Effect and the probable mechanisms of silibinin in regulating insulin resistance in the liver of rats with non-alcoholic fatty liver

Our previous study has shown that reduced insulin resistance (IR) was one of the possible mechanisms for the therapeutic effect of silibinin on non-alcoholic fatty liver disease (NAFLD) in rats. In the present study, we investigated the pathways of silibinin in regulating hepatic glucose production and IR amelioration. Forty-five 4- to 6-week-old male Sprague Dawley rats were divided into a control group, an HFD group (high-fat diet for 6 weeks) and an HFD + silibinin group (high-fat diet + 0.5 mg kg-1·day-1 silibinin, starting at the beginning of the protocol). Both subcutaneous and visceral fat was measured. Homeostasis model assessment-IR index (HOMA-IR), intraperitoneal glucose tolerance test and insulin tolerance test (ITT) were performed. The expression of adipose triglyceride lipase (ATGL) and of genes associated with hepatic gluconeogenesis was evaluated. Silibinin intervention significantly protected liver function, down-regulated serum fat, and improved IR, as shown by decreased HOMA-IR and increased ITT slope. Silibinin markedly prevented visceral obesity by reducing visceral fat, enhanced lipolysis by up-regulating ATGL expression and inhibited gluconeogenesis by down-regulating associated genes such as Forkhead box O1, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. Silibinin was effective in ameliorating IR in NAFLD rats. Reduction of visceral obesity, enhancement of lipolysis and inhibition of gluconeogenesis might be the underlying mechanisms.

Cellular and molecular studies of the effects of a selective COX-2 inhibitor celecoxib in the cardiac cell line H9c2 and their correlation with death mechanisms

Cardiovascular disease is one of the leading causes of death worldwide, and evidence indicates a correlation between the inflammatory process and cardiac dysfunction. Selective inhibitors of cyclooxygenase-2 (COX-2) enzyme are not recommended for long-term use because of potentially severe side effects to the heart. Considering this and the frequent prescribing of commercial celecoxib, the present study analyzed cellular and molecular effects of 1 and 10 µM celecoxib in a cell culture model. After a 24-h incubation, celecoxib reduced cell viability in a dose-dependent manner as also demonstrated in MTT assays. Furthermore, reverse transcription-polymerase chain reaction analysis showed that the drug modulated the expression level of genes related to death pathways, and Western blot analyses demonstrated a modulatory effect of the drug on COX-2 protein levels in cardiac cells. In addition, the results demonstrated a downregulation of prostaglandin E2 production by the cardiac cells incubated with celecoxib, in a dose-specific manner. These results are consistent with the decrease in cell viability and the presence of necrotic processes shown by Fourier transform infrared analysis, suggesting a direct correlation of prostanoids in cellular homeostasis and survival.

Effects of nitric oxide on magnocellular neurons of the supraoptic nucleus involve multiple mechanisms

Physiological evidence indicates that the supraoptic nucleus (SON) is an important region for integrating information related to homeostasis of body fluids. Located bilaterally to the optic chiasm, this nucleus is composed of magnocellular neurosecretory cells (MNCs) responsible for the synthesis and release of vasopressin and oxytocin to the neurohypophysis. At the cellular level, the control of vasopressin and oxytocin release is directly linked to the firing frequency of MNCs. In general, we can say that the excitability of these cells can be controlled via two distinct mechanisms: 1) the intrinsic membrane properties of the MNCs themselves and 2) synaptic input from circumventricular organs that contain osmosensitive neurons. It has also been demonstrated that MNCs are sensitive to osmotic stimuli in the physiological range. Therefore, the study of their intrinsic membrane properties became imperative to explain the osmosensitivity of MNCs. In addition to this, the discovery that several neurotransmitters and neuropeptides can modulate their electrical activity greatly increased our knowledge about the role played by the MNCs in fluid homeostasis. In particular, nitric oxide (NO) may be an important player in fluid balance homeostasis, because it has been demonstrated that the enzyme responsible for its production has an increased activity following a hypertonic stimulation of the system. At the cellular level, NO has been shown to change the electrical excitability of MNCs. Therefore, in this review, we focus on some important points concerning nitrergic modulation of the neuroendocrine system, particularly the effects of NO on the SON.

Impacts of capacity remunerative mechanisms on cross-border trade

The European ambitious targets to increase the share of renewable generation pose a challenge to the generation adequacy. Many European member states are concerned that energy-only markets alone might not be able to deliver sufficient capacity required to meet the future electricity demand and back up shortfalls of energy from renewable energy sources (RES) during periods of low wind and sun. Many EU members consider to re-design their energy-only markets and establish different forms of capacity remunerative mechanisms (CRMs) to maintain the security of supply. There is a certain concern that market design changes at the level of EU member countries might conflict with the European goal of a single market. As soon as many European markets are highly interconnected, uncoordinated CRMs might create negative crossborder effects and hinder the achievement of the Internal Electricity Market in Europe. The pros and cons of capacity markets are well examined at the national level. However, the cross-border effects of capacity markets within the European market aiming at higher integration have received less attention. This doctoral dissertation examines the cross-border effects of unilateral implementation of CRMs applying both theoretical and case study analyses. The results show that capacity remunerative mechanisms (CRMs) may cause negative cross-border effects, especially if they are implemented unilaterally.

Natural born weight gainers: The mechanisms of obesity in transgenic mice overexpressing neuropeptide Y

Neuropeptide Y (NPY) is a neurotransmitter promoting energy storage by activating Y-receptors and thus affecting food intake, thermogenesis and adipose tissue metabolism. NPY is expressed both in the central and sympathetic nervous system. Hypothalamic NPY is known to stimulate feeding, but the effects of noradrenergic neuron NPY are more ambiguous. Chronic stress stimulates fat accumulation via NPY release from noradrenergic neurons. Furthermore, polymorphism in the human Npy gene has been associated with metabolic disturbances and increased NPY secretion after sympathetic stimulation. The main objective of this study was to clarify the mechanisms of noradrenergic neuron NPY in the development of obesity. The metabolic phenotype of a homozygous mouse overexpressing NPY in the brain noradrenergic neurons and sympathetic nervous system (OE-NPYDβH mouse) was characterized. OE-NPYDβH mice had an increased fat mass and body weight, which caused impairments of glucose metabolism and hyperinsulinaemia with age. There were no differences in energy intake or expenditure, but the sympathetic tone was down-regulated and the endocannabinoid system activated. Furthermore, peripheral Y2-receptors in energy-rich conditions played an important role in mediating the fat-accumulating effect of NPY. These results indicate that noradrenergic neuron NPY promotes obesity via direct effects in the periphery and by modulating the sympatho-adrenal and endocannabinoid systems. Additionally, NPY in the central noradrenergic neurons is believed to possess many important roles. The phenotype of the OE-NPYDβH mouse resembles the situations of chronic stress and Npy gene polymorphism and thus these mice may be exploited in testing novel drug candidates for the treatment of obesity.

Resveratrol plays important role in protective mechanisms in renal disease - mini-review

Resveratrol (RESV) is a polyphenolic compound found in various plants, including grapes, berries and peanuts, and its processed foods as red wine. RESV possesses a variety of bioactivities, including antioxidant, anti-inflammatory, cardioprotective, antidiabetic, anticancer, chemopreventive, neuroprotective, renal lipotoxicity preventative, and renal protective effects. Numerous studies have demonstrated that polyphenols promote cardiovascular health. Furthermore, RESV can ameliorate several types of renal injury in animal models, including diabetic nephropathy, hyperuricemic, drug-induced injury, aldosterone-induced injury, ischemia-reperfusion injury, sepsis-related injury, and endothelial dysfunction. In addition, RESV can prevent the increase in vasoconstrictors, such as angiotensin II (AII) and endothelin-1 (ET-1), as well as intracellular calcium, in mesangial cells. Together, these findings suggest a potential role for RESV as a supplemental therapy for the prevention of renal injury.

The real mechanisms of the global economy

The paper presents the main arguments of Bresser Pereira's Globalization and Competition. Development strategies based on the 'conventional orthodoxy' are shown to carry serious drawbacks ("Dutch disease", pernicious effects of external saving, currency overvaluation), while a 'new developmentalism' is promoted, in spite of the widespread belief that the nation-states have been dispossessed of their room for manoeuvre because of the globalization process. The "new developmentalism" is based on domestic finance, balanced public budgets, moderate interest rates and competitiveness policies aimed at neutralizing the tendency to exchange rate overappreciation. The paper also points out a few theoretical questions the book raises.

Interactions of decision mechanisms in an entrepreneurial firm’s journey to become a major player in its industry

This study discusses the interactions of different decision-making mechanisms in the process of change of a successful entrepreneurial dairy firm in Vietnam. The purpose of the study is to construct a theoretical framework, which explains the interactions between effectual and causal decision-making processes in different phases of business, and to provide a real life example with practical recommendations for entrepreneurs and managers. In order to achieve this purpose, a preliminary theoretical framework was built, using process theories applied to different decision making modes, referred to as causation and effectuation. The case was studied through ethnographic research method, with three semi-structured interviews, one unstructured interview, secondary data and observations within four months in 2013-2014. After the data was analyzed, a modified framework was drawn from the result. The finding of this study shows that there was an interaction between effectual and causal decision-making processes in different stages of the company’s development. The entrepreneur applied effectual decision-making process to develop a unique business model and a new dairy market segment. However, when a new market demand arose, the company’s resources became insufficient, they thus had to shift to causation process to adapt to market change. Simultaneously, with better-accumulated resources, the entrepreneur continued the effectuation process to create another brand new dairy market segment. This study, thus, contributes to effectuation theory, emphasizing the necessity of combining effectual and causal decision-making processes in different phases of business. It is suggested that business would develop with an effectual process until a business model is viable for growth. It continues to use this process up to a certain degree. When the market changes, the company needs to collect more means to adapt to the changes. They need to set new goals and this is a shift to the use of causal process, which builds on prediction. It uses goals and teleology as driving mechanisms and tries to exploit and fill potential resource gaps to achieve these goals. At the same time, there are new iterations that look to establish new lines or types of business with the given means, which are now well established. This again employs effectual mechanisms, which are based on evolutionary process, until they reach the stage of viable tested business model. Moreover, this study hopes to provide know-how to entrepreneurs and managers of small companies in similar situations, suggesting how to combine effectual and causal decision-making processes to deal with various circumstances in different times.

Regional variations of deformation mechanisms in the Lorrain Quartzite near Whitefish Falls, Ontario, Canada /

The quartzite microfabric found in the Lorrain Formation was studied across the La Cloche syncline, along a regional north-south transect along highway 6, near Whitefish Falls, Ontario. The complete stratigraphic sequence across the syncline is preserved, and is present on each fold limb. The lithostratigraphic units with the smallest grains size and lowest mica content are located close to the core of the fold, while coarser grained mica and feldspar rich units are situated at the northern and southern most extent of the transect. Deformation mechanisms vary with lithology and with position across the fold. Pressure solution appears to be the dominant deformation mechanism in the feldspathic, micaceous and ferruginous units. In the finer grained, mica poor white medium grained and cherty sandstone units, grain boundary migration (GBM) characteristics show dominance over those of pressure solution and show high amounts of fracturing which cut migrated boundaries and therefore post date GBM. All samples across the fold display a preferred orientation of quartz c-axes. The senses of asymmetry of fabrics are found to be similar across the syncline, with the exception of the ferruginous sandstone unit. Formation of these similar fabrics synmietries can not be the result of strain related to first order folding. The mica content appears to be related to the percentage of quartz lost due to pressure solution as a result of strain; the more mica present, the less quartz was lost. Calculations based on the shape of initial grains suggest that conservatively 30% of the quartz volume has been dissolved out of the Lorrain quartzite, and potentially migrated hundreds of meters to other members of the Huronian Supergroup as there was no meso or macroscopic evidence observed in outcrop.

Mechanisms of endothelin-1 induced reactive oxygen species production in vascular adventitial fibroblasts

With the relationship between endothelin-1 (ET-1) stimulation and reactive oxygen species (ROS) production unknown in adventitial fibroblasts, I examined the ROS response to ET-1 and angiotensin (Ang II). ET-1 -induced ROS peaked following 4 hrs of ET-1 stimulation and was inhibited by an ETA receptor antagonist (BQ 123, 1 uM) an extracellular signal-regulated kinase (ERK) 1/2 inhibitor (PD98059, 10 uM), and by both a specific, apocynin (10 uM), and non-specific, diphenyleneiodonium (10 uM), NAD(P)H oxidase inhibitor. NOX2 knockout fibroblasts did not produce an ET-1 induced change in ROS levels. Ang II treatment increased ROS levels in a biphasic manner, with the second peak occurring 6 hrs following stimulation. The secondary phase of Ang II induced ROS was inhibited by an ATi receptor antagonist, Losartan (100 uM) and BQ 123. In conclusion, ET-1 induces ROS production primarily through an ETA-ERKl/2 NOX2 pathway, additionally, Ang II-induced ROS production also involves an ETa pathway.

Attenuation of skeletal muscle FFA-induced insulin resistance by the polyphenol resveratrol. Elucidation of the mechanisms involved

Excess plasma free fatty acids (FFA) are correlated with insulin resistance and are a risk factor for the development of type 2 diabetes. In this study we examined the effect of the polyphenol resveratrol on FF A-induced insulin resistance in skeletal muscle cells and the mechanisms involved. Incubation of L6 myotubes with the FF A palmitate significantly decreased the insulin-stimulated glucqse uptake. Importantly, the effect of palmitate was ameliorated by resveratrol. Palmitate significantly increased serine phosphorylation of IRS..; 1 and reduced insulin-stimulated Akt phosphorylation, an effect that was abolished by resveratrol. We then investigated the effect of palmitate and resveratrol on the expression and phosphorylation of JNK, mTOR, p70-S6K, and AMPK kinases. The results demonstrated that our treatments had no effect on the expression of these proteins. However, palmitate increased the phosphorylation of mTOR and p70- S6K, whereas resveratrol abolished this effect and increased the phosphorylation of AMPK. Furthermore, all effects of resveratrol were abolished with sirtuin inhibitors, sirtinol and nicotinamide. These results indicate that resveratrol ameliorated FF A-induced insulin resistance by regulating mTOR and p70-S6K phosphorylation in skeletal muscle cells, through a mechanism involving sirtuins.