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PubMedDate not supplied

Identification of antioxidants for prevention of peroxide-mediated oxidation of recombinant human ciliary neurotrophic factor and recombinant human nerve growth factor.

Peroxides present in non-ionic surfactants used to stabilize certain recombinant protein formulations (e.g. polysorbate 80) can result in the oxidative degradation of proteins. In this study, the ability of various pharmaceutically acceptable antioxidants to prevent the oxidative degradation of two therapeutic proteins, recombinant human Ciliary Neurotrophic Factor (rhCNTF) and recombinant human Nerve Growth Factor (rhNGF), caused by alkyl hydroperoxides and hydrogen peroxide was studied. For rhCNTF, the rank order of effectiveness of the antioxidants tested was: thiols (cysteine, glutathione, thioglycerol) >> thioethers (methionine). Other parenterally acceptable antioxidants (ascorbic acid, propyl gallate and sodium bisulfite) destabilized the protein. The thiol antioxidants (cysteine and glutathione) were also the most effective antioxidants for rhNGF; however, in contrast to rhCNTF, ascorbic acid did not destabilize rhNGF. The rank order of effective antioxidants for rhNGF was: thiols (cysteine, glutathione) > > thioethers (methionine) > ascorbic acid.

Antioxidants↗
PubMed2002

Potential therapeutic uses for S-nitrosothiols.

The S-nitrosothiols (RSNOs) are thought to represent a circulating endogenous reservoir of nitric oxide (NO), and may have potential as donors of NO, distinct from currently used agents. They have the general formula RSNO, and naturally occurring examples include S-nitrosocysteine, S-nitrosoglutathione and S-nitrosoalbumin, in which R is an amino acid, polypeptide and protein respectively. RSNOs have anti-platelet properties, a theoretical role in the treatment of asthma and the potential to be used as agents to treat infectious diseases ranging from the common cold to AIDS. RSNOs are relatively unstable, being degraded to release NO and the corresponding disulphide. Their stability is influenced by the properties of the R group, heat, light, the presence of transition metal ions (in particular copper) and the presence of other thiols. RSNOs participate in transnitrosation reactions in which the -NO group is transferred to another thiol to form a more stable RSNO. Thus the stability of RSNOs in vivo is difficult to predict, and this has led to the development of more stable analogues, in which the properties of R are modified. Potential interactions of RSNOs include that with ascorbic acid (vitamin C), which enhances the ability of copper to catalyse their degradation. Transnitrosation reactions with thiol-containing enzymes can influence protein function, and the intracellular thiol glutathione, levels of which are influenced by many disease states, can also influence stability. Thus, although RSNOs have many theoretically useful properties, there are also many aspects of their biochemistry that need to be addressed before their therapeutic potential can be fully realized.

Anti-Asthmatic Agents↗
PubMed2005

Genomic effect of vitamin 'C' and statins within human mononuclear cells involved in atherogenic process.

Deregulated crosstalk within nuclear receptor/transcription factor family, comprising of peroxisome proliferator-activated receptors (PPARs) and liver X receptor-alpha (LXR-alpha), can give rise to cooperativity between lipid peroxidation and inflammation leading to atherogenic process. The present study addressed to explore the effect of statins and vitamin 'C' on transcriptional expression of genes coding for this nuclear receptor/transcription factor family within mononuclear cells revealed for the first time that both mevastatin and vitamin 'C' have common action in that they significantly downregulate the expression of PPARs (alpha, gamma) genes and upregulate LXR-alpha gene expression as compared to the control. The similar phenomenon was observed in mononuclear cells obtained from coronary heart disease (CHD) patients who were receiving atorvastatin treatment (20 mg HS). Further, the observed upregulatory effect of LXR-alpha gene expression was in conformity with the downregulatory effect of LXR-alpha on its effector gene matrix metalloproteinase-9. Based on these results, we propose that LXR-alpha-dependent signaling pathway may be a crucial target for the therapeutic intervention in human CHD, and in addition to statins, vitamin 'C' deserves a close scrutiny for the treatment of CHD.

Animals↗
PubMed2000

Induction of apoptosis in human prostatic cancer cells with beta-glucan (Maitake mushroom polysaccharide).

PURPOSE: To explore more effective treatment for hormone-refractory prostate cancer, we investigated the potential antitumor effect of beta-glucan, a polysaccharide of the Maitake mushroom, on prostatic cancer cells in vitro. MATERIALS AND METHODS: Human prostate cancer PC-3 cells were treated with various concentrations of the highly purified beta-glucan preparation Grifron-D(R) (GD), and viability was determined at 24 h. Lipid peroxidation (LPO) assay and in situ hybridization (ISH) were performed to unravel the antitumor mechanism of GD. RESULTS: A dose-response study showed that almost complete (>95%) cell death was attained in 24 h with GD > or = 480 microg/mL. Combinations of GD in a concentration as low as 30 to 60 microg/mL with 200 microM vitamin C were as effective as GD alone at 480 microg/mL, inducing >90% cytotoxic cell death. Simultaneous use with various anticancer drugs showed little potentiation of their efficacy except for the carmustine/GD combination (approximately 90% reduction in cell viability). The significantly (twofold) elevated LPO level and positive ISH staining of GD-treated cells indicated oxidative membrane damage resulting in apoptotic cell death. CONCLUSION: A bioactive beta-glucan from the Maitake mushroom has a cytotoxic effect, presumably through oxidative stress, on prostatic cancer cells in vitro, leading to apoptosis. Potentiation of GD action by vitamin C and the chemosensitizing effect of GD on carmustine may also have clinical implications. Therefore, this unique mushroom polysaccharide may have great a potential as an alternative therapeutic modality for prostate cancer.

Agaricales↗
PubMed1980

[The follow up of patients with bronchial carcinoma (author's transl)].

The aims of follow up of patients with bronchial carcinoma are: 1. Complete use of all therapeutical possibilities. 2. Avoidance of preventable complications of therapeutical prescriptions. 3. Prevention of sicknesses beside the basic complaint. 4. The rehabilitation of the patient. The medical structure for realizing these aims, we suppose in the cooperation of the doctor of the family or the factory, who will see the patient in intervals of four weeks, and the ambulant working pulmologist, who will see the patient in intervals of 3 months, and the thorax-centre, what the patient will consult once or twice the year, and the centre for rehabilitation, where patients with limited cardiorespiratoric function will get an appropriated training of condition. Two cure-places with this special direction will satisfy the require in the GDR. The oncologist of the district where the patient lives will be the coordinator of all parts of this system and the controller to keep its function. The effectivity of follow up will be realised by clear and proofed recommendations by the therapeutical centres and the continued consultations on actual problem cases with the shared doctors. The data processing can do an useful help in this cooperation.

Aftercare↗
PubMedDate not supplied

[An antioxidant in pediatrics].

The authors review the state of the art regarding vitamin E in relation to its use during childhood. The report comments on a number of aspects which are still not entirely clear and stresses the prophylactic and therapeutic importance of antioxidants, even in pediatrics, and the severe damage that may result from free radicals even during this period of life.

Antioxidants↗
PubMedDate not supplied

Effect of Avemar and Avemar + vitamin C on tumor growth and metastasis in experimental animals.

Because of the observed immunostimulatory actions of a new fermented wheat germ extract--with standardized benzoquinone composition--we have investigated the eventual tumor growth- and metastasis-inhibiting effects of this preparation (Avemar) applied alone or in combination with vitamin C. Tumor models of different origin [a highly metastatic variant of the Lewis lung carcinoma (3LL-HH), B16 melanoma, a rat nephroblastoma (RWT-M) and a human colon carcinoma xenograft (HCR25)]--kept in artificially immunosuppressed mice were applied. The metastasis-inhibiting effects of the treatments have been studied both in the presence and in the absence (following surgical removal) of the transplanted primary tumors. Combined treatments with Avemar and vitamin C--administered synchronously--profoundly inhibited the metastasis formation in all the applied tumor models while, treatments with vitamin C alone did not exert such an inhibiting effect on the metastasizing process. The degree of the observed metastasis inhibition in certain models was significant, while in others--although it was meaningful--did not prove to be significant. It is noteworthy that treatment with Avemar alone in certain models exerted a more pronounced inhibiting effect on metastasis formation than the synchronous combined treatment with Avemar and vitamin C. Furthermore, if the time schedule of the combined treatment was changed (vitamin C--instead of being administered synchronously--was given one hour after the treatments with Avemar), the vitamin C rather decreased the metastasis inhibiting effect of Avemar. It should be mentioned however, that in the case of rat nephroblastoma, a different response was observed: while, in the case of synchronous combination significant inhibition of metastasis formation was observed, treatment with Avemar alone did not produce metastasis-inhibition. It is noteworthy that in this model the metastasis-inhibiting effect of the synchronous combination treatment proved to be even more pronounced if Avemar was administered in a 100 times smaller dose than its regularly applied dosage. Treatment with Avemar and vitamin C--administered in combination or separately--in the majority of experimental models (with the exception of rat nephroblastoma) did not inhibit the growth of the primary tumors. It is reasonable, therefore, to suppose that in the observed metastasis-inhibiting effect the eventual proliferation inhibiting effect of these remedies does not play an important role. According to the results of other experiments--carried out in our laboratory in parallel with those described here--Avemar proved to have a meaningful immunostimulatory effect. It might therefore be suggested that the observed metastasis-inhibiting effect of this preparation may be mainly due to its immunostimulatory properties. The possible therapeutic benefits of Avemar and Avemar plus vitamin C are also discussed.

Adenocarcinoma↗
PubMed1981

Assessment of oral ascorbate in three children with chronic granulomatous disease and defective neutrophil motility over a 2-year period.

Two brothers and their sister with chronic granulomatous disease, elevated levels of serum IgE and defective neutrophil motility were treated with a single oral daily dose of 1 g sodium ascorbate as a supplement to prophylactic trimethoprim--sulphamethoxazole therapy for 2 years. Laboratory tests of neutrophil functions were performed prior to ascorbate therapy and repeated at 1-monthly intervals for 6 months and at 6-monthly intervals thereafter. Introduction of ascorbate to the therapeutic regimen was accompanied by slight increases in neutrophil hexose monophosphate shunt activity and staphylocidal activity and good improvement of neutrophil motility in all three children. The improved staphylocidal activity was not due to ascorbate-mediated inhibition of neutrophil or serum catalase activities or to detectable increases in superoxide and H2O2 production or activity of the MPO/H2O2/halide system. Both male children have remained free from obvious infection since ascorbate was added to their therapeutic regimen; their sister has experienced one urinary tract infection during a period when treatment with prophylactic co-trimoxazole and ascorbate was inadvertently stopped. All three children have gained weight.

Ascorbic Acid↗
PubMed2000

The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer.

Flavonoids are nearly ubiquitous in plants and are recognized as the pigments responsible for the colors of leaves, especially in autumn. They are rich in seeds, citrus fruits, olive oil, tea, and red wine. They are low molecular weight compounds composed of a three-ring structure with various substitutions. This basic structure is shared by tocopherols (vitamin E). Flavonoids can be subdivided according to the presence of an oxy group at position 4, a double bond between carbon atoms 2 and 3, or a hydroxyl group in position 3 of the C (middle) ring. These characteristics appear to also be required for best activity, especially antioxidant and antiproliferative, in the systems studied. The particular hydroxylation pattern of the B ring of the flavonoles increases their activities, especially in inhibition of mast cell secretion. Certain plants and spices containing flavonoids have been used for thousands of years in traditional Eastern medicine. In spite of the voluminous literature available, however, Western medicine has not yet used flavonoids therapeutically, even though their safety record is exceptional. Suggestions are made where such possibilities may be worth pursuing.

Animals↗
PubMed1987

An internal clock reaction used in a one-step enzyme immunochromatographic assay of theophylline in whole blood.

We describe the development and performance of a second-generation enzyme immunochromatography method for visually quantifying theophylline in whole blood without the use of instrumentation. We have developed the novel concept of an internal chemical clock reaction to combine the capillary-migration and color-generation protocol of the two-step immunochromatographic assay into a single-step, simultaneous protocol. The two assay components are (a) chromatographic paper to which glucose oxidase (EC 1.1.3.4) and monoclonal antibody to theophylline have been immobilized, and (b) an enzyme reagent consisting of glucose, dicarboxidine, ascorbate, and theophylline-labeled horseradish peroxidase (EC 1.11.1.7). The ascorbate acts as an internal clock by inhibiting premature color formation until the ascorbate has been completely consumed in the peroxidase-mediated reaction. Color is then generated rapidly, producing a clearly visible front on the paper. Performance evaluations of the 20-min one-step assay show very good precision, analytical recovery, specificity, and accuracy. This simplified protocol is reliable and convenient for therapeutic drug monitoring in the physician's office.

Antibodies, Monoclonal↗
PubMed1978

[Influencing the automatized chelesterol determination using the Liebermann-Burchard technic through selected drugs in vitro].

The ascertained influences of this cholesterol determination in vitro mentioned in the survey literature for therapeutically relevant doses are astonishingly small. In the present paper the following drugs were tested: Dextran, vitamin C, procain, chlorpromazine, methyldopa, phenacetin, fluphenazine. With the exception of methyldopa pure substance was used. In every case twelve-fold determinations with the concentrations 0.02, 0.2 and 2 mmol/l were performed. Though particularly for vitamin C and methyldopa depending on dose, as well as for all other drugs with the exception of dextran increases can be proved, these, however, remain eventually in the normal region of the method. The influence of the determination of cholesterol proposed by the drugs tested under therapeutic conditions is only of insignificant practice relevance. This is a positive evidence for the use of this method in the routine laboratory.

Ascorbic Acid↗
PubMed1997

Comparative studies of enhanced iron-mediated production of hydroxyl radical by glutathione, cysteine, ascorbic acid, and selected catechols.

A sensitive electrochemical detection system was employed together with a specific salicylate hydroxylation assay to comparatively assess the effects of various substances on the iron-mediated generation of the hydroxyl radical (.OH). Hydroxyl radical production was found to be enhanced significantly by reduced glutathione, cysteine, ascorbic acid, and selected catechols, but not by mannitol, melatonin or tyramine. The data showed that over the range of concentrations examined, the augmented effects were linearly proportional to the amount of added reductant for a given amount of iron in the system. The pro-oxidant activity of thiols and ascorbate reduced and recycled iron providing both hydrogen peroxide (H2O2) and catalytic ferrous ions for augmented .OH production by the Fenton reaction. The enhanced production of .OH by catechols resulted from their oxidation either by molecular oxygen or ferric ions, with the accompanying formation of semiquinones, superoxide anion and H2O2. These data caution against therapeutic applications of thiols and ascorbate for ameliorating oxy-radical-induced tissue damage in environments where free redox-active metal ions may be present to function both as foci for site-specific peroxidative activity, and as catalysts to promote the pro-oxidant properties of certain endogenous reductants, thereby elevating rather than diminishing .OH levels.

Ascorbic Acid↗
PubMed2001

EPR analysis of radicals generated in ultrasound-assisted lipoplasty simulated environment.

The generation of various radicals by application of continuous wave (CW) high-intensity ultrasound energy (HIUE) to an aqueous biologic medium containing spin traps, under conditions simulating ultrasound-assisted lipoplasty (UAL), was demonstrated by EPR spectroscopy. The addition of water- soluble antioxidants, ascorbic acid and glutathione to the wetting solution substantially reduces the levels of hydroxyl radicals in the sonicated medium. These findings provide direct evidence for the generation of cavitation in the simulated intercellular environment, corroborating previous data, and pointing out that generation of transient cavitation in clinical UAL and other therapeutic and surgical applications of ultrasound is possible. The findings indicate that the effect of transient cavitation in aqueous biologic media may be similar to the effects of ionizing radiation, and raise the question of the long-term biosafety of the use of CW HIUE in UAL. The introduction of biocompatible water-soluble antioxidants to the sonicated medium may be utilized to suppress accumulation of radicals and reduce their possible adverse effects.

Adipose Tissue↗
PubMed1988

The iron chelators desferrioxamine and 1-alkyl-2-methyl-3-hydroxypyrid-4-ones inhibit vascular prostacyclin synthesis in vitro.

The iron chelators desferrioxamine (DFO), 1,2-dimethyl(L1)-, 1-ethyl-2-methyl(L1NEt)- and 1-propyl-2-methyl(L1NPr)-3-hydroxypyrid-4-ones inhibited rat aortic prostacyclin (PGI2) synthesis in vitro (rank order of potency: DFO greater than L1 greater than L1NEt greater than L1NPr) when stimulated with adrenaline, arachidonate and the Ca2+ ionophore A23187. The inhibitory action of the chelators was blocked by Fe3+ and Al3+ and reversed by washing and H2O2, but not by ascorbate. These data suggest that iron chelators inhibit prostanoid synthesis in intact tissue through the removal or binding of Fe3+ linked to cyclo-oxygenase. These iron chelators may be of therapeutic value in the treatment of inflammatory and other diseases via two mechanisms: (1) the inhibition of pro-inflammatory prostanoid synthesis and (2) the inhibition of toxic-free-radical generation by cyclo-oxygenase.

Aluminum↗
PubMed1989

S-nitrosothiols as vasodilators: implications regarding tolerance to nitric oxide-containing vasodilators.

1. The formation of an S-nitrosothiol compound, S-nitroso-N-acetylcysteine (SNAC) has recently been proposed to mediate the augmentation of the anti-aggregatory and haemodynamic effects of glyceryl trinitrate observed in the presence of N-acetylcysteine. This study investigated the effects on an isolated coronary artery preparation of acute and prolonged exposure to S-nitrosothiol compounds and nitric oxide (NO). 2. Single doses of NO and of the S-nitrosothiol compounds, SNAC and S-nitroso-N-acetyl-penicillamine (SNAP), induced rapid, but transient, relaxations in U46619-contracted bovine isolated coronary artery rings. Peak relaxation responses to SNAP and NO were attenuated in the presence of N-acetylcysteine, cysteine, ascorbic acid and methylene blue. The duration of the relaxation responses to SNAC was two to three times longer than those to SNAP and NO. In the presence of N-acetylcysteine (but not cysteine, ascorbic acid or methylene blue) the duration of the relaxation responses to SNAP and NO (but not to SNAC) was markedly increased. H.p.l.c. assay confirmed that, in the presence of N-acetylcysteine, SNAP and, to a lesser degree, NO were converted to the relatively more stable and longer acting vasodilator, SNAC. 3. When compared to control rings, coronary artery rings superfused with glyceryl trinitrate were subsequently markedly less responsive to the vasodilator actions of glyceryl trinitrate, whereas responsiveness to SNAC or NO was only marginally reduced. On the other hand, coronary artery rings superfused with SNAC or NO were subsequently less responsive to glyceryl trinitrate, SNAC and NO. Thus prolonged vascular exposure to SNAC or NO induced a form of tolerance different from that induced with glyceryl trinitrate and which is possibly associated with impaired guanylate cyclase activity. 4. Coronary artery rings superfused with NO were markedly less responsive to glyceryl trinitrate and NO, whereas responses to the endothelium-dependent vasodilator A23187 and to theophylline were not significantly attenuated. 5. It is concluded that formation of the more stable vasodilator SNAC occurs on incubation of N-acetylcysteine with SNAP or NO. While coronary artery responsiveness to SNAC and NO is virtually unchanged in the presence of glyceryl trinitrate-induced tolerance, after prolonged exposure to SNAC or NO tolerance may develop to these vasodilators with cross-tolerance to glyceryl trinitrate but not A23187. Thus, formation or therapeutic utilization of SNAC may acutely circumvent the problem of glyceryl trinitrate-induced tolerance but, during prolonged vascular exposure to SNAC, attenuation of vascular responsiveness may occur to a wide range of vasodilators.

Acetylcysteine↗