ascorbic-acid and Candidiasis

We have shown previously that pure polyphenol curcumin I (CUR-I) shows antifungal activity against Candida species. By employing the chequerboard method, filter disc and time-kill assays, in the present study we demonstrate that CUR-I at non-antifungal concentration interacts synergistically with azoles and polyenes. For this, pure polyphenol CUR-I was tested for synergy with five azole and two polyene drugs - fluconazole (FLC), miconazole, ketoconazole (KTC), itraconazole (ITR), voriconazole (VRC), nystatin (NYS) and amphotericin B (AMB) - against 21 clinical isolates of Candida albicans with reduced antifungal sensitivity, as well as a drug-sensitive laboratory strain. Notably, there was a 10-35-fold drop in the MIC(80) values of the drugs when CUR-I was used in combination with azoles and polyenes, with fractional inhibitory concentration index (FICI) values ranging between 0.09 and 0.5. Interestingly, the synergistic effect of CUR-I with FLC and AMB was associated with the accumulation of reactive oxygen species, which could be reversed by the addition of an antioxidant such as ascorbic acid. Furthermore, the combination of CUR-I and FLC/AMB triggered apoptosis that could also be reversed by ascorbic acid. We provide the first evidence that pure CUR-I in combination with azoles and polyenes represents a novel therapeutic strategy to improve the activity of common antifungals.

Topics: Antifungal Agents; Antioxidants; Apoptosis; Ascorbic Acid; Azoles; Candida albicans; Candidiasis; Curcumin; Drug Synergism; Flavonoids; Humans; Microbial Sensitivity Tests; Microbial Viability; Phenols; Polyenes; Polyphenols; Reactive Oxygen Species

1. The aim of the present study was to investigate the effects of ascorbic acid (AA) on the antifungal activity of fluconazole (FCZ) in a systemic murine candidiasis model as well as in vitro. 2. The murine model was established by infusion of Candida albicans via the tail vein. Control mice received no further treatment. Other groups of mice were injected with FCZ (0.5 mg/kg, i.p.) and then treated or not with 50 or 500 mg/kg AA intragastrically (i.g.) or i.p. In all groups, FCZ was administered i.p. 2 h after fungal inoculation, whereas AA was administered 6 h after fungal inoculation. Survival rate, kidney fungal burden and renal pathological changes were evaluated. 3. The in vitro effects of AA (5, 1 and 0.2 mmol/L) on the growth of various Candida strains in the presence of FCZ (0.125-64 microg/mL) were also investigated. The in vitro effects of two anti-oxidants, namely N-acetylcysteine (NAC; 5, 1 and 0.2 mmol/L) and reduced glutathione (GSH; 5, 1 and 0.2 mmol/L), on FCZ activity were evaluated to determine the mechanism of action of AA. 4. Intragastric administration of AA (50 or 500 mg/kg) significantly decreased the antifungal effect of 0.5 mg/kg FCZ. Although i.p. administration of AA (50 or 500 mg/kg) had no significant effect on the survival of mice, it dose-dependently inhibited the activity of FCZ, with significant inhibition observed with 500 mg/kg AA. 5. In vitro, AA decreased the activity of FCZ against various Candida strains. Both NAC and GSH dose-dependently decreased the activity of FCZ. 6. The results of the present study indicate that AA inhibits the antifungal activity of FCZ, suggesting that the two should not be used together clinically for the treatment of candidiasis.

Topics: Animals; Antifungal Agents; Antioxidants; Ascorbic Acid; Candida albicans; Candidiasis; Disease Models, Animal; Drug Antagonism; Drug Evaluation, Preclinical; Drug Resistance, Fungal; Fluconazole; Mice; Microbial Sensitivity Tests

The aim of this study is to determine the relation between diabetes and vaginal candidiasis in terms of oxidative biomarker levels in a vaginal candidiasis model of the diabetic rats by evaluating malondialdehyde (MDA), sulphydrile groups or glutathione (RSH), and ascorbic acid (C vit) levels. All rats were randomly divided into five groups. All of the groups were observed for 21 days. In the treated diabetes groups, MDA (0.90, 0.68 nmol/ml and 3.78, 3.79 nmol/g tissue, plasma and vaginal tissue, respectively) and RSH (227, 171 nmol/100 ml 0.38, 0.37 micromol/g tissue, plasma and vaginal tissue, respectively) levels were found to be decreased while the levels of C vit were found to be increased (0.49, 0.37 micromol/l 2.39, 2.01 nmol/g tissue plasma, and vaginal tissue, respectively) (P < 0.05). In the groups of untreated diabetes, vaginal candidiasis were found to be more serious and oxidative biomarkers were found to be increased (MDA 1.30, 1.26 nmol/ml and 7.82, 2.37 nmol/g tissue and RSH 258, 145 nmol/100 ml and 0.31, 0.46 micromol/g tissue) while the antioxidant C vit levels were found to be decreased (0.24, 0.17 micromol/l 1.33, 2.66 nmol/g tissue) (P < 0.05). RSH, plasma MDA, blood glucose, and tissue MDA levels of vaginal candidiasis embedeled diabetic rats, were found to be higher than those in untreated diabetic and untreated vaginitis enbedeled rats 'P < 0.05'. Vaginal candidiasis caused oxidative stress in diabetic rats working together. Systemic oxidative stress biomarkers were found to be affected from vaginal candidiasis although it was a local mucosal infection.

Topics: Animals; Ascorbic Acid; Biomarkers; Blood Glucose; Candidiasis; Diabetes Mellitus, Experimental; Disease Models, Animal; Female; Glutathione; Lipid Peroxides; Malondialdehyde; Oxidative Stress; Random Allocation; Rats; Rats, Wistar; Streptozocin; Vaginal Diseases

In some lower eukaryotes, D-erythroascorbic acid, a five-carbon analog of L-ascorbic acid, is present instead of L-ascorbic acid. We have cloned ALO1, the gene encoding D-arabinono-1,4-lactone oxidase, which catalyzes the final step of D-erythroascorbic acid biosynthesis in Candida albicans. The ALO1 gene contained a continuous open reading frame of 1,671 bp that encodes a polypeptide consisting of 557 amino acids with a calculated molecular mass of 63,428 Da. To investigate the functional roles of D-erythroascorbic acid in C. albicans, we disrupted or overexpressed the ALO1 gene. In the alo1/alo1 null mutants, the activity of D-arabinono-1,4-lactone oxidase was completely lost and D-erythroascorbic acid could not be detected. When ALO1 on a multicopy plasmid was transformed in C. albicans, the enzyme activity and the intracellular D-erythroascorbic acid level were increased up to 3.4-fold and 4.0-fold, respectively. The alo1/alo1 null mutants of C. albicans showed increased sensitivity towards oxidative stress. Overexpression of ALO1 made the cells more resistant to the same stress. The alo1/alo1 mutants showed defective hyphal growth and attenuated virulence. Taken together, our results suggest that D-erythroascorbic acid functions as an important antioxidant and can be considered one of the virulence factors enhancing the pathogenicity of C. albicans.

Topics: Amino Acid Sequence; Animals; Ascorbic Acid; Candida albicans; Candidiasis; Cloning, Molecular; Female; Gene Deletion; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Oxidative Stress; Sequence Analysis, DNA; Sugar Alcohol Dehydrogenases; Virulence

Topics: Animals; Ascorbic Acid; Candidiasis; Humans; Industrial Microbiology; Occupational Diseases; Rats; Respiratory Tract Infections; Thiamine

Guinea pigs were maintained for various periods of time on low (0.5 mg/day), intermediate (20 mg/day), or high (100 and 500 mg/day) levels of dietary ascorbic acid. Animals in each experimental group were challenged with Candida albicans via cardiac injection, and the course of infection in the kidneys was assessed. The results show that the animals receiving only 0.5 mg of ascorbic acid per day were significantly more susceptible to the infection than animals maintained on any higher level of dietary ascorbic acid. The greater susceptibility of the guinea pigs in the 0.5-mg level group was evident, however, only during "early" stages of the infection (until about day 3). Guinea pigs receiving high levels of dietary ascorbic acid were no more resistant at any time after infection, or with any challenge dose, than those receiving an intermediate dietary level. Although these data suggest that vitamin C may be involved in resistance to candidiasis, tissue levels of ascorbic acid do not change significantly with time after infection. These results indicate that low levels of dietary ascorbic acid increase susceptibility to candidiasis, yet high (or "megadose") levels of dietary vitamin C do not show any effect on resistance to this microorganism.

Topics: Animals; Ascorbic Acid; Candidiasis; Diet; Dose-Response Relationship, Drug; Dose-Response Relationship, Immunologic; Guinea Pigs; Immunity, Innate; Kidney Diseases; Time Factors

Topics: Adult; Animals; Ascorbic Acid; Blood Bactericidal Activity; Candidiasis; Cell Movement; Chediak-Higashi Syndrome; Chemotaxis, Leukocyte; Cyclic AMP; Cyclic GMP; Humans; Leukocytes; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Neutrophils

A Candida albicans corneal ulcer developed in a 24-year-old man with a history of eczema, asthma, and multiple bacterial infections since childhood. The infection responded well to oral flucytosine (12 g/day for 15 days) and topical amphotericin B. Positive laboratory findings included eosinophilla, hyperimmunoglobulinemia E, and impaired neutrophil and monocyte spontaneous migration and chemotactic responses. Ascorbic acid corrected the monocyte defect in vitro and in vivo, but had no effect on neutrophil function.

Topics: Adult; Ascorbic Acid; Bacterial Infections; Candidiasis; Chemotaxis, Leukocyte; Corneal Ulcer; Humans; Hypergammaglobulinemia; Hypersensitivity, Immediate; Immunoglobulin E; Infections; Male; Monocytes; Neutrophils; Recurrence; Syndrome

Amphotericin B methyl ester (AME) has been reported to possess in vitro antifungal activity similar to that of amphotericin B and to have less intrinsic toxicity in mice and dogs. For these reasons AME has been porposed as an alternative to amphotericin B in the therapy of deep mycoses. For comparison of the therapeutic efficacy of the two polyenes in laboratory animals before initiation of studies in humans, groups of mice were infected with Candida albicans, Cryptococcus neoformans, and Blastomyces dermatitidis. Treatment consisted of two or more doses of each drug given by the intravenous route. Concurrently, studies of subacute toxicity were conducted in the same species to permit calculation of therapeutic indices. These studies have shown that AME, as the ascorbate salt, is substantially less efficacious than amphotericin B (in colloidal dispersion with sodium deoxycholate) for treatment of the fungal infections and that amphotericin B had a higher therapeutic ratio for all infections studied than did AME.

Topics: Amphotericin B; Animals; Ascorbic Acid; Blastomyces; Blastomycosis; Candida albicans; Candidiasis; Cryptococcosis; Cryptococcus; Cryptococcus neoformans; Dose-Response Relationship, Drug; Drug Evaluation; Lethal Dose 50; Male; Mice

Topics: Agglutination Tests; Ascorbic Acid; Candida; Candidiasis; Humans; Immunodiffusion; In Vitro Techniques; Iron; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Lymphoma; Multiple Myeloma; Polycythemia Vera; Precipitin Tests; Transferrin