Human and animal studies have converged to suggest that caffeine consumption prevents memory deficits in aging and Alzheimer's disease through the antagonism of adenosine A2A receptors (A2ARs). To ...test if A2AR activation in the hippocampus is actually sufficient to impair memory function and to begin elucidating the intracellular pathways operated by A2AR, we have developed a chimeric rhodopsin-A2AR protein (optoA2AR), which retains the extracellular and transmembrane domains of rhodopsin (conferring light responsiveness and eliminating adenosine-binding pockets) fused to the intracellular loop of A2AR to confer specific A2AR signaling. The specificity of the optoA2AR signaling was confirmed by light-induced selective enhancement of cAMP and phospho-mitogen-activated protein kinase (p-MAPK) (but not cGMP) levels in human embryonic kidney 293 (HEK293) cells, which was abolished by a point mutation at the C terminal of A2AR. Supporting its physiological relevance, optoA2AR activation and the A2AR agonist CGS21680 produced similar activation of cAMP and p-MAPK signaling in HEK293 cells, of p-MAPK in the nucleus accumbens and of c-Fos/phosphorylated-CREB (p-CREB) in the hippocampus, and similarly enhanced long-term potentiation in the hippocampus. Remarkably, optoA2AR activation triggered a preferential p-CREB signaling in the hippocampus and impaired spatial memory performance, while optoA2AR activation in the nucleus accumbens triggered MAPK signaling and modulated locomotor activity. This shows that the recruitment of intracellular A2AR signaling in the hippocampus is sufficient to trigger memory dysfunction. Furthermore, the demonstration that the biased A2AR signaling and functions depend on intracellular A2AR loops prompts the possibility of targeting the intracellular A2AR-interacting partners to selectively control different neuropsychiatric behaviors.
Porous robust materials are typically the primary selection of several industrial processes. Many of these compounds are, however, not robust enough to be used as multifunctional materials. This is ...typically the case of Metal–Organic Frameworks (MOFs) which rarely combine several different excellent functionalities into the same material. In this report we describe the simple acid–base postsynthetic modification of isotypical porous rare-earth-phosphonate MOFs into a truly multifunctional system, maintaining the original porosity features: Ln(H3pptd)·xSolvent where Ln3+ = Y3+ (1) and (Y0.95Eu0.05)3+ (1_Eu) are converted into K3Ln(pptd)·zSolvent where Ln3+ = Y3+ (1K) and (Y0.95Eu0.05)3+ (1K_Eu) by immersing the powder of 1 and 1_Eu into an ethanolic solution of KOH for 48 h. The K+-exchanged Eu3+-based material exhibits a considerable boost in CO2 adsorption, capable of being reused for several consecutive cycles. It can further separate C2H2 from CO2 from a complex ternary gas mixture composed of CH4, CO2, and C2H2. This high adsorption selectivity is, additionally, observed for other gaseous mixtures, such as C3H6 and C3H8, with all these results being supported by detailed theoretical calculations. The incorporation of K+ ions notably increases the electrical conductivity by 4 orders of magnitude in high relative humidity conditions. The conductivity is assumed to be predominantly protonic in nature, rendering this material as one of the best conducting MOFs reported to date.
We present here a numerical study of the distribution of the local stress state associated with deformation twinning in Mg, both inside the twinned domain and in its immediate neighborhood, due to ...the accommodation of the twinning transformation shear. A full-field elastoviscoplastic formulation based on fast Fourier transformation is modified to include the shear transformation strain associated with deformation twinning. We have performed two types of twinning transformation simulations with: (i) the twin completely embedded inside a single crystal and (ii) the twin front terminating at a grain boundary. We show that: (a) the resulting stress distribution is more strongly determined by the shear transformation than by the intragranular character of the twin or the orientation of the neighboring grain; (b) the resolved shear stress on the twin plane along the twin direction is inhomogeneous along the twin-parent interface; and (c) there are substantial differences in the average values of the shear stress in the twin and in the parent grain that contains the twin. We discuss the effect of these local stresses on twin propagation and growth, and the implications of our findings for the modeling of deformation twinning.
A spatially-resolved crystal plasticity Fast Fourier Transform (FFT)-based model is employed to study the effect of alloying addition on twin thickening and twin transmission in hexagonal close ...packed (HCP) magnesium. In the simulations, the influence of alloying additions is represented through the differences in the critical resolved shear stress (CRSS) of different slip and twinning modes. The results show that for the same grain orientation, twin type and boundary conditions, anisotropy in the CRSS values have a significant effect on twin thickening and twin transmission. Those with large differences in CRSS favor both twin thickening and twin transmission, and vice versa for those with small differences. However, less difference among the CRSS values enhances the dependence of thickening and transmission on the neighboring grain orientation.
Previous studies have reported on the glucose and lipid-lowering effects of ferulic acid (FA) but its anti-obesity potential has not yet been firmly established. This study investigated the possible ...anti-obesitogenic effects of FA in mice fed a high-fat diet (HFD) for 15 weeks. To assess the antiobesity potential of FA, 32 male Swiss mice, weighing 20-25 g (n=6-8 per group) were fed a normal diet (ND) or HFD, treated orally or not with either FA (10 mg/kg) or sibutramine (10 mg/kg) for 15 weeks and at the end of this period, the body weights of animals, visceral fat accumulation, plasma levels of glucose and insulin hormone, amylase and lipase activities, the satiety hormones ghrelin and leptin, and tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCH-1) were analyzed. Results revealed that FA could effectively suppress the HFD-associated increase in visceral fat accumulation, adipocyte size and body weight gain, similar to sibutramine, the positive control. FA also significantly (P<0.05) decreased the HFD-induced elevations in serum lipid profiles, amylase and lipase activities, and the levels of blood glucose and insulin hormone. The markedly elevated leptin and decreased ghrelin levels seen in HFD-fed control mice were significantly (P<0.05) reversed by FA treatment, almost reaching the values seen in ND-fed mice. Furthermore, FA demonstrated significant (P<0.05) inhibition of serum levels of inflammatory mediators TNF-α, and MCH-1. These results suggest that FA could be beneficial in lowering the risk of HFD-induced obesity via modulation of enzymatic, hormonal and inflammatory responses.
Objectives The aims of this study were to test the essential oil from Lippia sidoides Cham. for antifungal activity, in vitro, against Candida spp. and Microsporum canis, to evaluate its acute and ...subchronic toxicological effects, in vivo, and to determine its chemical constituents. Methods The antifungal activity, in vitro, was initially evaluated by the agar-well diffusion technique, and the MIC and minimum fungicidal concentration (MFC) were determined by the broth microdilution method. The acute and subchronic toxicological effects were determined in mice and rats, respectively. The chemical composition of the essential oil was determined by gas chromatography coupled to mass spectroscopy. Results The essential oil obtained from L. sidoides was effective against all tested strains by the agar-well diffusion method. The MICs of L. sidoides essential oil for strains of M. canis ranged from 4 to 70 mg/L and the MFCs ranged from 9 to 150 mg/L. The MICs for strains of Candida spp. ranged from 620 to 2500 mg/L and the MFCs ranged from 1250 to 5000 mg/L. The main constituents of L. sidoides essential oil were thymol (59.65%), E-caryophyllene (10.60%) and p-cymene (9.08%). The acute administration of the essential oil up to 3 g/kg by the oral route to mice was devoid of overt toxicity. The 30 day oral administration of L. sidoides oil (117.95 mg/kg/day) to rats did not induce any significant histopathological, haematological or serum biochemical alterations. Conclusions The essential oil from L. sidoides may be a promising source in the search for new antifungal drugs due to its efficacy and low toxicity.
Consumption of certain substances during pregnancy can interfere with brain development, leading to deleterious long-term neurological and cognitive impairments in offspring. To test whether ...modulators of adenosine receptors affect neural development, we exposed mouse dams to a subtype-selective adenosine type 2A receptor (A2AR) antagonist or to caffeine, a naturally occurring adenosine receptor antagonist, during pregnancy and lactation. We observed delayed migration and insertion of γ-aminobutyric acid (GABA) neurons into the hippocampal circuitry during the first postnatal week in offspring of dams treated with the A2AR antagonist or caffeine. This was associated with increased neuronal network excitability and increased susceptibility to seizures in response to a seizure-inducing agent. Adult offspring of mouse dams exposed to A2AR antagonists during pregnancy and lactation displayed loss of hippocampal GABA neurons and some cognitive deficits. These results demonstrate that exposure to A2AR antagonists including caffeine during pregnancy and lactation in rodents may have adverse effects on the neural development of their offspring.
In this work, the evolution of internal lattice strains in face-centered cubic stainless steel under uniaxial tension is studied using a recently developed full-field elasto-viscoplastic formulation ...based on fast Fourier transforms. The shape of the diffraction peaks is simulated, and the predicted lattice strains (peak shift and broadening) are compared with the experimental measurements obtained by in situ tensile neutron diffraction. Detailed analysis of the lattice strain distributions reveal that {100} and {110} transverse families exhibit a bimodal nature, and that transverse lattice strains are more sensitive to local grain interactions compared with longitudinal lattice strains. A comparison with the results of a mean-field formulation indicates that type III (intragranular) stresses play a much larger role than type II (intergranular) stresses in diffraction peak broadening.
Caryocar coriaceum Wittm. fruit pulp fixed oil (CCFO) has been widely employed by communities from Brazil Northeastern in the treatment of skin inflammation, respiratory affections, wound healing and ...muscle pain. In this study, we evaluated the topical effect of CCFO against different irritant agents
in vivo, in order to verify its antiedematous effect as well to unravel its tentative mechanisms of action.
CCFO was obtained from
Caryocar coriaceum fruits using ethyl acetate as solvent. Ear edema provoked by the application of Croton oil (single and multiple applications), arachidonic acid (AA), capsaicin, phenol and histamine to Swiss mice was used to evaluate the topical anti-inflammatory effect of CCFO. Histological analysis from mice ears sensitized with Croton oil and AA single application was also performed.
Crude CCFO (20
μL/ear) demonstrated significant topical antiedematous effect against Croton oil single (inhibition of 32.0%;
P
<
0.05) and multiple (41.4% after 9 days,
P
<
0.001) applications, AA (inhibition of 49.7%;
P
<
0.01) and phenol (inhibition of 38.8%;
P
<
0.001). In contrast, CCFO did not antagonize the edema caused by topical treatment with capsaicin and histamine when compared to control group (
P
>
0.05). Histological analysis also revealed that CCFO was able to reduce the edema and the influx of inflammatory cells in mice ears sensitized with Croton oil and AA.
CCFO exhibited a similar profile of topical anti-inflammatory activity to that of drugs that classically modulate the production of arachidonic acid metabolites. The study also indicates the potential application of CCFO as an important herbal medicine to be used against skin inflammatory diseases.
Malaria is a parasitic infection responsible for high morbidity and mortality rates worldwide. During the disease, phagocytosis of infected red blood cells by the macrophages induces the production ...of reactive oxygen (ROS) and nitrogen species (RNS), culminating in parasite death. Curcumin (CUR) is a bioactive compound that has been demonstrated to reduce the production of pro-inflammatory cytokines and chemokines produced by macrophages but to reduce parasitemia in infected mice. Hence, the main purpose of this study is to investigate whether curcumin may interfere with macrophage function and polarization after Plasmodium berghei infection in vitro. In our findings, non-polarized macrophage (M0), classically activated (M1), and alternatively activated (M2) phenotypes showed significantly increased phagocytosis of infected red blood cells (iRBCs) when compared to phagocytosis of uninfected red blood cells (RBCs) 3 h after infection. After 24 h, M1 macrophages exposed to RBCs + CUR showed greater elimination capacity when compared to macrophages exposed to iRBCs + CUR, suggesting the interference of curcumin with the microbicidal activity. Additionally, curcumin increased the phagocytic activity of macrophages when used in non-inflammatory conditions (M0) and reduced the inducible nitric oxide synthase (iNOS) and arginase activities in all macrophage phenotypes infected (M0, M1, and M2), suggesting interference in arginine availability by curcumin and balance promotion in macrophage polarization in neutral phenotype (M0). These results support the view of curcumin treatment in malaria as an adjuvant, promoting a balance between pro- and anti-inflammatory responses for a better clinical outcome.
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