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PubMed2006

Effects of nitrofen and vitamins A, C and E on maturation of cultured human H441 pneumocytes.

BACKGROUND/AIM: Nitrofen (2,4-dichloro-4 -nitrodiphenyl ether), a teratogen with oxidant properties, induces congenital diaphragmatic hernia (CDH) with lung hypoplasia and delayed lung development and maturation in rat embryos. Several phenotypic features of the alveolar epithelium including surfactant proteins A and B synthesis and its regulation by transcription factors are reproduced in cultured human H441 pneumocytes. The aim of the present study was to test whether vitamins A, E and C with anti-oxidant properties were able to recover the expression of such regulators in an in vitro setting. MATERIALS AND METHODS: Cultured human H441 pneumocytes were treated with nitrofen with or without additional exposure to vitamins A, E and C. Thyroid transcription factor 1 (TTF-1), hepatocyte nuclear factor 3-beta (HNF-3beta) and hepatocyte nuclear factor 3-beta surfactant protein B (SP-B) mRNAs were measured by real-time polymerase chain reaction (RT-PCR). The cells were also immunohistochemically stained for assessment of proliferation (PCNA) and apoptosis (bis-benzimide) status and SP-B and TTF-1 protein expressions. Results were compared by ANOVA with a significant threshold of 5%. RESULTS: Nitrofen severely decreased TTF-1, HNF-3beta and SP-B mRNA expression by H441 pneumocytes in culture. Addition of vitamin E normalized the levels of the three transcripts, while vitamin A normalized only those of TTF-1 and SP-B mRNA. Vitamin C was significantly beneficial only for SP-B transcript. Nitrofen decreased proliferation and TTF-1 and SP-B protein expressions with no apparent effect on apoptosis. Additional exposure to vitamins A, C or E rescued near normal values. CONCLUSIONS: The changes induced by nitrofen in cultured H441 human pneumocytes are reverted in part by anti-oxidant vitamins by upregulating TTF-1, HNF-3beta and SP-B and stimulating proliferation and maturity in nitrofen-treated cells. These effects of anti-oxidant vitamins could be of some interest for developing new transplacental therapeutic strategies aimed at improving lung development and maturation in fetuses with CDH.

Ascorbic Acid↗
PubMed1998

[The efficacy of enterosorption and a combination of antioxidants in schizophrenics].

A total of 143 patients with schizophrenia, who ranged from 28 to 42 years old, were studied. Of these, 68 patients were running a continuously progredient course, 75 were in the phase of exacerbation of the attack-like progredient course of schizophrenia. Group I (n = 76) of patients received the enterosorbent polysorb and a complex of antioxidants (tocoferolum acetatum, ascorbic acid, quercetin) as a supplement to the conventional therapy, group II (n = 67) was placed on the conventional therapy only. A complex of the antioxidants as well as the enterosorbent had a positive effect on the clinical course of the condition in 63.2% of group I patients who managed, among other therapeutic benefits, to achieve a stable remission. They have also demonstrated a concomitant improvement or normalization of indices for lipid peroxidation.

Adult↗
PubMed1992

Antioxidant properties of nitecapone (OR-462).

Nitecapone [3-(3,4-dihydroxy-5-nitrophenyl)methylene-2,4-pentanedione] [OR-462] is a catechol-O-methyltransferase inhibitor with gastroprotective properties. Recently, its antioxidant properties have been discovered: It scavenges peroxyl radicals (ROO.) and thus spares glutathione. Further examination of the properties of nitecapone demonstrated a remarkable ability of this compound to act as an antioxidant: (1) to scavenge ROO. in solution with a stoichiometry factor of 2; (2) to scavenge ROO. in membranes; (3) to inhibit lipid peroxidation; (4) to act as a competitive inhibitor for xanthine oxidase with Ki of 8.8 microM; (5) to scavenge O2- with a second order kinetic rate constant of 1.0 x 10(4) M-1 s-1; and (6) to scavenge HO.. Nitecapone also interacts with oxidation product of ascorbate to participate in recycling of vitamin E. Thus, nitecapone potentially is an effective therapeutic antioxidant, and the use of this compound in a combination with other antioxidants may be beneficial.

Animals↗
PubMed2002

Intravenous nutrient therapy: the "Myers' cocktail".

Building on the work of the late John Myers, MD, the author has used an intravenous vitamin-and-mineral formula for the treatment of a wide range of clinical conditions. The modified "Myers' cocktail," which consists of magnesium, calcium, B vitamins, and vitamin C, has been found to be effective against acute asthma attacks, migraines, fatigue (including chronic fatigue syndrome), fibromyalgia, acute muscle spasm, upper respiratory tract infections, chronic sinusitis, seasonal allergic rhinitis, cardiovascular disease, and other disorders. This paper presents a rationale for the therapeutic use of intravenous nutrients, reviews the relevant published clinical research, describes the author's clinical experiences, and discusses potential side effects and precautions.

Administration, Oral↗
PubMed1997

Abnormal formation of collagen cross-links in skin fibroblasts cultured from patients with Ehlers-Danlos syndrome type VI.

Ehlers-Danlos syndrome type VI (EDS VI) is an autosomal recessive disorder of connective tissue characterized by hyperextensible, friable skin and joint hypermobility. Severe scoliosis and ocular fragility are present in some patients. This disease is caused by defective collagen lsyl hydroxylase, a vitamin C-dependent enzyme that converts lysyl residues to hydroxylysine on procollagen peptides. Hydroxylysine is essential for the formation of the covalent pyridinium cross-links pyridinoline (Pyr) and deoxypyridinoline (Dpyr), among mature collagen molecules. Pyr derives from three hydroxylysyl residues, whereas Dpyr derives from one lysyl and two hydroxylysyl residues. Patients with EDS VI have high urinary excretion of Dpyr, resulting in a high ratio of Dpyr-Pyr. In this study, we evaluate content and production of pyridinium cross-links in the skin and cultured fibroblasts from patients with EDS VI. The skin of normal controls contained both Pyr and Dpyr, with a marked predominance of Pyr as observed in normal urine. The skin of patients with EDS VI had reduced total content of pyridinium cross-links, with the presence of Dpyr but not Pyr. Long-term cultures of control fibroblasts produced both Pyr and Dpyr, with a pattern resembling that of normal skin. By contrast, cross-links were not detected in dermal fibroblasts cultured from patients with EDS VI. Vitamin C, which improves the clinical manifestations of some patients with EDS VI, decreased Dpyr accumulation though only minimally affecting Pyr content in control cells. By contrast, addition of vitamin C to fibroblasts from patients with EDS VI stimulated the formation of Dpyr more than that of Pyr and greatly increased total pyridinium cross-link formation. These results indicate that qualitative and quantitative alterations of pyridinium cross-links occur in skin and in cultured dermal fibroblasts of patients with EDS VI and may be responsible for their abnormal skin findings. The vitamin C-stimulated production of Dpyr and Pyr in fibroblasts from patients with EDS VI may explain at least in part the therapeutic effects of this vitamin in EDS VI.

Adolescent↗
PubMed1998

A nested case-control study of dietary factors and the risk of incident cytological abnormalities of the cervix.

Several earlier case-control studies reported inverse associations of cervical squamous intraepithelial lesions (SIL) with high dietary or biomarker levels of carotenoids, folate, and vitamins C and E. However, most studies did not measure the primary causal factor, cancer-associated genital human papillomaviruses (HPV), now detected by sensitive viral DNA tests. This nested case-control study assessed whether high dietary intakes of these nutrients, plus zinc and vitamin A, reduced SIL risk in cancer-associated HPV DNA-positive women. Using a 60-item food-frequency questionnaire, nutrient estimates were obtained for 33 incident cases with high-grade lesions, 121 with low-grade lesions, 97 with equivocal SIL, and 806 cytologically normal controls sampled from a large prospective cohort study. Baseline cervicovaginal lavages were tested for HPV DNA by the polymerase chain reaction. Among DNA-positive cases (n = 68) and controls (n = 69), age-adjusted odds ratios (ORs) of SIL in the highest vs. the lowest nutrient quartiles were 1.4 [95% confidence interval (CI) = 0.5-4.2] for vitamin A, 0.6 (CI = 0.2-2.0) for beta-carotene, 1.3 (CI = 0.4-3.6) for vitamin C, 1.0 (CI = 0.4-3.6) for vitamin E, 0.7 (CI = 0.3-2.1) for folate, and 0.8 (CI = 0.3-2.2) for zinc. ORs in HPV DNA-negative women approximated 1.0, with the exception of vitamin E (OR = 0.5, CI = 0.3-0.9). These results do not support a protective role for the above nutrients against low-grade or equivocal SIL, which constituted the majority of diagnoses in this study.

Adult↗
PubMed1995

Recombinant a2 interferon (a-IFN) with chemo-hormonal therapy in patients with hepatocellular carcinoma (HCC).

Recent studies on HCC treatment reveal a tendency to use combined immuno-chemo-therapy. Additionally, new agents have been suggested in this field. We therefore studied 7 patients with proven inoperable HCC who were treated in accordance with the following protocol, and 5 untreated patients used as controls. Therapeutic trial: 1) 1FNa (Roferon): 6 MU x 7 days consecutively every 3 weeks, 2) Adriamycin (doxorubicin): 60 mg/m2 i. v. once every 3 weeks (500 mg total dose), 3) Tamoxifen: 10 mg p.o. twice daily continuously 4) Desferrioxamine (DFO): 500 mg i.m. daily x 7 days consecutively every 3 weeks, 5) ascorbic acid: 300 mg p.o. daily 1 hour after DFO administration x 7 days consecutively every 3 weeks. Follow-up studies were performed monthly and comprised clinical, biochemical, radiological and immunological (T-cell subsets, NK cells, monocyte-macrophage function, IL-2r expression, HLA-DR expression) parameters. Compared with the control group, the treated group had a longer survival rate (p < 0.001), increased tumor regression and less progressive disease. Immunologically, the treated patients with the maintenance of a sufficient immune status were associated with a prolonged survival rate. No serious side effects of the regimen were observed. In conclusion, IFNa combined with chemohormonal therapy appears to be beneficial in HCC patients. In addition, a prolonged survival rate might correlate with the maintenance of an adequate immune status in the patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

Radiation-induced formation of 8-hydroxy-2'-deoxyguanosine and its prevention by scavengers.

Reactive oxygen species (ROS) induce 8-hydroxy-2'-deoxyguanosine (8-OHdG) formation, which has been proposed as a key biomarker relevant to carcinogenesis. 8-OHdG has been induced in a number of different ways, most often without knowledge of the specific type and amount of ROS generated. We have measured 8-OHdG formation in calf thymus DNA exposed to ionizing radiation under conditions generating either hydroxyl radicals (OH.), superoxide anions (O2-) or both. Additionally, we investigated the relationship between the scavenger effect of the drug 5-aminosalicylic acid (5-ASA) and increasing OH. exposure toward 8-OHdG formation. The effect of this drug was compared to those of the physiological scavengers ascorbate and reduced glutathione (GSH). We found that OH. generated 8-OHdG in a dose-dependent manner, whereas O2- did not cause 8-OHdG formation. 5-ASA, ascorbate and GSH all acted as hydroxyl radical scavengers, although with different concentration-effect curves, emphasizing the importance of using relevant pharmaco-/physiological concentrations in studies focusing on therapeutic applications of scavengers. The scavenger effect of 5-ASA at concentrations > or = 0.1 mM was similar at 30 and 100 Gy radiation, i.e. within a wide range of OH. exposure, which is useful information considering clinical applications where the exact amount of ROS formed is unknown. Both 5-ASA and ascorbate at low concentrations (< or = 0.1 mM) were less efficient in preventing 8-OHdG formation from X-ray generated OH. than was shown in a previous comparable study using light as the source of ROS. This differentiation probably reflects variations in both number and type of ROS formed in the two systems.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1998

Topical antiviral agents for herpes simplex virus infections.

Several antiviral agents against herpes simplex virus (HSV) infection have been clinically studied. Earlier therapies include gluteraldehyde, povidone-iodine, butylated hydroxytoluene and ether. Nucleoside analogs have been tested for efficacy in HSV. Although acyclovir and adenine arabinoside have shown minimal therapeutic benefit, cidofovir has been successful in the treatment of acyclovir-resistant strains of HSV, and idoxuridine 15% in dimethyl sulfoxide, edoxudine and penciclovir have significant clinical benefit against HSV. Interferon-alpha has shown synergism with other anti-HSV drugs such as caffeine, trifluorothymidine, dimethyl sulfoxide and nonoxynol-9, and ascorbic acid shows promising effects against HSV. Using a vehicle that enhances skin penetration of a drug or further exploring combination therapy may result in efficacious treatment of HSV. Vaccination or gene therapy may also prove beneficial in future studies.

Journal Article↗
PubMed2004

Arginine administration decreases cerebral cortex acetylcholinesterase and serum butyrylcholinesterase probably by oxidative stress induction.

In the present study we investigated the action of vitamins E and C on the inhibition of acetylcholinesterase and butyrylcholinesterase activities provoked by arginine in cerebral cortex and serum of 60-day-old rats. Animals were pretreated for 1 week with daily intraperitoneal administration of saline (control) or vitamins E (40 mg/kg) and C (100 mg/kg). Twelve hours after the last injection, animals received one injection of arginine (0.8 microM/g of body weight) or saline. Results showed that acetylcholinesterase and butyrylcholinesterase activities were decreased in the arginine-treated rats. Furthermore, pretreatment with vitamins E and C prevented these effects. The data indicate that the reduction of acetylcholinesterase and butyrylcholinesterase activities caused by arginine was probably mediated by oxidative stress. Assuming the possibility that these effects might also occur in the human condition, our findings may be relevant to explain, at least in part, the neurological dysfunction associated with hyperargininemia and might support a novel therapeutic strategy to slow the progression of neurodegeneration in this disorder.

Acetylcholinesterase↗
PubMed2006

Imaging myocardial metabolism.

The prevalence of coronary artery disease and heart failure is increasing in modern industrialized countries, fueling the search for novel therapies. Because metabolism and function in the heart are inextricably linked, energy substrate metabolism has provided a potential target for novel therapies and the development of technologies to image myocardial metabolism has been crucial in establishing new therapeutic approaches. Nuclear imaging probes have been used to successfully evaluate aerobic fatty acid metabolism, anaerobic glucose metabolism, and oxidative metabolism and can be used for the accurate, sensitive, and physiological evaluation of therapeutic effects. More recently, with the advent of stem-cell technologies, imaging approaches have been employed to track the fate of stem cells and to monitor the success of these treatments. In the future, our ability to image myocardial metabolism is likely to assist the development of other new therapies to improve the function of the failing heart.

Ascorbic Acid↗
PubMed2000

Cisternal irrigation therapy with urokinase and ascorbic acid for prevention of vasospasm after aneurysmal subarachnoid hemorrhage. Outcome in 217 patients.

BACKGROUND: Cisternal irrigation therapy with urokinase and ascorbic acid was introduced to prevent symptomatic vasospasm after aneurysmal subarachnoid hemorrhage (SAH). To dissolve and wash out the subarachnoid clot, cisternal irrigation with urokinase is used. Ascorbic acid is added to degenerate oxy-hemoglobin, one of the strongest spasmogenic substances, into verdohemelike products, which are nonspasmogenic. The efficacy and safety of this therapy were evaluated. METHODS: This therapy was performed consecutively in 217 patients. The degree of SAH of the patients was classified as Fisher CT Group 3, and the highest CT number (Hounsfield number) exceeded 60 in the SAH, which suggested a significant risk for symptomatic vasospasm. All patients underwent surgery within 72 hours from the onset of SAH. After clipping the aneurysm, irrigation tubes were placed in the Sylvian fissure (inlet) unilaterally or bilaterally and in the prepontine or chiasmal cistern (outlet). Lactated Ringer's solution with urokinase (120 IU/mL) and ascorbic acid (4 mg/mL) was infused at a rate of 30 mL/hour/side for approximately 10 days. RESULTS: Of the 217 patients studied, symptomatic vasospasm was observed in 6 cases (2.8%), and two of these six cases (0.9%) demonstrated sequelae. The average total blood volume calculated from the drainage fluid was approximately 114 mL. Analysis of the absorption spectrum of the drainage fluid revealed disappearance of the oxy-hemoglobin-specific 576-nm peak. Complications occurred in eight patients during irrigation therapy; two patients experienced seizures, two patients developed meningitis, and four patients had an intracranial hemorrhage. However, all of these patients recovered without neurological deficits. CONCLUSIONS: These results suggest that cisternal irrigation therapy with urokinase and ascorbic acid is effective in preventing symptomatic vasospasm after aneurysmal SAH.

Adult↗
PubMed1992

Evidence for a role of free radicals by synthesized scavenger, 2-octadecylascorbic acid, in cerulein-induced mouse acute pancreatitis.

To define the role of free radicals and of lipid peroxide involvement during the progress of cerulein-induced acute pancreatitis in mice, we evaluated the effect of a novel free radical scavenger, 2-octadecylascorbic acid (CV-3611), on pancreatic edema formation, and the levels of serum enzymes (amylase, lipase) and of lipid peroxide in pancreatic tissue. Mice were divided into three groups: control group, intraperitoneal injection of saline only; pancreatitis group, cerulein 50 micrograms/kg injected intraperitoneally six times at 1-hr intervals; treatment groups, CV-3611 10 mg/kg subcutaneously just after intraperitoneal cerulein injection. After the cerulein injection, the degree of pancreatic edema formation, serum amylase and lipase levels, and the amount of lipid peroxide in pancreatic tissue increased significantly during the observation period of 12 hr. Treatment with CV-3611 resulted in significant reduction in pancreatic edema formation at 3.5 hr (P less than 0.05) and 9 hr (P less than 0.05), serum amylase and lipase levels at 3.5 hr (P less than 0.05) and 12 hr (P less than 0.05), and lipid peroxide levels at 3.5 hr (P less than 0.05), 6 hr (P less than 0.05) and 12 hr (P less than 0.05). These results indicate that a novel free radical scavenger, CV-3611, has a strong therapeutic effect during the development of acute pancreatitis and suggest that oxygen-derived free radicals play an important role in the pathogenesis of acute pancreatitis.

Acute Disease↗
PubMed2006

Can ageing-related degenerative diseases be ameliorated through administration of vitamin C at pharmacological levels?

Man, with other primates, lost the ability to synthesize vitamin C through an inactivating mutation of the gene encoding gulonolactone oxidase (GULO) millions of years ago. Though the consequences of this prehistoric loss must have been favorable (and thus selected for) at the population level, the inability to produce vitamin C may have serious health implications for modern humans, especially for those conditions in which antioxidants (like vitamin C) have been implicated as potential therapeutic agents. Two general types of recent findings regarding vitamin C have made re-evaluation of this important nutrient imperative. First, vitamin C is now known to be involved in several novel physiological phenomena including stem cell differentiation and respiratory development, which likely require pharmacological levels of vitamin C. Secondly, the growing recognition that many ageing-related diseases, including heart disease, neural degeneration and cancer, may have a contributing oxidative damage factor that might be reduced by dietary antioxidants such as vitamin C. In this paper, we hypothesize that high serum-level vitamin C provides important, broad-ranging therapeutic benefits in treating ageing-related degenerative diseases. This hypothesis can be readily tested using traditional and newly-developed genetically-engineered animal models.

Aging↗
PubMed2005

The oxidative neurotoxicity of clioquinol.

Clioquinol is a metal chelator that may attenuate beta-amyloid deposition and mitigate the progression of Alzheimer's disease. Its prior use as a systemic antibiotic was associated with a neurodegenerative syndrome, subacute myelo-optico-neuropathy (SMON), although a mechanistic link has not been precisely defined. While testing clioquinol in murine cortical cultures, it was observed to have a pro-oxidant effect. Exposure to 1-3 microM for 24 h increased malondialdehyde, and resulted in death of approximately 40% of neurons; a higher concentration (30 microM) was paradoxically less toxic. Both malondialdehyde production and cell death were attenuated by concomitant treatment with the antioxidants ascorbic acid and Trolox C, or with the lipid-soluble metal chelator 1,10-phenanthroline. In contrast, injury was increased in cultures prepared from mice lacking heme oxygenase-2, which protects against non-heme mediated oxidative injury to neurons. Addition of vitamin B12 to the culture medium was not cytoprotective. These results suggest that therapeutically relevant concentrations of clioquinol are toxic to cultured neurons by an oxidative mechanism that is unrelated to vitamin B12 deficiency. In vivo evaluation of the pro-oxidant effect of clioquinol seems warranted prior to further clinical trials.

Animals↗
PubMed2002

Possible ameliorative effect of taurine in the treatment of iron-deficiency anaemia in female university students of Gaza, Palestine.

The aim of the study was to evaluate the haematological effects of adding the antioxidant taurine to iron sulfate in the treatment of iron-deficiency anaemia (IDA). A sample of 730 students from Al-Azhar University, Gaza, in Palestine underwent screening with complete blood counts and serum samples. In subjects with microcytosis/hypochromasia, Alpha2 delta2 (HbA2) and serum concentrations of iron, total iron binding capacity (TIBC), ferritin and taurine were determined. Samples from 17 normocytic, normochromic, and non-anaemic subjects were used as baseline controls. At base-line, 81 of the 730 subjects (11.1%) had microcytosis/hypochromasia, 26 (3.6%) were diagnosed as beta-thalassemia carriers, none of which was iron deficient. Four subjects had microcytosis of unknown cause. Fifty-one subjects (all females) had iron-deficiency anaemia and were included in the therapeutic study, which lasted for 20 wk. They were matched for Hb into pairs and were treated with oral iron (325 mg of slow-release iron sulfate). In addition, they were, in a double-blind procedure, randomised to additional oral taurine (1000 mg d(-1) at a cost comparable to that of adding ascorbic acid) or placebo. Mean S-taurine was significantly lower in the IDA subjects than in the controls. After 20 wk of iron supplementation, both the taurine and placebo group significantly improved their Hb concentrations and normalised the markers of iron deficiency. Apart from the expected, albeit in this study mild side-effects of oral iron, no significant side-effects were noted. In the taurine group, there was a statistically significant additive positive change from the baseline values on Hb (2.67 +/- 1.24 g dL(-1)), red blood cell (RBC) count [(0.57 +/- 0.25) x 1012 L(-1)] and serum ferritin (30.33 +/- 17.99 microg L(-1)) as compared to placebo group values, which were 1.80 +/- 1.10 g dL-1, (0.39 +/- 0.36) x 1012 L(-1), and 20.11 +/- 7.34 microg L(-1), respectively. Oral taurine appears to increase the effectiveness of oral iron in the treatment of IDA, and has no significant side-effects. This merits further cost-benefit and clinical analyses.

Adolescent↗
PubMed2001

Vitamins C and E: missing links in preventing preterm premature rupture of membranes?

We propose that generation of reactive oxygen species may be a potentially reversible pathophysiologic pathway leading to preterm premature rupture of the membranes. Reactive oxygen species generated by the body's response to diverse insults such as infection, cigarette smoking, bleeding, or cocaine use can activate collagenolytic enzymes and impair fetal membrane integrity. Vitamin E, a lipid-soluble antioxidant, inhibits membrane-damaging effects of reactive oxygen species-induced lipid peroxidation. Vitamin C, a water-soluble antioxidant in plasma, stimulates and protects collagen synthesis while recycling vitamin E. Prior evidence shows that (1) damage by reactive oxygen species can impair fetal membrane integrity, (2) reduced midgestation levels of vitamin C are associated with preterm premature rupture of membranes, and (3) these vitamins can be safely and effectively absorbed and delivered to gestational tissues. Current prenatal vitamin preparations contain vitamins C and E in concentrations that are less than 1/3 and 1/10, respectively; these levels have been suggested for effective antioxidant protection. We hypothesize that increased dietary consumption or supplementation of vitamins C and E during pregnancy may reduce physiologically the risks of that portion of preterm premature rupture of membranes that is mediated by excessive or undamped peroxidation of fetal membranes. This hypothesis, if confirmed, should stimulate initiation of therapeutic trials to test the efficacy of enhanced supplementation with vitamins C and E during pregnancy to prevent preterm premature rupture of membranes.

Amnion↗