SUMMARY Dysregulation of circadian rhythms is associated with metabolic dysfunction, yet it is unclear whether enhancing clock function can ameliorate metabolic disorders. In an unbiased chemical screen using fibroblasts expressing PER2::Luc, we identified Nobiletin (NOB), a natural polymethoxylated flavone, as a Clock amplitude-Enhancing small Molecule (CEM). When administered to diet-induced obese (DIO) mice, NOB strongly counteracted metabolic syndrome and augmented energy expenditure and locomotor activity in a Clock gene-dependent manner. In db/db mutant mice, the clock is also required for the mitigating effects of NOB on metabolic disorders. In DIO mouse liver, NOB enhanced clock protein levels and elicited pronounced gene expression remodeling. We identified retinoid acid receptor-related orphan receptors (RORs) as direct targets of NOB, revealing a pharmacological intervention that enhances circadian rhythms to combat metabolic disease via the circadian gene network.
Nanorods as one-dimensional nanostructured materials have attracted much attention due to their peculiar properties, which originate from their high surface area and low dimensionality. [1,2] Recently, much effort has been devoted to the synthesis of various nanorods, including metals, [3,4] oxides, [5±8] and chalcogenides. [9] Among them, metal-oxide nanorods have been shown to possess many interesting properties that make them useful for a wide range of applications such as catalysts, [8,10] electrochromic devices, [11] magnetic storages, [12] lasers, and sensors. [13] Many solution-based syntheses of nanorods have utilized a thermal decomposition reaction of delicate and costly organometallic precursors in mixed surfactants. [3,9] A template-directed synthesis has been studied as an alternative route. [8,14] However, it may contaminate the nanorods by the successive removal process of the template materials. Here, we report a novel and easy route to Fe 2 O 3 nanorods by a sol-gel-mediated reaction of ubiquitous Fe 3+ ions in reverse micelles. A plausible mechanism is proposed for the formation of these nanorods, and it is expected that this synthetic technique can be extended to obtain other metal oxides.The reaction was carried out utilizing a sol±gel reaction inside reverse micelles and followed by crystallization by reflux. This sol±gel reaction, which we utilized here, was first reported by A. E. Gash et al.[ gel in a container. Instead of producing a container-sized monolithic gel, we prepared a countless number of monolithic gel particles inside reverse micelles using the reported sol±gel reaction and water-in-oil type microemulsion stabilized by an oleic acid surfactant. Scheme 1 represents the transformations of materials in a reverse micelle. First, we prepared Fe 2 O 3 monolithic gel particles with a narrow size distribution. This was possible by slow gelation initiated by a proton scavenger inside the reverse micelles. Each reverse micelle acts as a microreactor, which produced a monolithic gel particle in itself. Next, the gel particles were washed with a polar solvent to remove chloride impurities and excess surfactants and then air-dried. Now, each gel particle is composed of a porous network of amorphous Fe 2 O 3 (confirmed by X-ray diffraction (XRD) pattern) and its surface is roughly coated with surfactants. At this stage, scanning electron microscopy (SEM) images of gel particles showed shapeless aggregates and could not give any meaningful information. Then, the gel powder was treated in a highboiling-point solvent with reducing properties while controlling the temperature and the atmosphere, inducing crystallization [16] with a controlled phase depending on the conditions. During crystallization, the partially crystallized monolithic gel particles seem to fuse together in an end-to-end manner and grow into a nanorod. At the same time, a decrease of the particle size by crystallization seems to occur. Figure 1 shows the representative FTIR spectra of Fe 2 O 3 gels and a-Fe 2 O 3 (hematite...
The circadian clock coordinates daily oscillations of essential physiological and behavioral processes. Conversely, aberrant clocks with damped amplitude and/or abnormal period have been associated with chronic diseases and aging. To search for small molecules that perturb or enhance circadian rhythms, we conducted a high-throughput screen of approximately 200,000 synthetic compounds using Per2∷lucSV reporter fibroblast cells and validated 11 independent classes of molecules with Bmal1:luciferase reporter cells as well as with suprachiasmatic nucleus and peripheral tissue explants. Four compounds were found to lengthen the period in both central and peripheral clocks, including three compounds that inhibited casein kinase I ε in vitro and a unique benzodiazepine derivative acting through a non-GABA A receptor target. In addition, two compounds acutely induced Per2∷lucSV reporter bioluminescence, delayed the rhythm, and increased intracellular cAMP levels, but caused rhythm damping. Importantly, five compounds shortened the period of peripheral clocks; among them, four compounds also enhanced the amplitude of central and/or peripheral reporter rhythms. Taken together, these studies highlight diverse activities of drug-like small molecules in manipulating the central and peripheral clocks. These small molecules constitute a toolbox for probing clock regulatory mechanisms and may provide putative lead compounds for treatment of clock-associated diseases.
Liu & Orfila (J. Fluid Mech. vol. 520, 2004, p. 83) derived analytical solutions for viscous boundary layer flows under transient long waves. Their analytical solutions were obtained with the assumption that the nonlinear inertia force was negligible in the momentum equations. In this paper, using Liu & Orfila's solution and the solutions for the nonlinear boundary layer equations, we examine the boundary layer flow characteristics under a solitary wave. It is found that while the horizontal component of the free-stream velocity outside the boundary layer always moves in the direction of wave propagation, the fluid particle velocity near the bottom inside the boundary layer reverses direction as the wave decelerates. Consequently, the bed shear stress also changes sign during the deceleration phase. Laboratory measurements, including the free-surface displacement, particle image velocimetry (PIV) resolved velocity fields of the viscous boundary layer, and the calculated bed shear stress were also collected to check the theoretical results. Excellent agreement is observed.
MUC1 is a membrane-tethered mucin glycoprotein expressed on the apical surface of mucosal epithelial cells. Previous in vivo and in vitro studies established that MUC1 counter-regulates airway inflammation by suppressing TLR signaling. In this report, we elucidate the mechanism by which MUC1 inhibits TLR5 signaling. Overexpression of MUC1 in human embryonic kidney HEK293 (293) cells dramatically reduced Pseudomonas aeruginosa (Pa)-stimulated IL-8 expression, and decreased the activation of NF-κB and MAPK compared with MUC1 non-expressing cells. Overexpression of MUC1 in 293 cells, however, did not affect NF-κB or MAKP activation in response to TNF-α. Overexpression of MyD88 abrogated the ability of MUC1 to inhibit NF-κB activation, and MUC1 overexpression inhibited flagellin-induced association of TLR5/MyD88, compared with controls. The MUC1 cytoplasmic tail (MUC1 CT) associated with TLR5 in all cells tested, including 293T cells, human lung adenocarcinoma cell line A549 cells, and human and mouse primary airway epithelial cells. Activation of EGFR tyrosine kinase with TGF-α induced phosphorylation of the MUC1 CT at the Y46 EKV sequence and increased association of MUC1/TLR5. Finally, in vivo experiments demonstrated increased immunofluorescence co-localization of Muc1/TLR5 and Muc1/phosphotyrosine staining patterns in mouse airway epithelium and increased Muc1 tyrosine phosphorylation in mouse lung homogenates following Pa infection. In conclusion, EGFR tyrosine phosphorylates MUC1, leading to an increase in its association with TLR5, thereby competitively and reversibly inhibiting recruitment of MyD88 to TLR5 and downstream signaling events. This unique ability of MUC1 to control TLR5 signaling suggests its potential role in the pathogenesis of chronic inflammatory lung diseases.
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