On Weighted Composition Operators on Hardy Space H2

In this paper we study some properties of weighted composition. In addition that we discuss the finite rank weighted composition on Hardy space H2 and discuss the eigenvalue equation for weighted composition operator inducing by Koenig's maps on Hardy space H2

Effects of Platelet-Activating Factor on Brain Microvascular Endothelial Cells.

Platelet-activating factor (PAF) is a potent phospholipid mediator that exerts various pathophysiological effects by interacting with a G protein-coupled receptor. PAF has been reported to increase the permeability of the blood-brain barrier (BBB) via incompletely characterized mechanisms. We investigated the effect of PAF on rat brain microvascular endothelial cells (RBMVEC), a critical component of the BBB. PAF produced a dose-dependent increase in cytosolic Ca2+ concentration; the effect was prevented by the PAF receptor antagonist, WEB2086. The effect of PAF on cytosolic Ca2+ was abolished in Ca2+-free saline or in the presence of L-type voltage-gated Ca2+ channel inhibitor, nifedipine, indicating that Ca2+ influx is critical for PAF-induced increase in cytosolic Ca2+. PAF produced RBMVEC depolarization; the effect was inhibited by WEB2086. In cells loaded with [(4-amino-5-methylamino-2\u27,7\u27-difluoro-fluorescein)diacetate] (DAF-FM), a nitric oxide (NO)-sensitive fluorescent dye, PAF increased the NO level; the effect was prevented by WEB2086, nifedipine or by l-NAME, an inhibitor of NO synthase. Immunocytochemistry studies indicate that PAF reduced the immunostaining of ZO-1, a tight junction-associated protein, increased F-actin fibers, and produced intercellular gaps. PAF produced a decrease in RBMVEC monolayer electrical resistance assessed with Electric Cell-Substrate Impedance Sensing (ECIS), indicative of a disruption of endothelial barrier function. In vivo studies indicate that PAF increased the BBB permeability, assessed with sodium fluorescein and Evans Blue methods, via PAF receptor-dependent mechanisms, consequent to Ca2+ influx and increased NO levels. Our studies reveal that PAF alters the BBB permeability by multiple mechanisms, which may be relevant for central nervous system (CNS) inflammatory disorders

Mechanisms of modulation of brain microvascular endothelial cells function by thrombin.

Brain microvascular endothelial cells are a critical component of the blood-brain barrier. They form a tight monolayer which is essential for maintaining the brain homeostasis. Blood-derived proteases such as thrombin may enter the brain during pathological conditions like trauma, stroke, and inflammation and further disrupts the permeability of the blood-brain barrier, via incompletely characterized mechanisms. We examined the underlying mechanisms evoked by thrombin in rat brain microvascular endothelial cells (RBMVEC). Our results indicate that thrombin, acting on protease-activated receptor 1 (PAR1) increases cytosolic C

Síntesis y evaluación antioxidante para monocarbonil curcuminoides y sus derivados

Introduction: Curcumin is a yellow pigment extracted from the Curcuma longa L, which have a several biological activities and pharmacological properties. Curcuminoids have a wide range as antioxidant not only in a food system, but also for biological systems. Materials and Methods: Acetone, 4-thiomethoxy benzaldehy, pepronal, thiosemicarbazide, 4-phenylthiosemicarbazide and chloroethylacetate. The two Analogous of monocarbonyl curcuminoids (MCCs) have been synthesized by claisen –Schmidt condensation from the reaction between one mole of acetone with two moles of appropriate aromatic aldehydes (4-thiomethoxy benzaldehyde and pepronal) then synthesized their hetero derivatives. The pyrazols derived from the reaction MCCs with hydrazine or one of their derivative (thiosemicarbazide, 4-phenylhydrazine).Results and Discussion:All synthesized compounds were characterized by various spectroscopic techniques such as FTIR, 1HNMR, 13CNMR, Mass spectroscopies and CHN analysis. The antioxidant activity of synthesized MCCs, 1, 2, 1a, 2a, 3, were determined by the ability to scavenge the stable 1,1-diphenyl-2-picryl hydrazyl (DPPH) free radical according to Blois method. The DPPH inhibition activity was measured by spectrophometric method. The polyhydroxy curcuminoid has showed a high activity for scavenging of DPPH radicals, the reason is the hydroxyl phenolic group OH give the compound high activity of scavenging the radical by donating hydrogen atom to the DPPH radicals and inhibition the radical activity by hydrogen atom transfer (HAT). Therefore the scavenge of radical activitywill be in the order: 3>2a>1a>2>1 andthe half maximal inhibitory concentration (IC50) between (17.35-135.2) μmol/L.Conclusions: The proposed struc ture of the synthesized compounds were confirmed by used a spectroscopic technique such as, FTIR, Mass spectra (EI),1H and 13C NMR, The antioxidant activity of curcuminoids were studied by using DPPH as a source of radicals. The higher activity of compounds can be attributed to present the phenolic OH group

Structural Mimicry in Class A G Protein-coupled Receptor Rotamer Toggle Switches

In this study, we tested the hypothesis that a CB1 TMH3-4-5-6 aromatic microdomain, which includes F3.25(190), F3.36(201), W5.43(280), and W6.48(357), is centrally involved in CB1 receptor activation, with the F3.36(201)/W6.48(357) interaction key to the maintenance of the CB1-inactive state. We have shown previously that when F3.36(201), W5.43(280), and W6.48(357) are individually mutated to alanine, a significant reduction in ligand binding affinity is observed in the presence of WIN 55,212-2 and SR141716A but not CP55,940 and anandamide. In the work presented here, we report a detailed functional analysis of the F3.36(201)A, F3.25(190)A, W5.43(280)A, and W6.48(357)A mutant receptors in stable cell lines created in HEK cells for agonist-stimulated guanosine 5′-3-O-(thio)triphosphate (GTPγS) binding and GIRK1/4 channel current effects in Xenopus oocytes where the mutant proteins were expressed transiently. The F3.36(201)A mutation showed statistically significant increases in ligand-independent stimulation of GTPγS binding versus wild type CB1, although basal levels for the W6.48(357)A mutant were not statistically different from wild type CB1. F3.36(201)A demonstrated a limited activation profile in the presence of multiple agonists. In contrast, enhanced agonist activation was produced by W6.48(357)A. These results suggest that a F3.36(201)/W6.48(357)-specific contact is an important constraint for the CB1-inactive state that may need to break during activation. Modeling studies suggest that the F3.36(201)/W6.48(357) contact can exist in the inactive state of CB1 and be broken in the activated state via a χ1 rotamer switch (F3.36(201) trans, W6.48(357) g+) → (F3.36(201) g+, W6.48(357) trans). The F3.36(201)/W6.48(357) interaction therefore may represent a “toggle switch” for activation of CB1

Mechanisms of activation of nucleus accumbens neurons by cocaine via sigma-1 receptor-inositol 1,4,5-trisphosphate-transient receptor potential canonical channel pathways.

Cocaine promotes addictive behavior primarily by blocking the dopamine transporter, thus increasing dopamine transmission in the nucleus accumbens (nAcc); however, additional mechanisms are continually emerging. Sigma-1 receptors (σ1Rs) are known targets for cocaine, yet the mechanisms underlying σ1R-mediated effects of cocaine are incompletely understood. The present study examined direct effects of cocaine on dissociated nAcc neurons expressing phosphatidylinositol-linked D1 receptors. Endoplasmic reticulum-located σ1Rs and inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) were targeted using intracellular microinjection. IP3 microinjection robustly elevated intracellular Ca(2+) concentration, [Ca(2+)]i. While cocaine alone was devoid of an effect, the IP3-induced response was σ1R-dependently enhanced by cocaine co-injection. Likewise, cocaine augmented the [Ca(2+)]i increase elicited by extracellularly applying an IP3-generating molecule (ATP), via σ1Rs. The cocaine-induced enhancement of the IP3/ATP-mediated Ca(2+) elevation occurred at pharmacologically relevant concentrations and was mediated by transient receptor potential canonical channels (TRPC). IP3 microinjection elicited a slight, transient depolarization, further converted to a greatly enhanced, prolonged response, by cocaine co-injection. The cocaine-triggered augmentation was σ1R-dependent, TRPC-mediated and contingent on [Ca(2+)]i elevation. ATP-induced depolarization was similarly enhanced by cocaine. Thus, we identify a novel mechanism by which cocaine promotes activation of D1-expressing nAcc neurons: enhancement of IP3R-mediated responses via σ1R activation at the endoplasmic reticulum, resulting in augmented Ca(2+) release and amplified depolarization due to subsequent stimulation of TRPC. In vivo, intra-accumbal blockade of σ1R or TRPC significantly diminished cocaine-induced hyperlocomotion and locomotor sensitization, endorsing a physio-pathological significance of the pathway identified in vitro

Can intravenous oxytocin infusion counteract hyperinflammation in COVID-19 infected patients?

Objectives Based on its well-documented anti-inflammatory and restorative properties we propose trials with the natural hormone oxytocin for treatment of hospitalised Covid-19 patients. Methods We searched for, retrieved, and commented on specific literature regarding multiple functions of oxytocin with a special focus on its modulation of inflammatory, immune, and restorative functions. Results Available data gathered in animals and humans support the anti-inflammatory properties of oxytocin. The multiple anti-inflammatory effects of oxytocin have been demonstrated in vitro and in vivo in various animal models and also in humans in response to intravenous infusion of oxytocin. Furthermore, oxytocin has been documented to activate several types of protective and restorative mechanisms and to exert positive effects on the immune system. Conclusions In addition, to being anti-inflammatory, it may be hypothesised, that oxytocin may be less suppressive on adaptive immune systems, as compared with glucocorticoids. Finally, by its restorative effects coupled with its anti-stress and healing properties, oxytocin may shorten the recovery period of the Covid-19 patients

Crucial Positively Charged Residues for Ligand Activation of the GPR35 Receptor

GPR35 is a G protein-coupled receptor expressed in the immune, gastrointestinal, and nervous systems in gastric carcinomas and is implicated in heart failure and pain perception. We investigated residues in GPR35 responsible for ligand activation and the receptor structure in the active state. GPR35 contains numerous positively charged amino acids that face into the binding pocket that cluster in two distinct receptor regions, TMH3-4-5-6 and TMH1-2-7. Computer modeling implicated TMH3-4-5-6 for activation by the GPR35 agonists zaprinast and pamoic acid. Mutation results for the TMH1-2-7 region of GPR35 showed no change in ligand efficacies at the K1.32A, R2.65A, R7.33A, and K7.40A mutants. However, mutation of arginine residues in the TMH3-4-5-6 region (R4.60, R6.58, R3.36, R(164), and R(167) in the EC2 loop) had effects on signaling for one or both agonists tested. R4.60A resulted in a total ablation of agonist-induced activation in both the β-arrestin trafficking and ERK1/2 activation assays. R6.58A increased the potency of zaprinast 30-fold in the pERK assay. The R(167)A mutant decreased the potency of pamoic acid in the β-arrestin trafficking assay. The R(164)A and R(164)L mutants decreased potencies of both agonists. Similar trends for R6.58A and R(167)A were observed in calcium responses. Computer modeling showed that the R6.58A mutant has additional interactions with zaprinast. R3.36A did not express on the cell surface but was trapped in the cytoplasm. The lack of surface expression of R3.36A was rescued by a GPR35 antagonist, CID2745687. These results clearly show that R4.60, R(164), R(167), and R6.58 play crucial roles in the agonist initiated activation of GPR35

Thienopyrimidine Derivatives as GPR55 Receptor Antagonists: Insight into Structure-Activity Relationship

GPR55 is an orphan G-protein coupled receptor involved in various pathophysiological conditions. However, there are only a few noncannabinoid GPR55 ligands reported so far. The lack of potent and selective GPR55 ligands precludes a deep exploration of this receptor. The studies presented here focused on a thienopyrimidine scaffold based on the GPR55 antagonist ML192, previously discovered by high-throughput screening. The GPR55 activities of the new synthesized compounds were assessed using β-arrestin recruitment assays in Chinese hamster ovary cells overexpressing human GPR55. Some derivatives were identified as GPR55 antagonists with functional efficacy and selectivity versus CB1 and CB2 cannabinoid receptors.M.E.A., P.H.R., and N.J. are supported by National Institutes of Health grant R01 DA0455698. M.E.A. and P.Z. thank the financial support NIH P30 DA013429. P.M. and N.J. are supported by the Ministry of Science, Innovation, and Universities, Spain (MCIU)/FEDER grant RTI2018-095544-B-I00 and the Spanish National Research Council (CSIC) grant PIE-201580E033. P.M. acknowledges the Comunidad de Madrid (CM) programme “Atraccion de Talento” number 2018-T2/BMD-10819 and “Juan de la Cierva Incorporación Programme-MICIU” (IJC 2019-042182-I

Resveratrol-Mediated Attenuation of Staphylococcus aureus Enterotoxin B-Induced Acute Liver Injury Is Associated With Regulation of microRNA and Induction of Myeloid-Derived Suppressor Cells

Resveratrol (RES) is a polyphenolic compound found abundantly in plant products including red grapes, peanuts, and mulberries. Because of potent anti-inflammatory properties of RES, we investigated whether RES can protect from Staphylococcal enterotoxin B (SEB)-induced acute liver injury in mice. SEB is a potent super antigen that induces robust inflammation and releases inflammatory cytokines that can be fatal. We observed that SEB caused acute liver injury in mice with increases in enzyme aspartate transaminase (AST) levels, and massive infiltration of immune cells into the liver. Treatment with RES (100 mg/kg body weight) attenuated SEB-induced acute liver injury, as indicated by decreased AST levels and cellular infiltration in the liver. Interestingly, RES treatment increased the number of myeloid derived suppressor cells (MDSCs) in the liver. RES treatment led to alterations in the microRNA (miR) profile in liver mononuclear cells (MNCs) of mice exposed to SEB, and pathway analysis indicated these miRs targeted many inflammatory pathways. Of these, we identified miR-185, which was down-regulated by RES, to specifically target Colony Stimulating Factor (CSF1) using transfection studies. Moreover, the levels of CSF1 were significantly increased in RES-treated SEB mice. Because CSF1 is critical in MDSC induction, our studies suggest that RES may induce MDSCs by down-regulating miR-185 leading to increase the expression of CSF1. The data presented demonstrate for the first time that RES can effectively attenuates SEB-induced acute liver injury and that this may result from its action on miRs and induction of MDSCs