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PubMed1992

Biotin transport in primary culture of astrocytes: effect of biotin deficiency.

The uptake of radioactive biotin has been studied in glial cell cultures from dissociated cerebral hemispheres of newborn rats. We describe saturable kinetics for the biotin uptake at biotin concentrations of less than 60 nM and linear at greater than 60 nM. The uptake appeared temperature sensitive, Na+ independent, nonsensitive to valinomycin, and not affected by metabolic inhibitors such as sodium fluoride or azide. Lipoic acid and biocytin were effective in inhibiting the biotin uptake. These findings are consistent with biotin uptake by the primary culture of astrocytes as a process of facilitated diffusion. Moreover, biotin uptake in astrocytes grown in biotin-restricted conditions was significantly higher compared with the control. This increase appeared mediated through a pronounced increase (10-fold) in the Vmax of the biotin uptake without any change in the apparent Km.

Animals↗
PubMed1990

Do beta-lactam antibiotics permeabilize the outer membrane of gram-negative bacteria? An electrochemical investigation.

The effects of cefotaxime and EDTA on the reducing activity of Escherichia coli and Staphylococcus aureus cultures growing in the presence of lipoic acid (LA) were investigated by potential-time measurements. The potentiometric responses of E. coli cultures exposed to EDTA indicated enhanced transmembrane transport of LA as a consequence of the outer membrane permeabilization by the chelator, whereas EDTA exerted no effect on the reducing activity of S. aureus cultures. In the same way, cefotaxime stimulated the reducing activity of E. coli, but not that of S. aureus. These results suggest that cefotaxime, and, more generally, a great variety of beta-lactam antibiotics, are able to permeabilize the outer membrane of Gram-negative bacteria.

Anti-Bacterial Agents↗
PubMed2006

Enzymatic activation of sulfur for incorporation into biomolecules in prokaryotes.

Sulfur is a functionally important element of living matter. Incorporation into biomolecules occurs by two basic strategies. Sulfide is added to an activated acceptor in the biosynthesis of cysteine, from which methionine, coenzyme A and a number of biologically important thiols can be constructed. By contrast, the biosyntheses of iron sulfur clusters, cofactors such as thiamin, molybdopterin, biotin and lipoic acid, and the thio modification of tRNA require an activated sulfur species termed persulfidic sulfur (R-S-SH) instead of sulfide. Persulfidic sulfur is produced enzymatically with the IscS protein, the SufS protein and rhodanese being the most prominent biocatalysts. This review gives an overview of sulfur incorporation into biomolecules in prokaryotes with a special emphasis on the properties and the enzymatic generation of persulfidic sulfur as well as its use in biosynthetic pathways.

Bacterial Proteins↗
PubMedDate not supplied

Reactive oxygen species, antioxidant mechanisms and serum cytokine levels in cancer patients: impact of an antioxidant treatment.

OBJECTIVE: So far, it is not well established whether oxidative stress found in cancer patients results from an increased production of oxidants in the body or from a failure of physiological antioxidant systems. To further investigate this question we have assessed the blood levels of reactive oxygen species as a marker of free radicals producing oxidative stress and the most relevant of the physiological body enzymes counteracting reactive oxygen species, namely glutathione peroxidase and superoxide dismutase. Serum levels of proinflammatory cytokines and IL-2 were also investigated. All these parameters were studied in relation to the clinically most important index of disease progression, namely Performance Status (ECOG PS). We also tested the reducing ability of different antioxidant agents on reactive oxygen species levels by measuring the increase in glutathione peroxidase activity, and the reduction of serum levels of IL-6 and TNF. DESIGN, SETTING AND SUBJECTS: We carried out an open non randomized study on 28 advanced stage cancer patients (stage III, 10.7%, and stage IV, 89.3%) with tumours at different (8) sites: all were hospitalized in the Medical Oncology Dept, University of Cagliari Interventions. The patients were divided into 5 groups and a different antioxidant treatment was administered to each group. The selected antioxidants were: alpha lipoic acid 200 mg/day orally, N-acetylcysteine 1800 mg/day i.v. or carboxycysteine-lysine salt 2.7 g/day orally, amifostine 375 mg/day i.v., reduced glutathione 600 mg/day i.v., vitamin A 30000 IU/day orally plus vitamin E 70 mg/day orally plus Vitamin C 500 mg/day orally. The antioxidant treatment was administered for 10 consecutive days. RESULTS: Our results show that all but one of the antioxidants tested were effective in reducing reactive oxygen species levels and 2 of them (cysteine-containing compounds and amifostine) had the additional effect of increasing glutathione peroxidase activity. Comprehensively, the "antioxidant treatment" was found to have an effect both on reactive oxygen species levels and glutathione peroxidase activity. The antioxidant treatment also reduced serum levels of IL-6 and TNF. Patients in both ECOG PS 0-1 and ECOG PS 2-3 responded to antioxidant treatment.

Adult↗
PubMed1993

Antibody to two forms of dihydrolipoamide acetyltransferase (PDC-E2) in primary biliary cirrhosis.

Dihydrolipoamide acetyltransferase, the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), is the major autoantigen in primary biliary cirrhosis. By immunoblotting with sera from patients with primary biliary cirrhosis, we observed a double band, of molecular weight 70 and 74 kD for PDC-E2, when a preparation of bovine heart mitochondria was not boiled prior to electrophoresis. This double band could also be detected using antisera raised in rats or rabbits against intact PDC or PDC-E2, but not in antisera raised against a synthetic decamer representing the lipoic acid binding sequence of PDC-E2; the latter reacted only with the 74 kD component. Antibody eluted from either the 70 or 74 kD component reacted with both 70 and 74 kD components. By ELISA, sera from patients with primary biliary cirrhosis reacted more strongly with a non-boiled than a boiled PDC-E2, whereas immune animal sera reacted equally with both preparations. Thus, according to whether preparations of PDC are boiled or not, two conformationally alternative forms of the PDC-E2 protein can be revealed by immunoblotting. The two forms in non-boiled preparations migrate at molecular weights corresponding to 70 and 74 kD.

Acetyltransferases↗
PubMed1983

Control of heart oxidative phosphorylation by creatine kinase in mitochondrial membranes.

Three important points must be emphasized in summary. First is the idea that a cellular microcompartment need not be limited by a semi-permeable membrane. We recognize microcompartments in multi-enzyme complexes where substrates are covalently transported from subunit to subunit. An example of this is the lipoic acid moiety of the pyruvate dehydrogenase complex. However, to act as a kinetic microcompartment, covalent transfer is not an obligatory requirement. Proximity effects may be sufficient for substantial rate enhancement. Our data clearly show that the kinetics of ADP translocation are influenced by the site of ADP formation. We contend that this represents a newly recognized and important form of cellular microcompartmentation. The second point is that we do not want our results misinterpreted as an overextension of the known data concerning tissue respiration. We believe that the primary parameter controlling heart mitochondrial oxygen consumption is the availability of ADP at the adenine nucleotide translocase. Our data show, however, that this is not a simple process. Secondary control is exerted by the localization of ADP formation, i.e. microcompartmentation. As a result of the kinetic data (Table 3), we conclude that the forward rate of mitochondrial creatine kinase is the preferential reaction controlling ADP delivery to the translocase. We are left, nonetheless, with questions concerning the secondary regulation of this enzyme in vivo by substrate (ATP and creatine) and inhibition by product (phosphocreatine). The nature of this control awaits further experimental data. Finally, the results are consistent with the creatine kinase energy transport hypothesis. Overall, the rate of tissue oxygen consumption reflects the metabolic activity of the organ, determined by the rate of ATP utilization (see right side of Figure 1). This results in the cytoplasmic production of ADP. In heart, this is coupled via the bound cytoplasmic isozymes of creatine kinase to the local rephosphorylation of ADP to ATP and the simultaneous production of creatine.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Diphosphate↗
PubMed2000

Differential regulation of MAP kinase signaling by pro- and antioxidant biothiols.

Some biologically derived thiol-containing compounds have potential for health benefits whereas others elicit biochemical events leading to pathogenesis. Effects of two biothiols, alpha-lipoic acid (alpha LA), a therapeutic antioxidant, and homocysteine (Hcy), a risk factor for age-associated cardiovascular disease, on cell signaling events involving p44 and p42 MAP kinases (p44/42 MAPK) were evaluated in cell culture. Treatment of serum-deprived NIH/3T3 cells with Hcy (20 microM) resulted in the activation of p44/42 MAPK as determined by Western blot analysis using the phospho-specific p44/42 MAPK antibody. p44/42 MAPK phosphorylation was rapid and transient with maximal activation occurring at 10-30 min. Transient activation of p44/42 MAPK was also observed in response to treatment of serum-deprived cells with alpha LA. In cells grown in serum, serum-dependent p44/42 MAPK phosphorylation was transiently enhanced by Hcy or Hcy thiolactone, but inhibited by alpha LA. Thus, alpha LA and Hcy differentially influence signal transduction events depending on the state of cells. These observations may be important in understanding how some biothiols are associated with pathogenic events while others have potential as therapeutic agents.

3T3 Cells↗
PubMed2002

Delaying brain mitochondrial decay and aging with mitochondrial antioxidants and metabolites.

Mitochondria decay with age due to the oxidation of lipids, proteins, RNA, and DNA. Some of this decay can be reversed in aged animals by feeding them the mitochondrial metabolites acetylcarnitine and lipoic acid. In this review, we summarize our recent studies on the effects of these mitochondrial metabolites and mitochondrial antioxidants (alpha-phenyl-N-t-butyl nitrone and N-t-butyl hydroxylamine) on the age-associated mitochondrial decay of the brain of old rats, neuronal cells, and human diploid fibroblast cells. In feeding studies in old rats, these mitochondrial metabolites and antioxidants improve the age-associated decline of ambulatory activity and memory, partially restore mitochondrial structure and function, inhibit the age-associated increase of oxidative damage to lipids, proteins, and nucleic acids, elevate the levels of antioxidants, and restore the activity and substrate binding affinity of a key mitochondrial enzyme, carnitine acetyltransferase. These mitochondrial metabolites and antioxidants protect neuronal cells from neurotoxin- and oxidant-induced toxicity and oxidative damage; delay the normal senescence of human diploid fibroblast cells, and inhibit oxidant-induced acceleration of senescence. These results suggest a plausible mechanism: with age, increased oxidative damage to proteins and lipid membranes, particularly in mitochondria, causes a deformation of structure of enzymes, with a consequent decrease of enzyme activity as well as substrate binding affinity for their substrates; an increased level of substrate restores the velocity of the reaction and restores mitochondrial function, thus delaying mitochondrial decay and aging. This loss of activity due to coenzyme or substrate binding appears to be true for a number of other enzymes as well, including mitochondrial complex III and IV.

Acetylcarnitine↗
PubMed2002

Can antioxidant diet supplementation protect against age-related mitochondrial damage?

Harman's free radical theory of aging and our electron-microscopic finding of an age-related mitochondrial degeneration in the somatic tissues of the insect Drosophila melanogaster as well as in the fixed postmitotic Leydig and Sertoli cells of the mouse testis led us to propose a mitochondrial theory of aging, according to which metazoan senescence may be linked to oxygen stress-injury to the genome and membranes of the mitochondria of somatic differentiated cells. These concepts attract a great deal of attention, since, according to recent work, the mitochondrial damage caused by reactive oxygen species (ROS) and concomitant decline in ATP synthesis seem to play a key role not only in aging, but also in the fundamental cellular process of apoptosis. Although diet supplementation with antioxidants has not been able to increase consistently the species-characteristic maximum life span, it results in significant extension of the mean life span of laboratory animals. Moreover, diets containing high levels of antioxidants such as vitamins C and E seem able to reduce the risk of suffering age-related immune dysfunctions and arteriosclerosis. Presently, the focus of age-related antioxidant research is on compounds, such as deprenyl, coenzyme Q10, alpha-lipoic acid, and the glutathione-precursors thioproline and N-acetylcysteine, which may be able to neutralize the ROS at their sites of production in the mitochondria. Diet supplementation with these antioxidants may protect the mitochondria against respiration-linked oxygen stress, with preservation of the genomic and structural integrity of these energy-producing organelles and concomitant increase in functional life span.

Aging↗
PubMed2005

Exercise and mononuclear cell DNA damage: the effects of antioxidant supplementation.

The purpose of this investigation was to determine the effects of antioxidant supplementation on DNA damage following exercise. Fourteen subjects were randomly assigned to one of two groups and required to ingest either antioxidants (400 mg alpha-lipoic acid, 200 mg co-enzyme Q10, 12 mg manganese, 600 mg vitamin C, 800 mg N-acetyl cysteine, 400 microg selenium, and 400 IU alpha-tocopherol per day) or placebos for 7 d. Exercise increased DNA damage, PS, FRAP, and LDH (P < 0.05), but not selectively between groups. LDH and PS concentration decreased 1 h post-exercise (P < 0.05), while LH concentration decreased 1 h post-exercise in the antioxidant group only (P < 0.05). The antioxidant group had a higher concentration of LH (P < 0.05), perhaps due to a selective difference between groups post-exercise (P < 0.05). The main findings of this investigation demonstrate that exhaustive aerobic exercise induces DNA damage, while antioxidant supplementation does not protect against damage.

Adult↗
PubMed1977

End products and fermentation balances for lactic streptococci grown aerobically on low concentrations of glucose.

Maximum acetate produced aerobically by Streptococcus diacetilactis and Streptococcus cremoris was 14% of 1 to 7 mumol of glucose/ml in a partially defined medium that contained lipoic acid. Y (glucose) values were 35.3 (S. diacetilactis) and 31.4 (S. cremoris) with low concentrations (1 to 7 mumol/ml) of glucose in the medium and 21 (S. diacetilactis) with higher concentrations (6 to 15 mumol/ml). Y (adenosine 5'-triphosphate) values for the bacteria, determined by taking into account the end products produced, were 15.6 and 13.9 for S. diacetilactis and S. cremoris, respectively, in the partially defined medium containing 1 to 7 mumol of glucose/ml and higher (21.5 and 18.9, respectively) in a complex medium that contained 2 mumol of glucose/ml. Addition of citrate in addition to glucose did not result in higher molar growth yields.

Acetates↗
PubMed1981

Features of rumen and sewage sludge strains of Eubacterium limosum, a methanol- and H2-CO2-utilizing species.

Eubacterium limosum was isolated as the most numerous methanol-utilizing bacterium in the rumen fluid of sheep fed a diet in which molasses was a major component (mean most probable number of 6.3 X 10(8) viable cells per ml). It was also isolated from sewage sludge at 9.5 X 10(4) cells per ml. It was not detected in the rumen fluid of a steer on a normal hay-grain diet, although Methanosarcina, as expected, was found at 9.5 X 10(5) cells per ml. The doubling time of E. limosum in basal medium (5% rumen fluid) with methanol as the energy source (37 degree C) was 7 h. Acetate, cysteine, carbon dioxide, and the vitamins biotin, calcium-D-pantothenate, and lipoic acid were required for growth on a chemically defined methanol medium. Acetate, butyrate, and caproate were produced from methanol. Ammonia or each of several amino acids served as the main nitrogen source. Other energy sources included adonitol, arabitol, erythritol, fructose, glucose, isoleucine, lactate, mannitol, ribose, valine, and H2-CO2. The doubling time for growth on H2-CO2 (5% rumen fluid, 37 degree C) was 14 h as compared with 5.2 h for isoleucine and 3.5 h for glucose. The vitamin requirements for growth on H2-CO2 were the same as those for methanol; however, acetate was not required for growth on H2-CO2, although it was necessary for growth on valine, isoleucine, and lactate and was stimulatory to growth on glucose. Acetate and butyrate were formed during growth on H2-CO2, whereas branched-chain fatty acids and ammonia were fermentation products from the amino acids. Heat tolerance was detected, but spores were not observed. The type strain of E. limosum (ATCC 8486) and strain L34, which was isolated from the rumen of a young calf, grew on methanol, H2-CO2, valine, and isoleucine and showed the same requirements for acetate as the freshly isolated strains.

Animals↗
PubMed1990

Nutritional Features of Syntrophomonas wolfei.

Syntrophomonas wolfei subsp. wolfei grew poorly in a defined medium with crotonate as the energy source in the absence of rumen fluid. Thiamine, lipoic acid, biotin, cyanocobalamin, and para-aminobenzoic acid were required for growth comparable to that obtained with the rumen fluid-based medium. Iron and cobalt were also required for the growth of S. wolfei in the chemically defined medium.

Journal Article↗
PubMed1997

L-cysteine biosynthesis in Bacillus subtilis: identification, sequencing, and functional characterization of the gene coding for phosphoadenylylsulfate sulfotransferase.

Random Tn917 mutagenesis of Bacillus subtilis followed by selection of lipoic acid auxotrophs led to the isolation of the cysH gene. The gene was sequenced and found to encode a phosphoadenylylsulfate sulfotransferase with a molecular mass of 27 kDa. Expression of lacZ fused to the cysH promoter was repressed by cysteine and sulfide and induced by sulfur limitation, indicating that cysH is controlled at the level of transcription.

Amino Acid Sequence↗
PubMed1963

METABOLIC ROLE OF THE BR FACTOR IN BUTYRIBACTERIUM RETTGERI.

Kline, Leo (University of California, Berkeley), L. Pine, and H. A. Barker. Metabolic role of the BR factor in Butyribacterium rettgeri. J. Bacteriol. 85:967-975. 1963.-The BR factor, which is replaceable by lipoic acid, was shown to be required for the decomposition of lactate by Butyribacterium rettgeri. Since the factor was not required for the fermentation of pyruvate or glucose by this organism, the results indicate that BR factor is essential only for some reaction involved in the oxidation of lactate to pyruvate, possibly the transport of electrons from lactate to the ultimate anaerobic electron-acceptor systems. The same products, namely, acetate, butyrate, and carbon dioxide, are formed from glucose or pyruvate in the presence or absence of BR factor and from lactate in the presence of the factor. Thus the factor is not required for the conversion of glucose or pyruvate to acetate, butyrate, or carbon dioxide. Although B. rettgeri does not require the BR factor for growth on glucose, growth of lactate-adapted cells on glucose is slow and is markedly stimulated by addition of the factor. Such cells growing on glucose do not show any ability to decompose lactate; consequently, an additional function of the BR factor, probably associated with the conversion of glucose to pyruvate, is indicated. Cells fully adapted to glucose grow rapidly on this substrate and do not respond to the factor. Lactate is formed during growth of glucose-adapted cells on glucose, although such cells cannot decompose lactate.

Acetates↗
PubMed1967

Transaminase activity and other enzymatic reactions involving pyruvate and glutamate in Chlamydia (psittacosis-trachoma group).

The agents of meningopneumonitis (MN) and of trachoma (TR) purified from chick embryo allantoic fluids and yolk sacs, respectively, were shown to produce CO(2) from the C(1) positions of pyruvate and glutamate, but not from the other carbon atoms. The reaction with pyruvate did not require did not require the addition of cofactors, but was stimulated to a small extent by alpha-lipoic acid and, in the case of TR, also by diphosphothiamine, and nicotinamide adenine dinucleotide (NAD). The reaction of MN with glutamate was greatly stimulated by the addition of NAD and pyruvate, and resulted in the accumulation of alanine. The reaction of TR with glutamate was also greatly enhanced by added NAD, but was not affected by added pyruvate. When eight intermediates of the citric acid cycle were added to MN cells incubated with glutamate-C(14), plus NAD and pyruvate, they reduced to varying degrees the evolution of C(14)O(2). It was shown by chromatography that the C(14) label extended to alpha-ketoglutarate and succinate, but not to fumarate and malate. A net gain in adenosine triphosphate could not be demonstrated in MN cells incubated with combined glutamate, pyruvate, oxaloacetate, and various cofactors. These results furnish additional examples of real or apparent gaps in enzyme sequences in Chlamydia.

Carbon Dioxide↗
PubMed2006

Diabetic neuropathy.

Diabetic neuropathy (DN) refers to symptoms and signs of neuropathy in a patient with diabetes in whom other causes of neuropathy have been excluded. Distal symmetrical neuropathy is the commonest accounting for 75% DN. Asymmetrical neuropathies may involve cranial nerves, thoracic or limb nerves; are of acute onset resulting from ischaemic infarction of vasa nervosa. Asymmetric neuropathies in diabetic patients should be investigated for entrapment neuropathy. Diabetic amyotrophy, initially considered to result from metabolic changes, and later ischaemia, is now attributed to immunological changes. For diagnosis of DN, symptoms, signs, quantitative sensory testing, nerve conduction study, and autonomic testing are used; and two of these five are recommended for clinical diagnosis. Management of DN includes control of hyperglycaemia, other cardiovascular risk factors; alpha lipoic acid and L carnitine. For neuropathic pain, analgesics, non-steroidal anti-inflammatory drugs, antidepressants, and anticonvulsants are recommended. The treatment of autonomic neuropathy is symptomatic.

Aldehyde Reductase↗
PubMed2001

Update on thiol status and supplements in physical exercise.

Strenuous physical exercise represents a condition that is often associated with increased production of reactive oxygen species in various tissues. One of the most reliable indices of exercise-induced oxidant production is tissue glutathione oxidation. In humans, exercise-induced blood glutathione oxidation is rapid and subject to control by antioxidant supplementation. The objective of this brief review is to provide an update of our current understanding of cellular thiols and thiol antioxidants. Cellular thiols are critically important in maintaining the cellular antioxidant defense network. In addition, thiols play a key role in regulating redox-sensitive signal transduction process. Lipoic acid is a highly promising thiol antioxidant supplement. Recent studies have clarified that while higher levels of oxidants may indeed inflict oxidative damage, oxidants are not necessarily deleterious. Under certain conditions oxidants may function as cellular messengers that regulate a multitude of signal transduction pathways. In light of this, the significance of oxidants in various aspects of biology needs to be revisited.

Animals↗