The glucagon stimulation test was performed in fasted rats and no significant difference was observed between fasted TGR and SD rats. However, this result can be attributed to the action of glucagon in all the metabolic sensitive tissues of the rat (such as muscle) and not exclusively in the liver. Glycogenolysis was evaluated through baseline hepatic glycogen concentration and levels of hepatic glycogen phosphorylase, an allosteric enzyme responsible for catalyzing the phosphorylation of glycogen to glucose1-P, playing a fundamental role in glycogen Selleckchem GSI-IX metabolism [7] and [26]. There was no significant

difference in hepatic glycogen phosphorylase levels analyzed by Western blotting. The absence of alteration in glycogenolysis pathway can explain the unaltered hepatic glycogen levels in TGR. To evaluate gluconeogenesis pathway separately we performed the pyruvate challenge test [18]. The first regulated step in the gluconeogenic pathway from pyruvate and its precursors is the pyruvate to oxaloacetate carboxylation, catalyzed by ATP-dependent pyruvate carboxylase [8], [9] and [10]. The pyruvate challenge experiment showed

that overnight fasted TGR rats have a decrease in PF-02341066 chemical structure the glucose synthesis when compared to overnight fasted SD rats, suggesting a downregulation in the gluconeogenesis pathway, since overnight fasted rats have negligible amounts of preformed glycogen. In order to confirm the downregulation of the gluconeogenesis pathway, it was evaluated the mRNA expression of the key enzymes of this route. The expression of G6Pase, a multicomponent enzyme system that hydrolyses glucose-6-phospate (G6P) to glucose in the final step of gluconeogenesis, showed no statistically difference in TGR and SD rats. PEPCK, one of the main rate-limiting enzymes of gluconeogenesis, simultaneously decarboxilates and phosphorylates oxaloacetate to phosphoenolpyruvate, had its expression significantly reduced in TGR when compared to SD rats. These results suggest that the gluconeogenesis downregulation could be due to the decreased expression of PEPCK. Recently, it has been documented that HNF4α has been implicated in gluconeogenesis through transcriptional

regulation of G6Pase and PEPCK, which are SDHB rate-limiting enzymes in this process as discussed previously [27]. The mRNA expression of HNF4α analysis by RT-PCR showed significantly decreased levels in TGR, when compared to SD rats. This finding pointed out to a relation between Ang-(1-7) and HNF4α, leading to an overall downregulation of gluconeogenesis. This result can be responsible, at least in part, for the improved circulating glycemic profile in TGR described previously [23]. In summary, the results obtained in the present study show that transgenic rats with increased Ang-(1-7) plasma levels, present a lower activation of the gluconeogenesis pathway responsible for glucose synthesis, without evidence of alteration in the hepatic glycogenolysis.

Consequently, lipid peroxidation causes damage to cell membrane. Oxidative stress induced by nanoparticles is reported to enhance inflammation through

upregulation of redox-sensitive transcription factors including nuclear factor kappa β (NFκβ), activating protein 1 (AP-1), extracellular signal regulated kinases (ERK) c-Jun, N-terminal kinases, JNK, and p38 mitogen-activated protein kinases pathways (Curtis et al., 2006 and Kabanov, 2006). The possible pathophysiological outcomes of effects due to nanomaterials have been concisely complied and presented in selleck chemicals Table 2. Generally speaking, biological systems are able to integrate multiple pathways of injury into a limited number of pathological outcomes, such as inflammation, apoptosis, necrosis, fibrosis, hypertrophy, metaplasia, and carcinogenesis (Table 2). However, even if nanomaterials do not introduce new pathology, there could be novel mechanisms of injury that require special tools, assays, and approaches to assess their toxicity. Specific biological and mechanistic pathways can be elucidated under controlled conditions in vitro; these, in conjunction with in vivo studies would reveal a link of the mechanism of injury to the pathophysiological outcome in the target organ ( Nel et al., 2006). Reactive oxygen species (ROS), due to their

high chemical reactivity can react with DNA, proteins, check details carbohydrates and lipids in a destructive manner causing cell death either by apoptosis or necrosis. The most frequently affected macromolecules are those genes or proteins, which have roles in oxidative stress, DNA damage, inflammation or injury to the immune system. For example, sub-micronic to nanometer-sized preparations of SiO2 were found to increase

arachidonic acid metabolism eventually leading to lung inflammation and pulmonary disease as well as expression in genes directly related to inflammation (Driscoll et al., 1996 and Englen et al., 1990). Similar results were obtained by Ishihara et al. (1999) for nanometer sized TiO2 particles and TiO2 whiskers (width of 140 nm). Based on detailed analyses of studies which investigated the mechanisms of these adverse effects, several researchers Phospholipase D1 have put forth the concept of primary versus secondary genotoxicity (Knaapen et al., 2004, MacNee and Donaldson, 2003 and Vallyathan and Shi, 1997). Genotoxicity directly related to the exposure of the ‘substance’ is referred to as primary genotoxicity. Secondary genotoxicity is the result of the ‘substance’ interacting with cells or tissues and releasing factors, which, in turn, cause adverse effects such as inflammation and oxidative stress. Most investigations on genotoxicity and cellular interactions of engineered nanomaterials are limited to screening for cytotoxicity. A few studies have focused on immunological responses of nanoparticles. Moghimi et al.