Ciprofloxacin and levofloxacin attenuate microglia inflammatory response via TLR4/NF-kB pathway

BACKGROUND: Neuroinflammation is the response of the central nervous system to events that interfere with tissue homeostasis and represents a common denominator in virtually all neurological diseases. Activation of microglia, the principal immune effector cells of the brain, contributes to neuronal injury by release of neurotoxic products. Toll-like receptor 4 (TLR4), expressed on the surface of microglia, plays an important role in mediating lipopolysaccharide (LPS)-induced microglia activation and inflammatory responses. We have previously shown that curcumin and some of its analogues harboring an α,β-unsaturated 1,3-diketone moiety, able to coordinate the magnesium ion, can interfere with LPS-mediated TLR4-myeloid differentiation protein-2 (MD-2) signaling. Fluoroquinolone (FQ) antibiotics are compounds that contain a keto-carbonyl group that binds divalent ions, including magnesium. In addition to their antimicrobial activity, FQs are endowed with immunomodulatory properties, but the mechanism underlying their anti-inflammatory activity remains to be defined. The aim of the current study was to elucidate the molecular mechanism of these compounds in the TLR4/NF-κB inflammatory signaling pathway. METHODS: The putative binding mode of five FQs [ciprofloxacin (CPFX), levofloxacin (LVFX), moxifloxacin, ofloxacin, and delafloxacin] to TLR4-MD-2 was determined using molecular docking simulations. The effect of CPFX and LVFX on LPS-induced release of IL-1β and TNF-α and NF-κB activation was investigated in primary microglia by ELISA and fluorescence staining. The interaction of CPFX and LVFX with TLR4-MD-2 complex was assessed by immunoprecipitation followed by Western blotting using Ba/F3 cells. RESULTS: CPFX and LVFX bound to the hydrophobic region of the MD-2 pocket and inhibited LPS-induced secretion of pro-inflammatory cytokines and activation of NF-κB in primary microglia. Furthermore, these FQs diminished the binding of LPS to TLR4-MD-2 complex and decreased the resulting TLR4-MD-2 dimerization in Ba/F3 cells. CONCLUSIONS: These results provide new insight into the mechanism of the anti-inflammatory activity of CPFX and LVFX, which involves, at least in part, the activation of TLR4/NF-κB signaling pathway. Our findings might facilitate the development of new molecules directed at the TLR4-MD-2 complex, a potential key target for controlling neuroinflammation

Spectroscopy near the proton drip line in the deformed A=130 mass region : the Pr-126 nucleus

The near proton drip line nucleus Pr-126 was studied via in-beam gamma-ray spectroscopy using the Ca-40 + Mo-92 reaction at 190 MeV. We observed for the first time excited states above the known isomer in this nucleus up to 31 h over bar. The observed band is discussed in the interacting boson-fermion-fermion model.The calculations and the experimental information suggest a spin 8(+) for the lowest observed state.With such a spin assignment the moment of inertia of Pr-126 gets larger than in the heavier Pr isotopes, suggesting a sudden change in deformation close to the proton drip line

Stable triaxiality at the highest spins in 138 Nd and 139 Nd

The nuclei ${}^{138}\mathrm{Nd}$ and ${}^{139}\mathrm{Nd}$ have been studied at very high spins via the ${}^{48}\mathrm{Ca}{+}^{94}\mathrm{Zr}$ reaction. Several new rotational bands were observed, four in ${}^{138}\mathrm{Nd}$ and two in ${}^{139}\mathrm{Nd}.$ The ${J}^{(2)}$ moments of inertia calculated from the observed \ensuremath{\gamma}-ray energies are very small and almost constant, indicating that these bands are triaxial. Cranked Nilsson-Strutinsky calculations reproduce the general behavior of the bands, supporting this interpretation and suggesting an approximately constant \ensuremath{\gamma} value of \ensuremath{\sim}+35\ifmmode^\circ\else\textdegree\fi{} over a large spin range up to the highest observed spins. These bands and a few similar bands in other nuclei of the N\ensuremath{\approx}80 region are a unique example of almost undisturbed triaxial bands

Population of neutron-rich nuclei around 48ca with deep inelastic collisions

The deep inelastic reaction 48Ca+64Ni at 6 MeV/A has been studied using the CLARA–PRISMA setup. Angular distributions for pure elastic scattering and total cross-sections of the most relevant transfer channels have been measured. The experimental results are compared with predictions from a semiclassical model, showing good agreement for the presently analyzed few neutrons transfer channels. The decay of the most intense reaction products has also been studied, giving indications of the population of states with very short lifetimes.Gadea Raga, Andrés, [email protected]

Population and y-decay studies of neutron-rich nuclei around 48Ca with deep inelastic collisions

The population and -decay of n-rich nuclei around 48Ca has been measured with the PRISMA-CLARA setup using deep-inelastic collisions (DIC) on 64Ni, at energies ~2.5 times above the Coulomb barrier. After a careful analysis of the response of the PRISMA magnetic spectrometer, a detailed investigation of the reaction properties is carried out. This provides total cross sections and energy integrated angular distributions of the most relevant transfer channels, which are compared with predictions from a semiclassical multi-nucleon transfer model. Good agreement is found for the 0p, 1p and 1n channels. In few cases, angular distributions of the first excited states are also measured and the experimental results are interpreted in terms of DWBA calculations, providing information on the basic ingredients of the theoretical models

Extended investigation of superdeformed bands in 151,152^{151,152}Tb nuclei

A detailed study of known and new SD bands in Tb isotopes has been performed with the use of the EUROBALL IV -ray array. The high-statistics data set has allowed for the extension of known SD bands at low and high spins by new -ray transitions. These transitions, as it turns out, correspond to the rotational frequencies where the principal superdeformed gaps (Z=66,N=86) close giving rise to up- or down-bending mechanisms. This enables to attribute the underlying theoretical configurations with much higher confidence as compared to the previous identifications. Five new SD bands have been discovered, three of them assigned to the 152Tb and the two others to the 151Tb nuclei. Nuclear mean-field calculations have been used to interpret the structure of known SD bands as well as of the new ones in terms of nucleonic configurations

Probing the nature of particle–core couplings in 49Ca with γ spectroscopy and heavy-ion transfer reactions

This work was supported by the Italian Istituto Nazionale di Fisica Nucleare and partially by the Spanish MICINN (ACI2009-1070 bilateral action) and Generalitat Valenciana (Grant Nos. BEST/2009/073 and PROMETEO/2010/101). The work has also been partially supported by the Polish Ministry of Science and Higher Education (Grant No. N N202 309135)

Susceptibility to COPD:Differential Proteomic Profiling after Acute Smoking

Cigarette smoking is the main risk factor for COPD (Chronic Obstructive Pulmonary Disease), yet only a subset of smokers develops COPD. Family members of patients with severe early-onset COPD have an increased risk to develop COPD and are therefore defined as "susceptible individuals". Here we perform unbiased analyses of proteomic profiles to assess how "susceptible individuals" differ from age-matched "non-susceptible individuals" in response to cigarette smoking. Epithelial lining fluid (ELF) was collected at baseline and 24 hours after smoking 3 cigarettes in young individuals susceptible or non-susceptible to develop COPD and older subjects with established COPD. Controls at baseline were older healthy smoking and non-smoking individuals. Five samples per group were pooled and analysed by stable isotope labelling (iTRAQ) in duplicate. Six proteins were selected and validated by ELISA or immunohistochemistry. After smoking, 23 proteins increased or decreased in young susceptible individuals, 7 in young non-susceptible individuals, and 13 in COPD in the first experiment; 23 proteins increased or decreased in young susceptible individuals, 32 in young non-susceptible individuals, and 11 in COPD in the second experiment. SerpinB3 and Uteroglobin decreased after acute smoke exposure in young non-susceptible individuals exclusively, whereas Peroxiredoxin I, S100A9, S100A8, ALDH3A1 (Aldehyde dehydrogenase 3A1) decreased both in young susceptible and non-susceptible individuals, changes being significantly different between groups for Uteroglobin with iTRAQ and for Serpin B3 with iTRAQ and ELISA measures. Peroxiredoxin I, SerpinB3 and ALDH3A1 increased in COPD patients after smoking. We conclude that smoking induces a differential protein response in ELF of susceptible and non-susceptible young individuals, which differs from patients with established COPD. This is the first study applying unbiased proteomic profiling to unravel the underlying mechanisms that induce COPD. Our data suggest that SerpinB3 and Uteroglobin could be interesting proteins in understanding the processes leading to COPD

Question of dynamic chirality in nuclei: The case of ^134 Pr

Tonev, D.; Angelis, G. de; Brant, Slobodan; Frauendorf, S.; Petkov, P.; Dewald, A.; Dönau, F.; Balabanski, D. L.; Zhong, Q.; Pejovic, P.; Bazzacco, D.; Bednarczyk, P.; Camera, F.; Curien, D.; Vedova, F. Della; Fitzler, A.; Gadea, A.; Bianco, G. Lo; Lenzi, S.; Lunardi, S.; Marginean, N.; Moller, O.; Napoli, D. R.; Orlandi, R.; Sahin, E.; Saltarelli, A.; Dobon, J. Valiente; Zell, K. O.; Zhang, Jing-ye; Zhang, Y. H