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PubMed2001

Glutathione and alpha-lipoate in diabetic rats: nerve function, blood flow and oxidative state.

BACKGROUND: Increased oxidative stress is considered to be a causal factor in the development of diabetic complications, among which peripheral neuropathy. The pathophysiology of nerve dysfunction in diabetes has been explained both by reduced endoneurial microcirculation and alterations in endoneurial metabolism. It is unclear whether antioxidants primarily improve nerve blood flow or normalise systemic or endoneurial oxidative metabolism. Therefore, we evaluated the effects of the antioxidants glutathione and alpha-lipoic acid on both nerve microcirculation and the antioxidative capacity and lipid peroxidation in experimentally diabetic rats. MATERIALS AND METHODS: Streptozotocin-diabetic rats were treated with different doses of alpha-lipoic acid, reduced glutathione or placebo, and were compared with nondiabetic controls. We measured systemic and endoneurial antioxidants, malondialdehyde and whole blood hydrogen peroxide. Furthermore, we evaluated sciatic and tibial motor and sensory nerve conduction velocity, caudal nerve conduction velocity, and assessed sciatic nerve blood flow and vascular resistance by Laser-Doppler flowmetry. RESULTS: We observed a rise in erythrocyte glutathione by 27 % (P < 0.05), and a trend towards decreased plasma malondialdehyde in alpha-lipoic acid, but not in glutathione-treated animals in comparison with the placebo group. Simultaneously, sciatic nerve blood flow and vascular resistance were improved by daily alpha-lipoic acid administration by 38% (P < 0.05). Peripheral nerve conduction velocity and endoneurial glutathione were not significantly influenced by antioxidant treatment. CONCLUSIONS: Only minor beneficial effects of alpha-lipoic acid on nerve blood flow and oxidative state occur at the given doses; these effects were insufficient to improve nerve conduction deficits.

Animals↗
PubMed2000

The function of endogenous protective systems in patients with insulin-dependent diabetes mellitus and polyneuropathy: effect of antioxidant therapy.

alpha-Lipoic acid is a very efficient antioxidants for the treatment and prevention of diabetic neuropathy. The aim of the present study was to evaluate the function of nitric oxide (NO) and stress proteins (HSP72) in insulin-dependent diabetes complicated by polyneuropathy and possible contribution of these systems to the therapeutic effects of alpha-lipoic acid. Plasma content of nitrites and nitrates in diabetic patients was almost 2-fold below the normal. The treatment with alpha-lipoic acid completely normalized the plasma content of these stable NO metabolites. The majority of patients had also low level of HSP72. Positive clinical effects of alpha-lipoic acid were accompanied by normalization of HSP72 synthesis. Thus, activation of the NO and HSP protective systems is involved in the therapeutic effect of alpha-lipoic acid in diabetic patients (type 1 diabetes mellitus) with polyneuropathy.

Adolescent↗
PubMed1999

Nerve conduction impairment in experimental diabetes-proximodistal gradient of severity.

We compared a conventional method of measurement of sciatic motor and sensory nerve conduction velocity, with a novel procedure that measures conduction in an 8-mm segment of the rat sural nerve. Conventional procedures gave reductions in velocity of 20% and 14% for motor and sensory fibers, respectively, whereas sural sensory fibers showed a 40% reduction (P <0.05). Changes were attenuated by treatment with either an aldose reductase inhibitor or a gamma-linolenic acid-alpha-lipoic acid conjugate, such that values from conventional procedures were not significantly different from controls and the sural sensory deficit halved. Putative motor fibers of the sural nerve showed no conduction velocity deficit in diabetic rats. Measurement of chronaxie and rheobase in sural sensory fibers revealed mild reductions in excitability in diabetics, with prevention of the chronaxie change by the treatments. Thus, measurement of sensory conduction in distal nerve segments show more profound defects in diabetic rats and may give a truer picture of preventive drug efficacy.

Animals↗
PubMed2004

Heme, iron, and the mitochondrial decay of ageing.

Heme, the major functional form of iron, is synthesized in the mitochondria. Although disturbed heme metabolism causes mitochondrial decay, oxidative stress, and iron accumulation, all of which are hallmarks of ageing, heme has been little studied in nutritional deficiency, in ageing, or age-related disorders such as Alzheimer's disease (AD). Biosynthesis of heme requires Vitamin B(6), riboflavin, biotin, pantothenic acid, and lipoic acid and the minerals zinc, iron, and copper, micronutrients are essential for the production of succinyl-CoA, the precursor for porphyrins, by the TCA (Krebs) cycle. Only a small fraction of the porphyrins synthesized from succinyl-CoA are converted to heme, the rest are excreted out of the body together with the degradation products of heme (e.g. bilirubin). Therefore, the heme biosynthetic pathway causes a net loss of succinyl-CoA from the TCA cycle. The mitochondrial pool of succinyl-CoA may limit heme biosynthesis in deficiencies for micronutrients (e.g. iron or biotin deficiency). Ageing and AD are also associated with hypometabolism, increase in heme oxygenase-1, loss of complex IV, and iron accumulation. Heme is a common denominator for all these changes, suggesting that heme metabolism maybe altered in age-related disorders. Heme can also be a prooxidant: it converts less reactive oxidants to highly reactive free radicals. Free heme has high affinity for different cell structures (protein, membranes, and DNA), triggering site-directed oxidative damage. This review discusses heme metabolism as related to metabolic changes seen in ageing and age-related disorders and highlights the possible role in iron deficiency.

Aconitate Hydratase↗
PubMed2006

Biotin uptake and cellular translocation in human derived retinoblastoma cell line (Y-79): a role of hSMVT system.

The objective of this research was to investigate the presence of a specialized carrier-mediated system for biotin and delineate uptake mechanism and intracellular trafficking of biotin in the human derived retinoblastoma cell line (Y-79). Human derived retinoblastoma cell line, Y-79, was used for uptake studies. Uptake of [3H]Biotin was determined at various concentrations, pH, temperatures, in the absence of sodium and in the presence of other vitamins and metabolic inhibitors to delineate the mechanism of uptake. Uptake was determined in the presence of various intracellular regulatory pathways (protein kinase A & C, protein tyrosine kinase and calcium-calmodulin) modulators. Reverse transcription polymerase chain reaction (RT-PCR) was performed to confirm the molecular identity of human sodium-dependent multivitamin transporter (hSMVT). Uptake of [3H]Biotin in Y-79 cells were found to be saturable at micromolar concentration range, with apparent Km of 8.53 microM and Vmax of 14.12 pmol/min/mg protein, but linear at nanomolar concentration range. Uptake was sodium, pH, temperature and energy-dependent, but chloride independent; inhibited by the structural analogue desthiobiotin, pantothenic acid and lipoic acid at milimolar concentrations and not at nanomolar concentrations. Uptake of [3H]Biotin was trans-stimulated by the intracellular biotin. Ca2+/calmodulin pathways appeared to play important roles in the regulation of riboflavin uptake in Y-79 cells via significant reduction in Vmax (66%) and Km (28%) of the uptake process. A human sodium-dependant multivitamin transporter, hSMVT, was identified by RT-PCR in Y-79. These studies demonstrated for the first time the existence of a human sodium dependant multivitamin transporter (hSMVT), a specialized carrier-mediated system for biotin uptake, in human derived retinoblastoma cells.

Biological Transport↗
PubMed2006

Diabetes--a man made disease.

The recent increase in both forms of diabetes must be caused by a modern change in the environment. Candidate agents must satisfy at least three criteria. Firstly, the agent must have increased in the environment recently, secondly that it causes diabetes in appropriate animal models, and thirdly that there is a plausible diabetogenic mechanism. Modern food processing can produce glycation end products, oxidised ascorbic acid and lipoic acid, all of which may cause diabetes. Infant formula in particular has high levels of glycation products, and added ascorbic acid. A casomorphin released from A1 beta-casein (but not the A2 variant) can become glycated and have adverse immune effects. Food processing and additives can be posited as a man made cause of the increase in both forms of diabetes. This hypothesis does not exclude other environmental agents which meet the above three criteria.

Antioxidants↗
PubMed2002

Synthesis of a rabbit polyclonal antibody to the human sodium-dependent multivitamin transporter.

In mammalian cells, biotin is covalently attached to carboxylases and histones and is required for cell proliferation and function. Cellular uptake of biotin (as well as pantothenic acid and lipoic acid) is mediated by the sodium-dependent multivitamin transporter, SMVT. Studies of cellular biotin homeostasis have been hampered by the lack of an antibody to SMVT. Here, we describe the synthesis of a rabbit polyclonal antibody to human SMVT. Using this antibody, SMVT has been identified in human peripheral blood mononuclear cells, Caco-2 cells, and HepG2 cells. Moreover, we observed that cells respond to proliferation with increased synthesis of SMVT.

Animals↗
PubMed1989

Purification and partial characterization of the glycine decarboxylase multienzyme complex from Eubacterium acidaminophilum.

The proteins P1, P2, and P4 of the glycine cleavage system have been purified from the anaerobic, glycine-utilizing bacterium Eubacterium acidaminophilum. By gel filtration, these proteins were determined to have Mrs of 225,000, 15,500, and 49,000, respectively. By sodium dodecyl sulfate-polyacrylamide gel electrophoresis, protein P1 was determined to have two subunits with Mrs of 59,500 and 54,100, indicating an alpha 2 beta 2 tetramer, whereas the proteins P2 and P4 showed only single bands with estimated Mrs of 15,500 and 42,000, respectively. In reconstitution assays, proteins P1, P2, P4 and the previously reported lipoamide dehydrogenase (P3) had to be present to achieve glycine decarboxylase or synthase activity. All four glycine decarboxylase proteins exhibited highest activities when NADP+ was used as the electron acceptor or when NADPH was used as the electron donor in the glycine synthase reaction. The oxidation of glycine depended on the presence of tetrahydrofolate, dithioerythreitol, NAD(P)+, and pyridoxal phosphate. The latter was loosely bound to the purified protein P1, which was able to catalyze the glycine-bicarbonate exchange reaction only in combination with protein P2. Protein P2 could not be replaced by lipoic acid or lipoamide, although lipoic acid was determined to be a constituent (0.66 mol/mol of protein) of protein P2. Glycine synthase activity of the four isolated proteins and in crude extracts was low and reached only 12% of glycine decarboxylase activity. Antibodies raised against P1 and P2 showed cross-reactivity with crude extracts of Clostridium cylindrosporum.

Amino Acid Oxidoreductases↗
PubMed1969

Growth and sporulation of Bacillus subtilis mutants blocked in the pyruvate dehydrogenase complex.

Two "ACE" mutants of Bacillus subtilis which require acetate for growth on glucose minimal medium have been isolated. They do not grow with acetoin, 2,3-butanediol, fatty acids, isoleucine, lipoic acid, malic acid, pyruvic acid, succinic acid, thiamine, or valine, but respond somewhat to glutamate or citrate. The mutants lack the activity of the pyruvate dehydrogenase complex; they excrete pyruvate and later acetoin. They grow in nutrient sporulation medium (NSMP) to one-half the normal turbidity and do not sporulate subsequently. When acetate is added to NSMP (at the optimal concentration of 0.07 m), the ACE mutants grow to the normal turbidity and then sporulate normally. Growth but not sporulation is restored in NSMP upon addition of 2,3-butanediol, citrate, glucose, glutamate, glycerol, or ribose, but not upon addition of acetoin, malate, oxaloacetate, pyruvate, and several other compounds. After growth in NSMP has stopped, the mutants incorporate uracil only at a very low rate, which can be increased by the addition of acetate, citrate, or glutamate. Furthermore, the metabolism of acetoin is prevented after growth has stopped but can be restored by the addition of acetate. All these results can be explained by a lack of reduced nicotinamide adenine dinucleotide (NADH) resulting from the deficiency in acetylcoenzyme A. In fact, after growth of the ACE mutants had stopped, the NADH concentration was at the borderline of measurability, whereas it increased significantly upon addition of glucose. The growing standard strain contains, at the same bacterial turbidity, at least 20 times more NADH (230 pmole/optical density unit at 600 nm) than the nongrowing ACE mutants. The isolated spores, obtained after growth in NSMP plus acetate, can be initiated to germinate in the presence of either l-alanine or the combination of l-asparagine, fructose, glucose, and potassium; addition of acetate is not required and has no effect.

Acetates↗
PubMed1993

Isolation and characterization of LIP5. A lipoate biosynthetic locus of Saccharomyces cerevisiae.

A number of mutants with pleiotropic effects on mitochondrial metabolism have been isolated in yeast Saccharomyces cerevisiae, and for many the biochemical function that is impaired is not yet known. We report here the isolation and characterization of the LIP5 gene involved in lipoic acid metabolism which complements the g189 mutant (Tzagoloff, A., and Dieckmann, C. L. (1990) Microbiol. Rev. 54, 211-225). DNA sequence analysis of complementing yeast genomic DNA revealed an open reading frame predicting a protein of 414 amino acids. The protein sequence deduced from the gene shares 43% identical residues with the product of the Escherichia coli lip gene, which codes an enzyme involved in lipoic acid synthesis. The LIP5 mutant is not capable of synthesizing lipoic acid but still possesses the activity necessary for attachment of lipoic acid to protein. Relative to the E. coli lip gene product, the LIP5 protein has an amino-terminal extension with characteristics of mitochondrial targeting signals. Cells carrying a disrupted copy of the LIP5 gene show slow growth on ethanol-rich media and barely detectable growth on glycerol-rich media. Unlike other strains with defects in the tricarboxylic acid cycle, LIP5 mutants undergo a high frequency of mitochondrial DNA deletions.

Amino Acid Sequence↗
PubMed1996

Potential carcinogenicity of the synthetic 1,3,6-triazine (6-aza) nucleic acid analogues determined by DC polarography. I. Nucleobases.

The polarographic reduction of several synthetic 1,3,6-triazine (6-aza) nucleobases in the strictly anhydrous solution was studied in the absence and presence of alpha-lipoic acid. The values of the half-wave potentials E1/2 and the parameter of potential carcinogenicity tg alpha were determined for one natural and 5 synthetic nucleobases. The current value of the first diffuse polarographic wave or a new diffuse polarographic wave belonging to the nucleobase-alpha-lipoic acid complex increased with the increased alpha-lipoic acid concentration for the all compounds only marginally. Although this diffuse current increase was linearly depended on the alpha-lipoic acid concentration in anhydrous solutions, the determined index tg alpha values ranging between 0.029 and 0.108 indicated a very low potential carcinogenicity of the all nucleobases investigated.

Aza Compounds↗
PubMed1992

Multiple autoepitope presentation for specific detection of antibodies in primary biliary cirrhosis.

Antimitochondrial autoantibodies are present in sera from close to 95% of patients with primary biliary cirrhosis. The so-called primary biliary cirrhosis-specific antigen, named M2, was found to be associated with an enzyme complex of the inner mitochondrial membrane and, more precisely, with the E2 component, dihydrolipoamide acetyltransferase, of the pyruvate dehydrogenase complex. We recently established that an immunodominant epitope recognized in direct enzyme-linked immunosorbent assay by primary biliary cirrhosis M2+ sera, but not by non-primary biliary cirrhosis M2+ sera, could be mimicked by a synthetic peptide encompassing residues 167-184 of the E2 component and associated with lipoic acid. This fragment is present in the natural inner lipoyl-binding site of the human enzyme, and the presence of lipoic acid located on lysine 173 was found to be essential to allow IgG antibody binding. In this study we have improved the enzyme-linked immunosorbent assay test based on the synthetic peptide-lipoic acid conjugate by using a multiple antigen peptide system containing eight copies of the peptide as antigen. This approach avoids the use of a peptide conjugated to a carrier protein and was found to be particularly efficient because 23 of 27 primary biliary cirrhosis M2+ sera (85%) could be identified. A multiple antigen peptide without lipoic acid was not recognized by primary biliary cirrhosis antibodies. The peptide used in the multiple antigen peptide construction was a short 13-mer peptide encompassing a highly conserved sequence present in both the outer (residues 40-52) and the inner (residues 167-179) lipoyl-binding sites of the enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetyltransferases↗
PubMed2003

Free radical scavengers improve the impaired endothelium-dependent responses in aorta and kidneys of diabetic rabbits.

The effects of two endogenous antioxidants, alpha-lipoic acid and reduced gluthathione (GSH), were evaluated in the response of the renal vasculature and aortic rings ex vivo of 4-week alloxan-diabetic rabbits to the endothelium-dependent agonists bradykinin (BK) and acetylcholine (Ach) or to the endothelium-independent agonist sodium nitroprusside (SNP) and compared with age and sex-matched euglycemic rabbits. The maximal decrease in perfusion pressure (R(max)) after BK infusion in the renal vasculature from diabetic rabbits was 5.4+/-1.3% (PD(2) 8 [12.6-3.4]) compared with 34.2+/-4.2% (PD(2) 9 [11.3-6.7]) (P<0.05) attained in tissues obtained from euglycemic rabbits. The addition of 1 microM lipoic acid or GSH improved (P<0.05) the R(max) to BK to 18.3+/-2.4% (PD(2) 8.6 [12.4-4.8]) and 19.5+/-3.7% (PD(2) 9.1 [13.3-4.9]), respectively. Similarly, the maximal vasorelaxant response to Ach in kidneys from diabetic rabbits was 16+/-2.0% (PD(2) 7.3 [10.4-4.2] whilst the R(max) in kidneys from euglycemic animals was 52.7+/-4.9% (PD(2) 11.3 [16.4-6.2]). Incubation with 1 microM alpha-lipoic acid or GSH restored the R(max) to Ach to 31+/-3.9% (PD(2) 9.8 [14.3-5.3]) and to 23+/-5.4% (PD(2) 7.6 [11.4-3.8], respectively. The vasodilatory response to SNP was unaltered among tissues from diabetic and euglycemic rabbits and was also unaffected by the treatments utilized. In addition, the R(max) to Ach in aortic rings of diabetic rabbits was 28.7+/-2.4% (PD(2) 8.3 [11.7-4.9]) compared with 100% (PD(2) 7.9 [12.1-3.7]) obtained in tissues gathered from euglycemic rabbits. The pretreatment of the tissues with alpha-lipoic acid restores the R(max) to 47.4+/-4% (PD(2) 11.1 [14.3-7.9]) and the pretreatment with GSH to 52+/-3.2% (PD(2) 9.8 [12.7-6.9]). Similarly, the response to SNP was unaltered in all groups. Lipoic acid and reduced gluthatione directly improved the endothelium-dependent response of renal arterioles and aortic rings of diabetic rabbits.

Animals↗
PubMed2005

Inhibition of gelatinase B (matrix metalloproteinase-9) by dihydrolipoic acid.

Alpha-lipoic acid (LA) is a disulphide-containing fatty acid that is absorbed from the diet and transported to tissues. Once it has been taken up by mammalian cells, LA is reduced to dihydrolipoic acid (DHLA), a vicinal dithiol, and rapidly effluxed into the extracellular milieu. We hypothesized that DHLA may be an effective inhibitor of human gelatinase B (GelB). Purified human GelB was incubated with 0 to 200 micromol/L DHLA, and residual enzyme activity was measured by HPLC using a fluorogenic substrate (matrix metalloproteinase substrate III). DHLA inhibited GelB in a dose-dependent fashion with an IC50 of 20 micromol/L. Oxidation of DHLA resulted in a loss of DHLA's capacity to inhibit GelB. The DHLA-mediated inhibition of GelB was independent of the zinc concentration in the reaction buffer. DHLA had no inhibitory effect on gelatinase A. Zymographs of activated neutrophil lysates demonstrated that higher concentrations of DHLA also prevent the activation of GelB proenzyme. Bronchoalveolar lavage fluid from mice fed a diet enriched with LA showed significantly increased GelB inhibitory capacity (p = 0.0002 vs. regular diet). We conclude that DHLA can modulate neutrophil-derived GelB activity through direct inhibition of enzyme activity and by preventing the activation of GelB proenzyme.

Animals↗
PubMed1999

Potential carcinogenicity of the synthetic 1,3,6-triazine (6-azapyrimidine) nucleic acid analogues determined by DC polarography. II. Nucleosides of 6-azauracil.

The polarographic reduction of six synthetic 1,3,6-triazine (6-aza) nucleosides with 6-azauracil as the nucleoside base in the strictly anhydrous solutions was studied in the absence and presence of alpha-lipoic acid. The values of the half-wave potentials E1/2 and the parameter of potential carcinogenicity tg alpha were compared for six nucleosides of 6-azauracil and two nucleosides of 4-thio-6-azauracil. The current value of the first diffuse polarographic wave or a new diffuse polarographic wave belonging to the nucleoside-alpha-lipoic acid complex increased with the increase of the alpha-lipoic acid concentration for the all compounds only marginally. Although this diffuse current increase was linear and dependent on the alpha-lipoic acid concentration in anhydrous solutions, the determined index tg alpha values ranged between 0.027 and 0.114. This is an indication of a very low potential carcinogenicity of the all nucleoside analogues investigated.

Azauridine↗
PubMed1993

[The neurohumoral systems of patients with ischemic heart disease and under emotional-pain stress: the means for their pharmacological regulation].

The sympathetic-adrenal and kallikrein-kinin systems were studied in 225 patients with various coronary heart diseases before and after therapy with lipoic acid (150 mg/day), tocopherol (100 mg/day), anaprilin (40 mg/day), prodectin (750 mg/day) or their combination. Myocardial and adrenal catecholamine levels were measured in experiments on animals exposed to emotional pain stress. Their levels were found to be affected by lipoic acid, tocopherol, obsidan or their combinations in the same doses, taking into account species specificity. Lipoic acid therapy for patients with coronary heart disease decreased epinephrine excretion, enhanced the elimination of vanillylmandelic acid and norepinephrine. Tocopherol lowered daily urinary epinephrine levels and increased the release of vanillylmandelic acid, without changing epinephrine excretion. Emotional pain stress resulted in myocardial epinephrine accumulation and adrenal norepinephrine in the animals. Lipoic acid prevented this accumulation, whereas tocopherol did not possess this effect.

Adolescent↗
PubMed1993

Lipoylated and unlipoylated domains of human PDC-E2 as autoantigens in primary biliary cirrhosis: significance of lipoate attachment.

Approximately 95% of patients with primary biliary cirrhosis have antimitochondrial antibodies against the E2 component of the pyruvate dehydrogenase complex (E2p). Immunodominant sites on E2p have been localized to the inner lipoyl domain, which serves as a covalent attachment site for the essential cofactor, lipoic acid. However, it is not clear whether the presence of lipoic acid is necessary for autoimmune recognition of human E2p. To facilitate further studies on the inner lipoyl domain and to assess the importance of lipoic acid in antibody binding, we used the previously cloned human E2p cDNA in the construction and high-level expression in Escherichia coli of a subgene encoding the domain. Purification and analysis of the gene product revealed that both lipoylated and unlipoylated forms of the intact domain are generated. Immunoblotting, enzyme-linked immunosorbent assay inhibition experiments and antibody affinity measurements using isolated lipoylated and unlipoylated domains demonstrated that the presence of the lipoyl residue is crucial for effective recognition by primary biliary cirrhosis patients' autoantibodies, which have a higher relative affinity for the lipoylated form. Contrary to some previous suggestions, these results indicate that antibodies in primary biliary cirrhosis patients' sera bind most effectively to a unique peptide-cofactor conformation in the lipoyl domain of the human E2p polypeptide. Moreover, the availability of large amounts of human lipoyl domain will permit further studies into the role of the antigen (if any) in disease pathogenesis.

Acetyltransferases↗
PubMed2006

Is there a role for reactive oxygen species in arterial medial elastocalcinosis?

Isolated systolic hypertension results from a gradual stiffening of large arteries, to which medial elastocalcinosis (calcification of elastic lamellae) contributes. There is compelling evidence that reactive oxygen species (ROS) are associated with several disease processes affecting the cardiovascular system, including hypertension. The present study was designed to investigate whether the inhibition of ROS production by alpha-lipoic acid can prevent vascular calcification. Sprague-Dawley rats were treated with warfarin (20 mg/kg/day) and vitamin K (15 mg/kg/day) (WVK) for 4 weeks to induce large artery calcification. Subgroups received either a normal diet or a diet supplemented with lipoic acid (1000 mg/kg/day). The WVK treatment produced a small elevation of aortic superoxide levels that did not reach statistical significance. Alpha-lipoic acid reduced the elevation below baseline levels. In rats treated with alpha-lipoic acid, the WVK-induced elevation of pulse wave velocity (an index of arterial stiffness), left ventricular hypertrophy, and aortic, femoral and carotid elastocalcinosis were not prevented. Although a contribution of oxidative stress has been suggested in the aging cardiovascular system, this alteration does not appear to contribute to the calcification process and the subsequent stiffening of large arteries in the animal model tested.

Animals↗