Spherical harmonics coeffcients for ligand-based virtual screening of cyclooxygenase inhibitors

Background: Molecular descriptors are essential for many applications in computational chemistry, such as ligand-based similarity searching. Spherical harmonics have previously been suggested as comprehensive descriptors of molecular structure and properties. We investigate a spherical harmonics descriptor for shape-based virtual screening. Methodology/Principal Findings: We introduce and validate a partially rotation-invariant three-dimensional molecular shape descriptor based on the norm of spherical harmonics expansion coefficients. Using this molecular representation, we parameterize molecular surfaces, i.e., isosurfaces of spatial molecular property distributions. We validate the shape descriptor in a comprehensive retrospective virtual screening experiment. In a prospective study, we virtually screen a large compound library for cyclooxygenase inhibitors, using a self-organizing map as a pre-filter and the shape descriptor for candidate prioritization. Conclusions/Significance: 12 compounds were tested in vitro for direct enzyme inhibition and in a whole blood assay. Active compounds containing a triazole scaffold were identified as direct cyclooxygenase-1 inhibitors. This outcome corroborates the usefulness of spherical harmonics for representation of molecular shape in virtual screening of large compound collections. The combination of pharmacophore and shape-based filtering of screening candidates proved to be a straightforward approach to finding novel bioactive chemotypes with minimal experimental effort

Antinociceptive activity of the S1P-receptor agonist FTY720

FTY720 is a novel immunosuppressive drug that inhibits the egress of lymphocytes from secondary lymphoid tissues and thymus. In its phosphorylated form FTY720 is a potent S1P receptor agonist. Recently it was also shown that FTY720 can reduce prostaglandin synthesis through the direct inhibition of the cytosolic phospholipase A2 (cPLA2). Since prostaglandins are important mediators of nociception, we studied the effects of FTY720 in different models of nociception. We found that intraperitoneal administration of FTY720 reduced dose-dependently the nociceptive behaviour of rats in the formalin assay. Although the antinociceptive doses of FTY720 were too low to alter the lymphocyte count, prostanoid concentrations in the plasma were dramatically reduced. Surprisingly, intrathecally administered FTY720 reduced the nociceptive behaviour in the formalin assay without altering spinal prostaglandin synthesis, indicating that additional antinociceptive mechanisms beside the inhibition of prostaglandin synthesis are involved. Accordingly, FTY720 reduced also the nociceptive behaviour in the spared nerve injury model for neuropathic pain which does not depend on prostaglandin synthesis. In this model the antinociceptive effect of FTY720 was similar to gabapentin, a commonly used drug to treat neuropathic pain. Taken together we show for the first time that FTY720 possesses antinociceptive properties and that FTY720 reduces nociceptive behaviour during neuropathic pain

Influenza di alcune pratiche di condizionamento sulla shelf-life di frutti di fico d'India della varietà "gialla"

"Gialla" cactus pears were subjected to various conditioning treatments (packaging, UV exposure and anaerobic shock) prior to were transferred to cold storage or retail conditions. Film packaging reduced significantly weight loss, chilling injury symptoms and maintained freshness of the fruit, while the anaerobic treatment acted only in reducing weight loss during the cold storage. Ultraviolet exposure was detrimental for the overall fruit quality

Consequences of altered eicosanoid patterns for nociceptive processing in mPGES-1-deficient mice

Cyclooxygenase-2 (COX-2)-dependent prostaglandin (PG) E2 synthesis in the spinal cord plays a major role in the development of inflammatory hyperalgesia and allodynia. Microsomal PGE2 synthase-1 (mPGES-1) isomerizes COX-2-derived PGH2 to PGE2. Here, we evaluated the effect of mPGES-1-deficiency on the noci-ceptive behavior in various models of nociception that depend on PGE2 synthesis. Surprisingly, in the COX-2-dependent zymosan-evoked hyperalgesia model, the nociceptive behavior was not reduced in mPGES-1-deficient mice despite a marked decrease of the spinal PGE2 synthesis. Similarly, the nociceptive behavior was unaltered in mPGES-1-deficient mice in the formalin test. Importantly, spinal cords and primary spinal cord cells derived from mPGES-1-deficient mice showed a redirection of the PGE2 synthesis to PGD2, PGF2α and 6-keto-PGF1α (stable metabolite of PGI2). Since the latter prostaglandins serve also as mediators of noci-ception they may compensate the loss of PGE2 synthesis in mPGES-1-deficient mice

Estensione della vita postraccolta di due varietà di pero estive del germoplasma autoctono con l'uso di trattamenti anaerobici

Pear fruits of "Cabudraxia" and "Arriabi", two summer ripening cultivars of the Sardinian germplasm, were exposed for 36 hours to N2 or air promptly after harvest and then transferred to 20°C and 70% of relative humidity to allow ripening. Respiration rate and ethylene production were recorded daily, while firmness and ethanol in the flesh were inspected at regular intervals. Taste tests were carried out by a panel of five tasters who were required to express their preference between the two groups. Nitrogen exposed fruits lost firmness at a lower rate than control fruits. Ethylene production was delayed by anaerobic treament and peaked five days after non exposed fruits. Upon removal from treatment an ethanol accumulation in the fruit flesh of exposed fruits was found, that promptly decreased during the ripening period, even if remained significantly higher than control fruits. Nevertheless, judges preferred anaerobic exposed fruits. Similar results were obtained for both cultivars. Thus, short term anaerobic exposition resulted in a drastic delay of fruit ripening and improved sensory attributes of the fruits of the two appreciable local cultivars. Frutti di pero delle varietà a maturazione estiva "Cabudraxia" e "Arriabi" appartenenti al germoplasma autoctono sono state esposte per 36 ore subito dopo la raccolta ad un atmosfera al 100% di N2 od in condizioni normali. Successivamente al trattamento i frutti sono stati posti a 20°C e 70% di umidità relativa, per permettere il normale processo di maturazione. Giornalmente sono stati determinati l'attività respiratoria e la produzione di etilene, mentre ad intervalli regolari si è proceduto alla misurazione della consistenza dei frutti e della produzione di etanolo nella polpa. Un gruppo di assaggiatori ha, inoltre, fornito giudizi di preferenza gustativa. I frutti trattati hanno mostrato una perdita di consistenza inferiore rispetto al controllo. L'inibizione temporanea della produzione di etilene nella tesi esposta alle condizioni anaerobiche ha consentito un ritardo del picco climaterico di cinque giorni, rispetto ai frutti non trattati. Immediatamente dopo il trattamento il contenuto di etanolo nella polpa è stato significativamente superiore nella tesi trattata, ma è comunque diminuito durante il periodo di maturazione. Comunque, il test di assaggio ha rivelato la preferenza verso i frutti trattati. I risultati ottenuti sono stati pressoché simili per entrambe le cultivar. L'esposizione in condizioni anaerobiche per breve periodo ha consentito, pertanto, un sensibile posticipo della maturazione e un miglioramento delle caratteristiche organolettiche dei frutti di due apprezzabili varietà del germoplasma locale

Bayesian Approach for Distribution System State Estimation With Non-Gaussian Uncertainty Models

To deal with the increasing complexity of distribution networks that are experiencing important changes, due to the widespread installation of distributed generation and the expected penetration of new energy resources, modern control applications must rely on an accurate picture of the grid status, given by the distribution system state estimation (DSSE). The DSSE is required to integrate all the available information on loads and generators power exchanges (pseudomeasurements) with the real-time measurements available from the field. In most cases, the statistical behavior of the measured and pseudomeasured quantities cannot be approximated by a Gaussian distribution. For this reason, it is necessary to design estimators that are able to use measurements and forecast data on power flows that can show a non-Gaussian behavior. In this paper, a DSSE algorithm based on Bayes's rule, conceived to perfectly match the uncertainty description of the available input information, is presented. The method is able to correctly handle the measurement uncertainty of conventional and synchronized measurements and to include possible correlation existing between the pseudomeasurements. Its applicability to medium voltage distribution networks and its advantages, in terms of accuracy of both estimated quantities and uncertainty intervals, are demonstrated

Spherical Harmonics Coefficients for Ligand-Based Virtual Screening of Cyclooxygenase Inhibitors

Molecular descriptors are essential for many applications in computational chemistry, such as ligand-based similarity searching. Spherical harmonics have previously been suggested as comprehensive descriptors of molecular structure and properties. We investigate a spherical harmonics descriptor for shape-based virtual screening.We introduce and validate a partially rotation-invariant three-dimensional molecular shape descriptor based on the norm of spherical harmonics expansion coefficients. Using this molecular representation, we parameterize molecular surfaces, i.e., isosurfaces of spatial molecular property distributions. We validate the shape descriptor in a comprehensive retrospective virtual screening experiment. In a prospective study, we virtually screen a large compound library for cyclooxygenase inhibitors, using a self-organizing map as a pre-filter and the shape descriptor for candidate prioritization.12 compounds were tested in vitro for direct enzyme inhibition and in a whole blood assay. Active compounds containing a triazole scaffold were identified as direct cyclooxygenase-1 inhibitors. This outcome corroborates the usefulness of spherical harmonics for representation of molecular shape in virtual screening of large compound collections. The combination of pharmacophore and shape-based filtering of screening candidates proved to be a straightforward approach to finding novel bioactive chemotypes with minimal experimental effort

Soluble epoxide hydrolase limits mechanical hyperalgesia during inflammation.

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.BACKGROUND: Cytochrome-P450 (CYP450) epoxygenases metabolise arachidonic acid (AA) into four different biologically active epoxyeicosatrienoic acid (EET) regioisomers. Three of the EETs (i.e., 8,9-, 11,12- and 14,15-EET) are rapidly hydrolysed by the enzyme soluble epoxide hydrolase (sEH). Here, we investigated the role of sEH in nociceptive processing during peripheral inflammation. RESULTS: In dorsal root ganglia (DRG), we found that sEH is expressed in medium and large diameter neurofilament 200-positive neurons. Isolated DRG-neurons from sEH(-/-) mice showed higher EET and lower DHET levels. Upon AA stimulation, the largest changes in EET levels occurred in culture media, indicating both that cell associated EET concentrations quickly reach saturation and EET-hydrolyzing activity mostly effects extracellular EET signaling. In vivo, DRGs from sEH-deficient mice exhibited elevated 8,9-, 11,12- and 14,15-EET-levels. Interestingly, EET levels did not increase at the site of zymosan-induced inflammation. Cellular imaging experiments revealed direct calcium flux responses to 8,9-EET in a subpopulation of nociceptors. In addition, 8,9-EET sensitized AITC-induced calcium increases in DRG neurons and AITC-induced calcitonin gene related peptide (CGRP) release from sciatic nerve axons, indicating that 8,9-EET sensitizes TRPA1-expressing neurons, which are known to contribute to mechanical hyperalgesia. Supporting this, sEH(-/-) mice showed increased nociceptive responses to mechanical stimulation during zymosan-induced inflammation and 8,9-EET injection reduced mechanical thresholds in naive mice. CONCLUSION: Our results show that the sEH can regulate mechanical hyperalgesia during inflammation by inactivating 8,9-EET, which sensitizes TRPA1-expressing nociceptors. Therefore we suggest that influencing the CYP450 pathway, which is actually highly considered to treat cardiovascular diseases, may cause pain side effects.Peer Reviewe

Hysteroscopic Endometrial Ablation: From Indications to Instrumentation and Techniques—A Call to Action

The development of minimally invasive techniques has led to the creation of innovative alternatives in cases where traditional methods are not applicable. In modern gynecology, hysteroscopy has become the gold standard for the evaluation and treatment of intrauterine pathology. Endometrial ablation (EA) is a procedure that uses different types of energy to destroy the endometrium and is currently used as an alternative technique in cases of heavy menstrual bleeding when medical treatment has failed and uterine preservation is desired. The aim of this review was to evaluate the feasibility, safety, and clinical outcomes of hysteroscopic EA as an alternative in patients with abnormal uterine bleeding. A detailed computerized search of the literature was performed in the main electronic databases (MEDLINE, EMBASE, Web of Science, PubMed, and Cochrane Library), from 1994 to June 2022, to evaluate the outcomes in patients with abnormal uterine bleeding (AUB) undergoing EA using hysteroscopic and non-hysteroscopic techniques. Only scientific publications in English were included. Twelve articles on the current use of endometrial ablation were included. Data on patient symptoms, tools used for EA, primary outcomes, and adverse events were recorded. EA should be considered an effective and safe approach in the management of patients with abnormal uterine bleeding caused by benign pathology, in whom medical treatment has failed or is contraindicated. Due to the lack of evidence, it would be interesting to determine whether EA would also have a role in the treatment of women with premalignant lesions, avoiding invasive surgical procedures or medical treatment in those patients for whom hysterectomy or the use of hormonal treatment is contraindicated

Subcellular distribution of FTY720 and FTY720-phosphate in immune cells - another aspect of Fingolimod action relevant for therapeutic application

FTY720 (Fingolimod; Gilenya®) is an immune-modulatory prodrug which, after intracellular phosphorylation by sphingosine kinase 2 (SphK2) and export, mimics effects of the endogenous lipid mediator sphingosine-1-phosphate. Fingolimod has been introduced to treat relapsing-remitting multiple sclerosis. However, little has been published about the immune cell membrane penetration and subcellular distribution of FTY720 and FTY720-P. Thus, we applied a newly established LC-MS/MS method to analyze the subcellular distribution of FTY720 and FTY720-P in subcellular compartments of spleen cells of wild type, SphK1- and SphK2-deficient mice. These studies demonstrated that, when normalized to the original cell volume and calculated on molar basis, FTY720 and FTY720-P dramatically accumulated several hundredfold within immune cells reaching micromolar concentrations. The amount and distribution of FTY720 was differentially affected by SphK1- and SphK2-deficiency. On the background of recently described relevant intracellular FTY720 effects in the nanomolar range and the prolonged application in multiple sclerosis, this data showing a substantial intracellular accumulation of FTY720, has to be considered for benefit/risk ratio estimates