pinecone/core-2020-05-10-deduplication huggingface dataset:
Antagonism of human CC-chemokine receptor 4 can be achieved through three distinct binding sites on the receptor

Chemokine receptor antagonists appear to access two distinct binding sites on different members of this receptor family. One class of CCR4 antagonists has been suggested to bind to a site accessible from the cytoplasm while a second class did not bind to this site. In this report, we demonstrate that antagonists representing a variety of structural classes bind to two distinct allosteric sites on CCR4. The effects of pairs of low-molecular weight and/or chemokine CCR4 antagonists were evaluated on CCL17- and CCL22-induced responses of human CCR4+ T cells. This provided an initial grouping of the antagonists into sets which appeared to bind to distinct binding sites. Binding studies were then performed with radioligands from each set to confirm these groupings. Some novel receptor theory was developed to allow the interpretation of the effects of the antagonist combinations. The theory indicates that, generally, the concentration-ratio of a pair of competing allosteric modulators is maximally the sum of their individual effects while that of two modulators acting at different sites is likely to be greater than their sum. The low-molecular weight antagonists could be grouped into two sets on the basis of the functional and binding experiments. The antagonistic chemokines formed a third set whose behaviour was consistent with that of simple competitive antagonists. These studies indicate that there are two allosteric regulatory sites on CCR4
Anti-inflammatory effects of the novel inhaled phosphodiesterase type 4 inhibitor CHF6001 on virus-inducible cytokines

Respiratory virus infections precipitate asthma and chronic obstructive pulmonary disease (COPD) exacerbations, with most exacerbations due to rhinovirus infection. Both asthma and COPD exacerbations are not well controlled by steroid therapies, and there is a much research interest in finding improved therapies or combinations of therapies for controlling exacerbations. CHF6001 is a new, inhaled highly potent and selective phosphodiesterase type 4 (PDE4) inhibitor. Using in vitro human bronchial epithelial cells (BEAS-2B), we investigated the potential anti-inflammatory effects of CHF6001 on rhinovirus (RV1B)-induced cytokines. Cytokine mRNA was measured by real-time PCR, while protein release was measured by ELISA. CHF6001 was used in a 7-point dose–response curve (1000–0.001 nmol/L) as a 1.5-h pretreatment prior to infection in comparison with roflumilast. Both roflumilast and CHF6001 reduced RV1B-induced IL-8, IL-29, IP-10, and RANTES mRNA and protein in a concentration-dependent manner. Generally, CHF6001 was 13- to 16-fold more potent (subnanomolar EC50 values) than roflumilast at reducing IL-8, IL-29, IP-10, and RANTES mRNA and protein release, but had similar efficacies. In combination with the steroid fluticasone propionate (1 nmol/L), CHF6001 had additive effects, significantly reducing RV-induced cytokines when compared with steroid or CHF6001 alone. Combined low-dose steroid and low-dose CHF6001 had a similar efficacy as high-dose steroid or CHF6001 alone, indicating the combination had steroid and PDE4 inhibitor sparing effects. Overall results indicate that PDE4 inhibitors have anti-inflammatory activity against virus-induced inflammatory mediators and that CHF6001 is more potent than roflumilast
Preclinical animal anxiety research - flaws and prejudices.\ud

The current tests of anxiety in mice and rats used in preclinical research include the elevated plus-maze (EPM) or zero-maze (EZM), the light/dark box (LDB), and the open-field (OF). They are currently very popular, and despite their poor achievements, they continue to exert considerable constraints on the development of novel approaches. Hence, a novel anxiety test needs to be compared with these traditional tests, and assessed against various factors that were identified as a source of their inconsistent and contradictory results. These constraints are very costly, and they are in most cases useless as they originate from flawed methodologies. In the present report, we argue that the EPM or EZM, LDB, and OF do not provide unequivocal measures of anxiety; that there is no evidence of motivation conflict involved in these tests. They can be considered at best, tests of natural preference for unlit and/or enclosed spaces. We also argued that pharmacological validation of a behavioral test is an inappropriate approach; it stems from the confusion of animal models of human behavior with animal models of pathophysiology. A behavioral test is developed to detect not to produce symptoms, and a drug is used to validate an identified physiological target. In order to overcome the major methodological flaws in animal anxiety studies, we proposed an open space anxiety test, a 3D maze, which is described here with highlights of its various advantages over to the traditional tests
A pilot study on the incidence of severe photosensitivity reactions leading to hospitalization linked to topical ketoprofen and other medications in selected European regions.

The aim of this study was to assess the prevalence of exposure to topical nonsteroidal anti-inflammatory drugs (NSAIDs), particularly ketoprofen, in a convenience sample of the population, to obtain estimates of the incidence of severe photosensitivity leading to hospitalization, and to assess causative factors in three catchment areas: the Paris metropolitan area, the Lombardy region (Italy) and the Prague area. All cases of severe photosensitivity not explained by underlying conditions and admitted to hospitals in the selected areas were included in the study. Controls were patients consecutively admitted to hospitals, in the same areas, for an acute condition or for an elective procedure not suspected of being related to medication use. From October 2012 to September 2013, 920 controls were recruited (median age 44 years, 50.8% females); 8 severe photosensitivity cases were reported in the population aged 18-74 years of the 3 geographical areas during the 1-year surveillance period, corresponding to an incidence rate of 4.81 cases per 10 million person-years (95% confidence interval - CI, 2.07-9.48). Six controls reported 1-month exposure to topical ketoprofen, with an estimated prevalence of 0.65% (95% CI, 0.24-1.42). The population attributable risk for severe photosensitivity reactions linked to ketoprofen was 11.92% (95% CI, -0.12-52.99). This study was conducted in selected European areas and showed that the incidence of severe photosensitivity reactions leading to hospitalization as well as the exposure rate to topical ketoprofen were low. Among topical NSAIDs, topical ketoprofen was the leading cause of photosensitivity reactions but accounted for a limited number of hospitalized cases. Probably most of the relevant reactions were managed in the outpatient setting and a community based case-control study is advisable
Mitochondrial fission – a drug target for cytoprotection or\ud
cytodestruction?

Mitochondria are morphologically dynamic organelles constantly undergoing processes of fission and fusion that maintain integrity and bioenergetics of the organelle: these processes are vital for cell survival. Disruption in the balance of mitochondrial fusion and fission is thought to play a role in several pathological conditions including ischemic heart disease. Proteins involved in regulating\ud
the processes of mitochondrial fusion and fission are therefore potential targets for pharmacological therapies. Mdivi-1 is a small molecule inhibitor of the mitochondrial fission protein Drp1. Inhibiting mitochondrial fission with\ud
Mdivi-1 has proven cytoprotective benefits in several cell types involved in a wide array of cardiovascular injury models. On the other hand, Mdivi-1 can also exert antiproliferative and cytotoxic effects, particularly in hyperproliferative cells. In this review, we discuss these divergent effects of Mdivi-1 on cell survival, as well as the potential and limitations of Mdivi-1 as a therapeutic\ud
agent
Inhibition of the dorsomedial hypothalamus, but not the medullary raphe pallidus, decreases hyperthermia and mortality from MDMA given in a warm environment.

The central mechanisms through which MDMA mediates life-threatening hyperthermia when taken in a warm environment are not well described. It is assumed that MDMA alters normal thermoregulatory circuits resulting in increased heat production through interscapular brown adipose tissue (iBAT) and decreased heat dissipation through cutaneous vasoconstriction. We studied the role of the dorsomedial hypothalamus (DMH) and medullary raphe pallidus (mRPa) in mediating iBAT, tail blood flow, and locomotor effects produced by MDMA. Rats were instrumented with guide cannulas targeting either the DMH or the mRPa-brain regions involved in regulating iBAT and cutaneous vascular beds. In all animals, core temperature and locomotion were recorded with surgically implanted telemetric transmitters; and additionally either iBAT temperature (via telemetric transmitter) or tail artery blood flow (via tail artery Doppler cuff) were also recorded. Animals were placed in an environmental chamber at 32°C and microinjected with either control or the GABA agonist muscimol (80pmol) followed by an intravenous injection of saline or MDMA (7.5 mg kg-1). To prevent undue suffering, a core temperature of 41°C was chosen as the surrogate marker of mortality. Inhibition of the DMH, but not the mRPa, prevented mortality and attenuated hyperthermia and locomotion. Inhibition of either the DMH or the mRPa did not affect iBAT temperature increases or tail blood flow decreases. While MDMA increases iBAT thermogenesis and decreases heat dissipation through cutaneous vasoconstriction, thermoregulatory brain regions known to mediate these effects are not involved. Rather, the finding that inhibiting the DMH decreases both locomotion and body temperature suggests that locomotion may be a key central contributor to MDMA-evoked hyperthermia
In vitro pharmacological characterization of a novel unbiased NOP receptor-selective nonpeptide agonist AT-403.

Nociceptin/orphanin FQ (N/OFQ) regulates several biological functions via selective activation of the N/OFQ receptor (NOP), a member of the opioid receptor family. We recently identified a new high affinity and highly selective NOP agonist AT-403. In this study, we characterized the functional profile of AT-403 and compared it to other known nonpeptide NOP agonists Ro 65-6570, Ro 2q, SCH-221510, MCOPPB, AT-202 and SCH-486757, using the following assays: GTPγ[35S] stimulated binding, calcium mobilization assay in cells-expressing human NOP or classical opioid receptors and chimeric G proteins, bioluminescence resonance energy transfer (BRET) based assay for studying NOP receptor interaction with G protein and arrestin, and the electrically stimulated mouse vas deferens bioassay. All compounds behaved as NOP full agonists consistently showing the following rank order of potency MCOPPB > AT-403 > Ro 65-6570 = Ro 2q > SCH-221510 >  AT-202 > SCH-486757. AT-403 and MCOPPB displayed the highest NOP selectivity both at human and murine receptors. Interestingly, while all the other nonpeptide NOP agonists displayed bias toward G protein-mediated signaling in the BRET assay, AT-403, similar to the natural ligand N/OFQ, behaved as an unbiased agonist, activating G-protein-mediated function as well as arrestin recruitment. AT-403 may be a useful nonpeptide tool compound to study the pharmacology of NOP activation in disease states.Peer-reviewedPublisher Versio
Conflicting evidence for the role of JNK as a target in breast cancer cell proliferation : comparisons between pharmacological inhibition and selective shRNA knockdown approaches

As a target, the JNK pathway has been implicated in roles including cell death, proliferation, and inflammation in variety of contexts which span cardiovascular disease, neurodegenerative pathologies, and cancer. JNK1 and JNK2 have recently been demonstrated to function independently, highlighting a new parameter in the study of the JNK pathway. In order for JNK1 and JNK2-specific roles to be defined, better tools need to be employed. Previous studies have relied upon the broad spectrum JNK inhibitor, SP600125, to characterize the role of JNK signaling in a number of cell lines, including the breast cancer cell line MCF-7. In line with previous literature, our study has demonstrated that SP600125 treatment inhibited c-Jun and JNK phosphorylation and MCF-7 proliferation. However, in addition to targeting JNK1, JNK2, and JNK3, SP600125 has been previously demonstrated to suppress the activity of a number of other serine/threonine kinases, making SP600125 an inadequate tool for JNK isoform-specific roles to be determined. In this study, lentiviral shRNA was employed to selectively knockdown JNK1, JNK2, and JNK1/2 in MCF-7 cells. Using this approach, JNK phosphorylation was fully inhibited following stable knockdown of respective JNK isoforms. Interestingly, despite suppression of JNK phosphorylation, MCF-7 cell proliferation, cell cycle progression, or cell death remained unaffected. These findings raise the question of whether JNK phosphorylation really is pivotal in MCF-7 cell growth and death or if suppression of these events is a result of one of the many off-targets cited for SP600125
Revisiting the putative role of heme as a trigger of inflammation

Activation of the innate immune system by free heme has been proposed as one of the principal consequences of cell-free hemoglobin (Hb) exposure. Nonetheless, in the absence of infection, heme exposures within a hematoma, during hemolysis, or upon systemic administration of Hb (eg, as a Hb-based oxygen carrier) are typically not accompanied by uncontrolled inflammation, challenging the assumption that heme is a major proinflammatory mediator in vivo. Because of its hydrophobic nature, heme liberated from oxidized hemoglobin is rapidly transferred to alternative protein-binding sites (eg, albumin) or to hydrophobic lipid compartments minimizing protein-free heme under in vivo equilibrium conditions. We demonstrate that the capacity of heme to activate human neutrophil granulocytes strictly depends on the availability of non protein-associated heme. In human endothelial cells as well as in mouse macrophage cell cultures and in mouse models of local and systemic heme exposure, protein-associated heme or Hb do not induce inflammatory gene expression over a broad range of exposure conditions. Only experiments in protein-free culture medium demonstrated a weak capacity of heme-solutions to induce toll-like receptor-(TLR4) dependent TNF-alpha expression in macrophages. Our data suggests that the equilibrium-state of free and protein-associated heme critically determines the proinflammatory capacity of the metallo-porphyrin. Based on these data it appears unlikely that inflammation-promoting equilibrium conditions could ever occur in vivo
Oral administration of the selective GPR120/FFA4 agonist compound A is not effective in alleviating tissue inflammation in mouse models of prototypical autoimmune diseases

ω3-polyunsaturated free fatty acids (ω3-PUFAs), particularly docosahexaenoic (DHA) and eicosapentaenoic acid (EPA), are thought to exert health promoting effects in metabolic and in inflammatory diseases. The molecular mechanisms of these beneficial effects are only partially understood. DHA and EPA activate Free Fatty Acid receptor 4 (GPR120/FFA4). Recently, the first orally available, synthetic ligand of FFA4, 3-[2-chloro-5-(trifluoromethoxy)phenyl]-3-azaspiro[5.5]undecane-9-acetic acid ("compound A"; cpd A) has been developed. Cpd A exhibits distinctly higher potency, efficiency, and selectivity at FFA4 than ω3-PUFAs and ameliorates insulin resistance and adipose tissue inflammation in the mouse. With GPR120/FFA4 activation believed to also attenuate tissue inflammation in autoimmune diseases, cpd A may also have a beneficial effect in these diseases. We have therefore addressed the therapeutic potential of cpd A in mouse models of three prototypical autoimmune diseases, specifically psoriasis, rheumatoid arthritis, and bullous pemphigoid. The effect of cpd A on the course of Aldara™-induced psoriasis-like dermatitis, K/BxN serum transfer arthritis, and antibody transfer pemphigoid disease-like dermatitis was scrutinized. Cpd A did not alter the course of Aldara-induced psoriasis-like dermatitis, K/BxN serum transfer arthritis, or antibody transfer pemphigoid disease-like dermatitis. Our results suggest that therapeutic regimens solely relying on FFA4 activation do not bear the potential to treat inflammatory diseases. With cpd A distinctly more potent in activating GPR120/FFA4 than ω3-PUFAs, this also suggests that GPR120/FFA4 activation by ω3-PUFAs does not significantly contribute to the health-promoting effects of ω3-PUFAs in autoimmune diseases
Dexmedetomidine preconditioning ameliorates kidney ischemia-reperfusion injury

Kidney ischemia-reperfusion (I/R) injury is a common cause of acute kidney injury. We tested whether dexmedetomidine (Dex), an alpha2 adrenoceptor (α2-AR) agonist, protects against kidney I/R injury. Sprague–Dawley rats were divided into four groups: (1) Sham-operated group; (2) I/R group (40 min ischemia followed by 24 h reperfusion); (3) I/R group + Dex (1 μg/kg i.v. 60 min before the surgery), (4) I/R group + Dex (10 μg/kg). The effects of Dex postconditiong (Dex 1 or 10 μg/kg i.v. after reperfusion) as well as the effects of peripheral α2-AR agonism with fadolmidine were also examined. Hemodynamic effects were monitored, renal function measured, and acute tubular damage along with monocyte/macrophage infiltration scored. Kidney protein kinase B, toll like receptor 4, light chain 3B, p38 mitogen-activated protein kinase (p38 MAPK), sirtuin 1, adenosine monophosphate kinase (AMPK), and endothelial nitric oxide synthase (eNOS) expressions were measured, and kidney transciptome profiles analyzed. Dex preconditioning, but not postconditioning, attenuated I/R injury-induced renal dysfunction, acute tubular necrosis and inflammatory response. Neither pre- nor postconditioning with fadolmidine protected kidneys. Dex decreased blood pressure more than fadolmidine, ameliorated I/R-induced impairment of autophagy and increased renal p38 and eNOS expressions. Dex downregulated 245 and upregulated 61 genes representing 17 enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, in particular, integrin pathway and CD44. Ingenuity analysis revealed inhibition of Rac and nuclear factor (erythroid-derived 2)-like 2 pathways, whereas aryl hydrocarbon receptor (AHR) pathway was activated. Dex preconditioning ameliorates kidney I/R injury and inflammatory response, at least in part, through p38-CD44-pathway and possibly also through ischemic preconditioning
Interaction of acoustic waves with flame front propagation

International audienceThe mechanisms of laminar premixed flame propagation have been intensively studied over the last century. Numerous authors have highlighted intrinsic phenomena in flame propagation such as Darrieus-Landau instability and Rayleigh-Taylor instability. Rayleigh-Taylor instability is often linked to the interaction between the flame front and an acoustic wave. To better characterize the interaction between a flame and aerodynamic conditions, we designed a special vertical closed tube apparatus. Our analysis focused on the behavior of a flame that propagates in a uniform stoichiometric mixture of H2 and O2 diluted with nitrogen. The experimental investigation revealed that acoustic waves emitted as the flame formed near the ignition point could increase the flame front surface by a factor of 10. An acoustic node with an amplitude of 1.3 m was identified and seemed to be responsible for the disappearance of one of the acoustic modes and for a reduction in the average flame surface. This could explain why the flame trajectory had two distinct parts: one corresponding to propagation at a high speed in the lower part of the tube, and the other with a slower speed in the upper part of the tube. The flame surface seemed to depend primarily on the frequencies of vibration and marginally on the nature of the reactive components. Propagation velocities, obtained by multiplying these flame surfaces by the fundamental burning velocity, strongly depended on the mixture reactivity
Highlights of the Flame Acceleration in a Confined Nonuniform H2/O2/N2 Mixture

International audienceGaseous explosion models generally assume the gas mixture to be uniform. However, in a real explosion, the vapor cloud may not be homogeneous, and repartitioning of the reactivity inside the cloud can be subject to wide spatial variations. In this work, experimental tests were run to study the flame propagation and acceleration in nonuniform mixtures. Experiments were performed in a long vertical confined tube with a square cross section, composed of four equal sections. A gate valve separated the tube into two parts, and the composition of the gases was different on each side of the valve. The opening of the valve permitted the mixing of gases by molecular diffusion. For nonuniform mixtures, a mode of propagation identical to that seen in uniform mixtures was observed; however, a third phase of propagation was found, in which the flame velocity increased strongly. This increase occurred with higher hydrogen concentration in an upwardpropagating flame. A concentration gradient can appreciably modify the trajectory and acceleration of a flame. Here, however, the incidence of pressure effects remained modest, since the combustion was confined and the final pressure depended mainly on the quantity of reactants available
Predicting explosibility properties of chemicals from quantitative structure-property relationships

National audienceQuantitative Structure-Property Relationship (QSPR) type methods have been up to now mainly devoted to biological, toxicological applications but their use to predict physico-chemical properties is a growing interest. In this context, an original approach associating QSPR methods and quantum chemical calculations for the prediction of chemicals explosibility properties is presented here. Indeed, the new European regulation of chemicals named REACH implies the new assessment of a tremendous number of substances for their hazardous properties. But, the complete characterization of toxicological, ecotoxicological, and physico-chemical hazards at experimental level is incompatible with the imposed calendar of REACH. Hence, there is a real need in evaluating capabilities of alternative methods for assessing hazardous properties as a screening process. This contribution focuses on models that have been established to predict accurately the thermal stability and electric spark sensitivity of a series of potentially explosive nitroaromatic molecules. Descriptors related to their molecular structure (topological, geometrical, electronic, quantum chemical), partially obtained from density functional theory (DFT) calculations, were computed and statistical analyses (multilinear regressions) were performed to link the adequate molecular descriptors with the experimental properties. These first results coupling theoretical calculations and QSPR methods open new perspectives for the prediction of other physico-chemical propertie