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PubMed2004

Therapeutic potential of natural compounds that regulate the activity of protein kinase C.

Protein kinase C (PKC) is a family of serine/threonine kinases that regulates a variety of cell functions including proliferation, gene expression, cell cycle, differentiation, cytoskeletal organization, cell migration, and apoptosis. The PKC signal transduction cascade coordinates complex physiological events including normal tissue function and repair. Disruption of the cellular environment through genetic mutation, disease, injury, or exposure to pro-oxidants, alcohol, or other insults can induce pathological PKC activation. Aberrant PKC activation can lead to diseases of cellular dysregulation such as cancer and diabetes. Can aberrant activation of PKC be reversed? Even 25 years after the identification of PKC, therapeutic regulation of PKC activity remains an emerging field. Because the function of each isoform remains to be elucidated, isoform specific control of gene expression is a current challenge. Natural compounds are important regulators of PKC activity, with both preventive and therapeutic efficacy. Antioxidants including vitamin A (retinoids), vitamin C (ascorbic acid) and vitamin E (tocopherols) show promise for reversal of PKC activation. beta-carotene and retinoids function as anticarcinogenic agents and antagonize the biological effects of pro-oxidants on PKC. Vitamin E reverses the deleterious effects of hyperglycemia and diabetes by down-regulating PKC activity. Antioxidants in red wine provide cardioprotective effects. However, alcohol consumption also induces oxidative stress and disrupts PKC and retinoid function in the fetus and the adult. This review examines modulation of PKC activity by natural compounds and pharmacologic analogues which can be used effectively to prevent or treat common diseases associated with aberrant activation of PKC.

Animals↗
PubMed1988

Oxygen and exposure kinetics as factors influencing the cytotoxicity of porfiromycin, a mitomycin C analogue, in Chinese hamster ovary cells.

Some factors affecting the cytotoxicity of porfiromycin (PM), an analogue of mitomycin C (MMC), were investigated in suspension cultures of wild-type (AA8-4) and repair-deficient (UV-20) Chinese hamster ovary cells. Oxygen was an important modulator of PM toxicity in AA8-4 cells. The aerobic toxicity was significantly less, and toxicity under extremely hypoxic conditions was significantly greater for PM than MMC. Porfiromycin cytotoxicity at intermediate O2 levels was similar to that observed previously for MMC. While the aerobic/hypoxic ratio was greater for PM than MMC, survival at intermediate oxygen concentrations could limit the therapeutic utility of these drugs as adjuncts to radiotherapy. Ascorbic acid was found to increase the aerobic, but not hypoxic, cytotoxicity of PM in AA8-4 cells, as was observed previously for MMC. Investigation of various exposure times and drug concentrations revealed that drug toxicity for both aerobic and hypoxic cells was dependent on the product of drug concentration and time, and that the aerobic/hypoxic differential observed in AA8-4 cells was constant over a broad range of exposure conditions. The sensitivity of UV-20 cells was also a linear function of concentration and time, but no aerobic/hypoxic differential was observed in these cells. It is suggested that the sensitivity of UV-20 to PM and MMC, and its lack of an hypoxic/aerobic differential could result from lethality being due to a different lesion than in wild-type cells.

Animals↗
PubMed2005

Effects of vitamin C and aspirin in ischemic stroke-related lipid peroxidation: results of the AVASAS (Aspirin Versus Ascorbic acid plus Aspirin in Stroke) Study.

A condition of oxidative stress is known to occur in ischemic stroke, the current therapeutic intervention of which is largely limited to thrombolysis. To assess the effect of vitamin C - in conjunction to aspirin - in ischemic stroke-related lipid peroxidation, we measured plasma levels of ascorbate, of 8,12-isoprostanes F2alpha-VI (8,12-iPF2alpha-VI) and activities and levels of a broad spectrum of antioxidant enzymes and micronutrients in stroke patients randomized to receive, from stroke onset and up to three months, either vitamin C (200 mg/day) plus aspirin (300 mg/day) or only aspirin (300 mg/day). By the end of the first week, patients treated with vitamin C plus aspirin had higher vitamin C levels (p = 0.02) and lower 8,12-iPF2alpha-VI levels (p = 0.01) than patients treated with aspirin alone. The significance was maintained for the increase of vitamin C after three months of therapy (p < 0.01). The clinical functional outcome for both groups of patients similarly ameliorated after three months of treatment. We conclude that vitamin C, at the dose of 200 mg/day and in conjunction with aspirin, significantly decreases ischemic stroke-related lipid peroxidation in humans. Further studies are warranted to clarify whether the use of vitamin C may add clinical long-term beneficial effects in patients with stroke.

Ascorbic Acid↗
PubMed2005

Ascorbic acid decreases oxidant stress in endothelial cells caused by the nitroxide tempol.

Stable nitroxide radicals have been considered as therapeutic antioxidants because they can scavenge more toxic radicals in biologic systems. However, as radicals they also have the potential to increase oxidant stress in cells and tissues. We studied the extent to which this occurs in cultured EA.hy926 endothelial cells exposed to the nitroxide Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl). Tempol was rapidly reduced by the cells, as manifest by an increase in the ability of the cells to reduce extracellular ferricyanide and by disappearance of the Tempol EPR signal. Cells loaded with ascorbic acid, which directly reacts with Tempol, showed increased rates of Tempol-dependent ferricyanide reduction, and a more rapid loss of the Tempol EPR signal than cells not containing ascorbate. In this process, intracellular ascorbate was oxidized, and was depleted at lower Tempol concentrations than was GSH, another important intracellular low molecular weight antioxidant. Further evidence that Tempol concentrations of 100-1000 microM induced an oxidant stress was that it caused an increase in the oxidation of dihydrofluorescein in cells and inhibited ascorbate transport at concentrations as low as 50-100 microM. The presence of intracellular ascorbate both prevented dihydrofluorescein oxidation and spared GSH from oxidation by Tempol. Such sparing was not observed when GSH was depleted by other mechanisms, indicating that it was likely due to protection against oxidant stress. These results show that whereas Tempol may scavenge other more toxic radicals, care must be taken to ensure that it does not itself induce an oxidant stress, especially with regard to depletion of ascorbic acid.

Antioxidants↗
PubMed1976

[Effect of Mecadox therapy on various organs of the reticulohistiocytary system in chickens].

Chickens received Mecadox treatment for 28 days, beginning at the age of five days, with the daily rations having been 1 g in 1 kg feedstuff. Changes were caused in two periods. The first therapeutic period, first to 14th days, was characterised by rise in total protein, DNA, RNA, amino nitrogen, and ascorbic acid in the adrenal gland as well as by rise in body mass, however, with no change of thymus and bursa mass. The second therapeutic period, between the 14th and 28 th days, led to decline in the above parameters and to involution of the lymphatic organs. The conclusion is suggested that biological stimulation can be achieved only in response to short-time Mecadox treatment.

Adrenal Glands↗
PubMedDate not supplied

Ascorbic acid with cupric ions as a chemotherapy for human lung tumor xenografts implanted beneath the renal capsule of immunocompetent mice.

The growth of human lung carcinoma xenografts implanted beneath the renal capsule of immunocompetent mice was investigated (the six-day subrenal capsule assay) by using combinations of ascorbic acid and cupric ions. A maximum suppression of growth of this human lung tumor, LX-1, was observed at an estimated consumption level by the mice of 6 to 8 g ascorbic acid and 2 to 5 mg cupric ions per day per kg body weight. The data suggest that more than one oxidative or degradative product of ascorbic acid or of some copper compounds may be responsible for the observed antitumor activities, and that the chemotherapeutic effect is being produced at some stoichiometric ratios of ascorbic acid to cupric ions. When such a combination of the two substances was consumed by the mice, optimal therapeutic effect was exerted on the implanted xenografts.

Animals↗
PubMed1982

A randomized trial of ascorbic acid in polyposis coli.

The possibility of pharmacological control of large bowel adenomas has been suggested by effectiveness of antioxidants in experimental tumor models and by the results of a limited clinical study using ascorbic acid. Over a two year period we tested this hypothesis in a randomized, double-blind study of 49 patients with polyposis coli. Of 36 patients who were evaluable at completion, 19 had received ascorbic acid, 3 g/day, and 17 had received a placebo. We found a reduction in polyp area in the ascorbic acid-treated group at nine months of follow-up (P less than 0.03) and trends toward reduction in both number and area of rectal polyps during the middle of the trial. A labeling study of rectal epithelium with tritiated thymidine also hinted at a treatment effect. Our data suggest that ascorbic acid temporarily influenced polyp growth or turnover. Although these results have no current therapeutic value, our findings support continued studies of chemoprevention in this and other high risk settings.

Adult↗
PubMed2003

Modulation of TNF-alpha-induced ICAM-1 expression, NO and H2O2 production by alginate, allicin and ascorbic acid in human endothelial cells.

Plant nutrients are believed to provide protection against various diseases including inflammation. Since interactions of the cell adhesion molecules are known to play important roles in mediating inflammation, inhibiting adhesion protein upregulation is a possible therapeutic target. In this study, the interacellular adhesion molecule-1 (ICAM-1) was induced in human umbilical endothelial cells (HUVECs) after stimulation with TNF-alpha. In addition, alginate, ascorbic acid and allicin were demonstrated to inhibit the TNF-alpha induced expression of ICAM-1 on the HUVECs in a dose-dependent manner. These compounds also inhibited the production of NO and H2O2 induced by TNF-alpha, which suggests that the inhibition of ICAM-1 expression by the three compounds may be due to the modulated production of the reactive oxygen/nitrogen components. Overall, these results indicate that these dietary components have a therapeutic potential in the treatment of various inflammatory disorders associated with an increase in endothelial leukocyte adhesion molecules.

Alginates↗
PubMed2007

Ascorbic acid increases healing of excision wounds of mice whole body exposed to different doses of gamma-radiation.

Because of the practical importance of acute radiation exposure associated with combined injuries, it is imperative to investigate the efficacy of cost-effective nutritional factors in the reconstruction of irradiated wounds. Therefore, effect of pretreatment of ascorbic acid was studied on the healing of excised wounds in mice exposed to 2, 4, 6 and 8 Gy whole body gamma-radiation. A full-thickness wound was created on the dorsum of the irradiated mice and the progression of wound contraction was monitored by capturing video images of the wound at various varying days after irradiation. Irradiation caused a dose dependent delay in wound contraction and wound healing time, while ascorbic acid pretreatment resulted in a significant acceleration in the rate of wound contraction and a decrease in the mean wound healing time. To understand the mechanism of healing, collagen, hexosamine, DNA, nitrite and nitrate contents were measured in the granulation tissue of wounded mice treated with ascorbic acid before exposure to 6 Gy gamma-radiation. Ascorbic acid treatment prior to irradiation enhanced the synthesis of collagen, hexosamine, DNA, nitrite and nitrate contents. The histological assessment of wound biopsy revealed an improved collagen deposition, and increase in fibroblast and vascular densities. The present study demonstrates that ascorbic acid pretreatment has a beneficial effect on the irradiated wound and could be a substantial therapeutic strategy to accelerate wound repair in irradiated wounds and in the cases of combined injury situations.

Animals↗
PubMedDate not supplied

Studies on iron deficiency anemia, rickets and zinc deficiency and their prevention among Chinese preschool children.

The incidence of iron deficiency anemia, rickets, and zinc deficiency is very high in Chinese preschool children and a method for prevention is urgently needed. From our studies, it can be seen that a soft drink powder is a convenient vehicle for the supplementation of iron, zinc, calcium, vitamin D, riboflavin, and ascorbic acid. Table salt is also a good, low-cost carrier for iron and zinc, and cow's milk can only be used for the enrichment of vitamins A and D. In our study the therapeutic dose of iron was lower than 3 mg/kg body weight recommended by the WHO Expert Committee. As ascorbic acid can enhance the absorption of iron in the body, so 300 mg vitamin C was added to 100 g of soft drink powder containing 100 mg of elemental iron. Ten g of powder is not only enough for the prevention of iron deficiency anemia but it can also cure iron deficiency anemia within 3 months. One hundred mg of iron in 100 g of table salt is an adequate level, because an adult or a child taking 10 or 5 g of salt will receive 10 and 5 mg of elemental iron respectively. This dosage is adequate for the prevention of anemia. From our results, 10 mg of zinc daily is enough for the prevention and treatment of zinc deficiency in preschool children. Four hundred IU of vitamin D (from fortified soft drink powder or enriched fresh cow's milk) orally-administered daily, is a good way to prevent rickets in infants and young children.

Anemia, Hypochromic↗
PubMed1983

Long-term observation of young cystinuric patients under ascorbic acid therapy.

Long-term results of ascorbic acid monotherapy in four young patients with cystine stone complaints are reported. The therapeutic program is based on the descriptions by Asper and Schmucki, who publicized the method for the first time in 1979. Clinical course observations, renal function checks as well as the excretion of cystine, uric acid and oxalic acid during ascorbic acid therapy of our patient pool will be discussed. Clinical observations made to date indicate that ascorbic acid therapy is a practical, inexpensive prophylaxis for cystine stone patients that is virtually free of side effects.

Adolescent↗
PubMed1975

The orthomolecular treatment of cancer. III. Reticulum cell sarcoma: double complete regression induced by high-dose ascorbic acid therapy.

The response of a patient with histologically proven reticulum cell sarcoma to no treatment other than large doses of ascorbic acid is described. At the time of first diagnosis, the disease was widely disseminated, and a very dramatic regression of all parameters of disease activity was induced by the continuous administration of large doses of ascorbic acid. Reduction in dosage some months later coincided with reactivation of the disease process. The reinstitution of regular high-dose ascorbic acid therapy induced a second complete remission. The case report is illustrated by serial radiographs. The significance of the therapeutic response is briefly discussed in relation to general schemes of cancer management.

Adult↗
PubMed1980

Lack of effect of ascorbic acid, hippuric acid, and methenamine (urinary formaldehyde) on the copper-reduction glucose test in geriatric patients.

Ascorbic acid and hippuric acid (from cranberry juice) are commonly used to acidify the urine for the purpose of enhancing the degradation of therapeutic methenamine mandelate to urinary formaldehyde. A study was made of 27 nondiabetic geriatric patients with indwelling Foley catheters and chronic bacteriuria who were treated with methenamine mandelate (4 gm), ascorbic acid (4 gm), and cranberry cocktail (1 liter) daily. All of 972 urine samples showed formaldehyde in mean concentrations between 14 and 25 microgram/ml. No glucose was found when the urine was tested by the copper-reduction method. In vitro false positive reactions reported in the literature do not appear to be duplicated as an in vivo problem.

Aged↗
PubMedDate not supplied

[The effect of paracetamol and its combinations with acetylsalicylic and ascorbic acids on lipid peroxidation processes in the rat liver].

Paracetamolum (PC) after i.p. administration to rats at the therapeutic (100.0 mg/kg) and subtoxic (500.0 mg/kg) doses was shown to induce significant and dose-dependent elevation of the level of malone dialdehyde (MDA) as well as the increase in a certain extent of chemiluminescence (CL) being injected at the higher dose. Acetylsalicylic acid (ASA) at the same doses being injected at the lower one, induced the tendency toward the reduction of MDA level, while at the higher dose the rise of MDA content and CL intensity compared to PC have been observed. PC combination with ASA at therapeutic doses range (50.0 + 50.0 mg/kg) significantly diminished MDA formation, while at subtoxic doses range (250.0 + 250.0 mg/kg) such effect was not detected, although subsequent tendency toward CL intensity reduction was observed. Ascorbinic acid being administered in combination with PC and ASA had no influence on MDA formation but significantly weakened CL intensity when subtoxic doses of indicated drugs were used.

Acetaminophen↗
PubMed1991

Creatine kinase determination: a European evaluation of the creatine kinase determination in serum, plasma and whole blood with the Reflotron system.

We evaluated a new dry-reagent carrier system for the determination of creatine kinase (EC 2.7.3.2) activity, Reflotron CK, with special attention to analytical performance with whole blood. We found a good within series imprecision. The median coefficient of variation was 3.1% for Reflotron CK (blood, serum and plasma) and 0.9% for the automatic analysers (serum and plasma only). The between-days imprecision with Reflotron CK (median CV: less than or equal to 3%) was similar to that for the comparison method on different analysers. Fresh samples of human blood, plasma and serum were examined by Reflotron CK and by a N-acetylcysteine activated creatine kinase method in six different clinical laboratories and in the Evaluation Department of Boehringer Mannheim GmbH. The correlation between these methods was excellent (r greater than or equal to 0.99), the median systematic deviation (bias) for all samples being smaller than -5%. Haematocrits between 0.25 and 0.50, haemolysis up to 6 g/l haemoglobin, and icteric samples with bilirubin concentrations up to 0.2 g/l showed no interference. No drug in therapeutic concentration was found to affect the Reflotron CK results; ascorbic acid, calcium dobesilate and sulphamethoxazole lowered the values only when present in high concentrations. Reflotron CK may be considered as a suitable alternative for decentralized testing sites, especially in situations where creatine kinase results are needed quickly.

Autoanalysis↗
PubMed1989

Measurement of free radical scavengers in the spinal cord of rats with experimental autoimmune encephalomyelitis.

Antioxidants (ascorbic acid, glutathione, cysteine, alpha-tocopherol) and uric acid were measured using two high-pressure liquid chromatographic methods in 3 regions (cervical, thoracic, lumbar) of the spinal cord and in blood of Lewis rats during the attack and recovery of experimental autoimmune encephalomyelitis (EAE). Uric acid, which is thought to be a marker of free radical release, was greatly increased and glutathione correspondingly decreased in lumbar and thoracic regions. Cysteine and ascorbic acid were practically unchanged, whereas alpha-tocopherol was significantly increased during attack and recovery. Results, which could have therapeutic implications, generally support the hypothesis that free radicals are released during EAE.

Animals↗