Cyclo-oxygenase (prostaglandin endoperoxide synthase) is the enzyme which metabolizes the conversion of arachidonic acid to prostaglandin. It exists in at least two isoforms:: the constitutive ...(cyclo-oxygenase-1 and the inducible (cyclo-oxygenase-2) which is controlled by a number of factors, including cytokines and intracellular messengers. These enzymes are the therapeutic targets of non-steroidal anti-inflammatory drugs such as aspirin and ibuprofen. The cyclo-oxygenase active site is a long, hydrophobic, channel where the substrate arachidonic acid gains access to the active site. Cyclo-oxygenase-2 differs form cyclo-oxygenase-1 in certain key characteristics, particularly important is the valine/leucine substitution at position 523 that creates a defect in the inner shell of the cyclo-oxygenase-2 enzyme channel leaving a side pocket by which drugs selective for cyclo-oxygenase-2 gain access. Although cyclo-oxygenase-1 seems to be expressed in physiological conditions and cyclo-oxygenase-2 in inflammatory conditions, it is not yet possible to identify all their different roles. Cyclo-oxygenase-2 may be expressed constitutively, whereas the generation of prostaglandin by cyclo-oxygenase-2 may replace that by cyclo-oxygenase-1 in some situations (or vice-versa). Both cyclo-oxygenase isoenzymes contribute to mucosal defence and the inhibition of the two isoforms contributes to the pathogenesis of non-steroidal anti-inflammatory drug-induced gastric damage.
We present experimental constraints on the spin-dependent WIMP (weakly interacting massive particle)-nucleon elastic cross sections from LUX data acquired in 2013. LUX is a dual-phase xenon time ...projection chamber operating at the Sanford Underground Research Facility (Lead, South Dakota), which is designed to observe the recoil signature of galactic WIMPs scattering from xenon nuclei. A profile likelihood ratio analysis of 1.4×10^{4} kg day of fiducial exposure allows 90% C.L. upper limits to be set on the WIMP-neutron (WIMP-proton) cross section of σ_{n}=9.4×10^{-41} cm^{2} (σ_{p}=2.9×10^{-39} cm^{2}) at 33 GeV/c^{2}. The spin-dependent WIMP-neutron limit is the most sensitive constraint to date.
Background & Aims:
The farnesoid X receptor (FXR) is an endogenous sensor for bile acids and inhibits bile acid synthesis by inducing small heterodimer partner (SHP) gene expression. The aim of this ...study was to investigate whether FXR is expressed by and modulates function of hepatic stellate cells (HSCs).
Methods:
The antifibrotic activity of FXR ligand was tested in 2 rodent models: the porcine serum and bile duct ligation (BDL).
Results:
Twelve-week administration of 1–10 mg/kg 6-ethyl chenodeoxycholic acid (6-ECDCA), a synthetic FXR ligand, to porcine serum-treated rats prevented liver fibrosis development and reduced liver expression of α1(I) collagen, TGF-β1 and α-SMA mRNA by ∼90%. Therapeutic administration of 6-ECDCA, 3 mg/kg, to BDL rats reduced liver fibrosis and α1(I) collagen, transforming growth factor (TGF)-β1, α-SMA, and tissue metalloproteinase inhibitor (TIMP)-1 and 2 messenger RNA (mRNA) by 70%–80%. No protection was observed in BDL rats treated with CDCA, 3 mg/kg, and ursodeoxycholic acid, 15 mg/kg. FXR expression was detected in HSCs. Exposure of HSCs to FXR ligands caused a 3-fold increase of SHP, reduced α1(I)collagen and TGF-β1 by ∼60%–70% and abrogates α1(I) collagen mRNA up-regulation induced by thrombin and TGF-β1. By retrovirus infection and small interference RNA, we generated SHP overexpressing and SHP-deficient HSC-T6. Using these cell lines, we demonstrated that SHP binds JunD and inhibits DNA binding of adaptor protein (AP)-1 induced by thrombin.
Conclusions:
By demonstrating that an FXR-SHP regulatory cascade promotes resolution of liver fibrosis, this study establish that FXR ligands might represent a novel therapeutic option to treat liver fibrosis.
Acetaminophen misuse is a leading cause of acute liver failure and liver transplantation for which therapy is poorly effective. FXR ligands have shown effective in reducing liver injury in several ...experimental and clinical settings. In this Letter, we have elaborated on the structure of GW4064, the first nonsteroidal agonist for FXR, to identify novel isoxazoles endowed with FXR agonistic activity and improved ADME properties. The pharmacological characterization and molecular docking studies for the structure–activity rationalization allowed the identification of several FXR agonists with nanomolar potency in transactivation and SRC-1 recruitment assays. This characterization resulted in the identification of a potent FXR agonist, compound 20 that was orally active, and rescued mice from acute liver failure caused by acetaminophen overdose in a FXR-dependent manner.
LUX-ZEPLIN (LZ) is a second-generation direct dark matter experiment with spin-independent WIMP-nucleon scattering sensitivity above
1.4
×
10
-
48
cm
2
for a WIMP mass of
40
GeV
/
c
2
and a
1000
days
...exposure. LZ achieves this sensitivity through a combination of a large
5.6
t
fiducial volume, active inner and outer veto systems, and radio-pure construction using materials with inherently low radioactivity content. The LZ collaboration performed an extensive radioassay campaign over a period of six years to inform material selection for construction and provide an input to the experimental background model against which any possible signal excess may be evaluated. The campaign and its results are described in this paper. We present assays of dust and radon daughters depositing on the surface of components as well as cleanliness controls necessary to maintain background expectations through detector construction and assembly. Finally, examples from the campaign to highlight fixed contaminant radioassays for the LZ photomultiplier tubes, quality control and quality assurance procedures through fabrication, radon emanation measurements of major sub-systems, and bespoke detector systems to assay scintillator are presented.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Dual-phase xenon detectors, as currently used in direct detection dark matter experiments, have observed elevated rates of background electron events in the low energy region. While this background ...negatively impacts detector performance in various ways, its origins have only been partially studied. In this paper we report a systematic investigation of the electron pathologies observed in the LUX dark matter experiment. We characterize different electron populations based on their emission intensities and their correlations with preceding energy depositions in the detector. By studying the background under different experimental conditions, we identified the leading emission mechanisms, including photoionization and the photoelectric effect induced by the xenon luminescence, delayed emission of electrons trapped under the liquid surface, capture and release of drifting electrons by impurities, and grid electron emission. We discuss how these backgrounds can be mitigated in LUX and future xenon-based dark matter experiments.
Neutrophil adherence within the gastric microcirculation is thought to be a major step in the pathogenesis of gastric mucosal damage induced by indomethacin. Pentoxifylline, a methylxanthine ...derivative, prevents leukocyte adherence to vascular endothelium and protects organs from shock by reducing tumour necrosis factor alpha (TNF alpha) concentrations. Rats were treated with 20 mg/kg oral indomethacin, pretreated with vehicle or with four different doses of pentoxifylline intraperitoneally, and killed after three hours. The gross gastric mucosal injury, neutrophil margination into the gastric microcirculation, mucosal concentrations of 6-keto-prostaglandin F1 alpha (PGF1 alpha), and PGE2 and serum TNF alpha values were measured. Whether the pentoxifylline induced protection involved nitric oxide mediated pathways or gastric acid secretion was evaluated. The data indicate that pentoxifylline reduces indomethacin induced mucosal damage and neutrophil margination in a dose dependent manner without exerting any effect on gastric mucosal prostaglandin concentrations. The maximally effective dose (200 mg/kg) of pentoxifylline reduced gastric damage by 90% and slightly stimulated acid secretion. The effect of pentoxifylline was not affected by pretreatment with the nitric oxide inhibitor. Pentoxifylline prevented the indomethacin induced increase in TNF alpha concentrations in a dose dependent fashion. Serum TNF alpha values were 30.5 (7.0) IU/ml (mean (SEM)) in rats treated with indomethacin alone and 5.0 (2.5) IU/ml (p < 0.01) in rats treated with indomethacin plus 200 mg/kg pentoxifylline. Pentoxifylline, therefore, prevents the acute gastric mucosal damage and neutrophil margination induced by indomethacin and reduces indomethacin induced release of TNF alpha.
Background
: Nitric oxide (NO)‐releasing NSAIDs are a new class of NSAID derivatives with markedly reduced gastrointestinal toxicity. Although it has been demonstrated that NO‐NSAIDs spare gastric ...mucosal blood flow, molecular determinants involved in this effect are unknown.
Aim
: To investigate the effect of aspirin, naproxen and flurbiprofen, and their NO‐derivatives, on gastric apoptosis and endothelial cell damage induced by tumour necrosis factor‐α (TNFα). In other systems, TNFα‐induced apoptosis is mediated by caspases, a growing family of cysteine proteases similar to the IL‐1β converting enzyme (ICE), and so we have investigated whether NO‐NSAIDs modulate ICE‐like endopeptidases.
Methods
: Rats were treated orally with aspirin, naproxen and flurbiprofen, or their NO‐releasing derivatives in equimolar doses, and were killed 3 h later to assess mucosal damage and caspase activity. Endothelial cells (HUVECs) were obtained from human umbilical cord by enzymatic digestion. Caspase 1 and 3 activities were measured by a fluorimetric assay using selective peptides as substrates and inhibitors. Apoptosis was quantified by ELISA specific for histone‐associated DNA fragments and by the terminal transferase nick‐end translation method (TUNEL).
Results
: In vivo NSAID administration caused a time‐dependent increase in gastric mucosal damage and caspase activity. NCX‐4016, NO‐naproxen and NO‐flurbiprofen did not cause any mucosal damage and prevented cysteine protease activation. NSAIDs and NO‐NSAIDs stimulated TNFα release. Exposure to TNFα resulted in a time‐ and concentration‐dependent HUVEC apoptosis, an effect that was prevented by pretreating the cells with NCX‐4016, NO‐naproxen, NO‐flurbiprofen, SNP or Z‐VAD.FMK, a pan‐caspase inhibitor. The activation of ICE‐like cysteine proteases was required to mediate TNFα‐induced apoptosis of HUVECs. Exogenous NO donors inhibited TNFα‐induced cysteine protease activation. Inhibition of caspase activity was due to S‐nitrosylation of ICE/CPP32‐like proteases. NO‐NSAIDs prevented IL‐1β release from endotoxin‐stimulated macrophages.
Conclusions
: NO‐releasing NSAIDs are a new class of non‐peptide caspase inhibitors. Inhibition of ICE‐like cysteine proteases prevents endothelial cell damage induced by pro‐inflammatory agents and might contribute to the gastro‐protective effects of NO‐NSAIDs.
Quercetin, one of the most representative flavonoid compounds, is involved in antiradical, antioxidant, and prooxidant biological processes. Despite a constant increase of knowledge on both positive ...and negative activities of quercetin, it is unclear which activated form (quinone, semiquinone, or deprotonated) actually plays a role in each of these processes. Structural, electronic, and energetic characteristics of quercetin, as well as the influence of a copper ion on all of these parameters, are studied by means of quantum chemical electronic structure calculations. Introduction of thermodynamic cycles together with the role of coreactive compounds, such as reactive oxygen species, gives a glimpse of the most probable reaction schemes. Such a theoretical approach provides another hint to clarify which reaction is likely to occur within the broad range of quercetin biological activities. Keywords: Quercetin; flavonoid; reactivity indices; electronic structures; solvent effect
PDF
