Direct adipotropic actions of atorvastatin: differentiation state-dependent induction of apoptosis, modulation of endocrine function, and inhibition of glucose uptake

Statins exert anti-inflammatory, anti-atherogenic actions. The mechanisms responsible for these effects remain only partially elucidated. Diabetes and obesity are characterized by low-grade inflammation. Metabolic and endocrine adipocyte dysfunction is known to play a crucial role in the development of these disorders and the related cardiovascular complications. Thus, direct modulation of adipocyte function may represent a mechanism of pleiotropic statin actions. We investigated effects of atorvastatin on apoptosis, differentiation, endocrine, and metabolic functions in murine white and brown adipocyte lines. Direct exposure of differentiating preadipocytes to atorvastatin strongly reduced lipid accumulation and diminished protein expression of the differentiation marker CCAAT/enhancer binding protein-beta (CEBP-beta). In fully differentiated adipocytes, however, lipid accumulation remained unchanged after chronic atorvastatin treatment. Furthermore, cell viability was reduced in response to atorvastatin treatment in proliferating and differentiating preadipocytes, but not in differentiated cells. Moreover, atorvastatin induced apoptosis and inhibited protein kinase B (AKT) phosphorylation in proliferating and differentiating preadipocytes, but not in differentiated adipocytes. On the endocrine level, direct atorvastatin treatment of differentiated white adipocytes enhanced expression of the pro-inflammatory adipokine interleukin-6 (IL-6), and downregulated expression of the insulin-mimetic and anti-inflammatory adipokines visfatin and adiponectin. Finally, these direct adipotropic endocrine effects of atorvastatin were paralleled by the acute inhibition of insulin-induced glucose uptake in differentiated white adipocytes, while protein expression of the thermogenic uncoupling protein-1 (UCP-1) in brown adipocytes remained unchanged. Taken together, our data for the first time demonstrate direct differentiation state-dependent effects of atorvastatin including apoptosis, modulation of pro-inflammatory and glucostatic adipokine expression, and insulin resistance in adipose cells. These differential interactions may explain variable clinical observations.

Frequency-domain source localization shows state-dependent diazepam effects in 47-channel EEG

The topic of this study was to evaluate state-dependent effects of diazepam on the frequency characteristics of 47-channel spontaneous EEG maps. A novel method, the FFT-Dipole-Approximation (Lehmann and Michel, 1990), was used to study effects on the strength and the topography of the maps in the different frequency bands. Map topography was characterized by the 3-dimensional location of the equivalent dipole source and map strength was defined as the spatial standard deviation (the Global Field Power) of the maps of each frequency point. The Global Field Power can be considered as a measure of the amount of energy produced by the system, while the source location gives an estimate of the center of gravity of all sources in the brain that were active at a certain frequency. State-dependency was studied by evaluating the drug effects before and after a continuous performance task of 25 min duration. Clear interactions between drug (diazepam vs. placebo) and time after drug intake (before and after the task) were found, especially in the inferior-superior location of the dipole sources. It supports the hypothesis that diazepam, like other drugs, has different effects on brain functions depending on the momentary functional state of the brain. In addition to the drug effects, clearly different source locations and Global Field Power were found for the different frequency bands, replicating earlier reports (Michel et al., 1992).

Glucocorticoids have state-dependent stimulant effects on the mesencephalic dopaminergic transmission.

An increase in the activity of mesencephalic dopaminergic neurons has been implicated in the appearance of pathological behaviors such as psychosis and drug abuse. Several observations suggest that glucocorticoids might contribute to such an increase in dopaminergic activity. The present experiments therefore analyzed the effects of corticosterone, the major glucocorticoid in the rat, both on dopamine release in the nucleus accumbens of freely moving animals by means of microdialysis, and on locomotor activity, a behavior dependent on accumbens dopamine. Given that glucocorticoids have certain state-dependent neuronal effects, their action on dopamine was studied in situations differing in dopaminergic tonus, including during the light and dark phases of the circadian cycle, during eating, and in groups of animals differing in their locomotor reactivity to novelty. Dopaminergic activity is increased in the dark period, further increased during food-intake, and is higher in rats defined as high responders to novelty than in low responders. Corticosterone, peripherally administered in a dose that approximates stress-induced plasma concentrations, increased extracellular concentrations of dopamine, and this increase was augmented in the dark phase, during eating, and in high responder rats. Corticosterone had little or no effects in the light phase and in low responder rats. Corticosterone also stimulated locomotor activity, an effect that paralleled the release of dopamine and was abolished by neurochemical (6-hydroxydopamine) depletion of accumbens dopamine. In conclusion, glucocorticoids have state-dependent stimulant effects on mesencephalic dopaminergic transmission, and an interaction between these two factors might be involved in the appearance of behavioral disturbances.

State-dependent microstructural white matter changes in bipolar I depression

Abnormalities in fronto-limbic-striatal white matter (WM) have been reported in bipolar disorder (BD), but results have been inconsistent across studies. Furthermore, there have been no detailed investigations as to whether acute mood states contribute to microstructural changes in WM tracts. In order to compare fiber density and structural integrity within WM tracts between BD depression and remission, whole-brain fractional anisotropy (FA) and mean diffusivity (MD) were assessed in 37 bipolar I disorder (BD-I) patients (16 depressed and 21 remitted), and 26 healthy individuals with diffusion tensor imaging. Significantly decreased FA and increased MD in bilateral prefronto-limbic-striatal white matter and right inferior fronto-occipital, superior and inferior longitudinal fasciculi were shown in all BD-I patients versus controls, as well as in depressed BD-I patients compared to both controls and remitted BD-I patients. Depressed BD-I patients also exhibited increased FA in the ventromedial prefrontal cortex. Remitted BD-I patients did not differ from controls in FA or MD. These findings suggest that BD-I depression may be associated with acute microstructural WM changes.

The Maximal Number of Particles in a Branching Process with State-Dependent Immigration

AMS subject classification: 60J80, 60J15.

Statements on chaos control designs, including a fractional order dynamical system, applied to a MEMS comb-drive actuator

In this work, we deal with a micro electromechanical system (MEMS), represented by a micro-accelerometer. Through numerical simulations, it was found that for certain parameters, the system has a chaotic behavior. The chaotic behaviors in a fractional order are also studied numerically, by historical time and phase portraits, and the results are validated by the existence of positive maximal Lyapunov exponent. Three control strategies are used for controlling the trajectory of the system: State Dependent Riccati Equation (SDRE) Control, Optimal Linear Feedback Control, and Fuzzy Sliding Mode Control. The controls proved effective in controlling the trajectory of the system studied and robust in the presence of parametric errors.

The rigid-flexible nonlinear robotic manipulator: Modeling and control

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

On a control design to an AFM microcantilever beam, operating in a tapping-mode, with irregular behavior

In last decades, control of nonlinear dynamic systems became an important and interesting problem studied by many authors, what results the appearance of lots of works about this subject in the scientific literature. In this paper, an Atomic Force Microscope micro cantilever operating in tapping mode was modeled, and its behavior was studied using bifurcation diagrams, phase portraits, time history, Poincare maps and Lyapunov exponents. Chaos was detected in an interval of time; those phenomena undermine the achievement of accurate images by the sample surface. In the mathematical model, periodic and chaotic motion was obtained by changing parameters. To control the chaotic behavior of the system were implemented two control techniques. The SDRE control (State Dependent Riccati Equation) and Time-delayed feedback control. Simulation results show the feasibility of the bothmethods, for chaos control of an AFM system. Copyright © 2011 by ASME.

Chaos suppression in NEMs resonators by using nonlinear control design

In this work the chaotic behavior of a micro-mechanical resonator with electrostatic forces on both sides is suppressed. The aim is to control the system in an orbit of the analytical solution obtained by the Method of Multiple Scales. Two control strategies are used for controlling the trajectory of the system, namely: State Dependent Riccati Equation (SDRE) Control and Optimal Linear Feedback Control (OLFC). The controls proved effectiveness in controlling the trajectory of the system. Additionally, the robustness of each strategy is tested considering the presence of parametric errors and measurement noise in control. © 2012 American Institute of Physics.

On the Chaotic Suppression of Both Ideal and Non-ideal Duffing Based Vibrating Systems, Using a Magnetorheological Damper

In this paper the dynamics of the ideal and non-ideal Duffing oscillator with chaotic behavior is considered. In order to suppress the chaotic behavior and to control the system, a control signal is introduced in the system dynamics. The control strategy involves the application of two control signals, a nonlinear feedforward control to maintain the controlled system in a periodic orbit, obtained by the harmonic balance method, and a state feedback control, obtained by the state dependent Riccati equation, to bring the system trajectory into the desired periodic orbit. Additionally, the control strategy includes an active magnetorheological damper to actuate on the system. The control force of the damper is a function of the electric current applied in the coil of the damper, that is based on the force given by the controller and on the velocity of the damper piston displacement. Numerical simulations demonstrate the effectiveness of the control strategy in leading the system from any initial condition to a desired orbit, and considering the mathematical model of the damper (MR), it was possible to control the force of the shock absorber (MR), by controlling the applied electric current in the coils of the damper. © 2012 Foundation for Scientific Research and Technological Innovation.

On elimination of chaotic behavior in a non-ideal portal frame structural system, using both passive and active controls

In this paper, an application is considered of both active and passive controls, to suppression of chaotic behavior of a simple portal frame, under the excitation of an unbalanced DC motor, with limited power supply (non-ideal problem). The adopted active control strategy consists of two controls: the nonlinear (feedforward) in order to keep the controlled system in a desirable orbit, and the feedback control, which may be obtained by considering state-dependent Riccati equation control to bringing the system into the desired orbit using a magneto rheological (MR) damper. To control the electric current applied in control of the MR damper the Bouc-Wen mathematical model was used to the MR damper. The passive control was obtained by means of a nonlinear sub-structure with properties of nonlinear energy sink. Simulations showed the efficiency of both the passive control (energy pumping) and active control strategies in the suppression of the chaotic behavior. © The Author(s) 2012.

Nonlinear control system applied to atomic force microscope including parametric errors

The performance of the optimal linear feedback control and of the state-dependent Riccati equation control techniques applied to control and to suppress the chaotic motion in the atomic force microscope are analyzed. In addition, the sensitivity of each control technique regarding to parametric uncertainties are considered. Simulation results show the advantages and disadvantages of each technique. © 2013 Brazilian Society for Automatics - SBA.