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PubMed1993

Antimutagenic efficacy of higher doses of vitamin C.

Vitamin C, when administered concurrently with a pesticide (endosulfan, phosphamidon or mancozeb), could significantly decrease the frequency of pesticide-induced clastogenic and mitosis-disruptive changes in the bone marrow cells of young Swiss albino mice. Of the three doses (10, 20 or 40 mg/kg b.wt./day) of the vitamin, the one which is double the human therapeutic dose (20 mg/kg b.wt./day) was most effective as an antimutagen to be followed by 40 mg and 10 mg. None of these doses of vitamin C showed any genotoxicity of their own for the parameters studied here.

Animals↗

PubMed2000

Natural treatment of perennial allergic rhinitis.

Perennial allergic rhinitis is an IgE-mediated inflammatory disorder of the nasal mucosa characterized by paroxysms of sneezing, nasal congestion, pruritus, and rhinorrhea. The condition may be caused by certain environmental agents, food sensitivities, structural abnormalities, metabolic conditions, or synthetic drugs. Recent health impairment outcome studies on allergic rhinitis sufferers reveal a measurable decline in physical and mental health status and the inability to perform daily activities. Antihistamines, decongestants, anticholinergic agents, and corticosteroid drug therapy, alone or in combination, are typically used in the treatment of allergic rhinitis. Reported adverse side effects include sedation, impaired learning/memory, and cardiac arrhythmias. Therapeutic strategies should seek to decrease the morbidity already associated with this condition. Urtica dioica, bromelain, quercetin, N-acetylcysteine, and vitamin C are safe, natural therapies that may be used as primary therapy or in conjunction with conventional methods.

Acetylcysteine↗

PubMed1987

[Effect of vitamin C (V.C) on thermal sensitivity of Lewis tumor].

In this paper, the effect of V.C on thermal sensitivity of the tumor and normal tissues was studied. Average peak reaction and RD50 (50% reaction dosage) were used to evaluate the effect of V.C on thermal sensitivity of the normal tissue. Tumor cure rate and TCD50 (50% tumor cure dosage) were used to evaluate the effect of V.C on that of the tumor tissue. In all mice injected by V.C locally, the average peak reaction markedly increased, RD50 decreased by 1-2 fold; the tumor cure rate was obviously elevated, TCD50 was significantly reduced except those treated by 20' hyperthermia. TGF (therapeutic gain factor) was 1.76. These results indicate that V.C can increase the thermal sensitivity of tumor and normal tissues but the effect on tumor tissue is selective.

Animals↗

PubMedDate not supplied

Intravascularly administered crosslinked immunoprecipitates of gulonolactone oxidase are toxic and rapidly cleared from the circulation.

Glutaraldehyde crosslinked, immunoprecipitated gulonolactone oxidase, injected intraperitoneally, has significant catalytic activity and is capable of providing long-term therapeutic benefit for the enzyme deficiency disease scurvy. The enzyme is tolerated even in repetitive doses. In the present study, however, we have found that when administered intra-arterially this modified enzyme is quite toxic even in single doses. Prior to administration the enzyme complex was filtered through a 5-microns filter. When administered intravascularly the enzyme is not nearly as active catalytically. In spite of this, activity can be detected in vivo as an elevation of plasma ascorbic acid and prolonged survival of guinea pigs fed without the vitamin. Following administration both activity and the enzyme complex are rapidly removed from the circulation. Liver and spleen are largely responsible for this uptake. Because of its toxicity intra-arterial injection of this form of the enzyme does not appear suitable for enzyme therapy.

Animals↗

PubMed2003

Prevention of acetic acid-induced colitis by desferrithiocin analogs in a rat model.

Iron contributes significantly to the formation of reactive oxygen species via the Fenton reaction. Therefore, we assessed whether a series of desferrithiocin analogs, both carboxylic acids and hydroxamates, could (1) either promote or diminish the iron-mediated oxidation of ascorbate, (2) quench a model radical species, 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+), and (3) when applied topically, prevent acetic acid-induced colitis in rats. Surprisingly, most of the desferrithiocin analogs inhibited the Fenton reaction to an approximately equivalent degree; however, substantial differences were observed in the capacity of the analogs to scavenge the model radical cation. Four carboxylic acid desferrithiocin analogs and their respective N-methylhydroxamates were tested along with desferrioxamine and Rowasa, a currently accepted topical therapeutic agent for inflammatory bowel disease (IBD), in a rodent model of acetic acid-induced colitis. The colonic damage was quantitated by two independent measurements. Although neither radical scavenging nor prevention of Fenton chemistry was a definitive predictor of in vivo efficacy, the overall trend is that desferrithiocin analogs substituted with an N-methylhydroxamate in the place of the carboxylic acid are both better free radical scavengers and more active against acetic acid-induced colitis. These results represent an intriguing alternative avenue to the development of improved IBD therapeutic agents.

Acetic Acid↗

PubMed2006

[Steroid (glucocorticoid)-induced cataract].

Glucocorticoids (GC) have been widely used as a therapeutic drug for various diseases. However, there are many complications of GC therapy including cataracts. In a series of studies to elucidate the actions of GC using 15-day-old developing chick embryos, we found that GC produced hyperglycemia, hyperlipemia, osteoporosis, and cataractous lenses with a high incidence (>90%) within 48 h. Cataract formation is caused by oxidative stresses, probably derived from GC effects on the main target organ, the liver, and can be prevented by radical scavengers including ascorbic acid, and insulin. Ascorbic acid does not inhibit the inflammatory and immunosuppressive effects of GC. Therefore by analyzing and decreasing risk factors producing side effects, it will be possible to improve GC therapy without the loss of GC activity.

Animals↗

PubMed1987

Cytotoxicity of oxidative metabolites of procainamide.

Indirect evidence suggests that metabolism of procainamide (PA) may be necessary for generation of its autoimmunity-inducing capacity. Reactive metabolites of PA produced by hepatic mixed function oxidases have been identified by their capacity to bind proteins covalently. The present study extends these findings by comparing the toxicity of various chemically synthesized metabolites of PA to a variety of cell lines and primary cultures. PA and its N-acetyl- and N-acetyl-N-oxide-derivatives were nontoxic to S49.1 cells at concentrations up to 5 mM, whereas nitro-Pa (4-nitro-N-(diethylaminoethyl)benzamide hydrochloride) and azoxy-PA (bis-N,N'-(diethylaminoethyl)-4,4'-azoxydibenzamide) displayed partial cytotoxicity at 1 and 0.1 mM, respectively. (The therapeutic range of PA is 0.02-0.05 mM.). In contrast, hydroxylamine-PA (4-hydroxylamino-N-(diethylaminoethyl)benzamide hydrochloride) was highly cytotoxic, producing a TD50 between 0.002 and 0.045 mM among the eight cell lines tested. Hydroxylamine-PA sensitivity correlated with cell reducing capacity, suggesting that redox cycling contributes to cytotoxicity. The hydroxylamine metabolite of PA undergoes spontaneous air oxidation to the nitroso-derivative (nitroso-PA). When this oxidation was minimized by rapid manipulations or inhibited by ascorbic acid, cytotoxicity was reduced or eliminated, suggesting that the nitroso-derivative may be the toxic metabolite. Quiescent peripheral blood lymphocytes, especially T-cells, were relatively insensitive to hydroxylamine-PA when evaluated by dye exclusion 1 day after drug exposure. However, massive DNA strand breaks were detectable in these cells immediately after drug exposure, and resting lymphocytes treated with 0.01 mM hydroxylamine-PA died slowly during the subsequent week.(ABSTRACT TRUNCATED AT 250 WORDS)

Ascorbic Acid↗

PubMed1997

Anti-inflammatory activity of the aqueous extract from Rhizoma smilacis glabrae.

Our previous paper has reported that the aqueous extract from Rhizoma smilacis glabrae (RSG) (RSG ext) selectively inhibited the effector phase of delayed-type hypersensitivity (DTH) without suppressing humoral immune response. In the present study, a remarkable inhibitory activity was exhibited by the extract against both primary and secondary hind paw swelling of adjuvant arthritis in rats. RSG ext also significantly reduced the inflammatory edema induced by carrageenan in either naive or bilaterally adrenalectomized rats, suggesting the independence of the anti-inflammatory action on the function of pituitary-adrenal axis. The PGE2 content in the carrageenan-induced inflammatory tissue was also decreased remarkably by the extract. Furthermore, RSG ext showed a distinct inhibition on the formation of cotton-induced granuloma formation. However, as compared with a steroidal agent, prednisolone, the extract did not affect the vitamin C content in adrenal gland as well as the weights of some organs. These results suggest that RSG ext may act as a therapeutic agent of immunoinflammatory diseases through a selective suppression on the cellular immune response involved in inflammations as well as through a direct anti-inflammatory mechanism including inhibiting PGE2.

Adrenal Glands↗

PubMed2005

Effect of sodium azulene sulfonate on capsaicin-induced pharyngitis in rats.

Sodium azulene sulfonate is a water-soluble derivative of azulene which is an antiinflammatory component of chamomile of the family of Asteraceae. Sodium azulene sulfonate is clinically used as a therapeutic agent in the treatment of pharyngitis as well as other inflammatory diseases such as tonsillitis, stomatitis and conjunctivitis. There has been no documentation on the effect of sodium azulene sulfonate on pharyngitis in laboratory models, probably because of no availability of such models. We recently established a pharyngitis model using capsaicin application on pharyngeal mucosa in rats. The present study investigated the antipharyngitis activity of sodium azulene sulfonate comparing with those of ruthenium red (vanilloid receptor antagonist, 8.5 and 85 mg/ml), ascorbic acid (antioxidative compound, 100 microg/ml), povidone iodine (gargle as disinfectant, oxidative compound, 5 and 20 mg/ml) and diclofenac sodium (cyclooxygenase inhibitor, 0.1 and 1 mg/ml). As an antipharyngeal effect, the capsaicin-induced plasma exudation in the pharyngeal mucosa of the rat was evaluated. The capsaicin-induced plasma exudation in the pharyngeal mucosa was inhibited by sodium azulene sulfonate (100 and 200 microg/ml) as well as ruthenium red and ascorbic acid, but not by povidone iodine and dicrofenac sodium; povidone iodine rather promoted the plasma exudation. In conclusion, the antipharyngitis effect of sodium azulene sulfonate was demonstrated for the first time in a laboratory model. Although the mechanism by which sodium azulene sulfonate inhibited the capsaicin-induced pharyngitis is not yet unraveled, antioxidative effect, but not inhibitory effect on cyclooxygenase pathway, might be involved.

Animals↗

PubMed2002

A reassessment of the peroxynitrite scavenging activity of uric acid.

Peroxynitrite is implicated in numerous human diseases. Hence, there is considerable interest in potential therapeutic peroxynitrite scavengers. It has been claimed that uric acid is a powerful peroxynitrite scavenger. We previously observed that uric acid is a powerful inhibitor of tyrosine nitration induced by peroxynitrite, but fails to prevent alpha(1)-antiproteinase (alpha(1)-AP) inactivation induced by peroxynitrite. However, the reactivity of peroxynitrite is significantly modified by bicarbonate and this has not been considered in evaluating the scavenging activity of uric acid and other endogenous antioxidant compounds. In the presence of bicarbonate (25 mM), the ability of uric acid, ascorbate, Trolox, and GSH to inhibit peroxynitrite-mediated tyrosine and guanine nitration is decreased. Protection against peroxynitrite-mediated alpha(1)-AP inactivation is also decreased by ascorbate, Trolox, and GSH, but it is enhanced by uric acid. Bicarbonate also inhibits the ability of these compounds to prevent peroxynitrite-mediated ABTS radical cation formation. However, the abilities of these antioxidants to prevent peroxynitrite-mediated bleaching of pyrogallol red are enhanced by bicarbonate. These results show that physiologic concentrations of bicarbonate substantially modify the ability of uric acid to prevent peroxynitrite-mediated reactions. This study highlights the need to use several different assays in the presence of physiologically relevant concentrations of bicarbonate when assessing compounds for peroxynitrite scavenging, in order to avoid misleading results.

Antioxidants↗

PubMedDate not supplied

The early influence of albumin administration on protein metabolism and wound healing in burned rats.

Hypoalbuminemia is often claimed to impair wound healing, and therefore albumin has traditionally been administered to derive beneficial effects on general physiologic conditions including the nutritional state. However, the influence of albumin administration on systemic protein metabolism and wound healing is still unclear. Therefore, the objective of this study was to investigate the influence of albumin administration on protein metabolism and wound healing in burned rats. After receiving basic total parenteral nutrition (TPN) for 4 days, Sprague-Dawley rats underwent a 6-cm skin incision in the back and a burn involving 20 percent of the whole body surface. The rats were divided into three groups. Group I continued to receive basic TPN. Group II was given basic TPN, but 20 percent of the total nitrogen was replaced by albumin. Group III was administered basic TPN plus albumin equivalent to 20 percent of the total nitrogen of basic TPN. Group IV had the skin incision but no burn, receiving only basic TPN. All the groups were euthanized 4 days after the burn or skin incision. The wound healing potential in terms of tensile strength was enhanced by replacement and addition of albumin (groups II and III, respectively) after a 20 percent burn. Hydroxyproline levels in the wound tended to increase in group II, and significantly increased in group III. Whereas albumin replacement (group II) did not remarkably change the protein metabolism, albumin addition (group III) significantly increased both protein synthesis (S) and breakdown (B) with the S/B ratio and nitrogen balance remaining the same as with albumin-free nutrition (group I). The urinary 3-methyl-histidine/creatinine ratio significantly increased after burn in group III. We conclude that intravenous albumin administration enhanced incisional wound healing in burned rats. Increased protein synthesis with concurrent myolysis and protein breakdown by albumin addition (group III) was observed during wound healing.

Albumins↗

PubMed1984

Hydrogen peroxide-mediated corneal endothelial damage. Induction by oxygen free radical.

Polymorphonuclear leukocytes and other inflammatory cells release superoxide anion and additional oxidant species following stimulation. Corneal endothelial cells were exposed to a flux of chemically generated superoxide anion (oxygen-free radical) produced by the combination of 1 mM hypoxanthine and 0.06 U/ml xanthine oxidase. Exposure of endothelial cells to the combination of hypoxanthine and xanthine oxidase resulted in anatomic disruption of the cells with interference in the function of endothelial water movement and resultant swelling of the corneal stroma. Catalase reduced the corneal swelling caused by exposure of endothelium to the oxygen-free radical generating system, whereas superoxide dismutase, ascorbic acid, D-mannitol, and ethanol did not prevent damage. The data suggest that hydrogen peroxide produced during the dismutation reaction of the superoxide anion is one of the toxic species, whereas the superoxide anion itself and the hydroxyl-free radical probably do not participate. The data suggest that corneal endothelial cells are susceptible to physiologic and anatomic damage induced by the products of reactive oxygen species, which, from previous studies, are known to be generated by inflammatory cells. The development of therapeutic modalities directed at the prevention of damage produced by hydrogen peroxide and other oxidant species may be of benefit in reducing corneal endothelial cell damage secondary to ocular inflammatory disease processes.

Animals↗

PubMed1995

Nitrosation of propranolol under simulated gastric conditions.

Nitrosation of propranolol, a beta-adrenergic blocking drug previously found to react with nitrite in HCl solution yielding a genotoxic nitrosamine, was examined under simulated gastric conditions. In the presence of a low concentration of nitrite (2.9 mM) and a therapeutic gastric concentration of the drug (5.4 mM), the yield of N-nitrosopropranolol was higher in simulated gastric juice, which contained both pepsin and thiocyanate, than in distilled water, and at pH 3.5 than at pH 1.0. A 55 microM concentration of N-nitrosopropranolol was reached after 180 min. It is reasonable to assume that the extremely small amounts of N-nitrosopropranolol formed in the human stomach should not represent a significant carcinogenic risk, but co-formulation of propranolol with ascorbic acid, which has been found to minimize the nitrosation reaction, might be useful to avoid a further, even if minimal, contribution to the already existing exposure to genotoxic chemicals.

Gastric Juice↗

PubMed2006

[A modified method to isolate and identify the adult mesenchymal stem cells from human bone marrow].

The study was aimed to establish a protocol of isolating and culturing adult mesenchymal stem cells (MSC) from human bone marrow aspirate and identify them by surface antigen analysis and committed differentiation in order to provide an experimental foundation for achieving a therapeutic benefit in applying MSC in hematopoietic stem cell transplantation. MSCs were obtained from fresh human bone marrow aspirate by gradient centrifugation with Percoll (1.073 g/ml) and anchoring culture in L-DMEM with 10% fetal bovine serum by a full medium exchange every 3 days. The MSC surface antigens, including CD34, CD45, CD73, CD105, CD166, were analyzed on FACScan flow cytometer. Under culture in conditioned medium for osteogenesis (the hormone cocktail containing 0.1 micromol/L dexamethasone, 10 mmol/L glycerol-2-phosphate and 50 micromol/L ascorbic acid) and adipogenesis (the cocktail containing 1 micromol/L dexamethasone, 5 mg/L insulin, 0.5 mmol/L 1-methyl-3-isobutylxanthine and 60 micromol/L indomethacin), MSCs committedly differentiated into osteoblasts and adipocytes. The differentiated mesenchymal stem cells were identified by morphological observation and immunohistochemical staining. The results showed that by gradient centrifugation and adhesion culture, MSCs could be isolated and culture-expanded from human bone marrow aspirate. These cells were uniformly negative for CD34, CD45 and positive for CD73, CD105 and CD166. The osteogenic differentiated cells were positive for alkaline phosphatase (ALP) and the adipogenic differentiated cells displayed accumulation of lipid vacuoles, as detected by oil red O. It is concluded that MSC can be isolated and expand-cultured from adult human bone marrow aspirate and committedly differentiate into osteoblasts and adipocytes. MSC primary identification can be accomplished by flow cytometry and induced differentiation. The set of methods in current experiment shows somewhat practical value for basic research and clinical application.

5'-Nucleotidase↗

PubMed1991

Evaluation of the ability of the angiotensin-converting enzyme inhibitor captopril to scavenge reactive oxygen species.

Captopril, an inhibitor of angiotensin-converting enzyme, has been suggested to have additional cardioprotective action because of its ability to act as an antioxidant. The rates of reaction of captopril with several biologically-relevant reactive oxygen species were determined. Captopril reacts slowly, if at all, with superoxide (rate constant less than 10(3) M-1 s-1) or hydrogen peroxide (rate constant less than M-1 s-1). It does not inhibit peroxidation of lipids stimulated by iron ions and ascorbate or by the myoglobin/H2O2 system. Indeed, mixtures of ferric ion and captopril can stimulate lipid peroxidation. Captopril reacts rapidly with hydroxyl radical (rate constant greater than 10(9) M-1 s-1) but might be unlikely to compete with most biological molecules for OH because of the low concentration of captopril that can be achieved in vivo during therapeutic use. Captopril did not significantly inhibit iron ion-dependent generation of hydroxyl radicals from hydrogen peroxide. By contrast, captopril is a powerful scavenger of hypochlorous acid: it was able to protect alpha 1-antiproteinase (alpha 1 AP) against inactivation by this species and to prevent formation of chloramines from taurine. We suggest that the antioxidant action of captopril in vivo is likely to be limited, and may be restricted to protection against damage by hypochlorous acid derived from the action of neutrophil myeloperoxidase.

Animals↗

PubMed2004

Peroxidase catalysed formation of cytotoxic prooxidant phenothiazine free radicals at physiological pH.

The antipsychotic phenothiazines may have other therapeutic applications because of their ability to kill bacteria, plasmids and tumor cells. They are also known to undergo a peroxidase-catalysed oxidation to form cation radicals that are stable at acid pH, but are not detected at a neutral pH. The objective of this project was to determine whether phenothiazine cation radical metabolites could cause oxidative stress at a neutral pH resulting in cytotoxicity. At a neutral pH, catalytic amounts of phenothiazines were found to be oxidised by a peroxidase/H2O2 system and also caused ascorbate, GSH and NADH cooxidation. NADH and GSH co-oxidation was accompanied by oxygen uptake and was increased by the addition of catalytic amounts of superoxide dismutase, indicating that the superoxide radical was formed. The phenothazines were different from other peroxidase substrates in that the NADH, ascorbate or GSH cooxidation was faster at pH 6.0 than pH 7.4, thereby partly reflecting the cation radical stability. The order of catalytic effectiveness found was promazine > chlorpromazine > trifluoperazine. Peroxidase/H2O2 also markedly increased phenothiazine cytotoxicity towards isolated rat hepatocytes at nontoxic phenothiazine concentrations. At both pH 6.0 and 7.4, the same order of phenothiazine catalytic effectiveness was observed as seen in the co-oxidation experiments. Cytotoxicity to hepatocytes could be attributed to oxidative stress as most hepatocyte glutathione oxidation and lipid peroxidation preceded phenothiazine induced cytotoxicity and that cytotoxicity was prevented by the antioxidant butylated hydroxyanisole. This hepatocyte/peroxidase/H2O2 system could be a useful model for studying drug induced idiosyncratic hepatic injury enhanced by inflammation.

Animals↗

PubMed1994

Vitamin C mediated amelioration of pesticide genotoxicity in murine spermatocytes.

The effect of vitamin C on the genotoxicity of three pesticides (Endosulfan, Phosphamidon, Mancozeb) was monitored by screening meiotic (metaphase I) chromosomes in the primary spermatocytes of Swiss albino mice, Mus musculus. A dose-dependent amelioration by vitamin C was observed in the Phosphamidon-treated group where quadruple the therapeutic dose produced maximum amelioration. In Endosulfan- and Mancozeb-treated groups, no further amelioration was achieved beyond the double dose of vitamin C, and the damage frequency did not come down to the control level. The possible mechanism of this effect is discussed.

Animals↗

PubMed2006

Spectrophotometric assay for calcineurin activity in leukocytes isolated from human blood.

The calcineurin inhibitors, cyclosporine and tacrolimus, still constitute the cornerstone of immunosuppressive regimen after organ transplantation. An efficient and feasible way to measure calcineurin activity and inhibition by these drugs may improve therapeutic monitoring of these drugs in transplant recipients. Calcineurin activity was measured in leukocyte lysates isolated from human blood using spectrophotometric phosphate quantification. The dephosphorylation of a 19-amino acid peptide substrate of calcineurin was determined using the Malachite green phosphate reagent in the presence of okadaic acid and with and without the calcium chelator EGTA. Sample storage and lysis buffer components were among the variables optimized, and the inhibitory effect of calcineurin inhibitors was investigated. Observed loss of calcineurin activity during sample storage was eliminated by adding ascorbic acid to lysis buffer. The final inter- and intraassay variation coefficients were 10 and 4.5%, respectively, and the detection limit was 15 pmol min(-1)x10(6) WBC(-1), where WBC is white blood cells (leukocytes). In vitro IC50 values were 212 and 34 microg/L for cyclosporine and tacrolimus, respectively. In vivo calcineurin inhibition was observed when calcineurin activity was measured in transplant recipients on maintenance therapy with cyclosporine and tacrolimus.

Calcineurin↗