Intracerebroventricular (icv) streptozotocin (STZ) administration induces pathological and behavioral alterations similar to those observed in Alzheimer's disease (AD) and is thus considered an ...experimental model of sporadic AD. Since caffeine (an adenosine receptor antagonist) and selective antagonists of adenosine A2A receptors modify the course of memory impairment in different amyloid-β-based experimental models of AD, we now tested the impact of caffeine on STZ-induced dementia and associated neurodegeneration in the hippocampus as well as on the expression and density of adenosine receptors. Adult male rats received a bilateral infusion of saline or STZ (3 mg/kg, icv), which triggered memory deficits after four weeks, as gauged by impaired object recognition memory. This was accompanied by a reduced NeuN immunoreactivity in the hippocampal CA1 region and an increased expression and density of adenosine A2A receptors (A2AR), but not A1R, in the hippocampus. Caffeine consumption (1 g/L in the drinking water starting 2 weeks before the STZ challenge) prevented the STZ-induced memory impairment and neurodegeneration as well as the upregulation of A2AR. These findings provide the first demonstration that caffeine prevents sporadic dementia and implicate the control of central A2AR as its likely mechanism of action.
Chasmagnathus granulata phosphoenolpyruvate carboxykinase (PEPCK) cDNA from jaw muscle was cloned and sequenced, showing a specific domain to bind phosphoenolpyruvate in addition to the kinase-1 and ...kinase-2 motifs to bind guanosine triphosphate (GTP) and Mg
2+, respectively, specific for all PEPCKs. In the kinase-1 motifs the GK was changed to RK. The first 19 amino acids of the putative enzyme contain hydrophobic amino acids and hydroxylated residues specific to a mitochondrial type signal. The PEPCK is expressed in hepatopancreas, muscles, nervous system, heart, and gills. Hyperosmotic stress for 24 h increased the PEPCK mRNA level, gluconeogenic and PEPCK activities in muscle.
To test the hypothesis of STC-1 participation in maintenance of glucose homeostasis in fed and fasting (48 h) rats, we investigated that this hormone may be implicated in the regulation of renal ...gluconeogenesis pathway from lactate and lactate oxidation in renal cortex and medulla. Our results demonstrate the hSTC-1 role on lactate metabolism in the renal cortex and medulla from fed and fasting rats. hSTC-1 increased the gluconeogenesis activity in fed state in renal cortex, and this increase was induced by raise in Pck1 gene expression. In fasting animals hSTC-1 increase the renal medulla gluconeogenesis activity, but Pck1 gene expression was not alter. The stimulatory effect of hSTC-1 on 14C-lactate oxidation occurred only in the renal cortex from fed rats. These findings show the hSTC-1 contribution to lactate homeostasis and supplies glucose to other tissues. This response may represent a strategy of action of STC-1 in response to fasting stress as postulated by different authors. On the other hand, hSTC-1 acts downstream of adenylcyclase pathway, decreasing the gluconeogenesis activity induced by cAMP intracellular increase or stimulating the phosphodiesterase activity in the renal cortex. However, no hSTC-1 effect on 14C-lactate oxidation was found after increase in the intracellular cAMP. The findings also revealed that the renal cortex and medulla respond differently to hSTC-1, possibly due to the higher level of STC-1 gene expression in inner renal medulla than in renal cortex.
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•hSTC-1 modulated renal gluconeogenesis in fed and fasted rats.•hSTC-1 increased Pck1 mRNA levels in renal cortex of fed rats.•Low hSTC-1 concentration modifies lactate oxidation in the renal cortex of fed rats.
Prostate cancer (PCa) is one of the most prevalent male tumours. Stanniocalcin-1 (STC1) is a glycoprotein and, although the role of STC1 in human cancer is poorly understood, it is suggested to be ...involved in the development and progression of different neoplasms. This study investigated the protein expression profile of STC1 in PCa and benign prostatic hyperplasia (BPH) samples and STC1 signalling during cell proliferation and cell death in vitro using cell lines. We found higher levels of STC1 in PCa when compared to BPH tissue and that STC1 inhibited forskolin stimulation of cAMP in PC-3 cells. A monoclonal antibody against STC1 was effective in reducing cell proliferation, in promoting cell cycle arrest, and in increasing apoptosis in the same cells. Since STC1 acts as a regulator of prostatic tissue signalling, we suggest that this protein is a novel candidate biomarker for prostate tumour clinical progression and a potential therapeutic target.
•Expression levels of STC1 in PCa were significantly higher in more aggressive tumours.•STC1 inhibits cAMP production in PCa cells in vitro.•Specific anti-STC1 antibody treatment reduces cell proliferation in PCa cell line.•Specific anti-STC1 antibody treatment increases apoptosis in PCa cell line.•STC1 signalling can be a potential target for PCa therapies.
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•STCs modulated hepatic gluconeogenesis in fed and fasted rats.•STCs do not modify glycogen level and synthesis and glucose oxidation.•STC-2 increased Pck1 mRNA levels in fed and ...fasting rat livers.•Fasted state influenced the expression of Stc1 and Stc2 in rat liver.•Data confirm the conservation of STCs metabolic functions in the vertebrates.
To test the hypothesis of conservation of stanniocalcin 1 and 2 (STC-1; STC-2) metabolic functions in vertebrates, we performed an in vitro study to determine if these hormones are implicated in regulation of the gluconeogenesis pathway, glycogen synthesis, and 14C-glucose conversion to 14CO2 in livers from fed and fasting rats (Rattus norvegicus). Stc1 and Stc2 gene expressions increased in the liver after fasting. STC-1 participated in the regulation of the hepatic gluconeogenesis pathway in rats when the precursor was 14C-lactate. STC-2 demonstrated variational signaling on rat hepatic gluconeogenesis activity and Pck1 gene expression, decreasing levels in the fed state when the substrate was 14C-alanine and increasing levels during fasting when the substrate was 14C-lactate. At the concentrations used in this study, STC-1 and STC-2 did not affect glycogen concentration and synthesis from 14C-glucose or 14C-glucose conversion to 14CO2 in the livers from fed or fasting rats. These findings highlight the role of stanniocalcins in the hepatic gluconeogenesis pathway in mammals and confirm the conservation of STC-1 and STC-2 metabolic functions in the vertebrates.
Resveratrol has been the focus of numerous studies reporting opposite effects that depend on its concentration. The GRX is an activated hepatic stellate cells model used to study liver fibrosis ...development and resolution. We recently showed that GRX treatment with RSV (0.1–50 µM) for 24 h triggered dose-dependent pro-oxidant effects, resulting in cytotoxicity and cell damage only at the highest concentration. Here, we evaluated whether the pro-oxidant effect of resveratrol treatment is accompanied by alterations on the GRX mitochondrial metabolism, and whether the concomitantly autophagy/mitophagy induction can influence on cell death or survival. We demonstrated that all concentrations of resveratrol promoted an increase of GRX cell death signals, altering the mitochondrial dynamics and function. Cells treated with all resveratrol concentrations presented higher autophagy/mitophagy features, but only treatments with 1 and 10 µM of resveratrol-induced mitochondrial biogenesis. Since cell damage was higher and there was no mitochondrial biogenesis in GRX treated with 50 µM of resveratrol, we suggest that these cells failed to remove and replace all damaged mitochondria. In conclusion, the cytotoxic effect of resveratrol that effectively promotes cell death could be related to the interrelation between the concomitant induction of apoptosis, autophagy/mitophagy and mitochondrial biogenesis in GRX.
The present work assesses in vitro the role of human Stanniocalcin 1 (hSTC-1) in 14C-glucose metabolism in brown adipose tissue (BAT) from fed rat. In the fed state, hSTC-1 decreases the ...incorporation of 14C from glucose into lipids in the rat BAT. The data support the hypothesis that the capacity of the glycerol-3-phosphate (G3P)-generating pathway (glycolysis) from glucose is regulated by hSTC-1, decreasing the adequate supply of G3P needed for fatty acid esterification and triacylglycerol (TG) storage in BAT. The results also suggest the effect of hSTC-1 on de novo fatty acid synthesis from pyruvate generated by 14C-glucose in the glycolysis pathway. In addition, by decreasing lipogenesis, hSTC-1 increased ATP levels and these two factors may decrease BAT thermogenic function. The presence of hSTC-1 in the incubation medium did not alter 14C-glucose and 14C-1-palmitic acid oxidation. The uncoupling protein 1 (UCP-1) expression was not altered by hSTC-1 either. In conclusion, hSTC-1 is one of the hormonal factors that control glucose metabolism in BAT in the fed state. The decrease of TG capacity synthesis from 14C-glucose by hSTC-1 compromises the BAT thermogenic capacity. Furthermore, the increase in ATP levels would inhibit a futile cycle via UCP-1, which dissipates oxidative energy as heat.
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•hSTC-1 inhibited lipid synthesis from 14C-glucose in rat brown tissue (BAT).•hSTC-1 increased ATP concentration but did not alter ADP/ATP ratio in BAT.•hSTC-1 did not change glucose or fatty acid oxidation in BAT.•hSTC-1 did not change UCP-1 expression in BAT.
The mammalian kidney contributes significantly to glucose homeostasis through gluconeogenesis. Considering that stanniocalcin 1 (STC1) regulates ATP production, is synthesized and acts in different ...cell types of the nephron, the present study hypothesized that STC1 may be implicated in the regulation of gluconeogenesis in the vertebrate kidney. Human STC1 strongly reduced gluconeogenesis from 14C-glutamine in rat renal medulla (MD) slices but not in renal cortex (CX), nor from 14C-lactic acid. Total PEPCK activity was markedly reduced by hSTC1 in MD but not in CX. Pck2 (mitochondrial PEPCK isoform) was down-regulated by hSTC1 in MD but not in CX. In fish (Dicentrarchus labrax) kidney slices, both STC1-A and -B isoforms decreased gluconeogenesis from 14C-acid lactic, while STC1-A increased gluconeogenesis from 14C-glutamine. Overall, our results demonstrate a role for STC1 in the control of glucose synthesis via renal gluconeogenesis in mammals and suggest that it may have a similar role in teleost fishes.
•STC1 inhibited gluconeogenesis from 14C-glutamine in rat renal medulla.•STC1 gluconeogenesis inhibition was absent from rat renal cortex or from 14C-lactic acid.•STC1 inhibited total PEPCK activity in medulla but not cortex.•STC1 reduced pck2 in medulla, but not pck1 or in cortex at the lowest concentrations.•STC1 also inhibited renal gluconeogenesis from 14C-lactic acid in a fish.
The present work assesses
in vitro
the role of human Stanniocalcin 1 (hSTC-1) in glucose metabolism in white retroperitoneal adipose tissue (WRAT) from fed rat. In the fed state, hSTC1 increases the ...incorporation of
14
C from glucose into lipids in the rat WRAT. The increase in lipogenesis capacity supports the hypothesis that the activity of the glycerol-3-phosphate-generating pathway (glycolysis) from glucose is regulated by hSTC-1. The effect of hSTC-1 on
de novo
fatty acid synthesis and on glucose oxidation in WRAT is supported by an 85 % increase in
14
CO
2
production from
14
C-glucose. The incubation of WRAT in the presence of hSTC-1 maintained the ADP/ATP ratio close to the control group. The presence of hSTC-1 in the incubation medium did not inhibit the lipolytic effect of epinephrine. In conclusion, hSTC-1 is one of the hormonal factors that control glucose metabolism in WRAT in the fed state.
The present study assesses the effects of starvation and refeeding on 1-14C-methyl aminoisobutyric acid (14C-MeAIB) uptake, 14C-total lipids, 14CO2 production from 14C-glycine, 14C-protein synthesis ...from 14C-leucine and Na+–K+-ATPase activity in jaw muscle of Neohelice granulata previously maintained on a carbohydrate-rich (HC) or high-protein (HP) diet. In N. granulata the metabolic adjustments during starvation and refeeding use different pathways according to the composition of the diet previously offered to the crabs. During starvation, 14CO2 production from 14C-glycine, and 14C-protein synthesis from 14C-leucine were reduced in HC-fed crabs. In crabs maintained on the HP or HC diet, 14C-total lipid synthesis increased after 15days of starvation. In crabs fed HP diet, 14C-MeAIB uptake and Na+–K+-ATPase activity decreased in refeeding state. In crabs refeeding HC diet, 14C-MeAIB uptake and 14CO2 production decreased during the refeeding. In contrast, the 14C-protein synthesis increased after 120h of refeeding. In both dietary groups, 14C-total lipid synthesis increased during refeeding. Changes in the carbon amino acid flux between different metabolic pathways in muscle are among the strategies used by this crab to face starvation and refeeding. Protein or carbohydrate levels in the diet administered to this crab modulate the carbon flux between the different metabolic pathways.
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