIF-tautomerase inhibitors is reported.

Distinct Uptake Routes Participate in Silver Nanoparticle Engulfment by Earthworm and Human Immune Cells.

The consequences of engineered silver nanoparticle (AgNP) exposure and cellular interaction with the immune system are poorly understood. The immunocytes of the earthworm are frequently applied in ecotoxicological studies and possess functional similarity to vertebrate macrophages. Hence, we characterized and compared the endocytosis mechanisms for the uptake of 75 nm AgNPs by earthworm coelomocytes, human THP-1 monocytes, and differentiated THP-1 (macrophage-like) cells.

[The importance of clinical risk assessment in reducing the pathway of acute coronary syndrome].

Introduction: Early diagnosis of acute coronary syndrome is emergency providers' task. In the last decade, vast amounts of clinical risk stratification scores were developed to decrease the hospital load of patients by selecting them properly. Objective: Together with the diagnostic and therapeutic challenges, decreasing treatment duration is essential for the improvement of acute coronary syndrome prognosis.

[Clinical risk assessment in decision making for hospital discharge of patients with pulmonary embolism].

Introduction: There are a vast number of studies that analyze the safest possible way of early at-home treatment of patients with pulmonary embolism after diagnosis. Objective: Our study aimed to find out how many patients could be discharged safely and without complications, if using the three validated score systems of the 2019 European Society of Cardiology guideline regarding pulmonary embolism. Method: Throughout our retrospective, quantitative study, we gathered data from the 2015-2018 period before the establishment of the new, 2019 guideline.

[“Decide and run!” The role of prehospital care providers in reducing time loss for patients with stroke diagnosis].

Unlabelled: Összefoglaló. Bevezetés: A stroke-betegek ellátásában arra kell törekedni, hogy a tünetek jelentkezését követően minél előbb a szakmai centrumba kerüljön a beteg. Célkitűzés: Kutatásunkban a terápiás időablak tarthatósága céljából vizsgáltuk, hogy mely tényezők bírnak hatással a prehospitális ellátás időtartamaira.

Olaparib: A Clinically Applied PARP Inhibitor Protects from Experimental Crohn's Disease and Maintains Barrier Integrity by Improving Bioenergetics through Rescuing Glycolysis in Colonic Epithelial Cells.

Crohn's disease (CD) is an inflammatory disorder of the intestines characterized by epithelial barrier dysfunction and mucosal damage. The activity of poly(ADP-ribose) polymerase-1 (PARP-1) is deeply involved in the pathomechanism of inflammation since it leads to energy depletion and mitochondrial failure in cells. Focusing on the epithelial barrier integrity and bioenergetics of epithelial cells, we investigated whether the clinically applied PARP inhibitor olaparib might improve experimental CD.

Tetralone derivatives are MIF tautomerase inhibitors and attenuate macrophage activation and amplify the hypothermic response in endotoxemic mice.

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine playing crucial role in immunity. MIF exerts a unique tautomerase enzymatic activity that has relevance concerning its multiple functions and its small molecule inhibitors have been proven to block its pro-inflammatory effects. Here we demonstrate that some of the -2-arylmethylene-1-tetralones and their heteroanalogues efficiently bind to MIF's active site and inhibit MIF tautomeric (enolase, ketolase activity) functions.

Modulation of Mitochondrial Quality Control Processes by BGP-15 in Oxidative Stress Scenarios: From Cell Culture to Heart Failure.

Heart failure (HF) is a complex chronic clinical disease characterized by among others the damage of the mitochondrial network. The disruption of the mitochondrial quality control and the imbalance in fusion-fission processes lead to a lack of energy supply and, finally, to cell death. BGP-15 (O-[3-piperidino-2-hydroxy-1-propyl]-nicotinic acid amidoxime dihydrochloride) is an insulin sensitizer molecule and has a cytoprotective effect in a wide variety of experimental models.

'The (second) year of first aid': a 15-month follow-up after a 3-day first aid programme.

Aim: First aid education in early childhood can be an effective method to increase the number of trained bystanders. Our aim was to evaluate the long-term effects of a 3-day first aid programme for all primary school-age groups (7-14 years old).

Methods: This study was a 15-month follow-up of our previous investigation.

[Examination of work-related stress and coping strategies among ambulance- and air-ambulance workers].

Introduction: Among Hungary's health sector workers the presence of a high level of stress is known, which can affect the individual.

Aim: The aim of the authors was to uncover major risk factors causing work-related stress, as well as its extent, and positive and negative coping strategies among ground and aerial rescue workers.

Method: From June until October 2015, a national survey was conducted among Hungarian rescue workers.

Eosinophils Contribute to Intestinal Inflammation via Chemoattractant Receptor-homologous Molecule Expressed on Th2 Cells, CRTH2, in Experimental Crohn's Disease.

Background And Aims: Prostaglandin [PG] D2 activates two receptors, DP and CRTH2. Antagonism of CRTH2 has been shown to promote anti-allergic and anti-inflammatory effects. We investigated whether CRTH2 may play a role in Crohn's disease [CD], focusing on eosinophils which are widely present in the inflamed mucosa of CD patients and express both receptors.

Phosphoinositide-dependent protein kinase 1 (PDK1) mediates potent inhibitory effects on eosinophils.

Prostaglandin E2 (PGE2 ) protects against allergic responses via binding to prostanoid receptor EP4, which inhibits eosinophil migration in a PI3K/PKC-dependent fashion. The phosphoinositide-dependent protein kinase 1 (PDK1) is known to act as a downstream effector in PI3K signaling and has been implicated in the regulation of neutrophil migration. Thus, here we elucidate whether PDK1 mediates inhibitory effects of E-type prostanoid receptor 4 (EP4) receptors on eosinophil function.

Anti-inflammatory effects of a triple-bond resveratrol analog: structure and function relationship.

Resveratrol is a polyphenol found in grapes and red wine, showing well-characterized anti-inflammatory and antiproliferative activities. In order to exceed resveratrol׳s biological effects and to reveal the structural determinants of the molecule׳s activity, numerous derivatives were synthesized recently. Most of these resveratrol analogs vary from the original molecule in the number, position or identity of the phenolic functional groups.

Opposing roles of prostaglandin D2 receptors in ulcerative colitis.

Proresolution functions were reported for PGD2 in colitis, but the role of its two receptors, D-type prostanoid (DP) and, in particular, chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2), is less well defined. We investigated DP and CRTH2 expression and function during human and murine ulcerative colitis (UC). Expression of receptors was measured by flow cytometry on peripheral blood leukocytes and by immunohistochemistry and immunoblotting in colon biopsies of patients with active UC and healthy individuals.

[Knowledge about basic life support in European students].

Introduction: Better knowledge and skills of basic life support can save millions of lives each year in Europe.

Aim: The aim of this study was to measure the knowledge about basic life support in European students.

Method: From 13 European countries 1527 volunteer participated in the survey.

TRAF6 is functional in inhibition of TLR4-mediated NF-κB activation by resveratrol.

Resveratrol was suggested to inhibit Toll-like receptor (TLR)4-mediated activation of nuclear factor-κB (NF-κB) and Toll/interleukin-1 receptor domain-containing adaptor inducing interferon-β (TRIF)-(TANK)-binding kinase 1, but the myeloid differentiation primary response gene 88-tumor necrosis factor receptor-associated factor 6 (TRAF6) pathway is not involved in this effect. However, involvement of TRAF6 in this process is still elusive since cross talk between TRIF and TRAF6 has been reported in lipopolysaccharide (LPS)-induced signaling. Using RAW 264.

Protective effect of the poly(ADP-ribose) polymerase inhibitor PJ34 on mitochondrial depolarization-mediated cell death in hepatocellular carcinoma cells involves attenuation of c-Jun N-terminal kinase-2 and protein kinase B/Akt activation.

Background: 2,4-Dimethoxyphenyl-E-4-arylidene-3-isochromanone (IK11) was previously described to induce apoptotic death of A431 tumor cells. In this report, we investigated the molecular action of IK11 in the HepG2 human hepatocellular carcinoma cell line to increase our knowledge of the role of poly (ADP-ribose)-polymerase (PARP), protein kinase B/Akt and mitogen activated protein kinase (MAPK) activation in the survival and death of tumor cells and to highlight the possible role of PARP-inhibitors in co-treatments with different cytotoxic agents in cancer therapy.

Results: We found that sublethal concentrations of IK11 prevented proliferation, migration and entry of the cells into their G2 phase.

Synthesis and study of new paramagnetic resveratrol analogues.

New resveratrol analogues containing five- and six-membered nitroxides and isoindoline nitroxides were synthesized. These new compounds were compared to resveratrol based on their ABTS radical scavenging ability as well on their capacity to suppress inflammatory process in macrophages induced by lipopolysaccharides. The ABTS and ROS scavenging activities of new molecules were the same or weaker than that of resveratrol, but some of paramagnetic resveratrol derivatives suppressed nitrite and TNFα production more efficiently than resveratrol.

Suppressing LPS-induced early signal transduction in macrophages by a polyphenol degradation product: a critical role of MKP-1.

Macrophages represent the first defense line against bacterial infection and therefore, play a crucial role in early inflammatory response. In this study, we investigated the role of MAPKs and MKP-1 activation in regulation of an early inflammatory response in RAW 264.7 macrophage cells.

Ferulaldehyde, a water-soluble degradation product of polyphenols, inhibits the lipopolysaccharide-induced inflammatory response in mice.

Antiinflammatory properties of polyphenols in natural products, traditional medicines, and healthy foods were recently attributed to highly soluble metabolites produced by the microflora of the intestines rather than the polyphenols themselves. To provide experimental basis for this hypothesis, we measured antiinflammatory properties of ferulaldehyde (FA), a natural intermediate of polyphenol metabolism of intestinal microflora, in a murine lipopolysaccharide (LPS)-induced septic shock model. We found that intraperitoneally administered FA (6 mg/kg) prolonged the lifespan of LPS-treated (40 mg/kg) mice, decreased the inflammatory response detected by T(2)-weighted in vivo MRI, decreased early proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin (IL)-1beta, and increased the antiinflammatory IL-10 in the sera of the mice.

A novel SOD-mimetic permeability transition inhibitor agent protects ischemic heart by inhibiting both apoptotic and necrotic cell death.

In ischemia-reperfusion injuries, elevated calcium and reactive oxygen species (ROS) induce mitochondrial permeability transition (mPT), which plays a pivotal role in mediating damages and cell death. Inhibition of mPT decreases necrotic cell death; however, during reperfusion, the continuous production of ROS may contribute to the temporary opening of the pore and thus the onset of the delayed apoptotic cell death. Based on amiodarone structure, we developed the first SOD-mimetic mPT inhibitor (HO-3538) that can eliminate ROS in the microenvironment of the permeability pore.

Salsolinol induces a decrease in cyclic AMP at the median eminence and an increase at the adenohypophysis in lactating rats.

Investigating the cellular events in the pituitary gland, the intracellular cyclic AMP (cAMP) of the median eminence (ME), neuro-intermediate lobe (NIL) and the anterior lobe (AL) have been measured following 15-min of intravenous injection of salsolinol (SAL). Parallel to the elevation of plasma prolactin (PRL), SAL induced a significant decrease of cAMP concentration in the ME. In contrast, SAL injection resulted in a significant increase of cAMP at the level of the AL.

Regulation of kinase cascades and transcription factors by a poly(ADP-ribose) polymerase-1 inhibitor, 4-hydroxyquinazoline, in lipopolysaccharide-induced inflammation in mice.

Activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) is involved in numerous pathophysiological conditions. Because PARP-1 knockout mice are resistant to endotoxin-induced shock and inhibitors of the enzyme were reported to have similar beneficial properties, we investigated the effect of 4-hydroxyquinazoline (4-HQN), a potent PARP-1 inhibitor, on the modulation of kinase cascades and the regulation of transcription factors in a rodent septic shock model. T2-weighted magnetic resonance imaging showed the pattern of anatomical localization of the inflammatory response in bacterial lipopolysaccharide (LPS)-treated mice and the anti-inflammatory effect of the PARP-1 inhibitor.