Half-sandwich ruthenium(II)-arene complexes: synthesis, spectroscopic studies, biological properties, and molecular modeling

In search for antitumor metal-based drugs that would mitigate the severe side-effects of cisplatin, Ru(II) complexes are gaining increasing recent interest. In this work, we report on the synthesis, characterization (1H- and 13C-NMR, FT-IR), and cytotoxicity studies of two new half-sandwich organometallic Ru(II) complexes of the general formula [Ru(η6-arene)(XY)Cl](PF6) where arene = benzene or toluene and XY = bidentates: dipyrido[3,2-a:2′,3′-c]phenazine (dppz) or 2-(9-anthryl)-1H-imidazo[4,5-f][1,10]phenanthroline (aip), which are bound to Ru(II) via two phenanthroline-N atoms in a characteristic “piano-stool” configuration of Ru(II)-arene complexes—as confirmed by vibrational and NMR spectra. In addition, cytotoxic studies were performed for similar half-sandwich organometallic [Ru(η6-p-cymene)(Me2dppz)Cl]PF6 complex (Me2dppz = 11,12-dimethyl-dipyrido[3,2-a:2′,3′-c]phenazine). This study is complemented with elaborate modeling with density functional theory (DFT) calculations, which provided insight into reactive sites of Ru(II) structures, further detailed by molecular docking on the B-DNA dodecamer, which identified binding sites and affinities: most pronounced for the [Ru(η6-benzene)(aip)Cl](PF6) in both A-T and G-C regions of the DNA minor groove. Cytotoxic activity was probed versus tumor cell lines B16, C6, and U251 (B16 mouse melanoma, C6 rat glioma, U251 human glioblastoma) and non-tumor cell line HACAT (HACAT normal human keratinocytes).This is the peer-reviewed version of the following article:Nikolić, S.; Grgurić-Šipka, S.; Djordjević, I. S.; Dahmani, R.; Dekanski, D.; Vidičević, S.; Tošić, J.; Mitić, D.; Grubišić, S. Half-Sandwich Ruthenium(II)-Arene Complexes: Synthesis, Spectroscopic Studies, Biological Properties, and Molecular Modeling. Journal of Coordination Chemistry 2019, 72 (1), 148–163. [https://doi.org/10.1080/00958972.2018.1553298].Supplementary material: [http://cherry.chem.bg.ac.rs/handle/123456789/3753

Graphene Quantum Dots show protective effect in animal model of neuroinflammation

Background: Experimental autoimmune encephalomyelitis (EAE) is one of the most studied model of neuroinflammation, used to test immunomodulatory and antiinflammatory drugs. Graphene quantum dots (GQD) are oval graphite twodimensional sheets with a diameter <100 nm, one carbon atom thickness, with potential applications in biomedicine. Objective: To investigate the potential protective effect of GQD in EAE model. Methods: Female DA rats were immunized with spinal cord homogenate and Freund’s complete adjuvant. GQD treatment (10 mg/kg, ip) was administrated during the inductive, effector and both phases of a disease. MAP kinase (MAPK) and Akt activity in popliteal lymph nodes (PLN) and CNS was determined by western blot. Quantitative PCR and flow cytometry were used to examine the expression of proinflammatory cytokines and specific transcription factors while infiltration of GQD in cells/tissues was detected by transmission electron microscopy. GQD antiinflamatory/direct cytoprotective effect was analyzed on oligodendrocyte and neuron cell cultures by MTT assay. Data were analized by Mann Whitney test (p<0.05 was considered as statistical significant difference). Results: GQD administration, in all phases of EAE, significantly reduced clinical score of a disease. Clinical improvement correlates with increase in activity of ERK, p38 and Akt that is followed by reduction of Th1 cell response in PLN and infiltrated spinal coard T cells. Due to its capacity to infiltrate cells and tissues, GQD exhibits direct cytoprotective effect on CNS. Additionaly, GQD reduced the expression of proinflammatory cytokines in ConA stimulated lymphocytes. Conclusion: GQD alleviate EAE, through direct cytoprotective effect on CNS and inhibition of Th1 cell response.Poster Session: Neuroimmunoendocrine Interaction

In Sicilia sbarcati 800 migranti, altri seicento in arrivo. Ad Augusta i 24 morti dell'ultimo naufragio, repubblica.it, 27/08/2014

"I dispersi al largo della Libia sarebbero un centinaio. Tra i profughi approdati a Pozzallo c'era anche un gatto. Salvata una bimba di 14 mesi aggrappata a una tavola C'erano anche 81 donne e 133 minori tra i 449 migranti siriani, palestinesi ed egiziani arrivati a Pozzallo, nel ragusano, le cui operazioni di sbarco sono terminate intorno alle due della scorsa notte. Con il gruppo degli immigrati c'era anche un gatto, sottoposto poi a visita veterinaria per verificare che non fosse portatore..

Prognostic value of presepsin (soluble CD14-subtype) in diagnosis of ventilator-associated pneumonia and sepsis in trauma patients

Background/Aim. Presepsin (soluble CD14-subtype) is a fragment of CD14 produced in response to bacterial infections and a novel biomarker of pneumonia, sepsis and septic shock. The aim of this study was to compare sensitivity and specificity of persepsin, soluble CD14-subtype (sCD14-ST) with other biomarkers: procalcitonine (PCT), C-reactive protein (CRP) and leukocyte count (Le) in mechanically ventilated injured patients, as a marker of pneumonia, sepsis and septic shock. Methods. The prospective study was undertaken in trauma and surgery intensive care unit of the Emergency Center, the Clinical Center of Serbia from January to April 2013. The study included 39 trauma patients requiring mechanical ventilation, and who developed one of the following inclusion criteria: Systemic Inflammatory Response Syndrome (SIRS), ventilator associated pneumonia (VAP), sepsis and/or septic shock. On admission Acute Physiology and Chronic Health Evaluation II (APACHE II) Score and Injury Severity Score (ISS) were calculated. Seventy-two measurements of four biomarkers (presepsin, PCT, CRP and Le) were performed in 39 patients at the moments of diagnosis of SIRS, VAP, sepsis and/or septic shock (21 when SIRS diagnosis was established, 21 after the diagnosis of VAP, 18 at the moment of diagnosis of sepsis and the remaining 12 measurements were conducted while diagnosing the septic shock). The Sequential Organ Failure Assessment (SOFA) score was calculated at these points as well. Results. Patients were mainly severely injured (mean ISS = 24.2) and had moderately severe medical condition at admission (mean Apache II score, 14.5). Presepsin concentration significantly differed among all the four groups, except between sepsis and septic shock. The strongest positive correlation of presepsin evinced with PCT (r = 0.741, p < 0.001). The sCD14-ST indicated better performance in diagnosis of both VAP (AUC = 0.909) and sepsis (AUC = 0.899), compared to PCT (AUCs: 0.863, 0.885, respectively), CRP (AUCs: 0.703, 0.677, respectively) and Le (AUCs: 0.668, 0.700, respectively). Conclusion. This study revealed that sCD14-ST is a reliable biomarker for distinguishing sepsis severity. It also showed a good correlation with the infection development as well as worsening in injured patients. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no.175046

Graphene quantum dots show protective effect on a model of experimental autoimmune encephalomyelitis

29th Congress of the European-College-of-Neuropsychopharmacology (ECNP), Sep 17-20, 2016, Vienna, Austri

Graphene quantum dots inhibit T cell-mediated neuroinflammation in rats

We investigated the therapeutic capacity of nano-sized graphene sheets, called graphene quantum dots (GQD), in experimental autoimmune encephalomyelitis (EAE), an animal model of immune-mediated central nervous system (CNS) damage. Intraperitoneally administered GQD (10 mg/kg/day) accumulated in the lymph node and CNS cells of Dark Agouti rats in which EAE was induced by immunization with spinal cord homogenate in complete Freund's adjuvant. GQD significantly reduced clinical signs of EAE when applied throughout the course of the disease (day 0–32), while the protection was less pronounced if the treatment was limited to the induction (day 0–7 post-immunization) or effector (from day 8 onwards) phase of the disease. GQD treatment diminished immune infiltration, demyelination, axonal damage, and apoptotic death in the CNS of EAE animals. GQD also reduced the numbers of interferon-γ-expressing T helper (Th)1 cells, as well as the expression of Th1 transcription factor T-bet and proinflammatory cytokines tumor necrosis factor, interleukin-1, and granulocyte-macrophage colony-stimulating factor in the lymph nodes and CNS immune infitrates. The protective effect of GQD in EAE was associated with the activation of p38 and p42/44 mitogen-activated protein kinases (MAPK) and Akt in the lymph nodes and/or CNS. Finally, GQD protected oligodendrocytes and neurons from T cell-mediated damage in the in vitro conditions. Collectively, these data demonstrate the ability of GQD to gain access to both immune and CNS cells during neuroinflammation, and to alleviate immune-mediated CNS damage by modulating MAPK/Akt signaling and encephalitogenic Th1 immune response. © 2018 Elsevier Lt