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 E-2-arylmethylene-1-tetralones and their heteroanalogues efficiently bind to MIF's active site and inhibit MIF tautomeric (enolase, ketolase activity) functions. A small set of the synthesised derivatives, namely compounds (4), (23), (24), (26) and (32), reduced inflammatory macrophage activation. Two of the selected compounds (24) and (26), however, markedly inhibited ROS and nitrite production, NF-κB activation, TNF-α, IL-6 and CCL-2 cytokine expression. Pre-treatment of mice with compound (24) exaggerated the hypothermic response to high dose of bacterial endotoxin. Our experiments suggest that tetralones and their derivatives inhibit MIF's tautomeric functions and regulate macrophage activation and thermal changes in severe forms of systemic inflammation.

'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. Five-hundred and twenty-four primary school children were involved in this study. Measurements were made on the following topics: adult basic life support, using an automated external defibrillator (AED), handling an unconscious patient, managing bleeding and calling the ambulance. Data collection was made with a self-made questionnaire and skill test. RESULTS: Knowledge and skills were significantly higher after 15 months than before training (p<0.01). However, these results were significantly worse than immediately and 4 months after training (p<0.01). Based on the questionnaire, more than three-quarters knew the emergency phone number 15 months after training. Approximately two-thirds of the children could use the correct hand position in cardiopulmonary resuscitation, the correct compression-ventilation ratio and an AED, and half of them could perform correct recovery position at 15 months. Correct assessment of breathing was similar in a situation game than before training. Self-efficacy improved significantly after training (p<0.01) and remained improved after 4 and 15 months when compared with before training (p<0.01). CONCLUSION: Participants could remember some aspects of first aid long term. However, knowledge and skills had declined after 15 months, so refresher training would be recommended. Self-efficacy towards first aid improved after training and remained high after 15 months.

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. Therefore, eosinophils were isolated from human peripheral blood or differentiated from mouse BM. PDK1 signaling was investigated in shape change, chemotaxis, CD11b, respiratory burst, and Ca(2+) mobilization assays. The specific PDK1 inhibitors BX-912 and GSK2334470 prevented the inhibition by prostaglandin E2 and the EP4 agonist ONO-AE1-329. Depending on the cellular function, PDK1 seemed to act through PI3K-dependent or PI3K-independent mechanisms. Stimulation of EP4 receptors caused PDK1 phosphorylation at Ser396 and induced PI3K-dependent nuclear translocation of PDK1. EP4-induced inhibition of shape change and chemotaxis was effectively reversed by the Akt inhibitor triciribine. In support of this finding, ONO-AE1-329 induced a PI3K/PDK1-dependent increase in Akt phosphorylation. In conclusion, our data illustrate a critical role for PDK1 in transducing inhibitory signals on eosinophil effector function. Thus, our results suggest that PDK1 might serve as a novel therapeutic target in diseases involving eosinophilic inflammation.

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. Receptor involvement in UC was evaluated in a mouse model of dextran sulfate sodium colitis. DP and CRTH2 expression changed in leukocytes of patients with active UC in a differential manner. In UC patients, DP showed higher expression in neutrophils but lower in monocytes as compared with control subjects. In contrast, CRTH2 was decreased in eosinophils, NK, and CD3(+) T cells but not in monocytes and CD3(+)/CD4(+) T cells. The decrease of CRTH2 on blood eosinophils clearly correlated with disease activity. DP correlated positively with disease activity in eosinophils but inversely in neutrophils. CRTH2 internalized upon treatment with PGD2 and 11-dehydro TXB2 in eosinophils of controls. Biopsies of UC patients revealed an increase of CRTH2-positive cells in the colonic mucosa and high CRTH2 protein content. The CRTH2 antagonist CAY10595 improved, whereas the DP antagonist MK0524 worsened inflammation in murine colitis. DP and CRTH2 play differential roles in UC. Although expression of CRTH2 on blood leukocytes is downregulated in UC, CRTH2 is present in colon tissue, where it may contribute to inflammation, whereas DP most likely promotes anti-inflammatory actions.

[Examination of work-related stress and coping strategies among ambulance- and air-ambulance workers]. / Munkahelyi stressz és megküzdési stratégiák vizsgálata földi és légi mentésben dolgozók körében.

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. An own questionnaire and Rahe Stress and coping validated short questionnaire online form were used. A total of 141 persons took part in the survey. RESULTS: As compared to air-ambulance workers, ground rescue workers were exposed to higher work-related stress effects (p<0.01), resulting in a much larger variety of physical and psychological symptoms (p<0.05). Based on Global Stress and Coping Index effective coping mechanisms were observed among air rescue workers (p<0.01). CONCLUSIONS: It is important to perform regular professional theoretical and practical training. Human resource management should pay attention on occupational stress reduction. Orv. Hetil., 2016, 157(45), 1802-1808.

[Knowledge about basic life support in European students]. / Európai fiatalok alapszintu életmentési ismeretei.

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. The questionnaire consisted of socio-demographic questions and knowledge regarding basic life support. The maximum possible score was 18. RESULTS: Those participants who had basic life support training earned 11.91 points, while those who had not participated in lifesaving education had 9.6 points (p<0.001). Participants from former socialist Eastern European countries reached 10.13 points, while Western Europeans had average 10.85 points (p<0.001). The best results were detected among the Swedish students, and the worst among the Belgians. CONCLUSIONS: Based on the results, there are significant differences in the knowledge about basic life support between students from different European countries. Western European youth, and those who were trained had better performance.

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. Many of these substituted benzylidene-1-tetralones and -indan-1-ones were potent MIF-tautomerase inhibitors (IC50 < 10 µmol/L), and the most potent inhibitors were the 1-indanone derivatives 16 and 20. Some of these compounds acted as selective enolase or ketonase inhibitors. In addition, compounds 16, 20, 26, 37 and 61 efficiently inhibited NO, TNFα and IL-6 production in lipopolysaccharide-induced macrophages. Compound 20, 37 and 61 also inhibited ROS generation, and compound 26 and 37 abolished activation of NF-κB. Compound 37 significantly augmented hypothermia induced by high dose of lipopolysaccharide in mice. The possible mechanisms of action were explored using molecular modelling and docking, as well as molecular dynamics simulations.

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. Here, we reveal that KRP-6, a potent and highly selective MIF ketonase inhibitor, reduces MIF-induced human blood eosinophil and neutrophil migration similarly to ISO-1, the most investigated tautomerase inhibitor. We equally discovered that KRP-6 prevents M1 macrophage polarization and reduces ROS production in IFN-γ-treated cells. During metabolic reprogramming, KRP-6 improved mitochondrial bioenergetics by ameliorating basal respiration, ATP production, coupling efficiency and maximal respiration in LPS+IFN-γ-treated cells. KRP-6 also reduced glycolytic flux in M1 macrophages. Moreover, the selective MIF ketonase inhibitor attenuated LPS+IFN-γ-induced downregulation of PARP-1 and PARP-2 mRNA expression. We conclude that KRP-6 represents a promising novel therapeutic compound for autoimmune diseases, which strongly involves M1 macrophage polarization.

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. At higher concentrations, IK11 induced reactive oxygen species (ROS) production, mitochondrial membrane depolarization, activation of c-Jun N-terminal kinase 2 (JNK2), and substantial loss of HepG2 cells. ROS production appeared marginal in mediating the cytotoxicity of IK11 since N-acetyl cysteine was unable to prevent it. However, the PARP inhibitor PJ34, although not a ROS scavenger, strongly inhibited both IK11-induced ROS production and cell death. JNK2 activation seemed to be a major mediator of the effect of IK11 since inhibition of JNK resulted in a substantial cytoprotection while inhibitors of the other kinases failed to do so. Inhibition of Akt slightly diminished the effect of IK11, while the JNK and Akt inhibitor and ROS scavenger trans-resveratrol completely protected against it. CONCLUSIONS: These results indicate significant involvement of PARP, a marginal role of ROS and a pro-apoptotic role of Akt in this system, and raise attention to a novel mechanism that should be considered when cancer therapy is augmented with PARP-inhibition, namely the cytoprotection by inhibition of JNK2.

Clinical risk assessment in decision making for hospital discharge of patients with pulmonary embolism / Klinikai kockázatbecslésen alapuló döntéshozatal a tüdoemboliás betegek kórházi elbocsátása során

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. We assessed patients who had a diagnosis of pulmonary embolism at the emergency room in the given period. With the help of the prognostic score systems, we retrospectively made a risk stratification using the main symptoms and vital parameters. We analyzed the categorical variables with chi-square test. For assessing two continuous variables, we used Pearson's correlation. We defined our level of significance at p<0,05. Results: 374 (199 female and 175 male) patients were enrolled in our study. Our retrospective calculation had the following results: based on the PESI score 151 patients, on the basis of the sPESI 101 patients and according to the Hestia criteria 50 patients could have been discharged, treated at home without complications and increasing the mortality. The negative predictive value (PESI: 98%, sPESI: 100%, Hestia: 100% with CI: 95%) and sensitivity (PESI: 91%, sPESI: 100%, Hestia: 100%) of the three prognostic scores showed applicable efficiency. Conclusion: We concluded that all three prognostic criteria can be used safely taking the local clinical experience and preference into consideration, aiming at early discharge. Adapting them nationally could decrease hospital load.

The importance of clinical risk assessment in reducing the pathway of acute coronary syndrome / A klinikai kockázatbecslés jelentosége az akut coronaria szindróma betegút csökkentésében

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. Our aim was to assess the HEART score's time-and therapy -related effects on acute coronary syndrome detection as a decision support system. Method: We conducted a retrospective, quantitative study at a county state emergency department amongst patients with the myocardial infarction ICD codes. We assessed their admission time, the way they were delivered to the hos-pital, their presenting symptoms, vital parameters, chronic medical conditions, laboratory and imaging results and the time of their admission to the percutan intervention center. We calculated the HEART score retrospectively from the collected data. Results: Our sample size consisted of 360 people. Coronary artery disease (80%) and hypertension (73.3%) were the most common risk factors, while chest pain (80%) and shortness of breath (48.6%) were the most common com-plaints. Coronary artery disease, hypertension and diabetes are not related to percutan coronary intervention admis-sion times (p = 0.110; p = 0.173; p = 0.507). We found a correlation between the presence of chest pain and mortal-ity (p = 0.009). The calculated HEART score had a correlation with the fact of coronary intervention admission (p = 0.005). Conclusion: We conclude that the retrospectively calculated HEART score correlates with percutan coronary inter-vention admission. Choosing the proper risk stratification can increase the lifespan of the patients and hospital cost-efficiency.

"Decide and run!" The role of prehospital care providers in reducing time loss for patients with stroke diagnosis / "Dönts és siess!" A prehospitális ellátók szerepe az idoveszteség csökkentésében stroke-iránydiagnózisú betegek esetén.

Összefoglaló. Bevezetés: A stroke-betegek ellátásában arra kell törekedni, hogy a tünetek jelentkezését követoen minél elobb a szakmai centrumba kerüljön a beteg. Célkituzés: Kutatásunkban a terápiás idoablak tarthatósága céljából vizsgáltuk, hogy mely tényezok bírnak hatással a prehospitális ellátás idotartamaira. Módszer: Keresztmetszeti, kvantitatív kutatásunkhoz az adatgyujtést két magyarországi város mentoállomásán, orvosi kompetenciával rendelkezo (eset-, rohamkocsi) és orvosi kompetenciával nem rendelkezo (mentogépkocsi) mentoegység szintjén végeztük 2017-es adatok feldolgozásával olyan betegek körében, akiknek a mentoegység általi iránydiagnózisa stroke volt (n = 220). Vizsgáltuk, hogy a mentoegységek által elvégzett vizsgálatok, a tapasztalt tünetek, a terápiás idoablakon belüliség miként befolyásolta a prehospitális idoket. Az adatfeldolgozást SPSS 26.0 statisztikai programmal végeztük. Az elemzéshez leíró statisztikát, χ2-próbát, F-próbát és T-próbát alkalmaztunk. Eredmények: Megállapítottuk, hogy az alkalmazott score-rendszer vizsgálati elemei közül, ha aphasia volt észlelheto a betegnél, úgy szignifikánsan meghosszabbodott a helyszínen töltött ido (p = 0,003). A gyors ABCDE-betegvizsgálat D-lépésében kötelezo a betegnél a vércukorszintmérés, ugyanakkor ez mintánk 25,45%-ában elmaradt. A helyszíni muszeres vércukorszintmérés hatással van a prehospitális késés alakulására az orvosi kompetencia nélküli egységek vonatkozásában (p<0,001). Következtetés: A helyszínen töltött ido az emelt szintu mentoegységek esetében hosszabb, mint az alacsonyabb szintu egységeknél. Következtetésként levonhatjuk, hogy a motoros vagy szenzoros aphasia nem befolyásolja a terápiát, pusztán a stroke-diagnózis valószínuségét növelo egyik tünet, így a helyszíni ido emiatti megnyúlása mindenképpen kerülendo, amire javasolt a továbbképzések alkalmával is felhívni az ellátók figyelmét. Az orvosi kompetencia nélküli egységek esetében beavatkozást igényel a muszeres vércukormérés idorabló hatásának csökkentése, hiszen látható, hogy az orvosi kompetenciával rendelkezo egységeknél ez a vizsgálat nem jelenik meg mint késést okozó tényezo. Orv Hetil. 2022; 163(7): 279-287. INTRODUCTION: When treating stroke patients, the aim should be to get the patient to a specialist stroke centre as soon as possible. OBJECTIVE: In our study, in order to be able to stay within the therapeutic window, we investigated which variables affect the time period of prehospital treatment. METHOD: For our cross-sectional quantitative study, we gathered data from two ambulance stations in Hungary, comparing the competence of physician and non-physician units. We processed information from 2017 regarding patients whose initial diagnosis was stroke (n = 220). We examined how investigations by the ambulance unit, symptoms experienced and therapeutic time window have affected prehospital times. As for the statistic software, we used SPSS 26.0. The analysis was conducted by performing χ2 test, F-test and T-test. RESULTS: We identified that if the aphasia component of the used score system was positive, the on-scene time increased significantly (p = 0.003). In the D section of the rapid ABCDE assessment, it is mandatory to measure the blood glucose level of the patient, however, in our sample it was omitted in 25.45% of the cases. We identified that on-site blood glucose measurement has an effect on prehospital delay for non-physician units (p<0.001). CONCLUSION: We found that the on-scene time is longer for physician units than for non-physician units. We concluded that motor or sensory aphasia does not affect the therapy, it is just one of the symptoms that can increase the likelihood of stroke diagnosis, therefore prolonging time for assessing aphasia in the field should be avoided. Moreover, it is recommended to make care providers aware of this during training sessions. Improvements are required in non-physician units to reduce the time consumed by blood glucose measurement, as it has been shown that within physician units this test does not appear to be a delay-causing factor. Orv Hetil. 2022; 163(7): 279-287.

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 Eisenia andrei 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. Our results indicate that microtubule-dependent, scavenger-receptor, and PI3K signaling-mediated macropinocytosis are utilized during AgNP engulfment by human THP-1 and differentiated THP-1 cells. However, earthworm coelomocytes employ actin-dependent phagocytosis during AgNPs uptake. In both human and earthworm immunocytes, AgNPs were located in the cytoplasm, within the endo-/lysosomes. We detected that the internalization of AgNPs is TLR/MyD88-dependent, also involving the bactericidal/permeability-increasing protein (BPI) in the case of human immunocytes. The exposure led to decreased mitochondrial respiration in human immunocytes; however, in coelomocytes, it enhanced respiratory parameters. Our findings provide more data about NP trafficking as nano-carriers in the nanomedicine field, as well as contribute to an understanding of the ecotoxicological consequences of nanoparticle exposure.

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. Based on these results the new nitroxide and phenol containing hybrid molecules can be considered as new antioxidant and anti-inflammatory agents.

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. We used the oral PARP inhibitor olaparib in the 2,4,6-trinitrobenzene sulfonic acid- (TNBS-) induced mouse colitis model. Inflammatory scoring, cytokine levels, colon histology, hematological analysis, and intestinal permeability were studied. Caco-2 monolayer culture was utilized as an epithelial barrier model, on which we used qPCR and light microscopy imaging, and measured impedance-based barrier integrity, FITC-dextran permeability, apoptosis, mitochondrial oxygen consumption rate, and extracellular acidification rate. Olaparib reduced the inflammation score, the concentration of IL-1ß and IL-6, enhanced the level of IL-10, and decreased the intestinal permeability in TNBS-colitis. Blood cell ratios, such as lymphocyte to monocyte ratio, platelet to lymphocyte ratio, and neutrophil to lymphocyte ratio were improved. In H2O2-treated Caco-2 monolayer, olaparib decreased morphological changes, barrier permeability, and preserved barrier integrity. In oxidative stress, olaparib enhanced glycolysis (extracellular acidification rate), and it improved mitochondrial function (mitochondrial coupling efficiency, maximal respiration, and spare respiratory capacity) in epithelial cells. Olaparib, a PARP inhibitor used in human cancer therapy, improved experimental CD and protected intestinal barrier integrity by preventing its energetic collapse; therefore, it could be repurposed for the therapy of Crohn's disease.

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. In our recent work, we aimed to clarify the mitochondrial protective effects of BGP-15 in a hypertension-induced heart failure model and "in vitro." Spontaneously hypertensive rats (SHRs) received BGP-15 or placebo for 18 weeks. BGP-15 treatment preserved the normal mitochondrial ultrastructure and enhanced the mitochondrial fusion. Neonatal rat cardiomyocytes (NRCMs) were stressed by hydrogen-peroxide. BGP-15 treatment inhibited the mitochondrial fission processes, promoted mitochondrial fusion, maintained the integrity of the mitochondrial genome, and moreover enhanced the de novo biogenesis of the mitochondria. As a result of these effects, BGP-15 treatment also supports the maintenance of mitochondrial function through the preservation of the mitochondrial structure during hydrogen peroxide-induced oxidative stress as well as in an "in vivo" heart failure model. It offers the possibility, which pharmacological modulation of mitochondrial quality control under oxidative stress could be a novel therapeutic approach in heart failure.

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. Additionally, FA inhibited LPS-induced activation of nuclear factor kappaB transcription factor in the liver of the mice. According to our data, these effects were probably due to attenuating LPS-induced activation of c-Jun N-terminal kinase and Akt. Furthermore, FA decreased free radical and nitrite production in LPS plus interferon-gamma-treated primary mouse hepatocytes, whose effects are expected to contribute to its antiinflammatory property. These data provide direct in vivo evidence, that a water-soluble degradation product of polyphenols could be responsible for, or at least could significantly contribute to, the beneficial antiinflammatory effects of polyphenol-containing healthy foods, natural products, and traditional medicines.

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. In isolated mitochondria, HO-3538 inhibited mPT and the release of proapoptotic mitochondrial proteins. It had a ROS scavenging effect and antiapoptotic effect in a cardiomyocyte line and it diminished release of mitochondrial proapoptotic proteins. Furthermore, HO-3538 significantly enhanced the recovery of mitochondrial energy metabolism and functional cardiac parameters; decreased infarct size, lipid peroxidation, and protein oxidation; and suppressed necrotic as well as apoptotic cell death pathways in Langendorff-perfused hearts. In these respects it was somewhat superior to its two constituents, amiodarone and a pyrrol-derivative free radical scavenger. These data suggest that the SOD-mimetic mPT inhibitors are ideal candidates for drug development for the alleviation of postinfarct myocardial injuries.

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. METHODS: Using the 2,4,6-trinitrobenzenesulfonic acid [TNBS]-induced colitis model, involvement of CRTH2 in colitis was investigated by pharmacological antagonism, immunohistochemistry, Western blotting, immunoassay, and leukocyte recruitment. Chemotactic assays were performed with isolated human eosinophils. Biopsies and serum samples of CD patients were examined for presence of CRTH2 and ligands, respectively. RESULTS: High amounts of CRTH2-positive cells, including eosinophils, are present in the colonic mucosa of mice with TNBS colitis and in human CD. The CRTH2 antagonist OC-459, but not the DP antagonist MK0524, reduced inflammation scores and decreased TNF-α, IL-1ß, and IL-6 as compared with control mice. OC-459 inhibited recruitment of eosinophils into the colon and also inhibited CRTH2-induced chemotaxis of human eosinophils in vitro. Eosinophil-depleted ΔdblGATA knockout mice were less sensitive to TNBS-induced colitis, whereas IL-5 transgenic mice with lifelong eosinophilia were more severely affected than wild types. In addition, we show that serum levels of PGD2 and Δ(12)-PGJ2 were increased in CD patients as compared with control individuals. CONCLUSIONS: CRTH2 plays a pro-inflammatory role in TNBS-induced colitis. Eosinophils contribute to the severity of the inflammation, which is improved by a selective CRTH2 antagonist. CRTH2 may, therefore, represent an important target in the pharmacotherapy of CD.

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. Changes in cAMP of the NIL as well as in the plasma level of vasopressin (VP) could not be detected. The observed changes in the level of cAMP following the acute treatment of SAL in the ME and the AL seems to be related to interacting neuroendocrine signals delivered from the ME to the AL through the long portal vessels to release PRL.