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PubMed1986

Gastric (H+ + K+)-ATPase: modulation of the inhibitory properties of the novel potent antisecretagogue Ro 18-5364 by sulfhydryl reagents and nucleotides.

The sulfoxide Ro 18-5364, a potential metabolite of the IND Ro 18-5362, is a powerful inhibitor of gastric mucosal (H+ + K+)-ATPase, decreasing enzymatic activity with an apparent Ki of 0.1 microM. Exposure of Ro 18-5364-treated gastric membranes to dithiothreitol fully restored (H+ + K+)-ATPase activity. ATP protected the enzyme against Ro 18-5364-induced inactivation of enzymatic activity. In addition, Ro 18-5364 inhibited vesicular proton uptake. In proton translocation experiments reduced lipoic acid methyl ester partially restored transport properties. Dithiothreitol and mercaptoethanol were without effect. The results are discussed with respect to the possible location of essential sulfhydryl groups for enzyme activity and proton transport.

Adenosine Triphosphatases↗

PubMed1995

Biliary epithelial expression of pyruvate dehydrogenase complex in primary biliary cirrhosis: an immunohistochemical and immunoelectron microscopic study.

It has been reported recently that there is a unique distribution of the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2) on biliary epithelial cells in patients with primary biliary cirrhosis (PBC) but not primary sclerosing cholangitis. This distribution has been demonstrated using a mouse monoclonal antibody, coined C355.1. The epitope recognized by C355.1 is near the lipoic acid binding site of PDC-E2. C355.1 inhibits PDC-E2 activity in vitro and, unlike a panel of other monoclonal antibodies against different regions of PDC-E2, appears to bind not only to mitochondria but also to a unique antigen expressed predominantly on the luminal side of biliary epithelial cells in PBC. We have extended these observations by studying the subcellular reactivity of C355.1 using postembedding immunoelectron microscopy on the intrahepatic small bile ducts of PBC livers, extrahepatic biliary obstruction (EBO) livers, and normal livers. We report that the reactivity of C355.1 can be classified into two categories. The first category is characterized by small foci of reaction products that were randomly dispersed in cytoplasm, particularly in supranuclear areas; the ultrastructural characterization of these foci was impossible to define but was similar in PBC and EBO. However, of particular interest was the second category of reactivity, which was characterized by deposition of reaction products around the biliary lumen, including microvilli and adjacent subluminal ectoplasm and secretory substances in the biliary lumen. This staining pattern was frequent in PBC livers, only occasionally evident in EBO livers, and not found in normal livers. These data further define and highlight the unique subcellular distribution of PDC-E2 around the biliary lumen in PBC livers and suggest that this abnormality is related to the pathogenesis of bile duct lesions.

Bile Ducts, Intrahepatic↗

PubMed1991

Morphological changes of isolated rat liver mitochondria during Fe2+/ascorbate-induced peroxidation and the effect of thioctacid.

Fe2+/ascorbate-induced peroxidation of isolated rat liver mitochondria leads to initial volume changes and, ultimately, to severe damage characterized by gross swelling and loss of cristae and matrix material. Only the last phase is associated with significant production of malondialdehyde. The shrinkage of mitochondria during the onset of peroxidation matches changes observed in mitochondria of aging animals. Thioctacid (alpha-lipoic acid) prevents this initial shrinkage. However, its main effect in the system studied here is inhibition of active respiration.

Animals↗

PubMed1993

Mechanisms of halothane toxicity: novel insights.

Exposure of individuals to halothane causes, in 20% of patients, a mild form of hepatotoxicity. In contrast, a very small subset of individuals only develops halothane hepatitis, which is thought to have an immunological basis. Sera of halothane hepatitis patients contain antibodies directed against some discrete liver trifluoroacetyl (TFA)-protein adducts, which arise upon oxidative biotransformation of halothane and include protein disulfide isomerase, microsomal carboxylesterase, calreticulin, ERp72, GRP 78 and ERp99. No immune response occurs in the majority of human individuals, although evidence suggests that TFA-protein adducts arise in all halothane-exposed individuals. The lack of immunological responsiveness of individuals might be due to tolerance, induced by a presumed repertoire of self-peptides that molecularly mimic TFA-protein adducts. Thus, constitutively expressed proteins of 52 and 64 kDa have been identified that confer molecular mimicry of TFA-protein adducts. The 64 kDa protein corresponds to the E2 subunit of the mitochondrial pyruvate dehydrogenase complex. Lipoic acid, the prosthetic group of the E2 subunit, is involved in the molecular mimicry process. A fraction of halothane hepatitis patients exhibit irregularities in the expression levels of the 52 kDa protein and the E2 subunit protein. Molecular mimicry of TFA-protein adducts by the 52 kDa protein and the E2 subunit protein might play a role in the susceptibility of individuals to development of halothane hepatitis.

Animals↗

PubMed1995

Alternative therapeutic principles in the prevention of microvascular and neuropathic complications.

Since the prevention of chronic diabetic complications by near normal metabolic control is not always achievable, alternative therapeutic principles have been developed. The specific intervention at metabolic abnormalities which seem to play a key role in the pathogenesis of complications has been shown to prevent the development of microangiopathy and neuropathy in experimental diabetes, e.g. inhibition of non-enzymatic glycation by aminoguanidine, inhibition of polyol pathway activity by aldose reductase inhibitors, prevention of hypoxia and oxidative stress by vasodilators and radical scavengers such as alpha-lipoic acid. Some of these drugs should soon be available for common clinical use.

Aldehyde Reductase↗

PubMed1981

Toward a "bio-energy supplement" -- a prototype for functional orthomolecular supplementation.

A broad-spectrum approach to the nutritional optimization of bioenergetics is discussed as a specific example of the principle of functional orthomolecular supplementation. Experimental and clinical studies with "metavitamins" such as lipoic acid, carnitine, coenzyme Q, and creatine, and with mitochondrial antioxidants, indicate that many nutritional agents involved in bioenergetics are often functionally sub-saturated. Numerous therapeutic applications for a well-designed "bio-energy supplement" can be postulated.

Animals↗

PubMed1981

An expanded concept of "insurance" supplementation--broad-spectrum protection from cardiovascular disease.

The preventive merits of "nutritional insurance" supplementation can be considerably broadened if meaningful doses of nutrients such as mitochondrial "metavitamins" (coenzyme Q, lipoic acid, carnitine), lipotropes, and key essential fatty acids, are included in insurance supplements. From the standpoint of cardiovascular protection, these nutrients, as well as magnesium, selenium, and GTF-chromium, appear to have particular value. Sophisticated insurance supplementation would likely have a favorable impact on many parameters which govern cardiovascular risk--serum lipid profiles, blood pressure, platelet stability, glucose tolerance, bioenergetics, action potential regulation--and as a life-long preventive health strategy might confer substantial benefit.

Antihypertensive Agents↗

PubMed1996

High-performance liquid chromatographic determination of lipoamidase (lipoyl-X hydrolase) activity with a novel substrate, lipoyl-6-aminoquinoline.

An HPLC lipoamidase (lipoyl-X hydrolase) assay method has been developed, which uses a novel fluorescent substrate, lipoyl-6-aminoquinoline (LAQ). LAQ is synthesized from lipoic acid and 6-aminoquinoline (AQ) through lipoyl chloride as an intermediate and is conveniently purified by washing with chloroform-methanol. Mechanistic studies on the time-course, the dependence on enzyme and substrate concentrations were performed by using LAQ and a model enzyme (milk lipoamidase). Moreover, this method was successfully applied to the direct determination of the lipoamidase (LAQ hydrolase) activity in samples of human liver, milk, stools and porcine serum. Using this novel synthetic lipoyl substrate, we demonstrated that LAQ hydrolase was present in some specific tissues; LAQ hydrolase was solely present in the grey matter and not in the white matter in the human cerebrum. Furthermore, LAQ hydrolase activity was shown to increase in human liver cancer. Thus, this enzyme assay method is expected to be applicable to the tissue distribution study and also to the basic research on human diseases such as cancer.

4-Aminobenzoic Acid↗

PubMed1991

Biotin uptake, utilization, and efflux in normal and biotin-deficient rat hepatocytes.

Biotin uptake, utilization, and efflux were studied in normal and biotin-deficient cultured rat hepatocytes. Biotin-deficient cells accumulate about 16-fold more biotin than do normal cells when incubated with a physiological concentration of biotin for 24 h. This difference is due to the greater amount of protein-bound biotin relative to free biotin in biotin-deficient hepatocytes, and is attributable to the presence of more apocarboxylases in deficient cells. The rate of biotin uptake and the rate of activation of the carboxylases, acetyl-CoA carboxylase, pyruvate carboxylase, propionyl-CoA carboxylase, and beta-methylcrotonyl-CoA carboxylase, are proportional to the concentration of exogenous biotin. Increases in carboxylase activities are proportional to the concentration of biotin only at exogenous biotin concentrations of less than 410 nM. Concentrations of 410 nM or more biotin increase carboxylase activities to normal or near normal. Biocytin inhibits biotin uptake at very high concentrations, whereas desthiobiotin and lipoic acid have no effect. Biocytin in the medium results in carboxylase activation either intracellularly or extracellularly by conversion to biotin by biotinidase. Investigation of the efflux of biotin from normal and biotin-deficient cells preincubated with the vitamin showed greater retention of biotin by biotin-deficient cells than by normal cells over 24 h. Retention of free biotin is similar in biotin-deficient and normal cells. The greater amount of biotin retained by biotin-deficient cells is accounted for by the greater amount of bound biotin in these cells. These results suggest that the free and bound biotin pools are independently regulated. The ready loss of free biotin from these cells has implications for the treatment of inherited, biotin-responsive carboxylase deficiencies.

Animals↗

PubMed2006

The activity of a thermostable lipoyl synthase from Sulfolobus solfataricus with a synthetic octanoyl substrate.

The protein lipoyl synthase (LipA) is essential for lipoic acid biosynthesis via sulfur insertions into a protein-bound octanoyl group. We have developed an in vitro assay for LipA using a synthetic tetrapeptide substrate, containing an N(epsilon)-octanoyl lysine residue, corresponding in sequence to the lipoyl binding domain of the E2 subunit of pyruvate dehydrogenase. A putative LipA from the hypothermophilic archaea Sulfolobus solfataricus was expressed in Escherichia coli and purified, and the activity was measured using this novel assay. The optimal temperature for the S. solfataricus LipA-dependent formation of the lipoyl group was found to be 60 degrees C.

Base Sequence↗

PubMed2004

Antioxidants effectively prevent oxidation-induced protein damage in OLN 93 cells.

Oxidative stress is supposed to play an important role in demyelinating diseases. Oligodendrocytes are the myelin-forming cells in the brain and are highly susceptible to oxidative stress due to their low antioxidative defense systems and high metabolic rate. In the present work, we tested the response of the oligodendrocyte cell line OLN 93 to oxidative stress. OLN 93 cell cultures are characterized by a loss of cell viability after oxidation. This loss of cell viability is accompanied by an increase in protein oxidation and consequently an elevated overall proteolysis. To minimize the oxidative damage, we tested the effects of the antioxidants alpha-lipoic acid and coenzyme Q(10). Both compounds were able to elevate cell viability and to decrease intracellular protein turnover and oxidant induced protein oxidation. Therefore, we concluded that the excessive oxidative damage of oligodendrocytes and their protein pool can be prevented by the usage of antioxidants.

Animals↗

PubMed2006

Menopause: a review on the role of oxygen stress and favorable effects of dietary antioxidants.

Menopause is often accompanied by hot flashes and degenerative processes such as arteriosclerosis and atrophic changes of the skin that suggest an acceleration of aging triggered by estrogen lack. Therefore, hormone replacement therapy (HRT) has been considered the most suitable treatment for the above symptoms and processes. However, because of the possible serious side effects of HRT (especially the increased risk of thrombo-embolic accidents and breast cancer) there is a growing demand for alternative treatments of the symptoms and pathological processes associated with menopause. In agreement with the above, we review research that supports the concept that oxygen stress contributes to menopause and that some of its physiopathological effects may be prevented and/or treated improving the antioxidant defense of menopausic and postmenopausic women. Accordingly, a selection of micronutrients may be useful as a dietary supplement for protection against the decline of physiological functions caused by age-related oxygen stress. Since aging is accompanied by a progressive oxidation of the physiological sulfur pool, we emphasize the role of the vitamins B that help to maintain the GSH/GSSG ratio in its normal reduced state. Nutritional supplements should also include the key antioxidant vitamins C and E, as well as beta-carotene and the mineral micronutrients found in the oxygen radical-detoxifying enzymes glutathione peroxidase and superoxide dismutase. Moreover, the reviewed data suport the concept that other antioxidants such as lipoic acid and the precursors of glutathione thioproline (TP) and l-2-oxothiazolidine-4-carboxylic acid (OTC), as well as the soy isoflavones and the "coantioxidants" of an hydroalcoholic extract of Curcuma longa may help to prevent antioxidant deficiency with resulting protection of mitochondria against premature oxidative damage with loss of ATP synthesis and especialized cellular functions. Therefore, the administration under medical advice of synergistic combinations of some of the above mentioned antioxidants in the diet as well as topically (for skin protection) may have favorable effects on the health and quality of life of women, especially of those who cannot be treated with HR, suffer high levels of oxygen stress, and do not consume a healthy diet that includes five daily rations of fresh fruit and vegetables.

Aging↗

PubMed2005

Characterization of the redox components of transplasma membrane electron transport system from Leishmania donovani promastigotes.

An investigation has been made of the points of coupling of four nonpermeable electron acceptors e.g., alpha-lipoic acid (ALA), 5,5'-dithiobis (2-nitroaniline-N-sulphonic acid) (DTNS), 1,2-naphthoquinone-4-sulphonic acid (NQSA) and ferricyanide which are mainly reduced via an interaction with the redox sites present in the plasma membrane of Leishmania donovani promastigotes. ALA, DTNS, NQSA and ferricyanide reduction and part of O2 reduction is shown to take place on the exoplasmic face of the cell, for it is affected by external pH and agents that react with the external surface. Redox enzymes of the transplasma membrane electron transport system orderly transfer electron from one redox carrier to the next with the molecular oxygen as the final electron acceptor. The redox carriers mediate the transfer of electrons from metabolically generated reductant to nonpermeable electron acceptors and oxygen. At a pH of 6.4, respiration of Leishmania cells on glucose substrate shut down almost completely upon addition of an uncoupler FCCP and K+-ionophore valinomycin. The most pronounced effects on O2 uptake were obtained by treatment with antimycin A, 2-heptadecyl-4-hydroxyquinone-N-oxide, paracholoromercuribenzene sulphonic acid and trifluoperazine. Relatively smaller effects were obtained by treatment with potassium cyanide. Inhibition observed with respect to the reduction of the electron acceptors ALA, DTNS, NQSA and ferricyanide was not similar in most cases. The redox chain appears to be branched at several points and it is suggested that this redox chain incorporate iron-sulphur center, b-cytochromes, cyanide insensitive oxygen redox site, Na+ and K+ channel, capsaicin inhibited energy coupling site and trifluoperazine inhibited energy linked P-type ATPase. We analyzed the influence of ionic composition of the medium on reduction of electron acceptors in Leishmania donovani promastigotes. Our data suggest that K+ have some role for ALA reduction and Na+ for ferricyanide reduction. No significant effects were found with DTNS and NQSA reduction when Na+ or K+ was omitted from the medium. Stimulation of ALA, DTNS, NQSA and ferricyanide reduction was obtained by omitting Cl- from the medium. We propose that this redox system may be an energy source for control of membrane function in Leishmania cells.

Aerobiosis↗

PubMed2004

Reduced cell replication and induction of apoptosis by advanced glycation end products in rat Schwann cells.

We investigated the effects of advanced glycation end products (AGEs) derived from glucose, glyceraldehyde, and glycolaldehyde (designated as AGE-1, -2, and -3, respectively) on the viability, replication rate, and cytokine production of cultured Schwann cells. AGE-2 and -3, but not AGE-1, induced apoptosis, and significantly decreased the viability measured by MTT assay. The decrease was prevented completely by antioxidant alpha-lipoic acid and was prevented partially by p38 mitogen-activated protein kinase inhibitor SB202190. The decrease in mitochondrial membrane potential by AGE-2 and -3 was also observed. In addition, AGE-2 and -3 significantly suppressed the replication rate as shown by reduced bromodeoxyuridine uptake, whereas they enhanced the release of TNF-alpha and IL-1beta into the medium and activated nuclear factor-kappaB. The effects of AGE-1 on these measures were equivocal. The series of events elicited by AGE-2 and -3 may be responsible for some of the aspects of pathogenetic mechanisms in patients with diabetic neuropathy.

Animals↗

PubMed2005

Obesity: the role of hypothalamic AMP-activated protein kinase in body weight regulation.

Obesity is rapidly increasing and is of great public health concern worldwide. Although there have been remarkable developments in obesity research over the past 10 years, the molecular mechanism of obesity is still not completely understood. Body weight results from the balance between food intake and energy expenditure. Recent studies have found that hypothalamic AMP-activated protein kinase plays a key role in regulating these processes. Leptin, insulin, glucose and alpha-lipoic acid have been shown to reduce food intake by lowering hypothalamic AMP-activated protein kinase activity, whereas ghrelin and glucose depletion increase food intake by increasing hypothalamic AMP-activated protein kinase activity. In addition, this enzyme plays a role in the central regulation of energy expenditure. These findings indicate that hypothalamic AMP-activated protein kinase is an important signal molecule, which integrates nutritional and hormonal signals and modulates feeding behavior and energy expenditure.

AMP-Activated Protein Kinases↗

PubMed2006

Thioredoxin interacting protein is increased in sensory neurons in experimental diabetes.

Diabetic neuropathy is a major complication of diabetes and has multifactoral aetiology. The exact cause of damage is unknown although high glucose and oxidative stress are known to contribute significantly. In order to identify molecular targets of the disease and possibly new therapeutic targets, we previously examined the effect of diabetes on dorsal root ganglia (DRG) neurons using Affymetrix gene chip arrays. A number of individual genes and groups of genes were found to be dysregulated; the most significant of these was thioredoxin interacting protein (Txnip). This gene was found to have increased expression in DRG from diabetic rats with all durations of diabetes examined, including those that preceded the onset of functional changes such as decreased nerve conduction velocity. Increased Txnip expression therefore represents an early change in diabetic neuropathy that could, at least in part, be responsible for causing the initial functional deficits. This study confirmed the changes in Txnip expression at the mRNA and protein levels and identified the cell types responsible for the change. Furthermore we investigated the mechanism of diabetes-induced Txnip gene induction. Neither the antioxidant dexlipotam (R-lipoic acid) nor the p38 MAP kinase inhibitor SB239063 could prevent increases in Txnip expression despite reducing oxidative stress. However, treatment of rats with insulin prevented diabetes-induced increases in Txnip gene expression. These results indicate another mechanism by which diabetes may cause oxidative damage in peripheral nerve, and may represent a novel target for therapeutic intervention.

Animals↗

PubMed2005

Preservation of pressure-induced cutaneous vasodilation by limiting oxidative stress in short-term diabetic mice.

OBJECTIVE: Pressure-induced vasodilation (PIV) allows skin blood flow to increase in response to locally applied pressure and may be protective against pressure ulcers. We previously showed that PIV was absent in 1-week diabetic mice exhibiting no neuropathy. Our aim was to determine whether the diabetes-induced PIV alteration could be prevented. METHODS AND RESULTS: Diabetic mice received no treatment or a daily treatment with either sorbinil, alagebrium or alpha-lipoic acid (LPA) for 1 week. Laser Doppler flowmetry was used to evaluate PIV as well as endothelium-dependent vasodilation following iontophoretic delivery of acetylcholine (ACh). The effect of each treatment on oxidative stress was examined by plasma 8-isoprostane assay. LPA was the sole treatment to prevent both PIV and ACh vasodilation alterations, with a significant reduction of oxidative stress in diabetic mice. Both PIV and ACh-vasodilation were abolished in LPA-treated diabetic mice following injection of Nomega-nitro-L-arginine (p<0.05). In contrast, alagebrium and sorbinil prevented neither diabetes-induced PIV abolition nor endothelial alteration. CONCLUSIONS: LPA treatment significantly reduced the oxidative stress and was able to preserve endothelial nitric oxide availability in the cutaneous microcirculation and then to preserve the PIV response in diabetic mice. LPA treatment could play a key role in limiting the risk of pressure-induced cutaneous ulcer during diabetes.

Acetylcholine↗

PubMed2006

Free radicals, metals and antioxidants in oxidative stress-induced cancer.

Oxygen-free radicals, more generally known as reactive oxygen species (ROS) along with reactive nitrogen species (RNS) are well recognised for playing a dual role as both deleterious and beneficial species. The "two-faced" character of ROS is substantiated by growing body of evidence that ROS within cells act as secondary messengers in intracellular signalling cascades, which induce and maintain the oncogenic phenotype of cancer cells, however, ROS can also induce cellular senescence and apoptosis and can therefore function as anti-tumourigenic species. The cumulative production of ROS/RNS through either endogenous or exogenous insults is termed oxidative stress and is common for many types of cancer cell that are linked with altered redox regulation of cellular signalling pathways. Oxidative stress induces a cellular redox imbalance which has been found to be present in various cancer cells compared with normal cells; the redox imbalance thus may be related to oncogenic stimulation. DNA mutation is a critical step in carcinogenesis and elevated levels of oxidative DNA lesions (8-OH-G) have been noted in various tumours, strongly implicating such damage in the etiology of cancer. It appears that the DNA damage is predominantly linked with the initiation process. This review examines the evidence for involvement of the oxidative stress in the carcinogenesis process. Attention is focused on structural, chemical and biochemical aspects of free radicals, the endogenous and exogenous sources of their generation, the metal (iron, copper, chromium, cobalt, vanadium, cadmium, arsenic, nickel)-mediated formation of free radicals (e.g. Fenton chemistry), the DNA damage (both mitochondrial and nuclear), the damage to lipids and proteins by free radicals, the phenomenon of oxidative stress, cancer and the redox environment of a cell, the mechanisms of carcinogenesis and the role of signalling cascades by ROS; in particular, ROS activation of AP-1 (activator protein) and NF-kappaB (nuclear factor kappa B) signal transduction pathways, which in turn lead to the transcription of genes involved in cell growth regulatory pathways. The role of enzymatic (superoxide dismutase (Cu, Zn-SOD, Mn-SOD), catalase, glutathione peroxidase) and non-enzymatic antioxidants (Vitamin C, Vitamin E, carotenoids, thiol antioxidants (glutathione, thioredoxin and lipoic acid), flavonoids, selenium and others) in the process of carcinogenesis as well as the antioxidant interactions with various regulatory factors, including Ref-1, NF-kappaB, AP-1 are also reviewed.

Animals↗