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At least 1,423 records · Page 79Linked to original sources
PubMed2006

GLUT4 repression in response to oxidative stress is associated with reciprocal alterations in C/EBP alpha and delta isoforms in 3T3-L1 adipocytes.

Insulin responsiveness of adipocytes is acquired during normal adipogenesis, and is essential for maintaining whole-body insulin sensitivity. Differentiated adipocytes exposed to oxidative stress become insulin resistant, exhibiting decreased expression of genes like the insulin-responsive glucose transporter GLUT4. Here we assessed the effect of oxidative stress on DNA binding capacity of C/EBP isoforms known to participate in adipocyte differentiation, and determine the relevance for GLUT4 gene regulation. By electrophoretic mobility shift assay, nuclear proteins from oxidized adipocytes exhibited decreased binding of C/EBPalpha-containing dimers to a DNA oligonucleotide harboring the C/EBP binding sequence from the murine GLUT4 promoter. C/EBPdelta-containing dimers were increased, while C/EBPbeta-dimers were unchanged. These alterations were mirrored by a 50% decrease and a 2-fold increase in the protein content of C/EBPalpha and C/EBPdelta, respectively. In oxidized cells, GLUT4 protein and mRNA levels were decreased, and a GLUT4 promoter segment containing the C/EBP binding site partially mediated oxidative stress-induced repression of a reported gene. The antioxidant lipoic acid protected against oxidation-induced decrease in GLUT4 and C/EBPalpha mRNA, but did not prevent the increase in C/EBPdelta mRNA. We propose that oxidative stress induces adipocyte insulin resistance partially by affecting the expression of C/EBPalpha and delta, resulting in altered C/EBP-dimer composition potentially occupying the GLUT4 promoter.

3T3-L1 Cells↗
PubMedDate not supplied

Oxidative stress in hypertension.

Several experimental and clinical evidences have linked an enhanced production of reactive oxygen species (ROS) to certain diseases of the cardiovascular system including hypertension and diabetes. However, it has never been clearly established whether the enhanced oxidative stress observed in those conditions is primary or secondary to the pathological process. Our experimental studies have permitted to demonstrate that ROS, mainly through the production of superoxide anion, can cause important alterations in the cellular signal transduction systems characterized by an enhanced production of inositol triphosphate and a reduced production of cyclic GMP in cultured vascular smooth muscle cells (SMC), thus favouring the vasoconstriction. Since those effects were found to be increased in SMC from spontaneously hypertensive rats (SHR), this suggested a greater sensitivity of the vascular tissue of SHR to the oxidative stress. Moreover, we also have observed an increased production of superoxide anion in the aorta of rats made hypertensive according to the SHR, glucose or angiotensin-induced and DOCA-salt models during the development of hypertension. Since the superoxide anion production could be correlated with the level of blood pressure and since the development of hypertension could be either totally prevented or markedly attenuated by chronic treatment with potent antioxidative therapies such as alpha lipoic acid or aspirin, this suggested a major contribution of vascular superoxide anion production in the development of hypertension in those models. Moreover, the development of insulin resistance, which is associated to the model of glucose-induced hypertension, was also found to be prevented by chronic antioxidant therapies, thus suggesting that oxidative stress plays an important role as well in the development of insulin resistance and type 2 diabetes. In conclusion, it appears that oxidative stress may constitute a major pathogenic factor in the development of hypertension and type 2 diabetes. Moreover, our studies suggest that the chronic treatment with appropriate antioxidative therapies could prevent the development of hypertension and diabetes as well as their complications in various experimental models of hypertension.

Animals↗
PubMed2001

Effects of thiol antioxidants on hepatocyte growth factor signaling in cardiac myocytes.

We describe here novel antioxidant-sensitive events in which activation kinetics are delayed, leading to inhibition of cell signaling. Hepatocyte growth factor (HGF) transiently phosphorylated p44/42 mitogen-activated protein kinase (MAPK) with a peak at 3-5 min in HL-1 adult cardiac myocytes. Pretreatment of cells with thiol antioxidants, N-acetylcysteine or alpha-lipoic acid attenuated MAPK phosphorylation induced by a 3-min incubation with HGF. However, kinetic analysis revealed that the apparent inhibition of HGF signaling was due to a delay in the activation because HGF phosphorylated MAPK with a peak at 5-7 min in cells treated with thiol antioxidants. This 2-min delay in HGF activation of MAPK resulted in >5-min delay in phosphorylation of MAPK targets such as p90RSK and GATA-4. Hydrogen peroxide did not mimic HGF signaling, and HGF did not induce reactive oxygen species production. Thus, in cardiac myocytes, thiol antioxidants delay HGF-mediated MAPK activation and suppress subsequent signaling eventsvia reactive oxygen species-independent mechanism.

Animals↗
PubMedDate not supplied

The molecular basis for oxidative stress-induced insulin resistance.

Reactive oxygen and nitrogen molecules have been typically viewed as the toxic by-products of metabolism. However, accumulating evidence has revealed that reactive species, including hydrogen peroxide, serve as signaling molecules that are involved in the regulation of cellular function. The chronic and/or increased production of these reactive molecules or a reduced capacity for their elimination, termed oxidative stress, can lead to abnormal changes in intracellular signaling and result in chronic inflammation and insulin resistance. Inflammation and oxidative stress have been linked to insulin resistance in vivo. Recent studies have found that this association is not restricted to insulin resistance in type 2 diabetes, but is also evident in obese, nondiabetic individuals, and in those patients with the metabolic syndrome. An increased concentration of reactive molecules triggers the activation of serine/threonine kinase cascades such as c-Jun N-terminal kinase, nuclear factor-kappaB, and others that in turn phosphorylate multiple targets, including the insulin receptor and the insulin receptor substrate (IRS) proteins. Increased serine phosphorylation of IRS reduces its ability to undergo tyrosine phosphorylation and may accelerate the degradation of IRS-1, offering an attractive explanation for the molecular basis of oxidative stress-induced insulin resistance. Consistent with this idea, studies with antioxidants such as vitamin E, alpha-lipoic acid, and N-acetylcysteine indicate a beneficial impact on insulin sensitivity, and offer the possibility for new treatment approaches for insulin resistance.

Animals↗
PubMedDate not supplied

Cell culture modeling to test therapies against hyperglycemia-mediated oxidative stress and injury.

The concept that oxidative stress is a key mediator of nerve injury in diabetes has led us to design therapies that target oxidative stress mechanisms. Using an in vitro model of glucose-treated dorsal root ganglion (DRG) neurons in culture, we can examine both free radical generation, using fluorimetric probes for reactive oxygen species, and cell death via the TUNEL assay. The cell culture system is scaled down to a 96-well plate format, and so is well suited to high-throughput screening. In the present study, we test the ability of three drugs, nicotinamide, allopurinol, and alpha-lipoic acid, alone and in combination to prevent DRG neuron oxidative stress and cell death. This combination of drugs is currently in clinical trial in type 1 diabetic patients. We demonstrate independent effects on oxidative stress and neuronal survival for the three drugs, and neuronal protection using the three drugs in combination. The data strengthen the rationale for the current clinical trial. In addition, we describe an effective tool for rapid preclinical testing of novel therapies against diabetic neuropathy.

Animals↗
PubMedDate not supplied

Diabetic retinopathy: mitochondrial dysfunction and retinal capillary cell death.

Oxidative stress is increased in the retina in diabetes; the levels of oxidatively modified DNA and nitrosylated proteins are elevated, and antioxidant defense enzymes are impaired. The levels of superoxides are elevated in the retina, and the mitochondria become dysfunctional with proapoptotic protein, Bax, translocating from the cytosol into the mitochondria, and cytochrome c leaking out from the mitochondria. This is accompanied by increased retinal capillary cell apoptosis, and the formation of acellular capillaries and pericyte ghosts, the early signs of retinopathy in animal models of diabetic retinopathy. Inhibition of superoxides inhibits glucose -induced mitochondrial dysfunction, activation of caspase-3, and cell death in retinal capillary cells. In animal models, long-term administration of lipoic acid or other antioxidants inhibits the development of diabetic retinopathy via inhibition of accumulation of oxidatively modified DNA and nitrotyrosine and capillary cell apoptosis in the retina. Understanding the role of mitochondria in the development of retinopathy in diabetes should help identify therapies that can neutralize superoxides and inhibit their dysfunction and, ultimately, the development of retinopathy.

Animals↗
PubMed2007

Effects of PGC-1alpha on TNF-alpha-induced MCP-1 and VCAM-1 expression and NF-kappaB activation in human aortic smooth muscle and endothelial cells.

Increased oxidative stress in vascular cells is implicated in the pathogenesis of atherosclerosis. Reactive oxygen species (ROS) induce vascular inflammation via the proinflammatory cytokine/NF-kappaB pathway. Several lines of evidence suggest that peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1alpha) is an important regulator of intracellular ROS levels. However, no studies have examined the effects of PGC-1alpha on this process. We investigated the effects of PGC-1alpha on inflammatory molecule expression and activity of the redox-sensitive transcription factor, NF-kappaB, in vascular cells. PGC-1alpha expressed in human aortic smooth (HASMCs) and endothelial cells (HAECs) is upregulated by AMP-activated protein kinase activators, including metformin, rosiglitazone and alpha-lipoic acid. Tumor necrosis factor-alpha (TNF-alpha), a major proinflammatory factor in the development of vascular inflammation, stimulates intracellular ROS production through an increase in both mitochondrial ROS and NAD(P)H oxidase activity. Adenovirus-mediated overexpression of the PGC-1alpha gene in HASMCs and HAECs leads to a significant reduction in intracellular and mitochondrial ROS production as well as NAD(P)H oxidase activity. Consequently, NF-kappaB activity and MCP-1 and VCAM-1 induced by TNF-alpha are suppressed. Our data support the possibility that agents stimulating PGC-1alpha expression in the vasculature aid in preventing the development of atherosclerosis.

Aorta, Thoracic↗
PubMed2000

Thiol homeostasis and supplements in physical exercise.

Thiols are a class of organic sulfur derivatives (mercaptans) characterized by the presence of sulfhydryl residues. In biological systems, thiols have numerous functions, including a central role in coordinating the antioxidant defense network. Physical exercise may induce oxidative stress. In humans, a consistent marker of exercise-induced oxidative stress is blood glutathione oxidation. Physical training programs have specific effects on tissue glutathione metabolism that depend on the work program and the type of tissue. Experimental studies show that glutathione metabolism in several tissues sensitively responds to an exhaustive bout of exercise. Study of glutathione-deficient animals clearly indicates the central importance of having adequate tissue glutathione to protect against exercise-induced oxidative stress. Among the various thiol supplements studied, N-acetyl-L-cysteine and alpha-lipoic acid hold the most promise. These agents may have antioxidant effects at the biochemical level but are also known to influence redox-sensitive cell signaling.

Acetylcysteine↗
PubMed2004

Diabetic neuropathy: an intensive review.

PURPOSE: The epidemiology, classification, pathology, and treatment of diabetic neuropathy are reviewed. SUMMARY: Diabetic peripheral neuropathy is a common complication of diabetes that can cause significant morbidity and mortality. Some 30% of hospitalized and 20% of community-dwelling diabetes patients have peripheral neuropathy; the annual incidence rate is approximately 2%. The primary risk factor is hyperglycemia. Sensorimotor neuropathy is marked by pain, paresthesia, and sensory loss. Cardiac autonomic neuropathy (CAN) may contribute to myocardial infarction, malignant arrhythmia, and sudden death. Gastroparesis is the most debilitating complication of gastrointestinal autonomic neuropathy. Genitourinary autonomic neuropathy can cause sexual dysfunction and neurogenic bladder. The pathology of diabetic neuropathy involves oxidative stress, advanced glycation end products, polyol pathway flux, and protein kinase C activation; all contribute to microvascular disease and nerve dysfunction. For symptom management current evidence from clinical trials supports the use of desipramine, amitriptyline, capsaicin, tramadol, gabapentin, bupropion, and venlafaxine as preferred medications. Citalopram, nonsteroidal antiinflammatory drugs, and opioid analgesics may be used as adjuvant agents. Lamotrigine, oxcarbazepine, paroxetine, levodopa, and alpha-lipoic acid are alternative considerations. Evidence supporting the use of zonisamide, fluoxetine, mexiletine, dextromethorphan, and phenytoin is considered equivocal. Complementary therapies have also shown efficacy. The symptoms of CAN may be ameliorated with fludrocortisone, clonidine, midodrine, dihydroergotamine or caffeine, octreotide, and beta-blockers. Gastroparesis may be treated with metoclopramide or erythromycin. The most promising disease-modifying therapy is ruboxistaurin, which is in Phase III trials. Glycemic control remains the foundation of prevention and the prerequisite of adequate treatment. CONCLUSION: Diabetic neuropathy is a many-faceted complication of diabetes that can be managed symptomatically with an array of drugs.

Analgesics, Opioid↗
PubMed1999

Structure and selectivity in post-translational modification: attaching the biotinyl-lysine and lipoyl-lysine swinging arms in multifunctional enzymes.

The post-translational attachment of biotin and lipoic acid to specific lysine residues displayed in protruding beta-turns in homologous biotinyl and lipoyl domains of their parent enzymes is catalysed by two different ligases. We have expressed in Escherichia coli a sub-gene encoding the biotinyl domain of E.coli acetyl-CoA carboxylase, and by a series of mutations converted the protein from the target for biotinylation to one for lipoylation, in vivo and in vitro. The biotinylating enzyme, biotinyl protein ligase (BPL), and the lipoylating enzyme, LplA, exhibited major differences in the recognition process. LplA accepted the highly conserved MKM motif that houses the target lysine residue in the biotinyl domain beta-turn, but was responsive to structural cues in the flanking beta-strands. BPL was much less sensitive to changes in these beta-strands, but could not biotinylate a lysine residue placed in the DKA motif characteristic of the lipoyl domain beta-turn. The presence of a further protruding thumb between the beta2 and beta3 strands in the wild-type biotinyl domain, which has no counterpart in the lipoyl domain, is sufficient to prevent aberrant lipoylation in E.coli. The structural basis of this discrimination contrasts with other forms of post-translational modification, where the sequence motif surrounding the target residue can be the principal determinant.

Acetyl-CoA Carboxylase↗
PubMed1992

Differing epitope selection of experimentally-induced and natural antibodies to a disease-specific autoantigen, the E2 subunit of pyruvate dehydrogenase complex (PDC-E2).

Naturally-occurring autoantibodies to a family of mitochondrial enzymes, the 2-oxoacid dehydrogenase complexes (2-OADC), characterize the human liver disease primary biliary cirrhosis. The immunodominant epitope for these autoantibodies is associated with the lipoyl-binding domain of the E2 subunit of the enzymes. The reactivity of these disease-associated autoantibodies was compared with that of antibodies raised in rats and rabbits, by immunization with various preparations derived from the 2-OADC enzymes, using immunization protocols that have successfully induced various organ-specific autoimmune diseases in animals. The immunogens included the intact pyruvate dehydrogenase complex (PDC) from bovine heart, human recombinant PDC-E2, and short synthetic peptides representing the immunodominant lipoic acid binding sequences of the 2-OADC enzymes. The techniques for antibody analysis included immunofluorescence, immunoblotting on mitochondrial extracts, ELISAs using entire PDC, PDC-E2, or synthetic peptides, epitope mapping by peptide scanning on overlapping octameric peptides representing the human PDC-E2 sequence, affinity purification on PDC-E2, and inhibition in vitro by sera of the catalytic function of PDC. Experimental immunization did not elicit any evidence of autoimmune disease. Moreover, the experimentally-induced antibodies in striking contrast to the natural autoantibodies showed preferential reactivity with PDC-E2 rather than with intact PDC, failed to inhibit in vitro the catalytic function of PDC, and, on peptide scanning, reacted with discrete epitopes, but at sites other than the lipoyl-binding region of PDC-E2. Our data indicate that 'multisystem' autoimmune diseases including primary biliary cirrhosis may not be elicitable experimentally because a critical disease-relevant autoepitope is not engaged by the immune system.

Amino Acid Sequence↗
PubMed1977

Changes of lipoamide dehydrogenase and mitochondrial structure in selenium-deficient chicks.

A selenium deficiency in chicks produces degeneration and fibrosis of the pancreas. An investigation was undertaken to determine whether or not the activity of lipoic acid is impaired in the pancreas of selenium-deficient chicks. Enzymatic analyses of selenium-deficient chick tissues showed a reduction in lipoamide dehydrogenase both in pancreas and liver at a very early stage of growth. Using both direct measurements and sucrose-gradient cellular fractionation, it was found that the lipoamide dehydrogenase activity of the supernatant increased, and that of the mitochondria decreased in selenium-deficient as compared to normal chick livers. These results indicate an increased fragility of the mitochondrial membranes in selenium-deficient chicks.

Animals↗
PubMed2000

A trail of research on cofactors: an odyssey with friends.

Over the span of 40 y and with the participation of over 60 students and postdoctoral colleagues, my laboratory has been able to elucidate numerous aspects of cofactor metabolism and function. Findings have been on the absorption, transport, utilization and excretion of vitamin B-6, riboflavin, biotin, lipoate and ascorbate. Specificity studies on those trace but essential enzymes that catalyze conversion of such vitamins as B-6 and riboflavin to their functional coenzymes led to our development of "biochemically specific absorbents" that prototypically exemplified what later was called "affinity chromatography." Characterization of the purified kinases for B-6 and riboflavin revealed preference for Zn2+ with the eucaryotic enzymes and delimited effects of inhibitors that relate to drug action. Flavin adenine dinucleotide synthetase, separable from flavokinase in mammals, prefers Mg2+. Specifics for binding and function of flavocoenzymes were delineated for several flavoproteins. The flavin mononucleotide-dependent oxidase that converts the 5'-phosphates of pyridoxine and of pyridoxamine to pyridoxal phosphate is a connection between riboflavin and B-6 that we characterized in mechanistic detail and found to be the primary control point for conversion of B-6 to its coenzyme. Sequencing and cloning of a side-chain oxidase for riboflavin was achieved. Isolation and identification of metabolites of biotin and of lipoic acid, first from bacteria obtained by enrichment culture and then from mammals, provided seminal information on catabolic pathways involved, as have our other studies with flavin catabolites isolated from milk and urine.

Animals↗
PubMed2003

Nutritional approaches to late toxicities of adjuvant chemotherapy in breast cancer survivors.

Adjuvant chemotherapy of breast cancer reduces recurrence rates and prolongs survival at the cost of both acute and chronic toxicities. Breast cancer survivors who have received adjuvant chemotherapy may suffer from late effects of chemotherapy including congestive heart failure, neuropathy, premature menopause, and osteoporosis. Nutritional approaches to these problems are distinct in their orientation and success. Study of free radical scavengers for anthracycline-induced cardiomyopathy was born from known pathogenetic mechanisms of cardiotoxicity but has been universally disappointing thus far in clinical trials. Application of agents used for diabetic neuropathy suggests that evening primrose oil, alpha-lipoic acid, and capsaicin may all play a role in the empiric options available to patients with chemotherapy-induced neuropathy. Plant-derived preparations including black cohosh (Actaea racemosa), dong quai (Angelica sinensis), evening primrose (Oenothera biennis), and red clover (Trifolium pretense) are used by patients experiencing hot flashes due to premature menopause despite a paucity of clinical trial data demonstrating either safety or efficacy. Calcium and vitamin D are widely accepted as an effective means to retard bone loss leading to osteoporosis. Nutritional approaches to late effects of breast cancer chemotherapy offer the prospect of preventing or ameliorating these sequelae of treatment. However, except for vitamin D and calcium for prevention of bone loss, current clinical evidence supporting use of nutritional agents remains sparse.

Antineoplastic Agents↗
PubMed2001

Radical SAM, a novel protein superfamily linking unresolved steps in familiar biosynthetic pathways with radical mechanisms: functional characterization using new analysis and information visualization methods.

A novel protein superfamily with over 600 members was discovered by iterative profile searches and analyzed with powerful bioinformatics and information visualization methods. Evidence exists that these proteins generate a radical species by reductive cleavage of S:-adenosylmethionine (SAM) through an unusual Fe-S center. The superfamily (named here Radical SAM) provides evidence that radical-based catalysis is important in a number of previously well- studied but unresolved biochemical pathways and reflects an ancient conserved mechanistic approach to difficult chemistries. Radical SAM proteins catalyze diverse reactions, including unusual methylations, isomerization, sulfur insertion, ring formation, anaerobic oxidation and protein radical formation. They function in DNA precursor, vitamin, cofactor, antibiotic and herbicide biosynthesis and in biodegradation pathways. One eukaryotic member is interferon-inducible and is considered a candidate drug target for osteoporosis; another is observed to bind the neuronal Cdk5 activator protein. Five defining members not previously recognized as homologs are lysine 2,3-aminomutase, biotin synthase, lipoic acid synthase and the activating enzymes for pyruvate formate-lyase and anaerobic ribonucleotide reductase. Two functional predictions for unknown proteins are made based on integrating other data types such as motif, domain, operon and biochemical pathway into an organized view of similarity relationships.

Amino Acid Sequence↗
PubMed1987

Effect of avidin binding to SH1 on the interface between subfragment-1 and F-actin.

The subfragment-1-avidin complex, in which avidin is attached to a well defined thiol group called SH1, was purified by CM cellulose column chromatography or affinity chromatography using lipoic acid agarose. The interaction of the purified complex with F-actin was compared to that of normal subfragment-1 using chemical cross-linking and limited tryptic digestion techniques. It was found that the binding of avidin to SH1 lowered the extent of cross-linking between the subfragment-1 heavy chain and actin. The amount of the 175K product decreased to about 50% of the normal level and that of the 165K product decreased to about 35%. It was also found that the binding of avidin abolished the protective effect of F-actin on the 50K-22K junction of the S-1 heavy chain against tryptic attack. Since more than 95% of the S-1-avidin complex was attached to F-actin under our experimental conditions, these changes are due to an alteration of the S-1-actin interface. Considering the facts that SH1 is located on the side of S-1 facing the F-actin, in the tertiary structure, and is close to the cross-linked site and to the 50K-22K junction, in the primary structure, it is quite likely that avidin bound to SH1 causes these effects by sterically preventing the close contact of S-1 and actin.

Actins↗
PubMed2005

Short-term hyperglycemia produces oxidative damage and apoptosis in neurons.

Dorsal root ganglia neurons in culture die through programmed cell death when exposed to elevated glucose, providing an in vitro model system for the investigation of the mechanisms leading to diabetic neuropathy. This study examines the time course of programmed cell death induction, regulation of cellular antioxidant capacity, and the protective effects of antioxidants in neurons exposed to hyperglycemia. We demonstrate that the first 2 h of hyperglycemia are sufficient to induce oxidative stress and programmed cell death. Using fluorimetric analysis of reactive oxygen species (ROS) production, in vitro assays of antioxidant enzymes, and immunocytochemical assays of cell death, we demonstrate superoxide formation, inhibition of aconitase, and lipid peroxidation within 1 h of hyperglycemia. These are followed by caspase-3 activation and DNA fragmentation. Antioxidant potential increases by 3-6 h but is insufficient to protect these neurons. Application of the antioxidant alpha-lipoic acid potently prevents glucose-induced oxidative stress and cell death. This study identifies cellular therapeutic targets to prevent diabetic neuropathy. Since oxidative stress is a common feature of the micro- and macrovascular complications of diabetes, the present findings have broad application to the treatment of diabetic patients.

Aconitate Hydratase↗
PubMed2003

Exercise training and antioxidants: relief from oxidative stress and insulin resistance.

There is evidence for an association between oxidative stress and insulin resistance, possibly due to downregulation of insulin signaling. This review will address the hypothesis that exercise training and the antioxidant R-(+)-lipoic acid interact at the level of insulin signaling to enhance glucose transport in insulin-resistant skeletal muscle.

Diabetes Mellitus↗