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PubMed1993

Polarographic reduction and carcinogenic index tg alpha of 5-aza nucleosides possessing antileukemic activity.

Polarographic behavior of arabinosyl-5-azacytosine (ara-AC) and 5-azacytidine in anhydrous dimethylformamide and in Britton Robinson buffer is described. 5-Azacytidine and ara-AC underwent two-electron reduction under the polarographic conditions used. Carcinogenic index tg alpha estimated in the presence of alpha-lipoic acid was 0.295 for 5-azacytidine and 0.275 for ara-AC.

Antineoplastic Agents↗
PubMed1994

[Preventive treatment of diabetic microangiopathy: blocking the pathogenic mechanisms].

The development of drugs in order to block metabolic pathway of glucose responsible for diabetic vascular dysfunction is in progress. Aldose reductase inhibitors prevent or reduce the different components of vascular dysfunction, cataract, neuropathy and nephropathy in animal models of diabetes. Promising results have been observed in diabetic patients concerning the prevention of neuropathy and of retinopathy. Larger scale studies with the second generation compounds are in progress. Glycation inhibitors, mainly aminoguanidine, have been shown to prevent or reduce vascular dysfunction and microvascular complications in animal models. Trials in diabetic patients with aminoguanidine are just beginning. Anti-oxidant therapy is also at its early stage of development (vitamin E, vitamin C, alpha lipoic acid). Antiplatelet agents (aspirin, ticlopidine) have been demonstrated to reduce the progression of non proliferative diabetic retinopathy. Angiotensin converting enzyme inhibitors are of particular interest in preventing diabetic glomerulopathy.

Aldehyde Reductase↗
PubMedDate not supplied

[New directions in the hypotensive therapy of open-angle glaucoma (experimental and clinical research)].

Clinical use of eye drops of a hybrid beta-alpha-adrenoblocker OF-4680 to reduce intraocular pressure has shown a high efficacy of the drug, not inferior to thymolol, for local hypotensive therapy of open-angle glaucoma. A combination of thymolol with taurin helped reduce the inhibiting effect of the beta-blocker on chamber humor secretion and simultaneously enhanced its discharge. The results evidence the desirability of correcting glutathion deficiency, detected in the patients with narrow-angle glaucoma, by lipoic acid.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

[Effect of various specific agents on the heat stability of human serum albumin].

Effect of lipoic acid, 5,5-dithiobis-2-nitrobenzoic acid, monoiodoacetic acid and cystine on thermal stability of human serum albumin was studied by differential scanning calorimetry and electrophoretic methods. Quantitative estimation of the protective effect of these reagents on resistance of 5% solutions of albumin to the temperature influence was studied. It is concluded that all the compounds used protect albumin from polymerization at heating.

Calorimetry, Differential Scanning↗
PubMed1994

Purification and characterization of lipoyl-AMP:N epsilon-lysine lipoyltransferase from bovine liver mitochondria.

Lipoyl-AMP:N epsilon-lysine lipolytransferase (lipolytransferase) catalyzes the transfer of the lipoyl group from lipoyl-AMP to a lysine residue of the specific enzyme proteins. We have shown previously that the lipoyltransferase activities locate in mitochondria using apoH-protein of the glycine cleavage system as an acceptor of the lipoyl group (Fujiwara, K., Okamura-Ikeda, K., and Motokawa, Y. (1990) J. Biol. Chem. 265, 17463-17467). Here we describe the purification and the characterization of two isoforms of lipolytransferase termed lipoyltransferase I and lipoyltransferase II from bovine liver mitochondria. Lipoyltransferase II was purified to apparent homogeneity, whereas the final product of lipoyltransferase I still contained a minor contaminant. Although the two forms could be resolved on a hydroxylapatite column chromatography, they were indistinguishable, as judged by: (a) behavior during purification on ion exchange, hydrophobic, or affinity columns; (b) molecular mass determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and gel exclusion chromatography (40 kDa); and (c) catalytic properties (substrate specificity, kinetic constants, and optimal pH). Both lipoyltransferase I and II could not use lipoic acid plus MgATP as a substrate in place of lipoyl-AMP. Surprisingly, the lipoyltransferases transferred not only the lipoyl group but also the acyl groups from hexanoyl-, octanoyl-, and decanoyl-AMP to apoH-protein to a similar extent.

Acyltransferases↗
PubMed1993

[Diabetes mellitus--a free radical-associated disease. Results of adjuvant antioxidant supplementation].

Our investigations carried out in patients with diabetes mellitus revealed oxidative stress loads. The study presented here was to clarify whether a therapy with antioxidants can contribute to an improvement of prognosis. 80 patients affected with a long term diabetic late syndrome were randomised and arranged to 4 groups of n = 20 each. In contrast to a control group these patients received 600 mg of alpha lipoic acid or 100 micrograms of selenium (sodium selenite) daily or 1200 IE of D-alpha-tocopherol respectively for a time of 3 months. In comparison with the control group all groups treated in an antioxidative way showed significantly diminished serum concentrations of thiobarbituric acid reactive substances and of urinary albumin excretion rates. The symptoms of distal symmetric neuropathy measured according to the thermo- and vibration sensitivity also improved in a highly significant manner. The results prove that oxidative stress plays a promoting role in developing of long term diabetic late complications and that a therapy with adjuvant antioxidants may lead to a regression of diabetic late complications.

Adult↗
PubMed1995

Inhibitory effect of pyruvate on release of glutathione and swelling of rat heart mitochondria.

Pyruvate prevents the permeability transition of rat heart mitochondria induced by the system calcium ions + phosphate or by the dithiol reagent phenylarsenoxide and measured as swelling. Since swelling induced by the latter is relieved by the dithiol 2,3-dimercaptopropanol (BAL), it is inferred that the effect of pyruvate might be mediated by the reduction of lipoic acid. In isolated mitochondria, pyruvate also exerts a protective effect when calcium + phosphate-induced swelling is exacerbated by hypoxic conditions. These results agree with our previous observations that pyruvate markedly prevents the loss of cytosolic and mitochondrial glutathione after ischemia or ischemia followed by reperfusion.

Animals↗
PubMed1997

Polarographic testing of carcinogenicity of some chemotherapeutics.

This work is devoted to the study of polarographic reduction of three antibiotic compounds including adriamycin, chloramphenicol and erythromycin and of a synthetic antibacterial chemotherapeutic compound--5-nitrofurantoin. The polarographic reduction was performed in the strictly anhydrous N,N-dimethylformamide with or without alpha-lipoic acid (LA) by the means of DC polarography. The values of half-wave potentials E1/2 and parameter of potential carcinogenicity were determined for the all compounds. Adriamycin was reduced during the five-step process, other compounds were reduced in two steps. The presence of LA in a polarographic solution resulted in a new polarographic one-electron wave in the range of -1.120 V to -1.790 V vs. SCE possessing a diffuse and reversible character. Its height is linearly dependent on the LA concentration in solution. The highest parameter of potential carcinogenicity tg alpha was determined for adriamycin (0.575) which belongs among compounds classified by WHO as "probably carcinogenic to humans". The lowest determined value of parameter tg alpha belonged to 5-nitrofurantoin (0.290) which has not yet been included into the IARC classification.

Anti-Bacterial Agents↗
PubMed1998

Evaluation of potential carcinogenicity of steroidal alkaloids from Veratrum album L. by the DC polarography method.

The presented work is devoted to the study of polarographic reduction in the series of 13 alkaloids isolated from various parts of Veratrum album subsp. lobelianum. The used compounds were evaluated from the point of view of their potential carcinogenicity in anhydrous N,N-dimethylformamide (DMF) by the method of DC polarography. All compounds were reduced during an one two-electron irreversible step. Their potential carcinogenicity characterized by a parameter tg alpha value determined in the presence of alpha-lipoic acid ranged from the highest value 0.257 obtained for the solanidane skeleton containing rubijervine to the value 0.070 for jervine. The tg alpha value determined for rubijervine (0.257) is comparable with the tg alpha of naphto-(2',1',2,3)fluoranthene (0.270)-compound classified by IARC as possible carcinogen for human. The tg alpha values determined for other alkaloids were relatively low and they do not indicate any possible carcinogenic activity.

Alkaloids↗
PubMed1988

Nucleotide sequence of a cDNA for the dihydrolipoamide acetyltransferase component of human pyruvate dehydrogenase complex.

Deoxynucleotide sequencing of a cDNA for the dihydrolipoamide acetyltransferase (PDC-E2) component of human pyruvate dehydrogenase complex (PDC) revealed an open reading frame of 1848 base pairs corresponding to a leader sequence of 54 amino acids and a mature protein of 561 amino acids (59,551 Da). Both an amino-terminal lipoyl-bearing domain and a carboxy-terminal catalytic domain are present in the deduced amino acid sequence. The lipoyl-bearing domain contains two repeating units of 127 amino acids, each harboring one lipoic acid-binding lysine. Thus, mammalian PDC-E2 differs as to the number of lipoic acid-binding sites from other dihydrolipoamide acyltransferases in both prokaryotic and eukaryotic organisms.

Acetyltransferases↗
PubMed2005

Increases of spinal kinin receptor binding sites in two rat models of insulin resistance.

An autoradiographic study was conducted to determine whether kinin receptors are altered in the rat spinal cord in two experimental models of chronic hyperglycemia and insulin resistance. Sprague-Dawley rats were given 10% d-glucose in their drinking water alone or with insulin (9 mU/kg/min with osmotic pumps) for 4 weeks. Both groups and control rats were treated either with a normal chow diet or with an alpha-lipoic acid-supplemented diet as antioxidant therapy. After 4 weeks of treatment, glycemia, insulinemia, blood pressure, insulin resistance index, the production of superoxide anion in the aorta and the density of B2 receptor binding sites in the dorsal horn were significantly increased in the two models. These effects were prevented or attenuated by alpha-lipoic acid. In contrast, B2 receptor binding sites of most spinal cord laminae were increased in the glucose group only and were not affected by alpha-lipoic acid. Results show that chronic hyperglycemia associated with insulin resistance increases B1 and B2 receptor binding sites in the rat spinal cord through distinct mechanisms, including the oxidative stress for the B1 receptor.

Animals↗
PubMed1995

The lipoamide arm in the glycine decarboxylase complex is not freely swinging.

Glycine decarboxylase consists of four protein components. Its structural and mechanistic heart is provided by the lipoic acid-containing H-protein which undergoes a cycle of reductive methylamination, methylamine transfer and electron transfer. Lipoic acid attached to a specific lysine side chain is assumed to act as a 'swinging arm' conveying the reactive dithiolane ring from one catalytic centre to another. The X-ray crystal structures of two forms of the H-protein have been determined. The lipoate cofactor is located in the loop of a hairpin configuration but following methylamine transfer it is pivoted to bind into a cleft at the surface of the H-protein. The lipoamide-methylamine arm is, therefore, not free to move in aqueous solvent.

Amino Acid Oxidoreductases↗
PubMed1999

[Drug prescriptions and costs in diabetic polyneuropathy].

BACKGROUND AND OBJECTIVE: Numerous medications are used in the treatment of diabetic polyneuropathy (PNP) without evidence of their efficacy. This study was undertaken to obtain the costs of drugs prescribed to patients with PNP throughout the Federal Republic of Germany in primary-care practices. PATIENTS AND METHODS: Data (stored in the Medi-Plus data bank of the Institute for Medical Statistics, Frankfurt) from 400 primary-care practices were analysed for the year 1996 with regard to diagnoses and prescriptions for 40,112 diabetics over the age of > or = 20 years. A polyneuropathy (PNP) had been diagnosed in 3548 patients (8.8%) (age: 68 +/- 12 years, 56% women). The cost of medications listed for the treatment of PNP was identified and extrapolated to the total prescription cost for treated diabetic PNP in the whole of Germany. In addition the proportion of costs for drugs with unproven efficacy was calculated. RESULTS: Antidepressives were prescribed for 13%, carbamazepine for 4%, and lipoic (thioctic) acid for 41% of diabetics with PNP. Annual costs per patient (mean value) were DM 203 for lipoic acid, DM 53 for vasoactive drugs and DM 42 for analgesics. Projection for the estimated total number of diabetic patients with PNP treated in primary care practices (n = 361,400) gave a total cost of DM 116 million (95% confidence limit: DM 109-123), of which DM 41 million (35%) was for medications of unproven efficacy. CONCLUSION: In Germany one third of drug costs for diabetic patients with PNP in primary care is for medications of unproven efficacy. Cost-effective guidelines for the treatment of diabetic PNP are urgently required.

Aged↗
PubMed1995

Refined structures at 2 and 2.2 A resolution of two forms of the H-protein, a lipoamide-containing protein of the glycine decarboxylase complex.

H-protein, a 14 kDa lipoic acid-containing protein is a component of the glycine decarboxylase complex. This complex which consists of four protein components (P-, H-, T- and L-protein) catalyzes the oxidative decarboxylation of glycine. The mechanistic heart of the complex is provided by the lipoic acid attached to a lysine residue of the H-protein. It undergoes a cycle of transformations, i.e. reductive methylamination, methylamine transfer, and electron transfer. We present details of the crystal structures of the H-protein, in its two forms, H-Pro(Ox) with oxidized lipoamide and H-Pro(Met) with methylamine-loaded lipoamide. X-ray diffraction data were collected from crystals of H-Pro(Ox) to 2 and H-Pro(Met) to 2.2 A resolution. The final R-factor value for the H-Pro(Ox) is 18.5% for data with F > 2sigma. in the range of 8.0-2.0 A resolution. The refinement confirmed our previous model, refined to 2.6 A, of a beta-fold sandwich structure with two beta-sheets. The lipoamide arm attached to Lys63, located in the loop of a hairpin conformation, is clearly visible at the surface of the protein. The H-Pro(Met) has been crystallized in orthorhombic and monoclinic forms and the structures were solved by molecular replacement, starting from the H-Pro(Ox) model. The orthorhombic structure has been refined with a final R-factor value of 18.5% for data with F > 2sigma in the range of 8.0-2.2 A resolution. The structure of the monoclinic form has been refined with a final R-factor value of 17.5% for data with F > 2sigma in the range of 15.0-3.0 A. In these two structures which have similar packing, the protein conformation is identical to the conformation found in the H-Pro(Ox). The main change lies in the position of the lipoamide group which has moved significantly when loaded with methylamine. In this case the methylamine-lipoamide group is tucked into a cleft at the surface of the protein where it is stabilized by hydrogen bonds and hydrophobic contacts. Thus, it is totally protected and not free to move in aqueous solvent. In addition, the H-protein presents some sequence and structural analogies with other lipoate- and biotin-containing proteins and also with proteins of the phosphoenolpyruvate:sugar phosphotransferase system.

Journal Article↗
PubMed1994

X-ray structure determination at 2.6-A resolution of a lipoate-containing protein: the H-protein of the glycine decarboxylase complex from pea leaves.

H-protein, a lipoic acid-containing protein of the glycine decarboxylase (EC 1.4.4.2) complex from pea (Pisum sativum) was crystallized from ammonium sulfate solution at pH 5.2 in space group P3(1)21. The x-ray crystal structure was determined to 2.6-A resolution by multiple isomorphous replacement techniques. The structure was refined to an R value of 23% for reflections between 15- and 2.6-A resolution (F > 2 sigma), including the lipoate moiety and 50 water molecules, for the two protein molecules of the asymmetric unit. The 131-amino acid residues form seven beta-strands arranged into two antiparallel beta-sheets forming a "sandwich" structure. One alpha-helix is observed at the C-terminal end. The lipoate cofactor attached to Lys-63 is located in the loop of a hairpin configuration. The lipoate moiety points toward the residues His-34 and Asp-128 and is situated at the surface of the H-protein. This allows the flexibility of the lipoate arm. This is the first x-ray determination of a lipoic acid-containing protein, and the present results are in agreement with previous theoretical predictions and NMR studies of the catalytic domains of lipoic acid- and biotin-containing proteins.

Amino Acid Oxidoreductases↗
PubMed1987

Isolation of a cDNA clone for the dihydrolipoamide acetyltransferase component of the human liver pyruvate dehydrogenase complex.

Dihydrolipoamide acetyltransferase (E2) forms the structural core of pyruvate dehydrogenase complex. A cDNA clone (lambda E2-1) for mammalian E2 was identified from a human liver lambda gt11 library using anti-E2 serum. Affinity-selected antibodies using the fusion protein from lambda E2-1 immuno-reacted specifically with E2 of purified pyruvate dehydrogenase complex on immuno-blot analysis. The cDNA insert was approximately 2.3 kb in length with an internal EcoR1 site generating 1.4 and 0.9 kb fragments. A synthetic 17-mer oligodeoxynucleotide mixture based on the amino acid sequence surrounding the lipoic acid-containing lysine residue in bovine kidney E2 hybridized with the 2.3 kb cDNA insert and the 1.4 kb fragment.

Acetyltransferases↗