Xanthohumol ameliorates atherosclerotic plaque formation, hypercholesterolemia, and hepatic steatosis in ApoE-deficient mice

SCOPE: Xanthohumol (XN), a prenylated antioxidative and anti-inflammatory chalcone from hops, exhibits positive effects on lipid and glucose metabolism. Based on its favorable biological properties, we investigated whether XN attenuates atherosclerosis in western-type diet-fed apolipoprotein-E-deficient (ApoE(-/-) ) mice. METHODS AND RESULTS: XN supplementation markedly reduced plasma cholesterol concentrations, decreased atherosclerotic lesion area, and attenuated plasma concentrations of the proinflammatory cytokine monocyte chemoattractant protein 1. Decreased hepatic triglyceride and cholesterol content, activation of AMP-activated protein kinase, phosphorylation and inactivation of acetyl-CoA carboxylase, and reduced expression levels of mature sterol regulatory element-binding protein (SREBP)-2 and SREBP-1c mRNA indicate reduced lipogenesis in the liver of XN-fed ApoE(-/-) mice. Concomitant induction of hepatic mRNA expression of carnitine palmitoyltransferase-1a in ApoE(-/-) mice-administered XN suggests increased fatty acid beta-oxidation. Fecal cholesterol concentrations were also markedly increased in XN-fed ApoE(-/-) mice compared with mice fed western-type diet alone. CONCLUSION: The atheroprotective effects of XN might be attributed to combined beneficial effects on plasma cholesterol and monocyte chemoattractant protein 1 concentrations and hepatic lipid metabolism via activation of AMP-activated protein kinase.

Cholesteryl ester accumulation and accelerated cholesterol absorption in intestine-specific hormone sensitive lipase-null mice

Hormone sensitive lipase (HSL) regulates the hydrolysis of acylglycerols and cholesteryl esters (CE) in various cells and organs, including enterocytes of the small intestine. The physiological role of this enzyme in enterocytes, however, stayed elusive. In the present study we generated mice lacking HSL exclusively in the small intestine (HSLiKO) to investigate the impact of HSL deficiency on intestinal lipid metabolism and the consequences on whole body lipid homeostasis. Chow diet-fed HSLiKO mice showed unchanged plasma lipid concentrations. In addition, feeding with high fat/high cholesterol (HF/HC) diet led to unaltered triglyceride but increased plasma cholesterol concentrations and CE accumulation in the small intestine. The same effect was observed after an acute cholesterol load. Gavaging of radioactively labeled cholesterol resulted in increased abundance of radioactivity in plasma, liver and small intestine of HSLiKO mice 4h post-gavaging. However, cholesterol absorption determined by the fecal dual-isotope ratio method revealed no significant difference, suggesting that HSLiKO mice take up the same amount of cholesterol but in an accelerated manner. mRNA expression levels of genes involved in intestinal cholesterol transport and esterification were unchanged but we observed downregulation of HMG-CoA reductase and synthase and consequently less intestinal cholesterol biosynthesis. Taken together our study demonstrates that the lack of intestinal HSL leads to CE accumulation in the small intestine, accelerated cholesterol absorption and decreased cholesterol biosynthesis, indicating that HSL plays an important role in intestinal cholesterol homeostasis.

Inducible nitric oxide synthase and the effect of aminoguanidine in experimental neonatal meningitis

This study explored the role of inducible nitric oxide (NO) synthase (iNOS) in an infant rat model of group B streptococcal meningitis. Brain iNOS activity increased during meningitis (P < .001), and iNOS was detected by immunocytochemistry in the walls of meningeal vessels and cells of the cerebrospinal fluid (CSF) inflammation. Animals treated with iNOS inhibitor aminoguanidine (AG; 130 mg/kg every 8 h) had reduced NO production (P < .05), higher CSF bacterial titers (P < .05), and increased incidence of seizures (P < .01) compared with untreated infected animals. AG also increased areas of severe hypoperfusion in the cortex (31% +/- 14% in controls vs. 56% +/- 16% in AG; P < .01) and the extent of cortical neuronal injury, both when administered at the time of infection (P < .05) and in established meningitis (P < .02). Thus, NO produced by iNOS may be beneficial in this model of experimental meningitis by reducing cerebral ischemia.

Improving outcome after stroke: overcoming the translational roadblock

Stroke poses a massive burden of disease, yet we have few effective therapies. The paucity of therapeutic options stands contrary to intensive research efforts. The failure of these past investments demands a thorough re-examination of the pathophysiology of ischaemic brain injury. Several critical areas hold the key to overcoming the translational roadblock: (1) vascular occlusion: current recanalization strategies have limited effectiveness and may have serious side effects; (2) complexity of stroke pathobiology: therapy must acknowledge the 'Janus-faced' nature of many stroke targets and must identify endogenous neuroprotective and repair mechanisms; (3) inflammation and brain-immune-system interaction: inflammation contributes to lesion expansion, but is also instrumental in lesion containment and repair; stroke outcome is modulated by the interaction of the injured brain with the immune system; (4) regeneration: the potential of the brain for reorganization, plasticity and repair after injury is much greater than previously thought; (5) confounding factors, long-term outcome and predictive modelling. These 5 areas are linked on all levels and therefore need to be tackled by an integrative approach and innovative therapeutic strategies.

Estimating Gesture Accuracy in Motion-Based Health Games

This manuscript details a technique for estimating gesture accuracy within the context of motion-based health video games using the MICROSOFT KINECT. We created a physical therapy game that requires players to imitate clinically significant reference gestures. Player performance is represented by the degree of similarity between the performed and reference gestures and is quantified by collecting the Euler angles of the player's gestures, converting them to a three-dimensional vector, and comparing the magnitude between the vectors. Lower difference values represent greater gestural correspondence and therefore greater player performance. A group of thirty-one subjects was tested. Subjects achieved gestural correspondence sufficient to complete the game's objectives while also improving their ability to perform reference gestures accurately.

Electroelasticity of charged black branes

We present the first-order corrected dynamics of fluid branes carrying higher-form charge by obtaining the general form of their equations of motion to pole-dipole order in the absence of external forces. Assuming linear response theory, we characterize the corresponding effective theory of stationary bent charged (an)isotropic fluid branes in terms of two sets of response coefficients, the Young modulus and the piezoelectric moduli. We subsequently find large classes of examples in gravity of this effective theory, by constructing stationary strained charged black brane solutions to first order in a derivative expansion. Using solution generating techniques and bent neutral black branes as a seed solution, we obtain a class of charged black brane geometries carrying smeared Maxwell charge in Einstein-Maxwell-dilaton gravity. In the specific case of ten-dimensional space-time we furthermore use T-duality to generate bent black branes with higher-form charge, including smeared D-branes of type II string theory. By subsequently measuring the bending moment and the electric dipole moment which these geometries acquire due to the strain, we uncover that their form is captured by classical electroelasticity theory. In particular, we find that the Young modulus and the piezoelectric moduli of our strained charged black brane solutions are parameterized by a total of 4 response coefficients, both for the isotropic as well as anisotropic cases.

Null-wave giant gravitons from thermal spinning brane probes

We construct and analyze thermal spinning giant gravitons in type II/M-theory based on spherically wrapped black branes, using the method of thermal probe branes originating from the blackfold approach. These solutions generalize in different directions recent work in which the case of thermal (non-spinning) D3-brane giant gravitons was considered, and reveal a rich phase structure with various new properties. First of all, we extend the construction to M-theory, by constructing thermal giant graviton solutions using spherically wrapped M2- and M5-branes. More importantly, we switch on new quantum numbers, namely internal spins on the sphere, which are not present in the usual extremal limit for which the brane world volume stress tensor is Lorentz invariant. We examine the effect of this new type of excitation and in particular analyze the physical quantities in various regimes, including that of small temperatures as well as low/high spin. As a byproduct we find new stationary dipole-charged black hole solutions in AdS m × S n backgrounds of type II/M-theory. We finally show, via a double scaling extremal limit, that our spinning thermal giant graviton solutions lead to a novel null-wave zero-temperature giant graviton solution with a BPS spectrum, which does not have an analogue in terms of the conventional weakly coupled world volume theory.

How fluids bend: the elastic expansion for higher-dimensional black holes

Hydrodynamics can be consistently formulated on surfaces of arbitrary co-dimension in a background space-time, providing the effective theory describing long-wavelength perturbations of black branes. When the co-dimension is non-zero, the system acquires fluid-elastic properties and constitutes what is called a fluid brane. Applying an effective action approach, the most general form of the free energy quadratic in the extrinsic curvature and extrinsic twist potential of stationary fluid brane configurations is constructed to second order in a derivative expansion. This construction generalizes the Helfrich-Canham bending energy for fluid membranes studied in theoretical biology to the case in which the fluid is rotating. It is found that stationary fluid brane configurations are characterized by a set of 3 elastic response coefficients, 3 hydrodynamic response coefficients and 1 spin response coefficient for co-dimension greater than one. Moreover, the elastic degrees of freedom present in the system are coupled to the hydrodynamic degrees of freedom. For co-dimension-1 surfaces we find a 8 independent parameter family of stationary fluid branes. It is further shown that elastic and spin corrections to (non)-extremal brane effective actions can be accounted for by a multipole expansion of the stress-energy tensor, therefore establishing a relation between the different formalisms of Carter, Capovilla-Guven and Vasilic-Vojinovic and between gravity and the effective description of stationary fluid branes. Finally, it is shown that the Young modulus found in the literature for black branes falls into the class predicted by this approach - a relation which is then used to make a proposal for the second order effective action of stationary blackfolds and to find the corrected horizon angular velocity of thin black rings.