Synthetic Phenolic Antioxidant TS-13 Suppresses the Growth of Lewis Lung Carcinoma and Potentiates Oncolytic Effect of Doxorubicin.

ROS are important intracellular messengers; their ambiguous role in malignant processes was demonstrated in many studies. The effects of a synthetic phenolic antioxidant sodium 3-(3'-tert-butyl-4'-hydroxyphenyl)propyl thiosulfonate sodium (TS-13) on the tumor growth and oncolytic properties of doxorubicin were studied in the experimental model of Lewis lung carcinoma in mice. In mice receiving TS-13 with drinking water (100 mg/kg), suppression of tumor growth by 32.3% was observed on day 21 after inoculation of Lewis lung carcinoma cells. Two-fold intraperitoneal injections of doxorubicin in a cumulative dose of 8 mg/kg were followed by inhibition of tumor growth by 49.5%. Combined treatment with TS-13 and doxorubicin suppressed the tumor growth by 55.4%. In contrast to doxorubicin, TS-13 inhibited NO generation by peritoneal macrophages. The results show the prospect of studying TS-13 in the context of overcoming drug-resistance of tumors.

Effect of Oxidized Dextran on Cytokine Production and Activation of IRF3 Transcription Factor in Macrophages from Mice of Opposite Strains with Different Sensitivity to Tuberculosis Infection.

We studied differences in the production of pro- and anti-inflammatory cytokines and IRF3 transcription factor by peritoneal macrophages from mice of opposite strains CBA/J and C57Bl/6 and the effect of 60-kDa oxidized dextran on these parameters. Macrophages from C57Bl/6 mice were mainly characterized by the production of proinflammatory cytokines TNFα, IL-12, and MCP-1 (markers of M1 polarization). By contrast, CBA/J mice exhibited a relatively high level of anti-inflammatory cytokine IL-10 and lower expression of proinflammatory cytokines (M2 phenotype). IRF3 content in peritoneal macrophages of CBA/J mice was higher than in C57Bl/6 mice. Oxidized dextran decreased the expression of IRF3 upon stimulation of cells from CBA/J mice with LPS, but increased this process in C57Bl/6 mice. Despite a diversity of oxidized dextran-induced changes in cytokine production, the data confirm our hypothesis that this agent can stimulate the alternative activation of macrophages.

Oxidized Dextran Enhances Alternative Activation of Macrophages in Mice of Opposite Lines.

Differences in peritoneal macrophage polarization in mice of opposite lines CBA and C57Bl/6 and the effects of 60 kDa oxidized dextran were studied. Macrophages of C57Bl/6 mice demonstrated a phenotype close to M1, with increasing expression of CD86 costimulatory molecule and unchanged CD206 expression in response to activation. Macrophages of CBA mice demonstrated higher plasticity in response to activating agents; expression of the markers increased irrespectively on stimulated receptor (TLR-4 or mannose receptor) and both CD86 (classical activation) and CD206 (alternative activation) increased. Macrophage response to addition of oxidized dextran (60 kDa) to the culture medium could be characterized as potentiation of their alternative activation: expression of CD86 in CBA mice in response to LPS and LPS+IL-4 and in C57Bl/6 mice in response to IFN-γ and LPS+IFN-γ decreased, while expression of CD206 by intact macrophages of CBA mice and by macrophages stimulated by IFN-γ and IL-4 increased under the effect of 60 kDa oxidized dextran.

Effects of Liposomal Compositions with Oxidized Dextrans on Functional Activity of U937 Macrophage-Like Cells In Vitro.

We studied the effects of liposomal pharmaceutical compositions with oxidized dextrans on functional activity of U937 monocyte/macrophage-like cells. Liposomes in the emulsion contained oxidized dextran with a molecular weights of 40 kDa or 70 kDa or isonicotinic acid hydrazide (INAH) conjugated with oxidized dextran (40 kDa). Cell viability was evaluated by MTT test; mitochondrial transmembrane potential and production of superoxide anion and H2O2 were studied by fluorescent methods. The studied compositions exhibited no cytotoxic effect and even improved cell viability and mitochondrial respiration. Liposomes with oxidized 40 kDa dextran, including those with INAH-conjugated dextran, inhibited production of superoxide anion, but increased H2O2 generation.

[Effect of antioxidant responsive element inducing phenol on D. melanogaster life span].

The effect of water-soluble synthetic antioxidant TS-13 (sodium 3-(3'-tert-butyl-4'-hydroxyphenyl) propyl thiosulfonate) on life span of different lines of Drosophila melanogaster under normal conditions and survival under oxidative stress induced by hydrogen peroxide and paraquat has been investigated. Introduction to the diet of 1% TS-13 prolonged the life span of males and females of D. melanogaster long-living line Canton S, had no effect on short-living Oregon R life span and reduced the life span of male D. melanogaster line IgI(558)OR/Cy, heterozygous on tumor suppressor recessive lethal mutation. When flies were exposed to hydrogen perexide, TS-13 significantly enhanced Canton Smale and Oregon R female survival. Under the influence of paraquat antioxidant protected Canton S female and Oregon R flies of both sexes. Despite the fact that the anti-aging and protective properties of synthetic phenol antioxidant TS-13 depend essentially on the genotype and gender, in the extreme conditions of oxidative stress its positive effect pronounced.

[Variability of the exogenic antioxidant effect on survival: modeling in Drosophila lines with different lifespan and l(2)gl-tumor suppressor dosage].

Different exogenic antioxidants and geroprotectors are used to decrease age abnormalities and enhance the human life span. However, the antioxidant effect on lifespan is variable and requires detailed analysis. In the present report, we modeled in Drosophila the peculiar character of action of various doses of a new phenol antioxidant TC-13. We studied the TC-13 effect on aging of two Drosophila lines with genetically determined contrast lifespan dynamics. In addition, we tested the TC-13 antioxidant influence on the background of heterozygozity on the loss-of-function mutation of the l(2)gl tumor suppressor. The differing effect of TS-13 on LS, the character of which depends on the antioxidant dosage, genotype of line, and sex of Drosophila, was found. TS-13 in the concentration 0.2% did not affect the lifespan in all studied lines and decreased survival, whereas the antioxidant in a concentration of 1% positively affected the lifespan in both males and females of long-living lines. The antioxidant effect on animal lines with a smaller dose of tumor suppressor l(2)gl resulted in a decrease of the lifespan.

Structural and functional characteristics for the antiinflammatory effect of new water-soluble sulfur-containing phenol antioxidants.

Structurally related phenols containing the p-alkylthiosulfonate substituent and partially hindered by tert-butyl groups were synthesized for the search and development of new synthetic antioxidant, which would be effective in vivo in preventing free radical-induced pathological processes. Sodium 3-(3'-tert-butyl-4'-hydroxyphenyl)propylthiosulfonate had high antiinflammatory activity and produced a dose-dependent effect (IC(50)=36 mg/kg). Changes in the length of the carbohydrate chain in the p-alkyl substituent had no effect on in vitro antiradical activity of the test compounds. However, the decrease in the length of this chain by one methylene unit was accompanied by reduction of antiinflammatory activity of the end product. Lengthening of the chain did not modulate these properties.

Generation of reactive oxygen species by mitochondria in senescence-accelerated OXYS rats.

Chemiluminescence assay showed that oxygen reduction and production of superoxide anion and hydrogen peroxide by liver mitochondria in OXYS rats highly sensitive to oxidative stress were less intensive than in Wistar rats. Experiments with cytochrome c oxidase inhibitors showed that decreased O2-. generation in mitochondria of OXYS rats is probably associated with changes in complex III of the electron transport chain.

[Normal NO synthases and in pathology of different origins]. / NO-sintazy v norme i pri patologii razlichnogo geneza.

The paper deals with the physicochemical properties of nitric oxide (NO) and with the mechanisms of its action and synthesis in man and animals. The cytotoxic, vasodilatory, neuromediator, and other properties of NO are analyzed. NO is shown to perform many functions in health and in diseases of various genesis. Analyzing the structure and functions of NO in health and in diseases suggests that they all have both structural and functional properties and their own features. The currently available data lead to the conclusion that the NO-synthase mechanism that is responsible for the production of NO is its synthesis in the presence of oxygen. During functional exercises and hypoxia of various origin, another mechanism of NO may become active, which is associated with the reduction of NO2- in NO.

[Change in the oxidative metabolism of macrophages during transformation into foam cells]. / Izmenenie okislitel'nogo metabolizma makrofagov pri transformatsii v penistye kletki.

Oxidative metabolism of murine peritoneal macrophages was studied after cultivation in a mixture containing acetylated low density lipoproteins within 24 and 48 hr using luminol- and lucigenin-dependent chemiluminescence. Chemiluminescence of foamy cells, induced by opsonized zymosan, was not distinctly altered as compared with native macrophages; at the same time, the rate of both lucigenin- and luminol-dependent spontaneous chemiluminescence was distinctly decreased. The imbalance of the oxidative reactions observed enables the authors to propose the antioxidative mechanism of atherosclerotic lesion.

[Granulocyte metabolic activity in chronic nonspecific lung diseases]. / Metabolicheskaia aktivnost' granulotsitov pri khronicheskikh nespetsificheskikh zabolevaniiakh legkikh.

Biochemiluminescent (BCL) investigation of oxidative metabolism in patients suffering from chronic nonspecific lung diseases (CNLD) has shown activation of granulocyte metabolism measured by zymosan-dependent luminol-amplified chemiluminescence and the intensification of lipid peroxidation estimated by spontaneous serum BCL. At the same time H2O2-induced BCL was decreased, attesting to the abatement of antioxidative activity. The revealed imbalance of oxidative and antioxidative processes may be the pathogenic factor in CNLD development.

[H2O2-induced blood serum biochemiluminescence]. / Indutsirovannaia H2O2 biokhemiliuminestsentsiia syvorotki krovi.

Significant differences in the intensities of H2O2-induced biochemiluminescence of venous and capillary blood sera were revealed, as was a direct relationship between this parameter and hemoglobin level in the samples; this permits a conclusion on the improper employment of H2O2-induced biochemiluminescence of blood serum in diagnostic studies.

[A comparative analysis of the chemiluminescence of capillary and venous blood granulocytes]. / Sravnitel'nyi analiz khemiliuminestsentsii granulotsitov kapilliarnoi i venoznoi krovi.

The parameters of zymosan-stimulated luminol-dependent chemiluminescence of whole capillary and venous blood were compared in patients with chronic nonspecific diseases of the lungs. The parameters of a chemiluminescence response were in good correlation in general, but the mean values of luminescence intensity of granulocytes from the blood collected from the finger were 1.6 times lower that may be explained by the inhibiting effects of the lymph and intercellular fluid.