Author: neuroscience research

In conclusion, we report that the pleotropic effects of metformin include alteration of the entero-hepatic recirculation of bile acids, modulation of gut microbiota and changes in gut hormones, especially GLP-1. These findings suggest that the gastrointestinal tract is an important target organ of metformin and are consistent with the evidence that oral formulations of metformin are more effective than intravenous administration. The tight glycaemic control required to attenuate chronic complications in type 1 diabetes mellitus often requires numerous daily injections of bolus insulin administered by subcutaneous needle injection, insulin pen and catheters connected to insulin pumps. These methods are, however, inconvenient and often lead to poor compliance, a major factor negating the quality of life of diabetic patients. In addition, studies suggest that bolus insulin injections cause adverse effects such as hyperinsulinaemia, insulin resistance, glucose intolerance, weight gain and cardiovascular complications. The key to strict glycaemic control with use of exogenous insulin lies in the creation of delivery methods that mimic the physiology of insulin secretion. The desire to deliver insulin conveniently and effectively has led to investigations of delivery systems such as oral, nasal, buccal, pulmonary, rectal, ocular and transdermal routes. The skin which has increasingly become a route of the delivery for a wide range of drugs has generated a great deal of interest. The route is an appealing alternative for insulin as this may offer patient compliance and controlled release over time by avoiding degradation in the gastrointestinal tract or first-pass liver effects. On the other hand, transdermal delivery is limited by the low permeability of skin caused mainly by stratum corneum, the skin’s outermost layer. However, the permeability can be increased by various techniques such as the use of chemical enhancers, electrical enhancers via iontophoresis or electroporation and ultrasonic enhancers. Reports suggest that pectin not only delivers drugs to the colonic region of the gastrointestinal tract, but also sustains drug release in vitro. More interestingly, Musabayane et al., succeeded in sustaining plasma insulin concentrations in diabetic rats using orally administered, insulinloaded amidated pectin hydrogel beads. Building off these previous studies, we sought to develop a pectin insulin-containing dermal patch formulation which can transport insulin across the skin and sustain controlled release into the bloodstream of streptozotocin -induced diabetic rats. The study was, therefore, designed to establish whether application of pectin insulin-containing dermal patches sustain controlled release of insulin into the bloodstream of STZ-induced diabetic rats with concomitant alleviation of some diabetic symptoms. The success of insulin delivery via this route can be assessed by the ability to lower blood glucose concentrations. In addition to LY2157299 700874-72-2 reduced insulin responsiveness in muscle in diabetes, recent evidence has emphasized the critical role of insulin in hepatic glucose homeostasis. Insulin exerts metabolic and cellular effects mediated.

Two proteins, hnRNP F and CAD, were identified to complex at high levels with TTP and BRF1 in a RNA-independent manner. Given its previously established role in mRNA regulatory events we focused our study on hnRNP F and found that it stimulates the degradation of a subset of TTP/BRF1-target mRNAs. Stimulation of TTP/BRF1-target mRNA decay did not correlate with the extent of hnRNP F mRNA binding, indicating a more complex mechanism than simple concentration-dependent recruitment. Taken together, our observations identify a new component of TTP/BRF-complexes, which serves as a co-factor in a subset of TTP/BRF-mediated decay events. The specific mechanism by which hnRNP F stimulates TTP/ BRF1-mediated decay, and how it interfaces with other TTP/ BRF co-factors, is an important question for future study. Given that hnRNP F is a sequence-specific member of the hnRNP class of RNA-binding proteins that are abundant components of mRNPs, an interesting possibility is that TTP/BRF mRNA-target specificity is dictated in part by the hnRNP composition of the mRNP. If true, this could help explain why TTP/BRF proteins act on only a subset of ARE-containing mRNAs. Our observations showed no correlation between the ability of hnRNP F to stimulate ARE-mRNA decay and the number of predicted hnRNP F binding sites or the extent of hnRNP F mRNA binding. Thus, the mechanism by which hnRNP F stimulates TTP/BRF-mediated degradation is likely more complex, and could depend for example on the position of hnRNP F binding within the mRNA or other aspects of mRNP structure or composition. Future studies should reveal whether the position of hnRNP F binding relative to the ARE or other mRNA BYL719 elements is important, or whether additional mRNP components facilitate the communication between hnRNP F and TTP/BRF proteins. Given that the hnRNP F-TTP/BRF complex is resistant to RNase, it is also possible that hnRNP F stimulates TTP/BRF proteins through mechanisms that do not require direct RNA binding by hnRNP F. hnRNP F could stimulate TTP/BRF activity as part of the TTP/BRF complex for example by affecting the ability of TTP/BRF proteins to recruit mRNA decay factors, to remodel the mRNP in preparation for mRNA degradation, or by influencing TTP/BRF regulation by phosphorylation. We observed a consistent – albeit moderate – reduction in the fraction of cellular TTP that complexes with hnRNP F over time of stimulation of RAW macrophages with LPS. Given that TTP is regulated by phosphorylation and dephosphorylation events during a time course of LPS stimulation, this reduction in hnRNP F association with TTP could signify that the interaction is modulated by phosphorylation. Alternatively, the dramatic increase in TTP levels that occurs during LPS stimulation could render the cellular levels of hnRNP F limiting for the interaction. The remodeling of mRNPs that takes place to allow mRNA degradation is generally associated with repression of translation initiation and hnRNP F has previously been implicated in translational repression ; thus, an important question for future study is whether this activity of hnRNP F plays a role in TTP/BRF-mediated degradation of ARE-mRNAs.

These processes also included the reinforcement and cross-linking of cell walls and cell defense compounds production. The production of high levels of ROS also induced synthesis of antioxidant compounds and detoxifying activities of ROS such as SOD, peroxidases and other antioxidant like phenolics compounds. The production of ROS can be achieved by the action of the RBOH and/or apoplastic peroxidases,. The phenilpropanoid metabolism is another defensive mechanism. Phenols play an important role as antioxidant and in the modification of the properties of cell walls, limiting polysaccharide degradation by exogenous enzymes and increasing cell wall rigidity. Some phenylpropanoids can polymerize and form defensive structures, such as lignin. Gayoso et al. concluded that Verticillium dahliae infection had a clear influence on phenolic metabolism in tomato, the increase in total phenolics being detected after 2 h inoculation in the resistant lines. So, a higher content of these compounds is indicative that strong defense reactions are being displayed by the plant. Nitric oxid is a highly reactive signal molecule, but the origin of NO in plants remains mainly unclear. In the cytosol the Nitrate reductase catalyzes the reduction of nitrate to nitrite using NADH. The NR-mediated NO production can be induced by LDN-193189 biotic or abiotic factors, including elicitors from fungal plant pathogens. More recently, a nitrite: NO reductase was discovered in PM from plant roots, involved in NO formation. In plants, NO is involved in morphogenetic and physiological processes including responses to biotic or abiotic stresses. Therefore, NO is involved in plant-pathogen and plant symbioses interactions, as well as plant responses induced by elicitors. High concentrations of NO can have a synergistic effect with ROS leading to defense reactions. In the reactions induced by pathogens or their avirulent strains, the O22 produced can react with NO to form peroxynitrite, an even more reactive agent to many pathogens. Nevertheless, the role of NO and ROS in symbiotic and pathogen interactions remains unclear. So, the ability of plants to sense and respond to the attack of fungal pathogens is one of the first events in the evolutionary process of land plants. Linked to this process is interesting to note the capacity developed by plants to establish fungal symbiosis, which demonstrates the ability to differentiate between pathogenic and symbiotic interactions. The involvement of oxidant and antioxidant systems in mycorrhizal symbiosis is well known. For instance, ROS production and activation of NOX/RBOH has been evidenced during mycorrhizal symbiosis, while Fester and Hause suggested that ROS play a role in the control of mycorrhizal interactions. Lambais et al. showed an induction of SOD activities in the establishment of arbuscular mycorrhiza, this activation perhaps associated with the high levels of H2O2 observed in bean roots colonized by Rhizophagus irregularis. These authors concluded that the production of H2O2 by SODs could be associated with fungal recognition and activation of the plant defense. Baptista et al. showed that two of three H2O2 peaks detected in the early.

Factors that are known to play a role in the autoregulation of muscle blood flow are e.g. flow/pressure-related effects such as the myogenic response, metabolic vasodilators such as adenosine, and local hypoxia. Local hypoxia appears to function as a regional second messenger to redirect organ-specific blood flow to the area of greatest need, and thus, systemic hypoxia drives the fine-tuned local flow regulation in peripheral organs and the brain out of balance. One of the well-known extrapulmonary cardiovascular effects of hypoxia is NO-mediated peripheral vasodilation, which, after rapid ascension to high altitude, leads to systemic arterial hypotension, and subsequently, to compensatory increases in heart rates. However, hypoxia is also capable of causing peripheral vasoconstriction in resistance arterioles, by triggering the release of the vasoconstrictor endothelin-1 from endothelial cells. Importantly though, while NO exerts its vasodilatory effect predominantly on 1st and 2nd order arterioles, endothelin-1 vasoconstricts only pre-capillary arterioles, and, via pericytes, also directly controls capillary diameter. Via endothelin-1 release, hypoxia is therefore capable of directly controlling capillary conductance. The importance of maintaining perfusion pressure during hypoxic vasodilation to enable efficient capillary blood flow has been recently addressed. In our study, ephedrine and MK-4827 ambrisentan exerted ergogenic effects only when ephedrine concentrations were used at doses that were sufficient to raise pulmonary and mean arterial blood pressure in anesthetized rats. Sympathetic activation, such as triggered by ephedrine or methylphenidate, specifically constricts larger, low-order peripheral arterioles. It is therefore plausible that the sympathomimetic treatment used in this study directly counteracted hypoxiatriggered, NO-mediated vasodilation, thereby reversing arterial hypotension and preserving perfusion pressure on the skeletal muscle. Sympathetic activation and endothelin blockade should therefore synergize to improve capillary perfusion and thus, increase oxygen transport to the hypoxic muscle. Indeed, the observed increase in muscle blood flow and oxygenation in anesthetized rats, in the absence of changes to HbO2 suggests that the observed enhancement of exercise performance in awake animals is mediated by changes in flow, rather than by arterial oxygen content. The observed increase in ventilation rate after treatment with ephedrine has been reported, but since it had no apparent impact on blood oxygen concentrations, this effect may not carry ergogenic significance. It is well known that the mammalian cardiovascular system responds to hypoxemia with increased cardiac output, which can, to some degree, be succeeded by increased muscle blood flow. This mechanism is probably responsible for the immediate, steep increase in muscle blood flow that was seen in many animals, following the onset of hypoxia shown in Figure 2B. Both the apparent extrapulmonary effect of ambrisentan on muscle, and the interaction between pharmaceutically-induced and hypoxia-stimulated increases in peripheral blood flow, will be important future topics.

This means that poor nutrition in utero may lead to permanent changes in insulinglucose metabolism. Indeed, by restricting the nutrient supply during the prenatal period, the fetus adapts to a low nutrient environment and makes metabolic adaptations to survive. However, when nutrition is adequate or overabundant in the postnatal life, a conflict between the programming and the postnatal conditions arises. The latter is referred to as the ‘fetal origins’ hypothesis, which states that it is the conflict between the prenatal metabolic programming and the postnatal conditions that leads to disease and malfunction. Prenatal protein undernutrition has been studied in several animal models. In these models, the maternal diet is manipulated, exerting MLN4924 direct nutritional effects as well as indirect effects such as hormonal changes on the fetus. As proposed by, the approach of albumen removal in avian eggs, as a model of prenatal protein undernutrition, offers a unique avian model to investigate the direct effect of reduced protein availability during embryogenesis on growth and metabolism. Recently, the effect of a low protein diet provided to the hens on metabolic programming of the offspring was investigated in the chicken. Both the investigation of the direct and indirect animals models of prenatal protein deprivation can contribute to unraveling the prenatal programming effects. Several studies have already been conducted examining the effects of albumen removal in chicken for various reasons. A long-term study was previously conducted to examine the importance of albumen as a protein source during embryonic development in the chicken. Before sexual maturation, the body weight and feed intake were reduced. In contrast, during adulthood, an increased body weight was accompanied by reduced reproduction performance, indicating long-lasting programming effects. The objective of the present study was to investigate if the chicken model of prenatal protein undernutrition already displays significant differences during the perinatal period, before the conflict between the prenatal and postnatal conditions arises and whether it is possible to detect effects on programming on the protein and gene expression during this period. For this purpose, 3 mL of albumen was removed from layer-type eggs and replaced with saline. During the perinatal period, the present model showed little differences in growth, hormones and metabolites and hepatic glycogen content, supporting the ‘fetal origins’ hypothesis. However, metabolic programming caused by prenatal protein undernutrition was revealed by the observed hepatic proteome changes related with amino acids catabolism and glucose metabolism. Interestingly, the differential protein expression of these enzymes was not accompanied by a differential mRNA expression, suggesting that the observed proteome changes are related.