Asthma and poly(ADP-ribose) polymerase inhibition: a new therapeutic approach

Raffaela Zaffini, Giovanni Gotte, Marta Menegazzi Department of Neuroscience, Biomedicine and Movement Science, Biochemistry Section, University of Verona, Verona, Italy Abstract: Asthma is a chronic lung disease affecting people of all ages worldwide, and it frequently begins in childhood. Because of its chronic nature, it is characterized by pathological manifestations, including airway inflammation, remodeling, and goblet cell hyperplasia. Current therapies for asthma, including corticosteroids and beta-2 adrenergic agonists, are directed toward relieving the symptoms of the asthmatic response, with poor effectiveness against the underlying causes of the disease. Asthma initiation and progression depends on the T helper (Th) 2 type immune response carried out by a complex interplay of cytokines, such as interleukin (IL) 4, IL5, and IL13, and the signal transducer and activator of transcription 6. Much of the data resulting from different laboratories support the role of poly(ADP-ribose) polymerase (PARP) 1 and PARP14 activation in asthma. Indeed, PARP enzymes play key roles in the regulation and progression of the inflammatory asthma process because they affect the expression of genes and chemokines involved in the immune response. Consistently, PARP inhibition achievable either upon genetic ablation or by using pharmacological agents has shown a range of therapeutic effects against the disease. Indeed, in the last two decades, several preclinical studies highlighted the protective effects of PARP inhibition in various animal models of asthma. PARP inhibitors showed the ability to reduce the overall lung inflammation acting with a specific effect on immune cell recruitment and through the modulation of asthma-associated cytokines production. PARP inhibition has been shown to affect the Th1–Th2 balance and, at least in some aspects, the airway remodeling. In this review, we summarize and discuss the steps that led PARP inhibition to become a possible future therapeutic strategy against allergic asthma. Keywords: allergic airway disease, PARP1, PARP14, remodeling, STAT6, Th1–Th2 balance, Th2 respons

Análise Semiótica dos elementos da marca "Floripa Inteligente"

Uma marca de cidade é um instrumento que faz uso de elementos gráfico-expressivos para simbolizar situações vividas em determinado lugar ou então representar o estabelecimento de diretrizes adotadas para sua promoção e desenvolvimento. O presente artigo traz uma leitura semióca da marca “Floripa Inteligente” como representação gráfica de um projeto de city branding desenvolvido pelo Laboratório de Orientação da Gênese Organizacional – LOGO/UFSC. Focase na apresentação da base teórica aplicada ao desenvolvimento da marca citada tendo em vista a comunicação de um pensamento e gestão de Florianópolis como smart city como eixo de construção de suas representações gráficas.ABSTRACT : A city brand is a tool that makes use of graphic-expressive elements to symbolize situaons experienced in a certain place or advocate the establishment of guidelines adopted for its promoon and development. This paper presents a semioc reading of "Floripa Inteligente" brand as a graphic representaon of a city branding project developed by LOGO/UFSC. It focuses on the presentaon of the theorecal basis applied to the development of this brand in order to communicate a thought and management polics for developing Florianópolis as a smart city as a focus for building its graphical representations.info:eu-repo/semantics/publishedVersio

Complex Coacervates between a Lactose-Modified Chitosan and Hyaluronic Acid as Radical-Scavenging Drug Carriers

Complex coacervation of two oppositely charged polysaccharides, namely a lactose-modified chitosan (CTL) and hyaluronan (HA), was investigated in this study. Coacervates of the two polysaccharides were prepared by drop-by-drop injection of HA into CTL. Transmittance and dynamic light scattering (DLS) measurements in combination with TEM analyses demonstrated the formation of spheroidal colloids in the nano-/microsize range showing good homogeneity. Strikingly, the presence of 150 mM supporting NaCl did not hamper the colloid formation. Stability studies on selected formulations demonstrated that HA/CTL coacervates were stable up to 3 weeks at 37 \ub0C and behaved as pH-responsive colloids since transition from entangled to disentangled chains was attained for a proper pH range. The possibility of freeze-drying the coacervates for storage purposes and the ability of encapsulating selected payloads were investigated as well, for two values of the fraction of the lactitol side-chain substitution (FL). Finally, biological tests using human neutrophils were undertaken at acidic pH value (pH = 6.0): under such experimental conditions, akin to those frequently occurring in the inflammatory microenvironment, coacervates scavenged reactive oxygen species (ROS) generated by these cells in basal conditions. Given the well documented bioactivity of CTL with respect to chitosan toward cartilage regeneration, these findings point to a possible application of HA/CTL-based colloids as scavenging and bioactive carriers for the delivery of therapeutic molecules at confined inflamed sites such as knee joints

Transcriptomics and immunological analyses reveal a pro-angiogenic and anti-inflammatory phenotype for decidual endothelial cells

Copyright © 2019 by the authors. Background: In pregnancy, excessive inflammation and break down of immunologic tolerance can contribute to miscarriage. Endothelial cells (ECs) are able to orchestrate the inflammatory processes by secreting pro-inflammatory mediators and bactericidal factors by modulating leakiness and leukocyte trafficking, via the expression of adhesion molecules and chemokines. The aim of this study was to analyse the differences in the phenotype between microvascular ECs isolated from decidua (DECs) and ECs isolated from human skin (ADMECs). Methods: DECs and ADMECs were characterized for their basal expression of angiogenic factors and adhesion molecules. A range of immunological responses was evaluated, such as vessel leakage, reactive oxygen species (ROS) production in response to TNF-α stimulation, adhesion molecules expression and leukocyte migration in response to TNF-α and IFN-γ stimulation. Results: DECs produced higher levels of HGF, VEGF-A and IGFBP3 compared to ADMECs. DECs expressed adhesion molecules, ICAM-2 and ICAM-3, and a mild response to TNF-α was observed. Finally, DECs produced high levels of CXCL9/MIG and CXCL10/IP-10 in response to IFN-γ and selectively recruited Treg lymphocytes. Conclusion: DEC phenotype differs considerably from that of ADMECs, suggesting that DECs may play an active role in the control of immune response and angiogenesis at the foetal-maternal interface.This work was supported by grants from the Institute for Maternal and Child Health, IRCCS “Burlo Garofolo” to G. Ricci, Trieste, Italy (RC 20/16, RC 23/18). Fondazione Cassa di Risparmio Trieste to R. Bulla

Unique Features of a Global Human Ectoparasite Identified Through Sequencing of the Bed Bug Genome

The bed bug, Cimex lectularius, has re-established itself as a ubiquitous human ectoparasite throughout much of the world during the past two decades. This global resurgence is likely linked to increased international travel and commerce in addition to widespread insecticide resistance. Analyses of the C. lectularius sequenced genome (650 Mb) and 14,220 predicted protein-coding genes provide a comprehensive representation of genes that are linked to traumatic insemination, a reduced chemosensory repertoire of genes related to obligate hematophagy, host-symbiont interactions, and several mechanisms of insecticide resistance. In addition, we document the presence of multiple putative lateral gene transfer events. Genome sequencing and annotation establish a solid foundation for future research on mechanisms of insecticide resistance, human-bed bug and symbiont-bed bug associations, and unique features of bed bug biology that contribute to the unprecedented success of C. lectularius as a human ectoparasite

Two Naturally Occurring Terpenes, Dehydrocostuslactone and Costunolide, Decrease Intracellular GSH Content and Inhibit STAT3 Activation

The main purpose of the present study is to envisage the molecular mechanism of inhibitory action ofdehydrocostuslactone (DCE) andcostunolide (CS), two naturally occurring sesquiterpene lactones, towards the activation of signal transducer and activator of transcription 3 (STAT3). We report that, in human THP-1 cell line, they inhibit IL-6-elicited tyrosine phosphorylation of STAT3 and its DNA binding activity with EC50 of 10 µM with concomitantdown-regulation ofthe phosphorylation of the tyrosine Janus kinases JAK1, JAK2 and Tyk2. Furthermore, these compounds that contain an α-β-unsatured carbonyl moiety and function as potent Michael reaction acceptor, induce a rapid drop in intracellular glutathione (GSH) concentration by direct interaction with it, thereby triggering S-glutathionylation of STAT3. Dehydrocostunolide (HCS), the reduced form of CS lacking only the α-β-unsaturated carbonyl group, fails to exert any inhibitory action. Finally, the glutathione ethylene ester (GEE), the cell permeable GSH form, reverts the inhibitory action of DCE and CS on STAT3 tyrosine phosphorylation. We conclude that these two sesquiterpene lactones are able to induce redox-dependent post-translational modification of cysteine residues of STAT3 protein in order to regulate its function

Human neutrophils phagocytose and kill Acinetobacter baumanii and A. pittii

Acinetobacter baumannii is a common cause of health care associated infections worldwide. A. pittii is an opportunistic pathogen also frequently isolated from Acinetobacter infections other than those from A. baumannii. Knowledge of Acinetobacter virulence factors and their role in pathogenesis is scarce. Also, there are no detailed published reports on the interactions between A. pittii and human phagocytic cells. Using confocal laser and scanning electron microscopy, immunofluorescence, and live-cell imaging, our study shows that immediately after bacteria-cell contact, neutrophils rapidly and continuously engulf and kill bacteria during at least 4 hours of infection in vitro. After 3 h of infection, neutrophils start to release neutrophil extracellular traps (NETs) against Acinetobacter. DNA in NETs colocalizes well with human histone H3 and with the specific neutrophil elastase. We have observed that human neutrophils use large filopodia as cellular tentacles to sense local environment but also to detect and retain bacteria during phagocytosis. Furthermore, co-cultivation of neutrophils with human differentiated macrophages before infections shows that human neutrophils, but not macrophages, are key immune cells to control Acinetobacter. Although macrophages were largely activated by both bacterial species, they lack the phagocytic activity demonstrated by neutrophils

Clinical practice: neonatal resuscitation. A Dutch consensus

The updated Dutch guidelines on Neonatal Resuscitation assimilate the latest evidence in neonatal resuscitation. Important changes with regard to the 2004 guidelines and controversial issues concerning neonatal resuscitation are reviewed, and recommendations for daily practice are provided and argued in the context of the ILCOR 2005 consensus

Unique features of a global human ectoparasite identified through sequencing of the bed bug genome

The bed bug, Cimex lectularius, has re-established itself as a ubiquitous human ectoparasite throughout much of the world during the past two decades. This global resurgence is likely linked to increased international travel and commerce in addition to widespread insecticide resistance. Analyses of the C. lectularius sequenced genome (650 Mb) and 14,220 predicted protein-coding genes provide a comprehensive representation of genes that are linked to traumatic insemination, a reduced chemosensory repertoire of genes related to obligate hematophagy, host–symbiont interactions, and several mechanisms of insecticide resistance. In addition, we document the presence of multiple putative lateral gene transfer events. Genome sequencing and annotation establish a solid foundation for future research on mechanisms of insecticide resistance, human–bed bug and symbiont–bed bug associations, and unique features of bed bug biology that contribute to the unprecedented success of C. lectularius as a human ectoparasite