Collybolide Is a Novel Biased Agonist of κ-Opioid Receptors With Potent Antipruritic Activity

Among the opioid receptors, the κ-opioid receptor (κOR) has been gaining considerable attention as a potential therapeutic target for the treatment of complex CNS disorders including depression, visceral pain, and cocaine addiction. With an interest in discovering novel ligands targeting κOR, we searched natural products for unusual scaffolds and identified collybolide (Colly), a nonnitrogenous sesquiterpene from the mushroom Collybia maculata. This compound has a furyl-δ-lactone core similar to that of Salvinorin A (Sal A), another natural product from the plant Salvia divinorum. Characterization of the molecular pharmacological properties reveals that Colly, like Sal A, is a highly potent and selective κOR agonist. However, the two compounds differ in certain signaling and behavioral properties. Colly exhibits 10- to 50-fold higher potency in activating the mitogen-activated protein kinase pathway compared with Sal A. Taken with the fact that the two compounds are equipotent for inhibiting adenylyl cyclase activity, these results suggest that Colly behaves as a biased agonist of κOR. Behavioral studies also support the biased agonistic activity of Colly in that it exhibits ∼10-fold higher potency in blocking non–histamine-mediated itch compared with Sal A, and this difference is not seen in pain attenuation by these two compounds. These results represent a rare example of functional selectivity by two natural products that act on the same receptor. The biased agonistic activity, along with an easily modifiable structure compared with Sal A, makes Colly an ideal candidate for the development of novel therapeutics targeting κOR with reduced side effects

Interleukin-1 regulates multiple atherogenic mechanisms in response to fat feeding

Background: Atherosclerosis is an inflammatory process that develops in individuals with known risk factors that include hypertension and hyperlipidaemia, influenced by diet. However, the interplay between diet, inflammatory mechanisms and vascular risk factors requires further research. We hypothesised that interleukin-1 (IL-1) signaling in the vessel wall would raise arterial blood pressure and promote atheroma. Methodology/Principal Findings: Apoe(-/-) and Apoe(-/-)/IL-1R1(-/-) mice were fed high fat diets for 8 weeks, and their blood pressure and atherosclerosis development measured. Apoe(-/-)/IL-R1(-/-) mice had a reduced blood pressure and significantly less atheroma than Apoe(-/-) mice. Selective loss of IL-1 signaling in the vessel wall by bone marrow transplantation also reduced plaque burden (p<0.05). This was associated with an IL-1 mediated loss of endothelium-dependent relaxation and an increase in vessel wall Nox 4. Inhibition of IL-1 restored endothelium-dependent vasodilatation and reduced levels of arterial oxidative stress. Conclusions/Significance: The IL-1 cytokine system links atherogenic environmental stimuli with arterial inflammation, oxidative stress, increased blood pressure and atherosclerosis. This is the first demonstration that inhibition of a single cytokine can block the rise in blood pressure in response to an environmental stimulus. IL-1 inhibition may have profound beneficial effects on atherogenesis in man

Ultrastructural changes of the intracellular surfactant pool in a rat model of lung transplantation-related events

<p>Abstract</p> <p>Background</p> <p>Ischemia/reperfusion (I/R) injury, involved in primary graft dysfunction following lung transplantation, leads to inactivation of intra-alveolar surfactant which facilitates injury of the blood-air barrier. The alveolar epithelial type II cells (AE2 cells) synthesize, store and secrete surfactant; thus, an intracellular surfactant pool stored in lamellar bodies (Lb) can be distinguished from the intra-alveolar surfactant pool. The aim of this study was to investigate ultrastructural alterations of the intracellular surfactant pool in a model, mimicking transplantation-related procedures including flush perfusion, cold ischemia and reperfusion combined with mechanical ventilation.</p> <p>Methods</p> <p>Using design-based stereology at the light and electron microscopic level, number, surface area and mean volume of AE2 cells as well as number, size and total volume of Lb were determined in a group subjected to transplantation-related procedures including both I/R injury and mechanical ventilation (I/R group) and a control group.</p> <p>Results</p> <p>After I/R injury, the mean number of Lb per AE2 cell was significantly reduced compared to the control group, accompanied by a significant increase in the luminal surface area per AE2 cell in the I/R group. This increase in the luminal surface area correlated with the decrease in surface area of Lb per AE2. The number-weighted mean volume of Lb in the I/R group showed a tendency to increase.</p> <p>Conclusion</p> <p>We suggest that in this animal model the reduction of the number of Lb per AE2 cell is most likely due to stimulated exocytosis of Lb into the alveolar space. The loss of Lb is partly compensated by an increased size of Lb thus maintaining total volume of Lb per AE2 cell and lung. This mechanism counteracts at least in part the inactivation of the intra-alveolar surfactant.</p

Emotional Voice and Emotional Body Postures Influence Each Other Independently of Visual Awareness

Multisensory integration may occur independently of visual attention as previously shown with compound face-voice stimuli. We investigated in two experiments whether the perception of whole body expressions and the perception of voices influence each other when observers are not aware of seeing the bodily expression. In the first experiment participants categorized masked happy and angry bodily expressions while ignoring congruent or incongruent emotional voices. The onset between target and mask varied from −50 to +133 ms. Results show that the congruency between the emotion in the voice and the bodily expressions influences audiovisual perception independently of the visibility of the stimuli. In the second experiment participants categorized the emotional voices combined with masked bodily expressions as fearful or happy. This experiment showed that bodily expressions presented outside visual awareness still influence prosody perception. Our experiments show that audiovisual integration between bodily expressions and affective prosody can take place outside and independent of visual awareness

X-ray pulsar GRO J1008−-57 as an orthogonal rotator

X-ray polarimetry is a unique way to probe geometrical configuration of highly-magnetized accreting neutron stars (X-ray pulsars). GRO J1008$-$57 is the first transient X-ray pulsar observed at two different flux levels by the Imaging X-ray Polarimetry Explorer (IXPE) during its outburst in November 2022. The polarization properties were found to be independent of the source luminosity, with the polarization degree varying between non-detection to about 15% over the pulse phase. Fitting the phase-resolved spectro-polarimetric data with the rotating vector model allowed us to estimate the pulsar inclination (130 deg, which is in good agreement with the orbital inclination), the position angle (75 deg) of the pulsar spin axis, and the magnetic obliquity (74 deg). This makes GRO J1008$-$57 the first confidently identified X-ray pulsar as a nearly orthogonal rotator. The results are discussed in the context of the neutron star atmosphere models and theories of pulsars' axis alignment.Comment: 11 pages, 7 figures, submitted to A&A. arXiv admin note: text overlap with arXiv:2209.0244

X-ray Polarization of the Eastern Lobe of SS 433

How astrophysical systems translate the kinetic energy of bulk motion into the acceleration of particles to very high energies is a pressing question. SS 433 is a microquasar that emits TeV gamma-rays indicating the presence of high-energy particles. A region of hard X-ray emission in the eastern lobe of SS 433 was recently identified as an acceleration site. We observed this region with the Imaging X-ray Polarimetry Explorer and measured a polarization degree in the range 38% to 77%. The high polarization degree indicates the magnetic field has a well ordered component if the X-rays are due to synchrotron emission. The polarization angle is in the range -12 to +10 degrees (east of north) which indicates that the magnetic field is parallel to the jet. Magnetic fields parallel to the bulk flow have also been found in supernova remnants and the jets of powerful radio galaxies. This may be caused by interaction of the flow with the ambient medium.Comment: 8 pages, accepted in the Astrophysical Journal Letter

X-ray polarimetry of the accreting pulsar GX 301-2

The phase- and energy-resolved polarization measurements of accreting X-ray pulsars (XRPs) allow us to test different theoretical models of their emission, as well as to provide an avenue to determine the emission region geometry. We present the results of the observations of the XRP GX 301-2 performed with the Imaging X-ray Polarimetry Explorer (IXPE). GX 301-2 is a persistent XRP with one of the longest known spin periods of ~680 s. A massive hyper-giant companion star Wray 977 supplies mass to the neutron star via powerful stellar winds. We do not detect significant polarization in the phase-averaged data using spectro-polarimetric analysis, with the upper limit on the polarization degree (PD) of 2.3% (99% confidence level). Using the phase-resolved spectro-polarimetric analysis we get a significant detection of polarization (above 99% c.l.) in two out of nine phase bins and marginal detection in three bins, with a PD ranging between ~3% and ~10%, and a polarization angle varying in a very wide range from ~0 deg to ~160 deg. Using the rotating vector model we obtain constraints on the pulsar geometry using both phase-binned and unbinned analysis getting excellent agreement. Finally, we discuss possible reasons for a low observed polarization in GX 301-2.Comment: 10 pages, 10 figures, submitted to A&

A polarimetrically oriented X-ray stare at the accreting pulsar EXO 2030+375

Accreting X-ray pulsars (XRPs) are presumably ideal targets for polarization measurements, as their high magnetic field strength is expected to polarize the emission up to a polarization degree of ~80%. However, such expectations are being challenged by recent observations of XRPs with the Imaging X-ray Polarimeter Explorer (IXPE). Here we report on the results of yet another XRP, EXO 2030+375, observed with IXPE and contemporarily monitored with Insight-HXMT and SRG/ART-XC. In line with recent results obtained with IXPE for similar sources, analysis of the EXO 2030+375 data returns a low polarization degree of 0%-3% in the phase-averaged study and variation in the range 2%-7% in the phase-resolved study. Using the rotating vector model we constrain the geometry of the system and obtain a value for the magnetic obliquity of ~$60^{\circ}$. Considering also the estimated pulsar inclination of ~$130^{\circ}$, this indicates that the magnetic axis swings close to the observer line of sight. Our joint polarimetric, spectral and timing analysis hint to a complex accreting geometry where magnetic multipoles with asymmetric topology and gravitational light bending significantly affect the observed source behavior.Comment: A&A accepted. Proofs versio

First X-ray polarization measurement confirms the low black-hole spin in LMC X-3

X-ray polarization is a powerful tool to investigate the geometry of accreting material around black holes, allowing independent measurements of the black hole spin and orientation of the innermost parts of the accretion disk. We perform the X-ray spectro-polarimetric analysis of an X-ray binary system in the Large Magellanic Cloud, LMC X-3, that hosts a stellar-mass black hole, known to be persistently accreting since its discovery. We report the first detection of the X-ray polarization in LMC X-3 with the Imaging X-ray Polarimetry Explorer, and find the average polarization degree of 3.2% +- 0.6% and a constant polarization angle -42 deg +- 6 deg over the 2-8 keV range. Using accompanying spectroscopic observations by NICER, NuSTAR, and the Neil Gehrels Swift observatories, we confirm previous measurements of the black hole spin via the X-ray continuum method, a ~ 0.2. From polarization analysis only, we found consistent results with low black-hole spin, with an upper limit of a < 0.7 at a 90% confidence level. A slight increase of the polarization degree with energy, similar to other black-hole X-ray binaries in the soft state, is suggested from the data but with a low statistical significance.Comment: 14 pages, 8 figures, submitted to Ap