Neurogenesis, a process of generation of new neurons, is reported to be reduced in several neurodegenerative disorders including Alzheimer's disease (AD). Induction of neurogenesis by targeting endogenous neural stem cells (NSC) could be a promising therapeutic approach to such diseases by influencing the brain self-regenerative capacity. Curcumin, a neuroprotective agent, has poor brain bioavailability. Herein, we report that curcumin-encapsulated PLGA nanoparticles (Cur-PLGA-NPs) potently induce NSC proliferation and neuronal differentiation in vitro and in the hippocampus and subventricular zone of adult rats, as compared to uncoated bulk curcumin. Cur-PLGA-NPs induce neurogenesis by internalization into the hippocampal NSC. Cur-PLGA-NPs significantly increase expression of genes involved in cell proliferation (reelin, nestin, and Pax6) and neuronal differentiation (neurogenin, neuroD1, neuregulin, neuroligin, and Stat3). Curcumin nanoparticles increase neuronal differentiation by activating the Wnt/β-catenin pathway, involved in regulation of neurogenesis. These nanoparticles caused enhanced nuclear translocation of β-catenin, decreased GSK-3β levels, and increased promoter activity of the TCF/LEF and cyclin-D1. Pharmacological and siRNA-mediated genetic inhibition of the Wnt pathway blocked neurogenesis-stimulating effects of curcumin. These nanoparticles reverse learning and memory impairments in an amyloid beta induced rat model of AD-like phenotypes, by inducing neurogenesis. In silico molecular docking studies suggest that curcumin interacts with Wif-1, Dkk, and GSK-3β. These results suggest that curcumin nanoparticles induce adult neurogenesis through activation of the canonical Wnt/β-catenin pathway and may offer a therapeutic approach to treating neurodegenerative diseases such as AD, by enhancing a brain self-repair mechanism.

We study the rheology of granular mixtures in a steady, fully developed, gravity-driven flow on an inclined plane, by means of discrete element method (DEM) simulations. Results are presented for a single component system and binary mixtures with particles of different size and density. Inclination angles, composition, size ratios and density ratios are varied to obtain different segregated configurations at equilibrium. Steady state profiles of the mean velocity, volume fractions, shear stress, shear rate, inertial number and apparent viscosity across the depth of the flowing layer are reported for the different cases. The viscosity varies with height and is found to depend on the local bulk density and composition, which, in turn, depend on the size ratio, the mass ratio and the degree of segregation. For a single component system, a viscoplastic rheological model [P. Jop et al., Nature 441, 727 (2006)] describes the data quite well. We propose a modification of the model for the case of mixtures. The mixture model predicts the viscosity for both well-mixed and segregated granular mixtures differing in size, density or both, using the same model parameters as obtained for the single component system. The predictions of a model for the volume fraction of the mixtures also agree well with simulation results.

We consider the segregation of spheres of equal size and different density flowing over an inclined plane, theoretically and computationally by means of distinct element method (DEM) simulations. In the first part of the work, we study the settling of a single higher-density particle in the flow of otherwise identical particles. We show that the motion of the high-density tracer particle can be understood in terms of the buoyancy and drag forces acting on it. The buoyancy force is given by Archimedes principle, with an effective volume associated with the particle, which depends upon the local packing fraction, $\phi $. The buoyancy arises primarily from normal forces acting on the particle, and tangential forces have a negligible contribution. The drag force on a sphere of diameter $d$ sinking with a velocity $v$ in a granular medium of apparent viscosity $\eta $ is given by a modified Stokes law, ${F}_{d} = c\pi \eta dv$. The coefficient ($c$) is found to decrease with packing fraction. In the second part of the work, we consider the case of binary granular mixtures of particles of the same size but differing in density. A continuum model for segregation is presented, based on the single-particle results. The number fraction profile for the heavy particles at equilibrium is obtained in terms of the effective temperature, defined by a fluctuation–dissipation relation. The model predicts the equilibrium number fraction profiles at different inclination angles and for different mass ratios of the particles, which match the DEM results very well. Finally, a complete model for the theoretical prediction of the flow and number fraction profiles for a mixture of particles of different density is presented, which combines the segregation model with a model for the rheology of mixtures. The model predictions agree quite well with the simulation results.

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Acute inflammation is a protective reaction by the immune system in response to invading pathogens or tissue damage. Ideally, the response should be localized, self-limited, and returning to homeostasis. If not resolved, acute inflammation can result in organ pathologies leading to chronic inflammatory phenotypes. Acute inflammation and inflammation resolution are complex coordinated processes, involving a number of cell types, interacting in space and time. The biomolecular complexity and the fact that several biomedical fields are involved, make a multi- and interdisciplinary approach necessary. The Atlas of Inflammation Resolution (AIR) is a web-based resource capturing an essential part of the state-of-the-art in acute inflammation and inflammation resolution research. The AIR provides an interface for users to search thousands of interactions, arranged in inter-connected multi-layers of process diagrams, covering a wide range of clinically relevant phenotypes. By mapping experimental data onto the AIR, it can be used to elucidate drug action as well as molecular mechanisms underlying different disease phenotypes. For the visualization and exploration of information, the AIR uses the Minerva platform, which is a well-established tool for the presentation of disease maps. The molecular details of the AIR are encoded using international standards. The AIR was created as a freely accessible resource, supporting research and education in the fields of acute inflammation and inflammation resolution. The AIR connects research communities, facilitates clinical decision making, and supports research scientists in the formulation and validation of hypotheses. The AIR is accessible through https://air.bio.informatik.uni-rostock.de

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Zinc oxide nanoparticles (ZNPs) have been used in dietary supplements and may cause an immunomodulatory effect. The present study investigated the effect of ZNPs on antigen-specific immune responses in mice sensitized with the T-cell-dependent antigen ovalbumin (OVA). BALB/c mice were intraperitoneally administered ZNPs (0.25, 0.5, 1 and 3mg) once, in combination with OVA, and the serum antibodies, splenocyte reactivity and activation of antigen-presenting cells were examined. The serum levels of OVA-specific IgG1 and IgE were found significantly enhanced by treatment with ZNPs over control. An increased level of IL-2, IL-4, IL-6, IL-17 and decreased level of IL-10 and TNF-α in splenocytes administered with ZNPs were observed in comparison with control. The ZNPs and OVA-stimulated T lymphocytes showed enhanced proliferation compared with control. Macrophages and B cells showed high expression of MHC class II, whereas higher expression of CD11b in macrophages of the ZNPs and ZNPs/OVA treated groups was observed. The lungs and spleen had increased eosinophils and mast cell numbers. Also, myeloperoxidase activity in lungs was found to be increased by 2.5-fold in the case of ZNPs and 3.75-fold increase in ZNPs/OVA, whereas in intestine, there was significant increase in both the groups. Increased expression of the genes for GATA-3, SOCS-3, TLR-4, IL-13 and IL-5 in the intestine was observed. Collectively, these data indicate that systemic exposure to a single administration of ZNPs could enhance subsequent antigen-specific immune reactions, including the serum production of antigen-specific antibodies, and the functionality of T cells.