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PubMed1992

Exogenous quinones directly inhibit the respiratory NADH dehydrogenase in Escherichia coli.

The ability of naphthoquinones to generate reactive oxygen species has been widely exploited in studies of oxidative stress. However, excess superoxide dismutase and catalase failed to protect Escherichia coli in rich medium against growth inhibition by plumbagin, indicating that its toxic effect was not due to the production of partially reduced oxygen species. Respiration failed immediately upon the addition of growth-inhibitory levels of plumbagin. Studies in vitro showed that plumbagin and other redox-active quinones intercept electrons from NADH dehydrogenase, the primary respiratory dehydrogenase in glucose-containing media. An excess of oxidative substrate, such as plumbagin, inactivates this enzyme, which appears to be redox-regulated. The resultant respiratory arrest is a cautionary example of metabolic dysfunction from redox-cycling drugs that cannot be attributed to superoxide or hydrogen peroxide.

Cell Membrane↗

PubMed1987

Heterogeneity of changes on the disposition of aspirin in rats with CCl4-induced chronic liver damage.

The profile of urinary salicylate metabolites was determined after the oral administration of acetylsalicylic acid (ASA) to CCl4-cirrhotic rats, CCl4-cirrhotic rats treated with colchicine for 1 month, and control groups. The following enzymatic activities were determined: liver and plasma ASA-esterase, liver UDP-glucuronyltransferase, and liver aniline hydroxylase. The time-course of plasma concentration of salicylates in similar groups was followed after the intraperitoneal administration of salicylic acid (SA) or gentisic acid (GA). The cirrhotic animals showed a lack of urinary glucuronates and an increase in urinary gentisic and salicylic acids. The activities of plasma and liver ASA-esterases were increased significantly in cirrhosis, whereas aniline hydroxylase was reduced and UDP-glucuronyltransferase remained unchanged. The plasma half-lives of salicylates were reduced in the cirrhotic animals regardless of the administered parent compound. Colchicine treatment reversed almost completely the alterations. The heterogeneity of liver metabolic dysfunctions present in chronic liver disease was demonstrated. It is emphasized that the pharmacokinetic alterations produced by liver damage are the result of a complex set of factors involving changes in the hepatic circulation, protein binding, and the existence of other routes of elimination.

Aniline Hydroxylase↗

PubMed1990

Fructose-1,6-bisphosphate reduces ATP loss from hypoxic astrocytes.

Hypoxia caused injury and metabolic dysfunction of astrocytes, as indicated by a time-dependent loss of lactate dehydrogenase (LDH) activity and ATP content. The combination of 3.5 mM fructose-1,6-bisphosphate (FBP) and 7.5 mM glucose (GLC) reduced the decrease of ATP and prevented the loss of LDH. These data indicate that the combination of GLC + FBP protects astrocytes from hypoxia. The results also suggest that the maintainance of ATP concentration is the mechanism by which FBP prevents hypoxic injury.

Adenosine Triphosphate↗

PubMed1991

Dynamic changes in local cerebral glucose utilization following cerebral conclusion in rats: evidence of a hyper- and subsequent hypometabolic state.

Following cerebral concussion, in which there is no evidence of direct morphological damage, cells are exposed to an increase in extracellular potassium as well as an accumulation of calcium. This concussion-induced ionic flux most likely alters the cellular energy demands thereby modifying metabolic processes. To investigate the metabolic changes after cerebral concussion, local cerebral metabolic rates for glucose (lCMRglc) utilizing [14C]2-deoxy-D-glucose were studied in rats (n = 98; 250-300 g) immediately, 30 min, 6 h, 1, 2, 3, 5 and 10 days following a unilateral frontoparietal fluid percussion (F-P) injury (3.7-4.3 atm). Compared to sham controls, animals exhibited bilateral hypermetabolism immediately following brain injury. However, this effect was more pronounced in structures ipsilateral to the site of F-P and was especially marked for the cerebral cortex (46.6-30.1% higher than control) and hippocampus (90.1-84.4% higher than control). By 30 min post-trauma many ipsilateral regions still showed evidence of hypermetabolism, although their lCMRglc had subsided. Beginning as early as 6 h following injury many regions within the ipsilateral cortex and hippocampus went into a state of metabolic depression (16.4-33.7% of control) which lasted for as long as 5 days. These results indicate that, although not mechanically damaged from the insult, cells exposed to concussive injury dramatically alter their metabolic functioning. This period of post-concussive metabolic dysfunction may delineate a period of time, following injury, during which cells are functionally compromised.

Animals↗

PubMed1993

beta-Amyloid peptides induce degeneration of cultured rat microglia.

Microglia are often associated with senile plaques, a primary pathological hallmark of Alzheimer's disease (AD) that consists largely of insoluble deposits of beta-amyloid (A beta) protein. Synthetic A beta peptides have been shown to induce neurite dystrophy and neuronal death in vitro when the peptides are assembled into aggregates. We now report that assembled A beta peptides induce morphological evidence of degeneration in process-bearing microglia in vitro, as well as metabolic dysfunction in microglial cultures, but a non-assembling scrambled sequence A beta peptide does not.

Amyloid beta-Peptides↗

PubMed1990

Heymann antigen GP330 demonstrates affinity for fibronectin, laminin, and type I collagen and mediates rat proximal tubule epithelial cell adherence to such matrices in vitro.

We have utilized monoclonal antibodies directed against glycoproteins on the surface of proximal tubule epithelial cells (PTEC) to study their interaction with matrix components. PTEC exposed to monoclonal antibodies directed against a 330-kDa cell surface glycoprotein exhibited a significant epitope-specific inhibition of attachment and proliferation on type I collagen-, fibronectin-, laminin-, and gelatin-coated tissue culture surfaces. This effect was not due to antibody toxicity since such cells did not exhibit metabolic dysfunction in suspension cultures and the inhibition could be reversed upon removal of the antibody from the cell surface. Furthermore, detergent-solubilized gp330 demonstrated specific affinity for fibronectin, laminin, and type I collagen which was not inhibited by Arg-Gly-Asp-containing peptides. A monoclonal antibody directed against the receptor epitope was capable of promoting PTEC adherence and growth when such an antibody was immobilized on cell culture dishes. Although gp330 acted as a receptor for matrix proteins in primary cultures of freshly isolated PTEC, this effect was not demonstrable in established cultures. These results suggest that freshly isolated PTEC depend on gp330 for their attachment to matrix molecules while in vitro-adapted PTEC rely on other receptors activated by culture conditions. The affinity of gp330 for matrix molecules may be of pathogenic relevance in the persistence of gp330-containing immune complexes formed in the glomerular capillary wall in experimental membranous nephropathy (Heymann nephritis).

Animals↗

PubMed1993

Metabolic disturbances in Plasmodium coatneyi-infected rhesus monkeys.

To investigate metabolic disturbances in an animal model of human malaria, four rhesus monkeys (Macaca mulatta) were infected with Plasmodium coatneyi, a parasite which induces cytoadherence of infected erythrocytes. When moribund or the parasitaemia had plateaued, the monkeys were sacrificed (3 animals) or treated with chloroquine (1 animal). Blood and cerebrospinal fluid (CSF) were sampled at intervals between inoculation and sacrifice or treatment. Arterial and CSF glucose and lactate rose during infection, indicating evolving insulin resistance. The arteriovenous difference in glucose concentration also increased, consistent with increased glucose consumption by parasitised tissues. Arterial plasma lactate rose but a positive arteriovenous concentration difference suggested tissue lactate uptake. The animal with the highest plasma lactate at sacrifice remained hyperglycaemic but also had the highest CSF lactate, the greatest cerebral sequestration and neurological depression, and biochemical and histological evidence of severe hepatic pathology. Serum cholesterol and corrected serum calcium fell consistently during infection; serum phosphate was also reduced in animals without renal impairment. These preliminary results indicate that lactic acidosis is a late complication of severe malaria and, by implication from this and other studies, hypoglycaemia occurs even later; other metabolic changes during P. coatneyi infection in rhesus monkeys also parallel those of severe falciparum malaria in humans. The model could be used in further studies of malaria-associated metabolic dysfunction and its management.

Animals↗

PubMed1985

Endochondral ossification of the condyle in rats on a strontium or low-calcium diet.

The mechanism of abnormal endochondral ossification induced by administration of strontium salts was studied in the mandibular condyles of rats by radiographic, histologic, and histochemical methods. It was shown by radiographic and histologic findings that ossification of the mandibular ramus was clearly inhibited in rats fed a low-calcium diet and rats fed a strontium diet. The change in appearance of the mandibular condyles of the rats fed strontium was more severe than that in those fed low amounts of calcium. From the histochemical findings, it was suggested that the metabolic dysfunction of chondroitin sulfate, periodic acid-Schiff positive materials, and collagen in the hypertrophic zone of the condylar cartilage (or in the part corresponding to trabecular bone of the mandibular ramus) was one factor inhibiting normal endochondral ossification.

Animals↗

PubMed1986

Trimethyltin as a selective adrenal chemosympatholytic agent in vivo: effect precedes both clinical and histopathological evidence of toxicity.

Trimethyltin (TMT) is a potent neuronotoxiciant but there is little data regarding its systemic effects. In this study, female BALB/c mice were administered either 0.9% saline or 2.75 mg TMT/kg intraperitoneally (i.p.). The animals were then housed in room air or in glass chambers flushed with either 10%, 40%, or 100% oxygen. Mice were sacrificed at 4, 8, 24, and 48 h after treatment and adrenals analyzed for various neurotransmitters by ion-pairing HPLC with electrochemical detection. In addition, adrenal S-adenosylmethionine (SAM) and blood ketone bodies were determined Sections of adrenals were evaluated by electron microscopy for histopathological changes. In vivo treatment with the toxicant resulted in a significant decrease in adrenal epinephrine and norepinephrine levels as early as 8 h following treatment. This effect preceded the appearance of both clinical signs and histopathological changes in the hippocampus by 12-24 h. With exposure to TMT in room air, mouse adrenal content of epinephrine fell from 1861.3 +/- 97.3 ng/4 mg to 1493.3 +/- 137.0 ng/4 mg while norepinephrine levels fell from 779.6 +/- 32.3 ng/4 mg to 503.4 +/- 44.3 ng/4 after 8 h. Supplementation with 40% oxygen did not attenuate this effect but in the case of mice treated with TMT and housed in 100% oxygen for 48 h, actually exacerbated the adrenal epinephrine depletion. Housing in approximately half normal atmospheric oxygen (10%) neither prevented nor enhanced the effects of TMT. The epinephrine/norepinephrine ratios were: control, 2.44; TMT (room air), 1.56; TMT (10% O2), 1.72; TMT (40% O2), 1.44; TMT (100% O2), 1.07. None of the conditions used in this study caused a decrease in adrenal dopamine, 5-hydroxyindole acetic acid (5-HIAA), 5-hydroxytryptamine (5-HT) or in the level of SAM. TMT treatment significantly increased blood ketone bodies indicating additional metabolic dysfunction. The significance of these findings in relation to TMT neuronotoxicity and fatty liver syndrome are discussed.

3-Hydroxybutyric Acid↗

PubMed1992

Neuroprotective effects of graded reoxygenation following chronic hypoxia in neuronal cell cultures.

The present study was undertaken to investigate the comparative effects of rapid vs graded correction of chronic hypoxia in vitro. Cerebral cortical cell cultures obtained from fetal mice were exposed to 5% O2 for 24 h and returned immediately to room air for the following 24 h (Group I); comparable cultures were exposed to 5% O2 for 24 h followed by 10% O2 for an additional 24 h before return to room air (Group II). At the conclusion of the experimental protocol (time 0), partial pressure of oxygen in the bathing medium of Group I cultures was significantly higher than that of Group II and non-hypoxic controls (151 mmHg vs 124 and 132 mmHg, respectively; P less than 0.05). Throughout the recovery period, Group II cultures evidenced improved neuronal survival (e.g. 35,800 vs 17,700 neurons/culture well at time 0, P less than 0.01), decreased lactate dehydrogenase efflux into the bathing medium, relative preservation of neuronal morphology, as well as higher specific and clonazepam-displaceable benzodiazepine binding and GABA uptake. Glutamate binding was not differentially affected and glutamine synthetase activity, a predominantly glial marker, was only modestly increased after graded reoxygenation. These results demonstrate that gradual reoxygenation after prolonged hypoxia in vitro (i) improves neuronal survival compared to rapid reoxygenation and (ii) delays the manifestations of metabolic dysfunction even though the length of hypoxic exposure is increased. The findings are also consistent with the concept that a period of relative hyperoxia may contribute to hypoxia-induced neuronal injury.

Animals↗

PubMed1985

Analysis of D-penicillamine by gas chromatography utilizing nitrogen--phosphorus detection.

A method is presented for the analysis of the "orphan" drug D-penicillamine (D-Pa), which is used for the treatment of the inherited rare copper metabolism dysfunction known as Wilson's disease, by assaying a derivative of the compound by gas chromatography employing a rubidium sensitized nitrogen--phosphorus detector. Analytical procedures are described for the analyses of residues of D-Pa X HCl salt in animal feed and for the analyses of the salt or free base from aqueous solutions by utilizing a single-step double derivatization with diazomethane--acetone. Stability data for D-Pa X HCl in animal feed and for the free base in water are presented. An ancillary fluorescence derivatization procedure for the analysis of D-Pa in water is also reported.

Animal Feed↗

PubMed1993

A maintained afterload model of ischemia in erythrocyte-perfused isolated working hearts.

The aim of this study was to develop an erythrocyte-perfused isolated working heart model of global ischemia that would allow controllable reductions in coronary perfusion pressure but with maintained afterload to facilitate the temporal association of myocardial ischemia with ventricular contractile or metabolic dysfunction. Isolated working rat hearts were perfused at 37 degrees C with a washed, resuspended porcine erythrocyte perfusate (40% hematocrit) at a preload of 10 mmHg and afterload of 75 mmHg, paced at 300 beats per min. A bifurcation above the aorta permitted imposition of two one-way valves, one opened by ventricular ejection in systole and closed by aortic afterload in diastole, the other closed by aortic pressure from ventricular ejection but opened to allow coronary perfusion in diastole according to an adjustable pressure head (75 mmHg initially). Ischemia was imposed by lowering the coronary perfusion pressure to 35 mmHg while maintaining diastolic afterload at 75 mmHg. The presence of erythrocytes provides oxygen delivery in the normal physiological range. This model permits the severity of ischemia to be graded by any specified level. The maintained afterload model of ischemia is a simple enhancement of the isolated working heart permitting a separation of workload and coronary perfusion pressure variables. This provides greater control over and direct monitoring of experimental ischemic events in progress.

Animals↗

PubMed2005

Synthesis and biological evaluation of sulfonamidooxazoles and beta-keto sulfones: selective inhibitors of 11beta-hydroxysteroid dehydrogenase type I.

The design, synthesis, and biological evaluation of arylsulfonamidooxazoles as 11beta-HSD1 inhibitors and the serendipitous discovery of beta-keto sulfones as potent 11beta-HSD1 inhibitors are described here. These two classes of compounds are not active against 11beta-HSD2 and therefore may have significant therapeutic potential for metabolic syndrome, type 2 diabetes and related metabolic dysfunctions.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗

PubMed2006

Effects of chronic risperidone treatment on the striatal protein profiles in rats.

Extrapyramidal symptoms (EPS) commonly occur as side effects of antipsychotic drugs (APDs) and are most likely to arise when the occupancy of dopamine D(2) receptors in the striatum by these drugs exceeds 80%. We aimed to characterize changes in the protein expression profile in the striatum of rats after chronic (4 week) supra-therapeutic (EPS-inducing) treatment with risperidone (RIS), an atypical antipsychotic drug. Administration of RIS (2.1 mg/kg/day, via subcutaneous osmotic minipumps) induced significant vacuous chewing movements and catalepsy in male Sprague-Dawley rats over a 28-day treatment period compared with a vehicle (VEH) control group (n=12) (Karl et al., unpublished observation). Using two-dimensional gel electrophoresis (2DE), total protein extracts from the rat brain striatum were separated and protein expression was analyzed by Phoretix 2D Expression and Image Beta V4.02 software followed by matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). 2DE gels resolved up to 450 protein spots, presumably different proteins and/or their isoforms. There were 30 protein spots showing statistically significant different densities between the RIS- and VEH-treated groups. All 30 proteins were successfully identified by MALDI-TOF MS, 28 of these were divided into groups based on their known functions. These included metabolic, signaling, transport, protein metabolism, chaperone, DNA binding and cell cycle categories. We conclude that chronic risperidone treatment accompanied by an EPS-like behavioral phenotype results in alterations in the striatal protein profile possibly subsequent to blockade of dopaminergic systems. These results suggest that possible mechanisms involved in APD-induced EPS include metabolic dysfunction and oxidative stress.

Analysis of Variance↗

PubMed2004

Evaluation of some biochemical changes in diabetic patients.

OBJECTIVE: Hyperglycemia is considered a primary cause of diabetic vascular complications and is associated with oxidative stress, impaired trace element and lipid metabolism as well as pancreatic enzyme abnormalities. The role of trace elements in some of the metabolic dysfunctions and their contributions in the development of vascular complications is not clear. Therefore, the present study investigates the relationship among diabetes mellitus, trace elements status, advanced glycation end products (AGEs), advanced oxidation protein products (AOPP), lipid profiles, antioxidant status, nitric oxide and pancreatic amylase activity in the sera of 55 non-insulin-dependent diabetes mellitus (NIDDM; 35 with microvascular complications and 20 without vascular complications), 40 insulin-dependent diabetes mellitus (IDDM; 25 with microvascular and 15 without microvascular complications), and 20 nondiabetic healthy control subjects. The mean age of the diabetic patients was similar to that of control. The mean duration of the disease was 11.8 +/- 6.8 years (3-27 years) in IDDM and 7.1 +/- 4.7 years (1-15 years) in NIDDM. METHODS: Plasma Cu, Zn, Mg, Ca, thiobarbituric acid-reactive substance (i.e. malondialdehyde; MDA), nitric oxide (NO), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), ceruloplasmin (Cp) and amylase activities as well as AOPP were assessed spectrophotometrically whereas AGEs were estimated spectrofluorometrically in two types of diabetes mellitus (DM) as well as control subjects of matched sex and ages. RESULTS: SOD, CAT and Cp activities were decreased whereas serum alpha-amylase activity was increased in two types of DM in comparison to the corresponding activities of the control subjects. The plasma levels of MDA, NO and Cu were increased but GSH, Zn, Mg and Ca levels were significantly diminished in diabetic patients as compared to the controls. The averages of total cholesterol (CHOL), triglyceride (TG) and low-density lipoprotein-cholesterol (LDLc) were higher in both types of diabetes mellitus in comparison to the control subjects. The mean value of high-density lipoprotein-cholesterol (HDLc) was lower in both types of diabetes mellitus. Further, the mean values of AGEs and AOPP were elevated in diabetic patients vs. control. These parameters are significantly higher in NIDDM patients when compared to the IDDM subjects. Slight but not significant differences in these parameters were observed in patients with diabetic complications when compared to that of without diabetic complications. CONCLUSION: These findings may explain the role of impaired trace element status, defect of antioxidants and increased of AGE and AOPP in the pathogenesis of pancreas and the vascular complications of diabetes mellitus. Oxidative stress is increased in both types of DM, but it is more in NIDDM patients than in IDDM subjects. In addition, oxidative stress also plays an important role in the formation of AGEs and AOPP in DM.

Aged↗

PubMed2005

Dietary and genetic control of glucose transporter 2 glycosylation promotes insulin secretion in suppressing diabetes.

Pancreatic beta cell-surface expression of glucose transporter 2 (Glut-2) is essential for glucose-stimulated insulin secretion, thereby controlling blood glucose homeostasis in response to dietary intake. We show that the murine GlcNAcT-IVa glycosyltransferase is required for Glut-2 residency on the beta cell surface by constructing a cell-type- and glycoprotein-specific N-glycan ligand for pancreatic lectin receptors. Loss of GlcNAcT-IVa, or the addition of glycan-ligand mimetics, attenuates Glut-2 cell-surface half-life, provoking endocytosis with redistribution into endosomes and lysosomes. The ensuing impairment of glucose-stimulated insulin secretion leads to metabolic dysfunction diagnostic of type 2 diabetes. Remarkably, the induction of diabetes by chronic ingestion of a high-fat diet is associated with reduced GlcNAcT-IV expression and attenuated Glut-2 glycosylation coincident with Glut-2 endocytosis. We infer that beta cell glucose-transporter glycosylation mediates a link between diet and insulin production that typically suppresses the pathogenesis of type 2 diabetes.

Animals↗

PubMed2005

Effects of KR-32570, a new Na+/H+ exchanger inhibitor, on functional and metabolic impairments produced by global ischemia and reperfusion in the perfused rat heart.

The present study was performed to evaluate the cardioprotective effects of [5-(2-methoxy-5-chloro-5-phenyl)furan-2-ylcarbonyl]guanidine (KR-32570) on ischemia/reperfusion-induced mechanical and metabolic dysfunction in isolated rat hearts. In addition, the effects of KR-32570 on the Na(+)/H(+)-exchanger (NHE) and lipid peroxidation were also evaluated. KR-32570 strongly inhibited the recovery from acidosis induced by an NH(4)Cl prepulse in PS120 fibroblast cells expressing the human NHE-1 isoform (IC(50): 0.05 and 1.16 microM for KR-32570 and cariporide, respectively). In isolated perfused rat hearts subjected to 30-min ischemia/30-min reperfusion, KR-32570 (1-10 microM) significantly and concentration dependently improved cardiac contractile function and severe contracture in conjunction with causing a marked reduction in lactate dehydrogenase release. Additionally, it (1-10 microM) significantly increased the content of ATP, creatine phosphate and glycogen as well as decreased the tissue lactate content in heart homogenates following ischemia and reperfusion. KR-32570 (1-10 microM) significantly decreased the concentration of 8-iso-prostaglandin F(2 alpha), a reliable marker for oxidant stress, in perfusates from rat hearts subjected to ischemia and reperfusion. In separate experiments, KR-32570 significantly lowered the concentration of malondialdehyde in rat liver homogenate and inhibited Cu(2+)-induced peroxidation of low-density lipoprotein. Taken together, these results suggest that KR-32570 possesses potent cardioprotective effects in perfused rat hearts, and its effects may be mediated by inhibition of NHE-1, preservation of high-energy phosphates, and inhibition of lipid peroxidation.

Adenosine Triphosphate↗

PubMed2006

Wld(S) mice are protected against the Parkinsonian mimetic MPTP.

The progressive loss of the nigrostriatal pathway is a distinguishing feature of Parkinson's disease. Because terminal field loss appears to precede cell body loss, we tested whether the mouse mutant Wld(S), which delays axonal degeneration in a variety of disorders, would ameliorate nigrostriatal degeneration following treatment with the Parkinsonian mimetic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The present findings show that the Wld(S) gene product enhances survival, prevents nigrostriatal axon degeneration, and attenuates neurotransmitter loss but does not rescue cell bodies. As MPTP is thought to impair mitochondrial energy production, these data suggest that disease pathology due to metabolic dysfunction could be improved by the Wld(S) gene product. These results suggest new therapeutic avenues for Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗