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PubMed2006

Intragastric generation of antimicrobial nitrogen oxides from saliva--physiological and therapeutic considerations.

Salivary nitrite is suggested to enhance the antimicrobial properties of gastric juice by conversion to nitric oxide (NO) and other reactive nitrogen intermediates in the stomach. Intubated patients exhibit extremely low gastric levels of NO, because they do not swallow their saliva. The present investigation was designed to examine the antibacterial effects of human saliva and gastric juice. Furthermore, we studied a new mode of NO delivery, involving formation from acidified nitrite, which could prevent bacterial growth in the gastric juice of intubated patients in intensive care units. The growth of Escherichia coli ATCC 25922 and the formation of NO and nitroso/nitrosyl species were determined after incubation of gastric juice with saliva from healthy volunteers that was rich (nitrate ingestion) or poor (overnight fasting) in nitrite. In a stomach model containing gastric juice from intubated patients, we inserted a catheter with a silicone retention cuff filled with ascorbic acid and nitrite and determined the resulting antibacterial effects on E. coli and Candida albicans. Saliva enhanced the bactericidal effect of gastric juice, especially saliva rich in nitrite. Formation of NO and nitroso/nitrosyl species by nitrite-rich saliva was 10-fold greater than that by saliva poor in nitrite. In our stomach model, E. coli and C. albicans were killed after exposure to ascorbic acid and nitrite. In conclusion, saliva rich in nitrite enhances the bactericidal effects of gastric juice, possibly through the generation of reactive nitrogen intermediates, including NO. Acidified nitrite inside a gas-permeable retention cuff may be useful for restoring gastric NO levels and host defense in critically ill patients.

Adult↗

PubMed2003

Melatonin protects against lipid peroxidation and membrane rigidity in erythrocytes from patients undergoing cardiopulmonary bypass surgery.

The first aim of this study was to test whether there are changes in erythrocyte lipid peroxidation products and membrane fluidity during cardiac surgery involving cardiopulmonary bypass. Secondly, in vitro tests were performed to examine whether melatonin alters induced lipid peroxidation and reduced membrane fluidity in erythrocytes from these patients. Fifteen patients undergoing cardiac surgery involving cardiopulmonary bypass (CPB) were selected. Five blood samples were taken at different times during surgery for analysis of thiobarbituric acid reactive substances (TBARS) content and membrane fluidity of the erythrocytes. TBARS are an index of the level of lipid peroxidation. The results revealed an increase in TBARS levels and a parallel decrease in erythrocyte membrane fluidity (increased membrane rigidity) after the onset of CPB with respect to the reference sample. Likewise, in vitro induction of lipid peroxidation in the erythrocyte samples from CPB patients followed a similar pattern. The changes in TBARS levels and membrane fluidity were suppressed by pre-incubation of erythrocytes with melatonin prior to the induction (by 70 microm Fe2+ + 250 microm ascorbate) of lipid peroxidation in a concentration-dependent manner. The results constitute a persuasive argument for the use of melatonin for preventive and therapeutic purposes during CPB.

Antioxidants↗

PubMed2003

Clinical management and control of alveolalgia ("dry socket") with vitamin C.

PURPOSE: To monitor the incidence of dry socket in a sample of 696 consecutive tooth extraction patients and to test the possible therapeutic effects of vitamin C. MATERIALS AND METHODS: Following standardized extractions, 24 dry socket patients were provided 4,000 mg/day dosages of Vitamin C. Demographic and health history data were collected. RESULTS: The occurrence of dry socket (3.5% overall) was greater in females and individuals with lower overall health status, and supplemental Vitamin C was associated with rapid recovery.

Adolescent↗

PubMed2005

Aldehyde sources, metabolism, molecular toxicity mechanisms, and possible effects on human health.

Aldehydes are organic compounds that are widespread in nature. They can be formed endogenously by lipid peroxidation (LPO), carbohydrate or metabolism ascorbate autoxidation, amine oxidases, cytochrome P-450s, or myeloperoxidase-catalyzed metabolic activation. This review compares the reactivity of many aldehydes towards biomolecules particularly macromolecules. Furthermore, it includes not only aldehydes of environmental or occupational concerns but also dietary aldehydes and aldehydes formed endogenously by intermediary metabolism. Drugs that are aldehydes or form reactive aldehyde metabolites that cause side-effect toxicity are also included. The effects of these aldehydes on biological function, their contribution to human diseases, and the role of nucleic acid and protein carbonylation/oxidation in mutagenicity and cytotoxicity mechanisms, respectively, as well as carbonyl signal transduction and gene expression, are reviewed. Aldehyde metabolic activation and detoxication by metabolizing enzymes are also reviewed, as well as the toxicological and anticancer therapeutic effects of metabolizing enzyme inhibitors. The human health risks from clinical and animal research studies are reviewed, including aldehydes as haptens in allergenic hypersensitivity diseases, respiratory allergies, and idiosyncratic drug toxicity; the potential carcinogenic risks of the carbonyl body burden; and the toxic effects of aldehydes in liver disease, embryo toxicity/teratogenicity, diabetes/hypertension, sclerosing peritonitis, cerebral ischemia/neurodegenerative diseases, and other aging-associated diseases.

Aldehydes↗

PubMed2003

Therapeutic efficacy of high-dose vitamin C on acute pancreatitis and its potential mechanisms.

AIM: To observe the therapeutic efficacy of high-dose Vitamin C (Vit. C) on acute pancreatitis (AP), and to explore its potential mechanisms. METHODS: Eighty-four AP patients were divided into treatment group and control group, 40 healthy subjects were taken as a normal group. In the treatment group, Vit. C (10 g/day) was given intravenously for 5 days, whereas in the control group, Vit. C (1 g/day) was given intravenously for 5 days. Symptoms, physical signs, duration of hospitalization, complications and mortality rate were monitored. Meanwhile, serum amylase, urine amylase and leukocyte counts were also determined. The concentration of plasma vitamin C (P-VC), plasma lipid peroxide (P-LPO), plasma vitamin E (P-VE), plasma beta-carotene (P-beta-CAR), whole blood glutathione (WB-GSH) and the activity of erythrocyte surperoxide dimutase (E-SOD) and erythrocyte catalase (E-CAT) as well as T lymphocyte phenotype were measured by spectrophotometry in the normal group and before and after treatment with Vit. C in the treatment and the control group. RESULTS: Compared with the normal group, the average values of P-VC, P-VE, P-beta-CAR, WB-GSH and the activity of E-SOD and E-CAT in AP patients were significantly decreased and the average value of P-LPO was significantly increased, especially in severe acute pancreatitis (SAP) patients (P<0.05. P-VC, P=0.045; P-VE, P=0.038; P=0.041; P-beta-CAR, P=0.046; WB-GSH, P=0.039; E-SOD, P=0.019; E-CAT, P=0.020; P-LPO, P=0.038). Compared with the normal group, CD3 and CD4 positive cells in AP patients were significantly decreased. The ratio of CD4/CD8 and CD4 positive cells were decreased, especially in SAP patients (P<0.05. CD4/CD8, P=0.041; CD4, P =0.019). Fever and vomiting disappeared, and leukocyte counts and amylase in urine and blood become normal quicker in the treatment group than in the control group. Moreover, patients in treatment group also had a higher cure rate, a lower complication rate and a shorter in-ward days compared with those in he control group. After treatment, the average value of P-VC was significantly higher and the values of SIL-2R, TNF-alpha, IL-6 and IL-8 were significantly lower in the treatment group than in the control group (P<0.05 P-VC, P=0.045; SIL-2R, P=0.012; TNF-alpha, P=0.030; IL-6, P=0.015; and IL-8, P=0.043). In addition, the ratio of CD4/CD8 and CD4 positive cells in the patients of treatment group were significantly higher than that of the control group after treatment (P<0.05. CD4/CD8, P=0.039; CD4, P=0.024). CONCLUSION: High-dose vitamin C has therapeutic efficacy on acute pancreatitis. The potential mechanisms include promotion of anti-oxidizing ability of AP patients, blocking of lipid peroxidation in the plasma and improvement of cellular immune function.

Acute Disease↗

PubMed2007

Labelling chemistry and characterization of [90Y/177Lu]-DOTA-ZHER2:342-3 Affibody molecule, a candidate agent for locoregional treatment of urinary bladder carcinoma.

The direct instillation of radiolabelled conjugates in the urinary bladder is a promising path for the treatment of bladder carcinoma. The targeting of HER2/neu receptors expressed on the surface of many bladder carcinoma cells shows potential to be developed as a therapeutic strategy, and patients identified with a high risk of progression may benefit from adjuvant targeted radionuclide therapy. A phage-display selected Affibody molecule (Z(HER2:342)) which binds to HER2/neu with picomolar affinity, can be used for targeting HER2/neu-expressing bladder carcinomas. A DOTA-derivative of Z(HER2:342), designated as DOTA-Z(HER2:342)-3, is considered as a suitable targeting agent for therapy. The DOTA chelator provides stable labelling with radiometals, and the low molecular weight (7.2 kDa) of the DOTA-Z(HER2:342)-3 compound is expected to enable efficient tumor penetration. DOTA-Z(HER2:342)-3 was radiolabelled with 90Y and 177Lu in 1 M ammonium acetate buffer, at pH 5.5, and in the presence of ascorbic acid. Nearly quantitative labelling yields were achieved for both nuclides after 15 min of incubation at 60 degrees C. After chelation, the conjugates retained their capacity to specifically bind to HER2/neu-expressing SKOV-3 cells. The radiolabelled affibody conjugate (DOTA-Z(HER2:342)-3) demonstrated high antigen-binding capacity and good cellular retention. Biodistribution in normal mice demonstrated low uptake in all organs and tissues except for kidneys.

Animals↗

PubMed2001

Hydroxyurea-induced oxidative damage of normal and sickle cell hemoglobins in vitro: amelioration by radical scavengers.

Hydroxyurea (HU) induces fetal hemoglobin (Hb F) production in patients with sickle cell anemia. The therapeutic dosage of HU used for Hb F induction often elicits myelosuppression, which becomes its major associated complication. We examined the effect of HU on hemoglobin modulation and the role of radical scavengers on these induced changes. In vitro exposure of human blood to various concentrations of HU at predetermined time intervals induced a progressive dose-dependent oxidation (MetHb formation) of both adult (Hb AA) and sickle (Hb SS) hemoglobins. The oxidative effect of HU on Hb SS was 3 times greater than its effect on Hb AA. Similar but less profound changes were observed in H2O2-treated samples. Hb F was, however, observed to be relatively resistant to HU-induced oxidative damage. A substantial protective effect of Hb by alpha-tocopherol, ascorbic acid, and D-mannitol was observed during pretreatment of Hb AA and Hb SS blood samples. Analyses of the hemoglobins and their globin chain components by high-performance liquid chromatography revealed a considerable protective effect by these free radical scavengers. These results indicate that the HU-induced damage of hemoglobin and their component globin chains can be reduced by radical scavengers.

Adolescent↗

PubMed1990

New biological properties of pyrroloquinoline quinone and its related compounds: inhibition of chemiluminescence, lipid peroxidation and rat paw edema.

Pyrroloquinoline quinone (PQQ) inhibited the chemiluminescence (CL) from mouse peritoneal cells initiated by zymosan, carrageenin and N-formyl-methionyl-leucyl-phenylalanine and CL generated by the xanthine-xanthine oxidase reaction and the lipid peroxidation in the rat brain homogenate. The inhibitory activity of PQQ was more potent than that of idebenone, alpha-tocopherol and ascorbic acid in all the three assay systems. In the xanthine-xanthine oxidase reaction, PQQ had no effect on the formation of uric acid at the concentration of CL inhibition. These results suggest that PQQ might have a radical scavenger-like activity. Structure-activity relationship of PQQ and its six related compounds showed that the 7- and 9-carboxyl groups of PQQ as well as the orthoquinone structure are responsible for the radical scavenger-like activity. In addition, the -NH group in the pyrrole ring of PQQ seemed to be essential for the antilipid peroxidative activity in the rat brain homogenate. When administered i.p., PQQ inhibited the development of 0.1% carrageenin-induced paw edema in rats. These results suggest that PQQ might have therapeutic effects on various diseases, of which development or exacerbation has been known to be associated with radical oxygens.

Animals↗

PubMed1995

[Changes in vitreous structure caused by oxygen free radicals].

Vitreous liquefaction in humans is considered to be part of the normal ocular aging process and is associated with vitreoretinal pathology. Because hyaluronic acid (HA), one of the main components of the vitreous gel structure, is degraded by reactive oxygen species (ROS) including oxygen free radicals, the structural changes in the vitreous may be caused by ROS. To investigate the effect of ROS on the vitreous gel structure, we treated animal vitreous with ROS, which was generated from various sources. Using riboflavin as a photosensitizer, calf vitreous was irradiated with visible light (two 15-W fluorescent lamps) and found to be considerably liquefied. The liquefaction resulted from HA depolymerization induced by ROS. Because of the small amount of riboflavin naturally present in the vitreous, a riboflavin-sensitized photochemical reaction may contribute to age-related vitreous liquefaction. Hematoporphyrin (HP), which is similar in chemical structure to heme in blood, was also used as a photosensitizer. Irradiation with HP destroyed the calf vitreous gel structure and caused liquefaction. A HP-sensitized photochemical reaction may contribute to vitreous liquefaction observed after vitreous hemorrhage. Because metal ions, including Fe2+ and Cu2+, can catalyze to generate ROS, liquefaction occurred when we treated calf vitreous with Fe2+ or Cu2+ at 4 degrees C. Adding ascorbic acid to the vitreous during the reaction increased the rate of liquefaction. Therefore, metal ion catalyzed ROS may also contribute to vitreous liquefaction, such as that found in an injured eye with siderosis. To investigate the relation between inflammatory cell mediated ROS and vitreous liquefaction, an endotoxin-induced uveitis model was created in the rabbit eye. Upon inflammation, the vitreous gel contracted and released a water-like liquid. Because superoxide dismutase can suppress the liquefaction, the destruction of the vitreous gel structure resulted from ROS generated from inflammatory cells. Although many unknown factors contribute to vitreous liquefaction, ROS may be the main cause of vitreous structure alterations. To prevent or delay the progress of vitreous liquefaction in the normal aging process or vitreous pathology, a new therapeutic procedure based on clear scientific studies is needed.

Aging↗

PubMed2005

Endothelial dysfunction and antioxidants.

The vascular endothelium plays a crucial role in the physiology of blood vessels and the pathological processes of atherosclerotic disease and acute coronary syndromes. Endothelial dysfunction is the core problem; it is an impairment of endothelium-dependent vasorelaxation caused by a loss of nitric oxide activity in the vessel wall, which results in impairment in the regulation of vascular homeostasis. Further understanding of its mechanisms of action and possible therapeutic targets will be of great importance. The group of antioxidant vitamins, A, C and E, would seem uniquely situated to reduce cardiovascular events by improving endothelial function by reducing the concentration of reactive oxygen species in the vessel wall and by preventing oxidative modification of low-density lipoprotein. Unfortunately, despite extensive studies in both observational and randomized trials, the weight of evidence points to little or no benefit from antioxidant therapy.

Antioxidants↗

PubMed1986

Perspectives in the treatment of reversible airway obstruction.

The pharmacological therapy of asthmatic syndromes is based essentially on the programmed use of disodium cromoglycate, beta-2-stimulants, antimuscarinics, theophyllines and corticosteroids. However, the continual progress being made in pathogenesis and pharmacology suggests, to an ever-increasing extent, the application of new therapeutic approaches for these diseases, some of which are fairly interesting from a speculative point of view although they are as yet of limited practical value. Calcium antagonists and alpha-blockers have a mild anti-reactive effect but this is not sufficiently potent to justify use of these products in the treatment of asthma unless there are also cardiovascular disorders for which these drugs are particularly indicated. Despite the initial promising prospects, all attempts to obtain PGE analogues of therapeutic value as antiasthmatics have proved fruitless. Research into orally active chromone derivatives has proved equally unproductive. On the other hand, certain new inhalatory chromones are decidedly more promising. Specific antagonization of mediators (histamine, prostaglandin, leukotrienes) did not produce the effect hoped for in asthma, but this was foreseeable insofar as the major pathogenic mediators are too vast in number (and no doubt there are still many more to be discovered) to allow one to conceive it possible to achieve a satisfactory therapeutic effect by merely blocking some of them. Inflammation of the bronchial wall is currently considered to be one of the basic pathogenic factors provoking the recurrence of asthma: this is proved indirectly by the potent antiasthmatic effect of corticosteroids which are the most effective anti-inflammatory agents. As regards nonsteroidal anti-inflammatory drugs (NSAID), however, matters are more complicated.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex Hormones↗

PubMed1998

Potent inhibitory activities of hydrophobic aci-reductones (2-hydroxytetronic acid analogs) against membrane and human low-density lipoprotein oxidation.

The effects of selected aci-reductones, which are hydrophobic ascorbate-related analogs including 4-chlorophenyl-2-hydroxytetronic acid (Cpd A), 4-(1,1'-biphenyl)-2-hydroxytetronic acid (Cpd B), and 4-(4'-chloro-1,1'-biphenyl)-2-hydroxytetronic acid (Cpd C), on membrane and low density lipoprotein (LDL) oxidation were assessed. Hepatic microsomal lipid peroxidation was induced by the ascorbate + Fe(II) chemical system. All three agents inhibited membrane lipid peroxidation in a concentration-dependent manner with the order of potency: Trolox (vitamin E) < or = Cpd A << Cpd B < Cpd C; based on the EC50 values, Cpd B and Cpd C were 11- and 19-fold, respectively, more potent than Trolox. In contrast to ascorbic acid, all three agents did not display any membrane prooxidative effect in the presence of iron. When human LDL was incubated with 10 microM of Cu(II), LDL oxidation, determined by the formation of thiobarbituric acid reactive substances, followed a typical sigmoidal curve with an initial lag phase. Preincubation of the LDL samples with low micromolar concentrations (1 and 3 microM) of each agents for 30 min before the addition of copper resulted in significant delays of the lag time of LDL oxidation, and the effectiveness of Cpd B and Cpd C was more prominent than that mediated by either Trolox or probucol. Since clinical evidence strongly supports the hypothesis that atherogenesis is initiated by LDL oxidation, the results suggest that these aryl tetronic acid analogs may serve as promising candidates for future therapeutic use as anti-atherogenic agents.

Animals↗

PubMed1985

Extravasation of dactinomycin, vincristine, and cisplatin: studies in an animal model.

Extravasation of some cytotoxic drugs results in chemical cellulitis. Management of suspected extravasation has been empiric and difficult to evaluate clinically. We investigated dactinomycin, vincristine, and cisplatin by means of intradermal injections in Balb-c mice. Reproducible skin lesions with concentric areas of induration, erythema, and ulceration developed in a time- and dose-dependent fashion following injection of dactinomycin. Vincristine caused no lesions following initial intradermal administration, but repeat injection 7 days later was followed by a diffuse punctate ulcerative lesion suggesting a hypersensitivity reaction. Three concentrations (1.0, 0.1, and 0.01 mg/ml) of cisplatin elicited cellulitis following initial injection, but there was no correlation between lesion size and dose. Injection of saline, hydrocortisone, ascorbic acid, sodium thiosulfate, buffered DNA solution, and beta adrenergic agonists and antagonists after the injection of dactinomycin failed to prevent development of lesions. Heat application was also ineffective; however, local cold application prevented or markedly reduced reactions to dactinomycin. We conclude that the intradermal mouse model may be appropriate for the evaluation of the three drugs studied and that cold application is the best antidote among those tested for dactinomycin-induced ulceration in this model.

Adrenal Cortex Hormones↗

PubMed2003

Protection against ionizing radiation by antioxidant nutrients and phytochemicals.

The potential of antioxidants to reduce the cellular damage induced by ionizing radiation has been studied in animal models for more than 50 years. The application of antioxidant radioprotectors to various human exposure situations has not been extensive although it is generally accepted that endogenous antioxidants, such as cellular non-protein thiols and antioxidant enzymes, provide some degree of protection. This review focuses on the radioprotective efficacy of naturally occurring antioxidants, specifically antioxidant nutrients and phytochemicals, and how they might influence various endpoints of radiation damage. Results from animal experiments indicate that antioxidant nutrients, such as vitamin E and selenium compounds, are protective against lethality and other radiation effects but to a lesser degree than most synthetic protectors. Some antioxidant nutrients and phytochemicals have the advantage of low toxicity although they are generally protective when administered at pharmacological doses. Naturally occurring antioxidants also may provide an extended window of protection against low-dose, low-dose-rate irradiation, including therapeutic potential when administered after irradiation. A number of phytochemicals, including caffeine, genistein, and melatonin, have multiple physiological effects, as well as antioxidant activity, which result in radioprotection in vivo. Many antioxidant nutrients and phytochemicals have antimutagenic properties, and their modulation of long-term radiation effects, such as cancer, needs further examination. In addition, further studies are required to determine the potential value of specific antioxidant nutrients and phytochemicals during radiotherapy for cancer.

Animals↗

PubMed1993

[Effectiveness of dapsone on refractory immune thrombocytopenia in a patient with systemic lupus erythematosus associated with sarcoidosis].

A 57-year-old man was admitted with massive nasal bleeding and blurred vision in January, 1991. Laboratory examination showed a prominent decrease of platelet number (1,000/microliters) and a marked elevation of PAIgG (4,025 ng/10(7) cells). Serological test revealed positive antinuclear factor, low concentration of C3 and C4, high level of immune complex and polyclonal hypergammaglobulinemia. The patient had uveitis and bilateral hilar lymphadenopathy with a high level of serum lysozyme and negative PPD skin test. The diagnosis of SLE complicated with thrombocytopenia and sarcoidosis was made. In spite of the various trials of treatment, such as oral prednisolone (PSL), methyl-PSL pulse therapy, plasma exchange, high-dose intravenous gammaglobulin, cyclophosphamide, azathioprine, vincristine, colchicine, cyclosporine-A, mizoribine, danazol, ascorbic acid and interferon alpha 2b, the platelet number could not be raised enough to keep more than 10,000/microliters, though the level of PAIgG decreased to 200 ng/10(7) cells. Finally, the administration of 75 mg/day of dapsone brought about a significant rise in platelet number within 2 weeks. The maximum number of 6.2 x 10(4)/microliters was obtained after 2 months. Then the patient stopped himself to take the drug, but the platelet number remained around 4-5 x 10(4)/microliters. Same dose of the drug was again prescribed to confirm the effect of dapsone. The platelet number increased to 7.9 x 10(4)/microliters in 2 weeks, and gradually returned to 5 x 10(4)/microliters after cessation of the drug. Thus being certainly effective against thrombocytopenia, dapsone should be considered as one of the therapeutic choice for refractory autoimmune thrombocytopenia.

Autoimmune Diseases↗

PubMed2001

Asp-Ala-His-Lys (DAHK) inhibits copper-induced oxidative DNA double strand breaks and telomere shortening.

Both DNA and the telomeric sequence are susceptible to copper-mediated reactive oxygen species (ROS) damage, particularly damage attributed to hydroxyl radicals. In this study, ROS-induced DNA double strand breaks and telomere shortening were produced by exposure to copper and ascorbic acid. Asp-Ala-His-Lys (DAHK), a specific copper chelating tetrapeptide d-analog of the N-terminus of human albumin, attenuated DNA strand breaks in a dose dependent manner. d-DAHK, at a ratio of 4:1 (d-DAHKCu), provided complete protection of isolated DNA from double strand breaks and, at a ratio of 2:1 (d-DAHKCu), completely protected DNA in Raji cells exposed to copper/ascorbate. Southern blots of DNA treated with copper/ascorbate showed severe depletion and shortening of telomeres and Raji cell treated samples showed some conservation of telomere sequences. d-DAHK provided complete telomere length protection at a ratio of 2:1 (d-DAHKCu). The human albumin N-terminus analog, d-DAHK, protects DNA and telomeres against copper-mediated ROS damage and may be a useful therapeutic adjunct in ROS disease processes.

Cell Line↗

PubMed1984

Neutrophils kill pulmonary endothelial cells by a hydrogen-peroxide-dependent pathway. An in vitro model of neutrophil-mediated lung injury.

Neutrophil-mediated injury to lung parenchymal cells has been proposed as an important step in the pathogenesis of many acute and chronic lung disorders. As an in vitro model of neutrophil-mediated injury, this study used activated human neutrophils as effector cells in an 18-h cytotoxicity assay with 51Cr-labeled bovine pulmonary artery endothelial cells serving as target cells. Neutrophils effectively injured pulmonary endothelial cells, expressed as cytotoxic index (CI), of 63.8 +/- 5.4, and this injury could be significantly reduced by several agents, including 1% dimethyl sulfoxide (CI, 51.3 +/- 3.7), 50 micrograms/ml ascorbic acid (CI, 40.8 +/- 4.7), and especially 1,100 U/ml catalase (CI, 14.3 +/- 4.1). As cell-free models of neutrophil-mediated endothelial cell injury, H2O2 (30 microM), O2- (generated by 0.5 mU xanthine oxidase), and the myeloperoxidase-dependent (0.32 U) hypohalite ion were each capable of injuring the target cells with CI of 6.21 +/- 2.8, 53.6 +/- 5.3, and 21.2 +/- 1.5, respectively. Catalase was effective in reducing the injurious effect of each of these oxidant-generating systems (p less than 0.01, all comparisons), confirming the important role for H2O2 in the mediation of this injury. The data indicate that neutrophils are capable of killing pulmonary endothelial cells by a pathway largely dependent on the generation of H2O2, and suggest the possibility that removal of H2O2 from the alveolar structures in subjects with these disorder might be an effective future therapeutic approach.

Animals↗

PubMed1999

High doses of multiple antioxidant vitamins: essential ingredients in improving the efficacy of standard cancer therapy.

Numerous articles and several reviews have been published on the role of antioxidants, and diet and lifestyle modifications in cancer prevention. However, the potential role of these factors in the management of human cancer have been largely ignored. Extensive in vitro studies and limited in vivo studies have revealed that individual antioxidants such as vitamin A (retinoids), vitamin E (primarily alpha-tocopheryl succinate), vitamin C (primarily sodium ascorbate) and carotenoids (primarily polar carotenoids) induce cell differentiation and growth inhibition to various degrees in rodent and human cancer cells by complex mechanisms. The proposed mechanisms for these effects include inhibition of protein kinase C activity, prostaglandin E1-stimulated adenylate cyclase activity, expression of c-myc, H-ras, and a transcription factor (E2F), and induction of transforming growth factor-beta and p21 genes. Furthermore, antioxidant vitamins individually or in combination enhance the growth-inhibitory effects of x-irradiation, chemotherapeutic agents, hyperthermia, and biological response modifiers on tumor cells, primarily in vitro. These vitamins, individually, also reduce the toxicity of several standard tumor therapeutic agents on normal cells. Low fat and high fiber diets can further enhance the efficacy of standard cancer therapeutic agents; the proposed mechanisms for these effects include the production of increased levels of butyric acid and binding of potential mutagens in the gastrointestinal tract by high fiber and reduced levels of growth promoting agents such as prostaglandins, certain fatty acids and estrogen by low fat. We propose, therefore, a working hypothesis that multiple antioxidant vitamin supplements together with diet and lifestyle modifications may improve the efficacy of standard and experimental cancer therapies.

Animals↗