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PubMed2002

Effect of increased concentration of D-glucose or L-fucose on monocyte adhesion to endothelial cell monolayers and activation of nuclear factor-kappaB.

Increased adhesion of monocytes to endothelial cells has been linked to the development and progression of atherosclerosis in humans with diabetes. Previous studies have shown that increased concentration of glucose and subsequent generation of reactive oxygen species and the activation of the transcription factor nuclear factor-kappaB (NF-kappaB) may mediate this response. However, our studies have shown that in addition to glucose, other monosaccharides, such as L-fucose, which is increased in circulation in diabetes, may also contribute to the development of diabetic complications. In these studies, we examined the effect of an increased concentration of L-fucose on monocyte adhesion to cultured bovine aorta endothelial cells. Exposing cultured bovine aorta endothelial cells to an increased concentration of either glucose or L-fucose caused a concentration-dependent increase in adhesion of monocytes. The increase in monocyte adhesion induced by glucose or L-fucose was preceded by the activation to NF-kappaB and the generation of reactive oxygen species. The combination of glucose and L-fucose at a submaximal concentration did not appear to have an additive effect on the induction of monocyte adhesion. The addition of alpha-lipoic acid partially prevented the glucose and L-fucose-induced activation of NF-kappaB, generation of reactive oxygen species, and increase in monocyte adhesion. This suggests that the effect of an increased concentration of glucose or L-fucose on monocyte adhesion to endothelial cells is at least partially due to the production oxygen-derived free radicals. Furthermore, these studies provide evidence that monosaccharides other than glucose that are increased in the circulation of humans with diabetes may contribute to vascular defects in diabetes.

Animals↗
PubMed1999

Toward a new definition of essential nutrients: is it now time for a third 'vitamin' paradigm?

The concepts of vitamin 'deficiency' diseases and the recommended dietary allowances (RDAs) have not kept pace with the growing understanding of the cellular and molecular functions of vitamins and other micronutrients. As a consequence, many researchers and clinicians rely on outdated signs and symptoms in assessing nutritional deficiencies. A new paradigm, presented here, proposes that: (1) deficiencies can be identified on biochemical and molecular levels long before they become clinically visible; (2) the definition of essential micronutrients be broadened to include some carotenoids and flavonoids, as well as various human metabolites, such as coenzyme Q10, carnitine, and alpha-lipoic acid, which are also dietary constituents; (4) individual nutritional requirements are partly fixed by genetics but also dynamically influenced by variations in the body's biochemical milieu and external stresses; and (5) the distinction between nutritional and pharmacological doses of vitamins is meaningless, since high doses of micronutrients may be required to achieve normal metabolic processes in some people.

Animals↗
PubMedDate not supplied

Attenuation of oxalate-induced nephrotoxicity by eicosapentaenoate-lipoate (EPA-LA) derivative in experimental rat model.

Hyperoxaluria is one of the major risk factors for the formation of urinary calcium oxalate stones. Calcium oxalate crystals and their deposition have been implicated in inducing renal tubular damage. Lipoic acid (LA) and eicosapentaenoic acid (EPA) have been shown to ameliorate the changes associated with hyperoxaluria. This prompted us to investigate the nephroprotectant role of EPA-LA, a new derivative, in vivo in hyperoxaluric rats. Elevation in the levels of calcium, oxalate and phosphorus, the stone-forming constituents, were observed in calculogenic rats as a manifestation of crystal deposition. Tubular damage to the renal tissue was assessed byassaying the excretion of marker enzymes in the urine. Damage to the tubules was indicated by increased excretion of alkaline phosphatase (ALP), lactate dehydrogenase (LDH), gamma-glutamyl transferase (gamma-GT), beta-Glucuronidase (beta-GLU) and N-Acetyl beta-D glucosaminidase (NAG). Fibrinolytic activity was found to be reduced. Administration of EPA, LA and EPA-LA reduced the tubular damage and decreased the markers of crystal deposition markedly, which was substantiated by the reduction in weight of bladder stone formed. Our results highlight that EPA-LA is the most effective drug in inhibiting stone formation and mitigating renal damage caused by oxalate toxicity, thus confirming it as a nephroprotectant. Further work in this direction is warranted to establish the therapeutic effectiveness of this new derivative.

Acetylglucosaminidase↗
PubMed2004

An accelerated assay for the identification of lifespan-extending interventions in Drosophila melanogaster.

Recent advances in aging research have uncovered genes and genetic pathways that influence lifespan in such diverse organisms as yeast, nematodes, flies, and mice. The discovery of genes and drugs that affect lifespan has been delayed by the absence of a phenotype other than survivorship, which depends on the measurement of age at death of individuals in a population. The use of survivorship to identify genetic and pharmacological interventions that prolong life is time-consuming and requires a large number of homogeneous animals. Here, we report the development of an assay in Drosophila melanogaster using the expression of molecular biomarkers that accelerates the ability to evaluate potential lifespan-altering interventions. Coupling the expression of an age-dependent molecular biomarker to a lethal toxin reduces the time needed to perform lifespan studies by 80%. The assay recapitulates the effect of the three best known environmental life-span-extending interventions in the fly: ambient temperature, reproductive status, and calorie reduction. Single gene mutations known to extend lifespan in the fly such as Indy and rpd3 also extend lifespan in this assay. We used this assay as a screen to identify drugs that extend lifespan in flies. Lipoic acid and resveratrol were identified as being beneficial in our assay and shown to extend lifespan under normal laboratory conditions. We propose that this assay can be used to screen pharmacological as well as genetic interventions more rapidly for positive effects on lifespan.

Age Factors↗
PubMed2004

Cell-density-dependent regulation of neural precursor cell function.

Stress-induced reductions of neural precursor cells from the subgranular zone of the hippocampal dentate gyrus have been linked to impaired neurogenesis and cognitive dysfunction. Given the importance of redox state in regulating multiple damage-responsive pathways in the CNS, we hypothesize that oxidative stress plays a major role in affecting neurogenesis and subsequent cognitive function after cell injury/depletion. Using an in vitro system, we showed that the level of reactive oxygen species (ROS), which depend critically on changes in cell density, were significantly higher in neural precursor cells when compared with other primary and transformed cell lines. ROS were significantly elevated ( approximately 4-fold) under low- (<1 x 10(4) cells per cm(2)) versus high-density (>1 x 10(5) cells per cm(2)) conditions. Higher ROS levels found at lower cell densities were associated with elevated proliferation and increased metabolic activity. These ROS were likely a result of altered mitochondrial function that ultimately compromised the growth rate of cells. At high cell densities, intracellular ROS and oxidative damage were reduced in concert with an increased expression of mitochondrial superoxide dismutase 2. Our finding that DNA-damage-induced depletion of neural precursor cells in the subgranular zone of mice also led to increased ROS and altered proliferation validated our in vitro system. Increased ROS and proliferation associated with the reduction of precursor cell numbers both in vitro and in vivo could be reversed with the antioxidant alpha-lipoic acid. These data showed that neural precursor cells were predisposed to microenvironmental cues that regulate redox-sensitive pathways to control cellular proliferation after CNS damage.

Animals↗
PubMed2006

The Mycobacterium tuberculosis LipB enzyme functions as a cysteine/lysine dyad acyltransferase.

Lipoic acid is essential for the activation of a number of protein complexes involved in key metabolic processes. Growth of Mycobacterium tuberculosis relies on a pathway in which the lipoate attachment group is synthesized from an endogenously produced octanoic acid moiety. In patients with multiple-drug-resistant M. tuberculosis, expression of one gene from this pathway, lipB, encoding for octanoyl-[acyl carrier protein]-protein acyltransferase is considerably up-regulated, thus making it a potential target in the search for novel antiinfectives against tuberculosis. Here we present the crystal structure of the M. tuberculosis LipB protein at atomic resolution, showing an unexpected thioether-linked active-site complex with decanoic acid. We provide evidence that the transferase functions as a cysteine/lysine dyad acyltransferase, in which two invariant residues (Lys-142 and Cys-176) are likely to function as acid/base catalysts. Analysis by MS reveals that the LipB catalytic reaction proceeds by means of an internal thioesteracyl intermediate. Structural comparison of LipB with lipoate protein ligase A indicates that, despite conserved structural and sequence active-site features in the two enzymes, 4'-phosphopantetheine-bound octanoic acid recognition is a specific property of LipB.

Acyltransferases↗
PubMed1982

Regulation of pyruvate dehydrogenase kinase activity by protein thiol-disulfide exchange.

Endogenous kinase activity of highly purified pyruvate dehydrogenase complex from bovine kidney is markedly inhibited by N-ethylmaleimide and by certain disulfides. Inhibition by disulfides is highly specific and is reversed by thiols. 5,5'-Dithiobis(2-nitrobenzoate) is the most potent inhibitor, showing significant inhibition at a concentration as low as 1 microM. Cystamine, oxidized glutathione, pantethine, lipoic acid, lipoamide, ergothionine, insulin, oxytocin, and vasopressin were ineffective. Hydrogen peroxide and t-butyl hydroperoxide were inactive. The data indicate pyruvate dehydrogenase kinase (EC 2.7.1.99) contains a thiol group (or groups) that is involved in maintaining a conformation of the enzyme that facilitates phosphorylation and inactivation of its protein substrate, pyruvate dehydrogenase (EC 1.2.4.1). These findings suggest that modulation of pyruvate dehydrogenase kinase activity by thiol-disulfide exchange may be an important physiological mechanism for regulation of kinase activity and, hence, activity of the pyruvate dehydrogenase complex.

Animals↗
PubMed1983

Evidence for a multiple random coupling mechanism in the alpha-ketoglutarate dehydrogenase multienzyme complex of Escherichia coli: a computer model analysis.

A computer modeling system was used to analyze experimental data for inactivation of the Escherichia coli alpha-ketoglutarate dehydrogenase complex accompanying release of lipoic acid residues by lipoamidase and by trypsin [Stepp, L. R., Bleile, D. M., McRorie, D. K., Pettit, F. H. & Reed, L. J. (1981) Biochemistry 20, 4555-4560]. The results provide insight into the active-site coupling mechanism in the alpha-ketoglutarate dehydrogenase complex. The model studies indicate that the overall activity of the alpha-ketoglutarate dehydrogenase complex is influenced by redundancies and random processes that we describe as a multiple random coupling mechanism. More than one lipoyl moiety services each E1 subunit (alpha-ketoglutarate dehydrogenase, EC 1.2.4.2), and an extensive lipoyl-lipoyl interaction network for exchange of electrons and possibly acyl groups must also be present. The best fit between computed and experimental data was obtained with a model that has two lipoyl moieties servicing each E1 subunit and a lipoyl-lipoyl interaction network that links all lipoyl moieties on the E2 cube (dihydrolipoamide succinyltransferase, EC 2.3.1.61). The single lipoyl moiety on an E2 subunit is assumed to service the coenzyme A-dependent succinyltransferase site of that E2 subunit as well as an E3 subunit (dihydrolipoamide dehydrogenase, EC 1.6.4.3) if the latter is bound to that particular E2 subunit.

Acyltransferases↗
PubMed1996

The levels of ribonucleotide reductase, thioredoxin, glutaredoxin 1, and GSH are balanced in Escherichia coli K12.

The dithiol forms of thioredoxin and glutaredoxin are hydrogen donors for ribonucleotide reductase. We have determined the intracellular levels of ribonucleotide reductase (RRase), thioredoxin (Trx), glutaredoxin 1 (Grx1), and glutathione (GSH) and the glutathione redox status in new Escherichia coli K12 strains lacking thioredoxin (trxA-), glutaredoxin 1 (grxA-), and/or GSH (gshA-) or overproducing Trx or Grx1 from multicopy plasmids. We propose a regulatory network in which RRase levels are balanced with those of Trx, Grx1, and GSH so that deficiency or overproduction of one component would promote the opposite effect on the others to maintain a balanced supply of deoxyribonucleotides. GSH deficiency strongly increased both Grx1 levels and RRase activity, even more than Trx deficiency. Double gshA-trxA- bacteria were viable, whereas additional deficiency in lipoate synthesis (gshA-trxA-lipA-) caused the inability to grow in minimal medium plates supplemented with acetate plus succinate instead of lipoic acid. Thus, lipoate might be the only substitute of GSH for glutaredoxin reduction in gshA-trxA- cells, although the extremely high Grx1 content (55-fold) of these bacteria suggests that electron transfer from lipoate might be an inefficient reduction mechanism of glutaredoxins. Moreover, the enhanced Grx1 level of gshA-trxA- cells could obviate the need for a large increase in RRase activity, in contrast to grxA-trxA- double mutant cells. Impairment of the sulfate assimilation pathway, leading to very low GSH concentrations, and an oxidized glutathione redox state might explain the inability of grxA-trxA- cells to grow in minimal medium. Restoration of nearly normal levels of both GSH content and redox status cure the growth defect.

Bacterial Proteins↗
PubMed1999

Importance of redox potential for the in vivo function of the cytoplasmic disulfide reductant thioredoxin from Escherichia coli.

The thioredoxin superfamily consists of enzymes that catalyze the reduction, formation, and isomerization of disulfide bonds and exert their activity through a redox active disulfide in a Cys-Xaa(1)-Xaa(2)-Cys motif. The individual members of the family differ strongly in their intrinsic redox potentials. However, the role of the different redox potentials for the in vivo function of these enzymes is essentially unknown. To address the question of in vivo importance of redox potential for the most reducing member of the enzyme family, thioredoxin, we have employed a set of active site variants of thioredoxin with increased redox potentials (-270 to -195 mV) for functional studies in the cytoplasm of Escherichia coli. The variants proved to be efficient substrates of thioredoxin reductase, providing a basis for an in vivo characterization of NADPH-dependent reductive processes catalyzed by the thioredoxin variants. The reduction of sulfate and methionine sulfoxide, as well as the isomerization of periplasmic disulfide bonds by DsbC, which all depend on thioredoxin as catalyst in the E. coli cytoplasm, proved to correlate well with the intrinsic redox potentials of the variants in complementation assays. The same correlation could be established in vitro by using the thioredoxin-catalyzed reduction of lipoic acid by NADPH as a model reaction. We propose that the rate of direct reduction of substrates by thioredoxin, which largely depends on the redox potential of thioredoxin, is the most important parameter for the in vivo function of thioredoxin, as recycling of reduced thioredoxin through NADPH and thioredoxin reductase is not rate-limiting for its catalytic cycle.

Cytoplasm↗
PubMed1999

Structural and functional characterization of H protein mutants of the glycine decarboxylase complex.

The mitochondrial glycine decarboxylase complex (GDC) consists of four component enzymes (P, H, T, and L proteins) involved in the breakdown of glycine. In order to investigate structural interactions involved in the stabilization of the methylamine-loaded H protein (a transient species in the GDC reaction), we designed several mutants of H apoprotein. Structural analysis of the wild-type and mutants of H apoprotein emphasized the necessity to carefully assess, by biophysical techniques, the correct folding of mutated proteins prior to investigate their biochemical properties. The correctly folded wild-type and mutants of H apoprotein were in vitro lipoylated and then characterized in the context of GDC reaction by studying the reconstituted complex and partial reactions. We showed that Val(62) and Ala(64), surrounding the lipoyl-lysine, play an important role in the molecular events that govern the reaction between P and H protein but do not intervene in the recognition of the binding site of lipoic acid by lipoyl ligase. The biochemical results obtained with the HE14A mutant of H protein pointed out the major role of the Glu(14) amino acid residue in the GDC catalysis and highlighted the importance of the ionic and hydrogen bounds in the hydrophobic cleft of H protein for the stabilization of the methylamine-loaded lipoyl arm.

Amino Acid Oxidoreductases↗
PubMed2005

Differential impact of environmental stresses on the pea mitochondrial proteome.

Exposure to adverse environmental conditions causes oxidative stress in many organisms, leading either to disease and debilitation or to response and tolerance. Mitochondria are a key site of oxidative stress and of cellular response and play important roles in cell survival. We analyzed the response of mitochondria in pea (Pisum sativum) plants to the common stresses associated with drought, cold, and herbicides. These treatments all altered photosynthetic and respiratory rates of pea leaves to various extents, but only herbicides significantly increased lipid peroxidation product accumulation. Mitochondria isolated from the stressed pea plants maintained their electron transport chain activity, but changes were evident in the abundance of uncoupling proteins, non-phosphorylating respiratory pathways, and oxidative modification of lipoic acid moieties on mitochondrial proteins. These data suggest that herbicide treatment placed a severe oxidative stress on mitochondria, whereas chilling and particularly drought were milder stresses. Detailed analysis of the soluble proteome of mitochondria by gel electrophoresis and mass spectrometry revealed differential degradation of key matrix enzymes during treatments with chilling being significantly more damaging than drought. Differential induction of heat shock proteins and specific losses of other proteins illustrated the diversity of response to these stresses at the protein level. Cross-species matching was required for mass spectrometry identification of nine proteins because only a limited number of pea cDNAs have been sequenced, and the full pea genome is not available. Blue-native separation of intact respiratory chain complexes revealed little if any change in response to environmental stresses. Together these data suggest that although many of the molecular events identified by chemical stresses of mitochondria from a range of model eukaryotes are also apparent during environmental stress of plants, their extent and significance can vary substantially.

Cold Temperature↗
PubMed2001

Use of antioxidant nutrients in the prevention and treatment of type 2 diabetes.

Type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), is increasingly common throughout the world. The World Health Organization has predicted that between 1997 and 2025, the number of diabetics will double from 143 million to about 300 million. The incidence of NIDDM is highest in economically developed nations, particularly the U.S., where approximately 6.5% of the population (17 million people) have either diagnosed or undiagnosed diabetes. The two most important factors contributing to the development of NIDDM are obesity and physical inactivity. The leading cause of mortality and morbidity in people with NIDDM is cardiovascular disease caused by macro- and microvascular degeneration. Current therapies for NIDDM focus primarily on weight reduction. Indeed, several investigations indicate that 65% to 75% of cases of diabetes in Caucasians could be avoided if individuals in this subgroup did not exceed their ideal weight. The success of this approach has been, at best, modest. An alternate approach to the control of Type 2 diabetes is to arrest the progress of the pathology until a cure has been found. To this end, some investigators suggest that dietary antioxidants may be of value. Several studies in humans and laboratory animals with NIDDM indicate that vitamin E and lipoic acid supplements lessen the impact of oxidative damage caused by dysregulation of glucose metabolism. In this brief review, we discuss the incidence, etiology, and current therapies for NIDDM and further explore the usefulness of dietary antioxidants in treating this disorder.

Antioxidants↗
PubMed2004

Plasma C-reactive protein concentrations in active and passive smokers: influence of antioxidant supplementation.

OBJECTIVE: C-reactive protein (CRP) may directly affect the progression of atherosclerosis, and therefore, may be a target for reducing disease risk. The objective was to determine whether antioxidant supplementation reduces plasma CRP in active and passive smokers. DESIGN: Randomized, double-blind, placebo-controlled, parallel group trial with 2 months exposure to study supplements. SETTING: Berkeley and Oakland, California. SUBJECTS: Healthy adult men and women, consuming <4 daily servings of fruits and vegetables, and who were actively or passively exposed to cigarette smoke. Analysis was limited to participants with detectable baseline CRP concentrations and no evidence of inflammation associated with acute illness at baseline or follow-up as reflected in CRP elevations (> or =10.0 mg/L). A total of 1393 individuals were screened, 216 randomized, 203 completed the study, and 160 were included in the analysis. INTERVENTIONS: Participants were randomized to receive a placebo or vitamin C (515 mg/day) or antioxidant mixture (per day: 515 mg vitamin C, 371 mg alpha-tocopherol, 171 mg gamma-tocopherol, 252 mg mixed tocotrienols, and 95 mg alpha-lipoic acid). MEASURES OF OUTCOME: Change in plasma CRP concentration. RESULTS: Vitamin C supplementation yielded a 24.0% reduction (95% confidence interval, -38.9% to -5.5%, p = 0.036 compared to control) in plasma CRP, whereas the antioxidant mixture and placebo produced a nonsignificant 4.7% reduction (-23.9% to 19.3%) and 4.3% increase (-15.1% to 28.2%), respectively. Results were adjusted for baseline body mass index and CRP concentrations. CONCLUSIONS: Plasma CRP itself may serve as a potential target for reducing the risk of atherosclerosis, and antioxidants, including vitamin C, should be investigated further to confirm their CRP-lowering and anti-inflammatory effects.

Antioxidants↗
PubMed1984

Radical reactions in aqueous disulphide-thiol systems.

Absolute rate constants have been measured for the reaction of (CH3SSCH3)+. and sulphur centred radical cations of lipoic acid, lip (SS)+., with various thiols including penicillamine, cysteamine and cysteine. Under pulse radiolysis conditions no reactions was observed between the disulphide radical cations and the neutral thiols, RSH, i.e. kappa less than or equal to 10(7) M-1 s-1. Rate constants in the order of 10(9) M-1 s-1, i.e. close to the diffusion controlled limit, were, however, found for the corresponding reactions with the thiolates, RS-. In systems containing lipoate and cysteamine the lip (S therefore S)+. induced oxidation of CyaS- proceeds via CyaS., (CyaS therefore SCya)- and lip (S S)- as intermediates, i.e. results in a cysteamine mediated conversion of an oxidizing lip (S therefore S)+. radical cation to a reducing lip (S S)- radical anion along the reaction route. In other cases the reaction of disulphide radical cations with thiolate anions was found to proceed via an optically absorbing transient (lambda max approximately 380 nm) which is suggested to be an adduct radical. The mechanism of the (RSSR)+. induced oxidation of thiolate appears to depend on the stability of the 3-electron bonded disulphide radical anion.

Cysteamine↗
PubMed2000

Antioxidants and herbal extracts protect HT-4 neuronal cells against glutamate-induced cytotoxicity.

Antioxidant therapy has been shown to be beneficial in neurological disorders including Alzheimer's disease and cerebral ischemia. Glutamate-induced cytotoxicity in HT-4 neuronal cells has been previously demonstrated to be due to oxidative stress caused by depletion of cellular glutathione (GSH). The present study demonstrates that a wide variety of antioxidants inhibit glutamate-induced cytotoxicity in HT-4 neuronal cells. Low concentrations of alpha-tocopherol and its analogs were highly effective in protecting neuronal cells against cytotoxicity. Purified flavonoids and herbal extracts of Gingko biloba (EGb 761) and French maritime pine bark (Pycnogenol) were also effective. We have previously shown that pro-glutathione agents can spare GSH and protect cells from glutamate insult in a C6 glial cell model. The protective effects of nonthiol-based antioxidants tested in the HT-4 line were not mediated via GSH level modulation. In contrast, protective effects of thiol-based pro-glutathione agents alpha-lipoic acid (LA) and N-acetyl cysteine (NAC) corresponded with a sparing effect on GSH levels in glutamate-treated HT-4 cells. Glutamate-induced cytotoxicity in HT-4 cells is a useful model system for testing compounds or mixtures for antioxidant activity.

Animals↗
PubMed2003

Preventing superoxide formation in epineurial arterioles of the sciatic nerve from diabetic rats restores endothelium-dependent vasodilation.

We have previously reported that in streptozotocin-induced diabetic rats that increased formation of superoxide and peroxynitrite is associated with impairment in vascular relaxation in epineurial arterioles of the sciatic nerve. In this study we demonstrate that pretreating epineurial arterioles from diabetic rats in vitro with alpha-lipoic acid, dihydrolipoic acid, tempol or arginine restores acetylcholine-mediated vascular relaxation to near the reactivity observed in vessels from control rats. Suggesting that increased oxidative stress and reduction in nitric oxide availability is partially responsible for the impairment in endothelium-dependent vasodilation observed in epineurial arterioles from diabetic rats. In contrast, pretreating epineurial arterioles from diabetic rats with aminoguanidine or allopurinol had no effect. Studies designed to investigate the source of superoxide formation provided results suggesting that complex I of the mitochondrial electron transport chain and NAD(P)H oxidase are responsible for the increase in superoxide formation observed with epineurial arterioles from the sciatic nerve. Pretreating epineurial arterioles from diabetic rats with the protein kinase C inhibitor bisindolymaleimide I (GF 109203X) improved acetylcholine-mediated vascular relaxation but did not prevent the increase in superoxide formation suggesting that activation of protein kinase C by oxidative stress is downstream of superoxide formation. These studies imply that increased superoxide formation via the mitochondrial electron transport chain and perhaps NAD(P)H oxidase is partially responsible for reduced vascular reactivity observed in epineurial arterioles of the sciatic nerve from diabetic rats.

Animals↗
PubMed2003

The impact of different antioxidant agents alone or in combination on reactive oxygen species, antioxidant enzymes and cytokines in a series of advanced cancer patients at different sites: correlation with disease progression.

In the present study we tested the ability of different antioxidant agents, used alone or in combination, to reduce the reactive oxygen species (ROS) levels and to increase the glutathione peroxidase (GPx) activity. Moreover, we tested the ability of such antioxidant agents to reduce the serum levels of proinflammatory cytokines IL-6 and TNFalpha. Fifty-six advanced stage cancer patients with tumors at different sites were included in the study: they were mainly stage III (12.5%) and stage IV (82.1%). The study was divided into two phases. In the 1st phase 28 patients were divided into five groups and a single different antioxidant agent was administered to each group. The selected antioxidant agents were: alpha lipoic acid or carboxycysteine-lysine salt, amifostine, reduced glutathione, vitamin A plus vitamin E plus Vitamin C. In the 2nd phase of the study 28 patients were divided into five groups and a combination of two different antioxidant agents was administered to each group. The antioxidant treatment was administered for 10 consecutive days. The patients were studied at baseline and after antioxidant treatment. Our results show that all single antioxidants tested were effective in reducing the ROS levels and three of them in increasing GPx activity, too. Among the combinations of antioxidant agents, three were effective in reducing ROS, while three were effective in increasing GPx activity (arm 4 was effective in both instances). Comprehensively, the "antioxidant treatment" was found to be effective both on ROS levels and GPx activity. Moreover, the antioxidant treatment was able to reduce serum levels of IL-6 and TNFalpha. Furthermore, a correlation was shown between the Eastern Cooperative Oncology Group Performance Status of patients and blood levels of ROS, GPx activity, serum levels of proinflammatory cytokines.

Adult↗