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Serotonin receptors play central roles in neuromodulation and are critical drug targets for psychiatric disorders. Optical control of serotonin receptor subtypes has the potential to greatly enhance our understanding of the spatiotemporal dynamics of receptor function. While other neuromodulatory receptors have been successfully rendered photoswitchable, reversible photocontrol of serotonin receptors has not been achieved, representing a major gap in GPCR photopharmacology. Herein, we develop the first tools that allow for such control. Azo5HT‐2 shows light‐dependent 5‐HT2AR agonism, with greater activity in the cis‐form. Based on docking and test compound analysis, we also develop photoswitchable orthogonal, remotely‐tethered ligands (PORTLs). These BG‐Azo5HTs provide rapid, reversible, and repeatable optical control following conjugation to SNAP‐tagged 5‐HT2AR. Overall, this study provides a foundation for the broad extension of photopharmacology to the serotonin receptor family. [ABSTRACT FROM AUTHOR]

Summary: Because of their importance as chemical mediators, the presence of a rich and varied family of lipoxygenase (LOX) products, collectively named oxylipins, has been investigated thoroughly in diatoms, and the involvement of these products in important processes such as bloom regulation has been postulated. Nevertheless, little information is available on the enzymes and pathways operating in these protists.Exploiting transcriptome data, we identified and characterized a LOX gene, PaLOX, in Pseudo‐nitzschia arenysensis, a marine diatom known to produce different species of oxylipins by stereo‐ and regio‐selective oxidation of eicosapentaenoic acid (EPA) at C12 and C15.PaLOX RNA interference correlated with a decrease of the lipid‐peroxidizing activity and oxylipin synthesis, as well as with a reduction of growth of P. arenysensis. In addition, sequence analysis and structure models of the C‐terminal part of the predicted protein closely fitted with the data for established LOXs from other organisms.The presence in the genome of a single LOX gene, whose downregulation impairs both 12‐ and 15‐oxylipins synthesis, together with the in silico 3D protein modelling suggest that PaLOX encodes for a 12/15S‐LOX with a dual specificity, and provides additional support to the correlation between cell growth and oxylipin biosynthesis in diatoms. [ABSTRACT FROM AUTHOR]

Many research groups are working to find new possible anti-inflammatory molecules, and marine sponges represent a rich source of biologically active compounds with pharmacological applications. In the present study, we tested different concentrations of the methanol extract from the marine sponge, Geodia cydonium, on normal human breast epithelial cells (MCF-10A) and human breast cancer cells (MCF-7). Our results show that this extract has no cytotoxic effects on both cell lines whereas it induces a decrease in levels of VEGF and five proinflammatory cytokines (CCL2, CXCL8, CXCL10, IFN-γ, and TNF-α) only in MCF-7 cells in a dose-dependent manner, thereby indicating an anti-inflammatory effect. Moreover, interactomic analysis suggests that all six cytokines are involved in a network and are connected with some HUB nodes such as NF-kB subunits and ESR1 (estrogen receptor 1). We also report a decrease in the expression of two NFKB1 and c-Rel subunits by RT-qPCR experiments only in MCF-7 cells after extract treatment, confirming NF-kB inactivation. These data highlight the potential of G. cydonium for future drug discovery against major diseases, such as breast cancer. [ABSTRACT FROM AUTHOR]

Volatile organic compounds ( VOCs) may play the role of infochemicals and trigger chemotaxis and ecologically relevant responses in freshwater and marine invertebrates. Aquatic grazers use these signals as chemical cues to trace the presence of their food or to detect their predators. However, detailed data are still needed to fully understand the role of these relationships in marine plankton. We investigated the ability of the copepod Centropages typicus to perceive the odour of three planktonic diatoms ( Skeletonema marinoi, Pseudonitzschia delicatissima and Chaetoceros affinis) and a dinoflagellate ( Prorocentrum minimum). This information is ecologically relevant for orientation, habitat selection, predator avoidance and communication. In addition, as the pH of the medium influences the perception of chemical cues in aquatic environments, we tested the effect of seawater acidification resulting from increasing levels of CO2, and its influences on the olfactory reactions of copepods. For this reason, our tests were repeated in normal ( pH 8.10) and acidified ( pH 7.76) seawater in order to simulate future ocean acidification scenarios. Using replicated chemokinetic assays we demonstrated that VOCs produced by Ps. delicatissima and Pr. minimum attract copepods at normal pH, but this effect is lowered in acidified water. By contrast, the odour of S. marinoi mainly induces a reaction of repulsion, but in acidified water and at higher concentrations this toxic diatom becomes attractive for copepods. Our experiments demonstrate, for the first time, that copepods are sensitive to the volatile compounds contained in various microalgae; VOCs prompt chemokinesis according to algal species and odour concentrations. However, seawater acidification induces changes in copepods' perception of odours. These findings highlight the sensitivity of chemically mediated interactions to global changes [ABSTRACT FROM AUTHOR]

• In recent years, oxylipins (lipoxygenase-derived oxygenated fatty acid products) have been reported in several bloom-forming marine diatoms. Despite increasing attention on the ecophysiological role of these molecules in marine environments, their biosynthesis is largely unknown in these microalgae. • Biochemical methods, including tandem mass spectrometry, nuclear magnetic resonance and radioactive probes were used to identify structures, enzymatic activities and growth-dependent modulation of oxylipin biosynthesis in the pennate diatom Pseudo-nitzschia delicatissima. • Three major compounds, 15S-hydroxy-(5 Z,8 Z,11 Z,13 E,17 Z)-eicosapentaenoic acid (15S-HEPE), 15-oxo-5Z,9 E,11 E,13 E-pentadecatetraenoic acid and 13,14- threo-13 R-hydroxy-14 S,15 S- trans-epoxyeicosa-5 Z,8 Z,11 Z,17 Z-tetraenoic acid (13,14-HEpETE), were produced by three putative biochemical pathways triggered by eicosapentaenoic acid-dependent 15S lipoxygenase. Oxylipin production increases along the growth curve, with remarkable changes that precede the demise of the culture. At least one of the compounds, namely 15-oxoacid, is formed only in the stationary phase immediately before the collapse of the culture. • Synthesis and regulation of phyco-oxylipins seem to correspond to a signaling mechanism that governs adaptation of diatoms along the growth curve until bloom termination. Factors triggering the process are unknown but synthesis of 15-oxoacid, constrained within a time-window of a few days just before the collapse of the culture, implies the involvement of a physiological control not directly dependent on distress or death of diatom cells. [ABSTRACT FROM AUTHOR]

Liver involvement in Cystic Fibrosis (CF) is much less frequent than both pulmonary and pancreatic diseases that are present in 80-90% of CF patients; liver disease (LD) affects only one third of CF patients, however, because of the decreasing mortality from extrahepatic causes, its recognition and management is becoming a relevant clinical issue. Recent observations suggest that clinical expression of LD in CF may be influenced by genetic modifiers; their identification is an important issue because it may allow recognition of patients at risk for the development of LD at the time of diagnosis of CF and early institution of prophylactic strategies. Oral bile acid therapy, aimed at improving biliary secretion in terms of bile viscosity and bile acid composition, is currently the only available therapeutic approach for CF-associated LD. However, the impact of this therapy on the natural history of LD remains to be defined and long-term effectiveness on clinically relevant outcomes should be further investigated. Liver transplantation should be offered to CF patients with progressive liver failure and/or with life-threatening sequelae of portal hypertension, who also have mild pulmonary involvement that is expected to support long-term survival. The 1-year survival rate after transplantation in CF patients is approximately 80%, with beneficial effects on lung function, nutritional status, body composition and quality of life in most cases. [ABSTRACT FROM AUTHOR]

Diatom oxylipins have been observed to deleteriously impact copepod reproductive success. However, field studies have revealed very variable and case-dependent results. Therefore, the plasticity of diatom oxylipin metabolism was studied among four clones of the marine diatom Skeletonema marinoi Sarno et Zingone. Diatom oxylipin metabolism was studied by two lipoxygenase (LOX) activity assays carried out at different pH values and by oxylipin quantification. The four clones showed no major metabolic differences in terms of protein content or growth rate. However, two of the clones produced significantly higher levels of oxylipins than the other two. LOX activity measurements also indicated clonal variability in fatty acid oxidative metabolism. The presence of clone-specific differences in oxylipin metabolism may play a role in shaping diatom population dynamics by conferring selective advantages to certain clones. [ABSTRACT FROM AUTHOR]