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PubMed2006

TIGAR, a p53-inducible regulator of glycolysis and apoptosis.

The p53 tumor-suppressor protein prevents cancer development through various mechanisms, including the induction of cell-cycle arrest, apoptosis, and the maintenance of genome stability. We have identified a p53-inducible gene named TIGAR (TP53-induced glycolysis and apoptosis regulator). TIGAR expression lowered fructose-2,6-bisphosphate levels in cells, resulting in an inhibition of glycolysis and an overall decrease in intracellular reactive oxygen species (ROS) levels. These functions of TIGAR correlated with an ability to protect cells from ROS-associated apoptosis, and consequently, knockdown of endogenous TIGAR expression sensitized cells to p53-induced death. Expression of TIGAR may therefore modulate the apoptotic response to p53, allowing survival in the face of mild or transient stress signals that may be reversed or repaired. The decrease of intracellular ROS levels in response to TIGAR may also play a role in the ability of p53 to protect from the accumulation of genomic damage.

Amino Acid Sequence↗
PubMed2005

Fructose-1,6-bisphosphate enhances hypothermic preservation of cardiac myocytes.

BACKGROUND: Previous studies from our project found that fructose-1,6-bisphosphate (FBP) enhanced the functional recovery of animal hearts after hypothermic preservation, and that rat cardiac myocytes take up FBP at 3 degrees C. In this study we tested the effects of FBP, as well as other compounds related to glycolysis and pyruvate oxidation, on the hypothermic preservation of myocytes. METHODS: Isolated myocytes were incubated in ischemic suspensions at 3 degrees C, and aliquots examined over 72 hours for retention of rod-shaped morphology. In some experiments adenine nucleotide levels were measured by high-performance liquid chromatography (HPLC). RESULTS: FBP at 1 to 10 mmol/liter markedly reduced the death rate (65% reduction at 5 mmol/liter). Glucose at 2 to 10 mmol/liter was less beneficial (20% reduction). Insulin increased the death rate by about 25% when present alone, and it did not enhance the beneficial effects of FBP or glucose. Dichloroacetate (DCA), which stimulates pyruvate dehydrogenase, had little effect at 0.5 to 10 mmol/liter. Glucose and DCA did not increase the beneficial effects of FBP. After 6 to 24 hours of hypothermia, FBP- and glucose-treated cells had 25% to 50% higher ATP levels and 10% to 20% higher ATP:ADP ratios than untreated cells. Effects of FBP on preservation of morphology were much greater than effects on ATP levels. CONCLUSIONS: The results suggest that the effects of FBP and glucose were through glycolytic ATP production rather than through sugar oxidation via pyruvate dehydrogenase. The divergence in effects on preservation and effects on ATP suggests a role for a sub-cellular compartment of ATP in preservation.

Adenosine Diphosphate↗
PubMed2006

Fructose 1,6-diphosphate administration attenuates post-ischemic ventricular dysfunction.

BACKGROUND: Cardiomyocyte energy production during ischemia depends upon anaerobic glycolysis inefficiently yielding two ATP per glucose. Substrate augmentation with fructose 1,6-diphosphate (FDP) bypasses the ATP consuming steps of glucokinase and phosphofructokinase thus yielding four ATP per FDP. This study evaluated the impact of FDP administration on myocardial function after acute ischemia. METHODS: Male Wistar rats, 250-300 g, underwent 30 min occlusion of the left anterior descending coronary artery followed by 30 min reperfusion. Immediately prior to both ischemia and reperfusion, animals received an intravenous bolus of FDP or saline control. After 30 min reperfusion, myocardial function was evaluated with a left ventricular intracavitary pressure/volume conductance microcatheter. For bioenergetics studies, myocardium was isolated at 5 min of ischemia and assayed for ATP levels. RESULTS: Compared to controls (n=8), FDP animals (n=8) demonstrated significantly improved maximal left ventricular pressure (100.5+/-5.4 mmHg versus 69.1+/-1.9 mmHg; p<0.0005), dP/dt (5296+/-531 mmHg/s versus 2940+/-175 mmHg/s; p<0.0028), ejection fraction (29.1+/-1.7% versus 20.4+/-1.4%; p<0.0017), and preload adjusted maximal power (59.3+/-5.0 mW/microL(2) versus 44.4+/-4.6 mW/microL(2); p<0.0477). Additionally, significantly enhanced ATP levels were observed in FDP animals (n=5) compared to controls (n=5) (535+/-156 nmol/g ischemic tissue versus 160+/-9.0 nmol/g ischemic tissue; p<0.0369). CONCLUSIONS: The administration of the glycolytic intermediate, FDP, by intravenous injection, resulted in significantly improved myocardial function after ischemia and improved bioenergetics during ischemia.

Adenosine Triphosphate↗
PubMed2005

Effects of brazilin on the production of fructose-2,6-bisphosphate in rat hepatocytes.

Increased hepatic glucose output is one of the major mechanisms of hyperglycemia in diabetic patients. Fructose-2,6-bisphosphate (F-2,6-BP), a gluconeogenic intermediate, plays a critical role in hepatic glucose output by regulating gluconeogenesis and glycolysis in the liver. Brazilin, an active component of sappan wood (Caesalpinia sappan), decreases blood glucose in diabetic animals. In this study, the effect of brazilin on gluconeogenic intermediate production and enzyme activity were examined to investigate the hypoglycemic mechanism of brazilin. Brazilin increased the production of F-2,6-BP in hepatocytes by elevating intracellular levels of fructose-6-phosphate (F-6-P) and hexose-6-phosphate (H-6-P). Brazilin was also found to significantly increase the activity of 6-phosphofructo-2-kinase (PFK-2) and pyruvate kinase in glucagon-treated hepatocytes. However, glucose-6-phosphatase activity was not affected by brazilin. This data suggests that brazilin inhibits hepatic gluconeogenesis by elevating the F-2,6-BP level in hepatocytes, possibly by elevating cellular F-6-P/H-6-P levels and PFK-2 activity. Increased pyruvate kinase activity may also play a role in the anti-gluconeogenic action of brazilin.

Animals↗
PubMed2006

Influence of fructose-1,6-diphosphate on endotoxin-induced lung injuries in sheep.

BACKGROUND: Fructose-1,6-diphosphate (FDP) is reported to have a salutary effect in endotoxin shock and sepsis. This investigation describes the effect of FDP on pulmonary and systemic hemodynamics, lung lymph protein clearance, and leukocyte count in sheep infused with Escherichia coli endotoxin. MATERIALS AND METHODS: Anesthetized sheep (n = 18), some of which underwent thoracotomy to cannulate lymphatic nodes, were used in this study. After stabilization, all sheep received E. coli endotoxin, 5 microg/kg i.v. infusion over 30 min. Concomitant with the endotoxin infusion, half of the animals were randomly selected to receive an i.v. bolus of FDP (10%), 50 mg/kg, followed by a continuous infusion of 5 mg.kg(-1).min(-1) for 4 h; the rest were treated in the same manner with glucose (10%) in 0.9% NaCl. RESULTS: Pulmonary artery pressure (PAP) and resistance in the glucose group increased from 20.8 +/- 1.6 to 36.7 +/- 3.2 mmHg (P < 0.007) and from 531 +/- 114 to 1137 +/- 80 dyn.s(-1).cm(-5), respectively (P < 0.005). Despite an increase during endotoxin infusion, these parameters in the FDP group returned to control values. There were no differences in left ventricular pressures, cardiac output, heart rate, and arterial oxygen tension between the groups. In the glucose group, lymph protein clearance was higher (P < 0.01) and blood leukocyte count was lower (P < 0.02). The wet/dry lung weight ratio (g/g) for the glucose group was 5.57 +/- 0.04 and for the FDP-treated group 4.76 +/- 0.06 (P < 0.0005). CONCLUSION: FDP treatment attenuated significantly the characteristic pulmonary hypertension, lung lymph protein clearance, and pulmonary vascular leakage seen in sheep infused with endotoxin.

Animals↗
PubMed2006

Effect of normothermic perfusion using fructose-1,6-bisphosphate for maintenance of liver function during in situ extended hepatectomy by the total hepatic vascular exclusion technique.

BACKGROUND: Recently, hepatic surgery has made remarkable progress, and it is important to use appropriate liver perfusion. We evaluated the effect of normothermic liver perfusion with the addition of fructose-1, 6-bisphosphate (FBP) and oxygenation to maintain liver parenchymal, non-parenchymal, and Kupffer cell function. MATERIALS AND METHODS: The rats were divided into five groups according to the perfusate and continuous perfusion was performed: Control group = 4 degrees C lactate Ringer with 10% glucose (LRG) solution; normothermic group = 25 degrees C LRG solution; normothermic oxygenated group = 25 degrees C oxygenated LRG solution; normothermic FBP group = 25 degrees C LRG solution with addition of 10 mmol/L FBP; normothermic oxygenated FBP group = 25 degrees C oxygenated LRG solution with addition of 10 mmol/L FBP. Parameters under evaluation were oxygen consumption, liver energy level (adenosine triphosphate, total adenine nucleotide), glutathione, lipid peroxide, hyaluronic acid uptake ratio, apoptosis, and histomorphology. Moreover, we studied the effect of FBP and normothermia on Kupffer cells activation in vitro. RESULTS: Liver energy level was lower in the normothermic group than the control group. But, it was improved by oxidation or addition of FBP, and it was satisfactorily maintained up to 120 min in the group with normothermic oxygenated FBP. Hyaluronic acid uptake was maintained highly at all times as measured in normothermic oxygenated FBP group. The uptake of lipopolysaccharide was significantly higher as a result of adding FBP, compared with that in the control group and the normothermic group. Moreover, the apoptotic index in the liver was decreased in normothermic FBP group compared to control group. CONCLUSIONS: The normothermic liver perfusion under additional FBP and oxygenation protects both parenchymal and non-parenchymal cells from reperfusion injury.

Adenosine Triphosphate↗
PubMed2005

Effect of intracellular delivery of energy metabolites on intracellular Ca2+ in mouse islets of Langerhans.

Regulation of glucose-induced oscillations in intracellular Ca2+ concentration ([Ca2+]i) was investigated by using a novel technique, electroporation from an electrolyte-filled capillary, to deliver energy metabolites to the intracellular compartment of mouse islets. Intracellular application of ATP resulted in a nifedipine-sensitive increase in [Ca2+]i, consistent with a KATP-channel dependent mechanism of Ca2+ influx. [Ca2+]i in islets exposed to 10 mM glucose oscillated with a period of approximately 3 min, often superimposed with faster oscillations. Electroporation of ATP blocked all types of oscillations and elevated [Ca2+]i while delivery of ADP had no effect on oscillations. Intracellular delivery of glucose-6-phosphate or fructose-1,6-bisphosphate tended to transform slow oscillations to fast oscillations. These results demonstrate that modulation of ATP concentrations and glycolytic flux are important in development of slow oscillations.

Adenine Nucleotides↗
PubMed2004

Unique kinetic mechanism of Plasmodium falciparum adenylosuccinate synthetase.

Adenylosuccinate synthetase (AdSS) catalyses the Mg(2+) dependent formation of adenylosuccinate from IMP and aspartate, the reaction being driven by the hydrolysis of GTP to GDP. All characterized AdSS thus far exhibit a random kinetic mechanism. We present here kinetic evidence that unlike all other AdSS, Plasmodium falciparum AdSS (PfAdSS) has ordered substrate binding. Inhibition studies show that binding of GTP requires IMP binding while aspartate binds to the enzyme-IMP-GTP complex. A structural basis for this difference in mechanism is presented. Kinetically, PfAdSS is closer to the mouse acidic isozyme rather than to the mouse basic isozyme. The mouse acidic isozyme is thought to play a role in the purine nucleotide biosynthetic pathway. Regulation of PfAdSS in vivo can therefore, be expected to be similar to the mouse acidic isozyme, in agreement with the role of PfAdSS as the only pathway for the synthesis of adenine nucleotides in the parasite. However, PfAdSS differs from both the mammalian homologs in that fructose-1,6-bisphosphate, a potent inhibitor of the mammalian enzyme, is an activator of PfAdSS. The differences highlighted here are promising in terms of species-specific drug design, targeting this essential enzyme in the parasite.

Adenylosuccinate Synthase↗
PubMed2006

Treatment-induced prevention of learning deficits in newborn mice with brain lesions.

Perinatal brain injuries often result in irreversible learning disabilities, which manifest in early childhood. The molecular and cellular mechanisms of these injuries and potential pharmacological treatments are emerging, chiefly from studies in newborn rodents. In newborn mice, experimentally induced lesions can be dramatically reduced by appropriate neuroprotective treatments. However, the early effectiveness of these treatments in preserving cognition remained unknown. Here, we addressed this issue by using intracerebral ibotenate to induce excitotoxic brain lesions in 5-day-old mice (postnatal day 5). On postnatal days 6-7, we tested spontaneous preference for maternal odors, as an index of odor memory, and conditioned preference for an artificial odor previously paired with stroking, as an index of associative learning. Brain-lesioned newborn mice showed normal general status and preference for maternal odors. In contrast, odor conditioning was severely impaired. A previous study showed that fructose 1,6-biphosphate acted as a neuroprotective agent which significantly reduced neocortical lesion size. In the present study, treating the newborn mice with fructose 1,6-biphosphate 15 min before the ibotenate injection reduced neocortical lesion size and restored conditioning. This demonstrates, for the first time, that neuroprotective treatment can protect some features of early cognition.

Animals↗
PubMedDate not supplied

Itaconate reduces visceral fat by inhibiting fructose 2,6-bisphosphate synthesis in rat liver.

OBJECTIVE: Itaconate is an analog of phosphoenolpyruvate, which is an inhibitor of fructose-6-phosphate 2-kinase (F6P2Kinase), an enzyme that synthesizes fructose 2,6-bisphosphate (F26BP). Carbohydrates ingested are preferentially used for glycogen synthesis in the liver and muscles, and excess carbohydrates are metabolized by glycolysis in the liver and used for fatty acid synthesis. We hypothesized that itaconate is incorporated into liver cells and suppresses fat synthesis by inhibiting liver glycolysis at the step of phosphofructokinase, which is activated by F26BP. METHODS: Rats were allowed to eat ad libitum for 3 wk or, in separate experiments, to limit food intake by pair feeding. One group was given drinking water (control group) and the other group was given a 10 g/L itaconate solution (itaconate group). We measured body weight gain, visceral fat accumulation, and F6P2Kinase activity. RESULTS: Body weight gain in the itaconate group was lower than that in the control group (P < 0.05). In the dietary-controlled rats, there was no difference in body weight increase between groups, but visceral fat content (P < 0.01), plasma free fatty acid, and triacylglycerol levels (P < 0.05) were lower in the itaconate group than in the control group. Further, itaconate decreased the F26BP level (P < 0.05) in vivo and partly inhibited rat liver-type F6P2Kinase in vitro. CONCLUSIONS: These results indicate that itaconate, which is a decarboxylate and resembles phosphoenolpyruvate, is incorporated into liver cells and suppresses glycolysis by decreasing the level of F26BP, resulting in decreased visceral fat.

Adipose Tissue↗
PubMed2006

Amyotrophic lateral sclerosis in an Italian professional soccer player.

Amyotrophic lateral sclerosis (ALS) is a rare devastating neurodegenerative disease of unknown etiology. Two recent epidemiological studies showed a high risk for ALS among Italian male soccer players. We present the clinical and occupational history of an Italian professional soccer player affected by sporadic ALS. The early onset of ALS (45 years), the bulbar form, the playing position (midfielder) and the duration of the job as professional soccer (17 years) are four characteristics of this patient that are in good agreement with the findings in the previous epidemiological studies. This patient reports the frequent consumption of fructose 1,6 biphosphate, extracts of suprarenal cortex, crotetamide and cropropamide, and dietary supplements (branched chain amino acids and creatine) during his playing career. Some hypotheses have been proposed to explain this high excess of deaths for ALS among soccer players: (a) vigorous physical activity; (b) soccer specific trauma or microtrauma; (c) use of illegal toxic substances or chronic misuse of drugs (most often anti-inflammatory) and dietary supplements; and (d) exposure to pesticides used on playing fields. The overall available clinical and epidemiological evidence supports the possible relation between the specific occupational environment (soccer) and the occurrence of ALS in this patient.

Amino Acids, Branched-Chain↗
PubMed2004

Anti-inflammatory effects of fructose-1,6-bisphosphate on carrageenan-induced pleurisy in rat.

In the present study, we evaluated the effect of fructose-1,6-bisphosphate (FBP), a high energy intermediate metabolite of glycolysis, in an acute model of lung injury. Injection of carrageenan into the pleural cavity of rats elicited an acute inflammation response characterized by a fluid accumulation in the pleural cavity which contained a large number of polymorphonuclear neutrophils. FBP (500mg/kg) attenuated the inflammation parameters: exudate volume, total leukocytes and the number of polymorphonuclear leukocytes, but the protein concentration in the exudate was not significantly affected by treatment with FBP. The precise site and mechanism of the anti-inflammatory effect was not addressed, considering the diverse pharmacological actions of FBP. This drug has anti-inflammatory actions suggesting that it may represent a novel strategy for the modulation of inflammatory response.

Animals↗
PubMed2004

Effect of the chlorpropamide and fructose-1,6-bisphosphate of soluble TNF receptor II levels.

Inflammatory cytokines are central to the pathogenesis of septic shock, and future therapies will depend on interfering with the effects of these cytokines. The aim of this study was to investigate the effect of the two drugs, Fructose-1,6-bisphosphate (FBP), a high-energy glycolytic pathway intermediate, and chlorpropamide (sulfonylurea) on proliferation of T-lymphocytes and on the levels of soluble receptors of tumor necrosis factor (sTNFRII). Peripheral blood mononuclear cells (PMBCs) were isolated from the blood of healthy humans by gradient centrifugation. T-lymphocytes were stimulated for 96h with phytohemagglutinin (PHA) and varying concentrations of chlorpropamide and FBP. They were stimulated for 24h with lipopolysaccharide (LPS) and varying concentrations of chlorpropamide and FBP were used. Chlorpropamide at concentrations between 2.5 and 10mM and FBP at concentrations between 1.25 and 10mM decreased proliferation of T-lymphocytes. The chlorpropamide reduced the viability only at a concentration of 10mM and FBP at concentrations of 5.0 and 10mM. The levels of sTNFRII were reduced at chlorpropamide concentrations between 2.5 and 5mM and FBP between 1.25 and 2.5mM. In conclusion, our results suggest that FBP acts, as does chlorpropamide, to inhibit the cellular proliferation and thereby reducing the sTNFRII levels through blockage of the potassium channels. In this way it acts as a powerful immunomodulatory agent.

Cell Survival↗
PubMed2004

Sucrose synthase isoforms in cultured tobacco cells.

The plant enzyme sucrose synthase (SuSy; EC 2.4.1.13) catalyzes the reversible conversion of sucrose and UDP into UDP-glucose (UDP-Glc) and fructose. The enzyme exists in different isoforms and is both located in the cytosol, membrane-bound and associated to the actin cytoskeleton. We here investigate sucrose synthase from tobacco (Nicotiana tabacum L.) BY-2 heterotrophic cell suspensions. Two different isoforms of sucrose synthase SuSy1 and SuSy2, could be purified from cytosolic extracts of these cells using a combination of poly(ethylene glycol) (PEG) precipitation, gel filtration, ion-exchange chromatography and affinity chromatography. They were clearly distinct, both with regard to the binding to the ion-exchange column and with regard to their kinetic and regulatory properties. SuSy1, the more abundant species, showed lower V(max) and K(m) for sucrose and UDP compared to the less abundant SuSy2. The activity of SuSy2 in the breakdown direction was stimulated by 60% by actin, in contrast to that of SuSy1, which showed a 17% inhibition. An indication of interaction between SuSy1 and actin was obtained by partitioning in aqueous Dextran-PEG two-phase systems. Furthermore, fructose 2,6-bisphosphate (F26BP) at micromolar concentrations stimulated SuSy2 in the presence of actin while SuSy1 was strongly inhibited by fructose. Possible roles of these two isoforms in the sucrose turnover in BY-2 cells are discussed.

Catalase↗
PubMed2004

Protective effects of exogenous fructose-1,6-biphosphate during small bowel transplantation in rats.

BACKGROUND: We assessed the effect of adding exogenous fructose-1,6-biphosphate (F16BP) to the preservation solution (University of Wisconsin storage solution) used during an experimental procedure of small bowel transplantation in rats. METHODS: We studied levels of the nucleotides hypoxanthine/xanthine and adenosine in tissue after cold ischemia, as well as histologic changes and associated deleterious processes such as bacterial translocation produced by the reperfusion associated with the transplantation. RESULTS: The groups of rats treated with F16BP showed the lowest levels of hypoxanthine/xanthine and uric acid, the highest levels of adenosine, and the lowest levels of histologic damage and lactate dehydrogenase release to the bloodstream. Consumption of intestinal hypoxanthine during reperfusion was lowest in the groups treated with F16BP, as was the incidence of bacterial translocation. CONCLUSIONS: This study shows a protective effect of exogenous F16BP added to University of Wisconsin solution during experimental intestinal transplantation in rats. This protective effect, reflected by decreased intestinal damage and bacterial translocation, was related to a decrease in adenosine triphosphate depletion during cold ischemia before intestinal transplantation, and to the reduced availability of xanthine oxidase substrates for free radical generation during reperfusion.

Adenosine↗
PubMed2004

Fructose-2,6-bisphosphate: a traffic signal in plant metabolism.

Fructose-2,6-bisphosphate (Fru-2,6-P(2)) regulates key reactions of the primary carbohydrate metabolism in all eukaryotes. In plants, Fru-2,6-P(2) coordinates the photosynthetic carbon flux into sucrose and starch biosynthesis. The use of transgenic plants has allowed the regulatory models to be tested by modifying the Fru-2,6-P(2) levels and the enzymes regulated by Fru-2,6-P(2). Genes for the bifunctional plant enzyme that synthesizes and degrades Fru-2,6-P(2) have been isolated and molecular characterization has provided new insight into structure and molecular regulation of the enzyme. Advances in Fru-2,6-P(2) physiology and molecular biology are discussed. These advances have not only enlightened in vivo operation of Fru-2,6-P(2) but also revealed that the Fru-2,6-P(2) regulatory system is highly complex and interacts with other regulatory mechanisms.

Fructosediphosphates↗
PubMed2004

Protective effect of fructose-1,6-bisphosphate in the cold storage solution for liver preservation in rat hepatic transplantation.

Fructose-1,6-bisphosphate (FBP) has been reported to have a protective effect on liver injury following ischemic/reperfusion periods. FBP maintains ATP levels and thereby cellular energy metabolism, which is important to the liver during cold preservation. In the present study, we evaluated the effects of FBP on the composition of storage solutions for cold liver preservation. Adult male Wistar rats were randomly divided into three experimental groups. Hepatic perfusion and preservation were performed with UW, UW plus 10 mmol/L FBP (UWM), and FBP 10 mmol/L (FBPS) alone solutions. Biochemical measurements of AST, ALT, and TBARS were performed on samples of the cold storage solution at 0, 12, 18, and 24 hours preservation. FBPS and UW solutions showed similar preservation grades during 18 hours. Addition of 10 mmol/L of FBP to UW solution induced liver injury and a poor preservation grade. FBP appears to protect the liver from injury caused by free radicals when the preservation time is less than 18 hours. Therefore, FBP may exert a protective effect for the preservation of livers during cold storage, and could represent an important component of new cold storage solutions.

Adenosine↗