An experimental approach to determining the protective properties of drugs against ionizing radiation in low and sublethal doses]

In experiments with mice, the efficiency of radioprotective agents against acute gamma-irradiation with nonlethal and low doses (0.5-4 Gy) was estimated by nine parameters. The treatment with cystamine, cysteamine and riboxine prior to irradiation (< 2 Gy) did not influence the postirradiation values of the parameters under study. With a dose of up to 4 Gy, the effect of riboxine was noted. The determinations of the number of aberrant mitoses, cellularity and mitotic activity of the bone marrow have proved to be most informative. The data obtained are discussed with due regard for the specific effect of low-level radiation and mechanisms of the protective action of the agents under study.     

The effect of therapy with cytostatics and immunomodulators on mitotic pathology in Lewis tumor cells in mice]

The effect of cytostatics (methylnitrosourea and methotrexate), immunomodulators (thymalin and reaferon) and their combinations on the mitotic pathology of mice Lewis tumour cells was studied. It was revealed that chemotherapy with these agents changed the interrelation between mitotic phases and somewhat enhanced the incidence of pathologic mitoses mainly connected with the damage of mitotic apparatus. Immunomodulators differently affected the cytostatic activity of antitumour agents that may be associated with their mechanisms of action.     

Role of multipolar mitoses in the proliferation of multinucleate cells induced by cytochalasin B

A prolonged action of cytochalasin B results in the formation of numerous multipolar mitoses (26%) in Chinese hamster cell cultures. The transition to multipolar mitoses in the presence of cytochalasin B is not accompanied by K-mitotic delay. It is shown that a multipolar mitosis without cytoplasmic division is one of the main causes of multinucleation development in cytochalasin B-treated cultures. After stopping the drug action the cytochalasin B-induced multinucleate cells continue to divide by multipolar mitosis. In this case it completes with cytokinesis and, probably, leads to a decrease in the number of nuclei per cell. The origin of multipolar mitotic apparatus after the action of cytochalasin B is discussed in addition to the role of multipolar mitosis in formation and proliferation of multinucleate cells.     

Carcinogens and carcinogenesis enhancers

The concept that chemical agents may lead to enhancement of carcinogenesis, rather than to its complete induction, is explored to explain the inexact correlation between carcinogen prescreening tests and the results of whole animal bioassays. It is suggested that carcinogenesis-enhancing agents are non-genotoxic chemicals which are positive in animal carcinogenesis bioassays. The importance of understanding the mechanisms of action of carcinogenesis-enhancing agents is emphasized.     

The effects of solcoseryl on the growth and multiplication of chick embryo fibroblasts cultivated "in vitro"

The action of Solcoseryl, a free protein extract of calf blood, was studied on chick embryo fibroblasts cultivated in vitro. Solcoseryl stimulates the permitotic DNA synthesis and increases the number of mitoses.,     

The influence of damage factors of the different nature on the lipid composition in the mice liver

The combined effect of the X-rays at the dose of 4 and 5 Gy and the Tween 80 (the 0.3% solution) in the 10% solution of the water acetone on the lipid composition in the mice Balb/c liver is studied after 1 month. It is revealed that the disturbance of the linear dependence of "biological effect-dose" is due to the enhancement of the action of the acute X-rays with sublethal doses after the preliminary administration of the low toxic chemical agents at low doses on the lipid composition of the mice liver. The decrease of differences in the scale of the correlation between the generalized phospholipid composition parameters in the mice liver after combined action of the chemical and physical factors is shown. The interrelation between the mice Balb/c survival and the ratio of the general phospholipid fractions of the lipid liver in the age control groups is found.     

The synchronizing effect of cyclic 3',5'-adenosine monophosphate on the mitotic cycle of Ehrlich ascitic carcinoma cells]

A study was made of the number of mitoses and of the DNA-synthesizing cells in the ascitic Ehrlich carcinoma in the course of 24 hours after the injection of cyclic 3',5'-adenosinmonophosphate to mice. It was found that as the result of the preprrophase inhibition and, possibly, of stimulation of the cell entry into the S-phase, 8 hours after the action a great number of cells began to divide almost simultaneously. The effect of mitosis synchronization was assessed in the tumour cell population.     

Action of hepatic chalones on the proliferation of hepatocytes from intact and denervated livers

The paper is concerned with the action of chalones, tissue-specific inhibitors of cell proliferation, on DNA synthesis and mitotic activity of hepatocytes in the intact and denervated liver during regeneration. Experiments were made on Wistar rats. Liver denervation was performed by bilateral subdiaphragmal vagotomy. In control and vagotomized animals, two thirds of the liver was resected. The data obtained indicate that chalones noticeably reduce the number of DNA-synthesizing cells and mitoses in the regenerating liver of intact animals. During regeneration of the denervated liver, chalones do not produce any inhibitory action on the intensity of proliferation. Analysis of the data obtained allows a conclusion that preservation of adequate innervation of the organ is needed for realization of the action of hepatic chalones.     

Ratio of acentrics to dicentrics in human lymphocytes exposed to X rays and misonidazole

A 0.8 mM concentration of misonidazole was added to human blood samples before exposure to graded X-ray single doses, in order to investigate the dependence of the frequency ratio of acentrics to dicentrics, produced in lymphocytes, on treatment with radiation, the substance and the combination of the 2 agents. The results confirm the findings of a previous experiment carried out using sodium iothalamate, showing that this ratio is markedly influenced by the relative action of the physical and the chemical agents, especially at low radiation doses, because of the enhancement of the frequency of acentrics, and not of dicentrics, caused by the presence of the drug compared to the spontaneous level.     

The characteristics of the course of mitosis in polykaryons formed during cell fusion]

A new method of cell fusion is proposed utilizing treatment with 15% solution of DMSO in serum before and after PEG treatment. With such treatments in SPEV cell culture a higher rate of cell fusion was obtained than that with other known methods of cell fusion. In the first wave of mitoses (0.5-4 h) mainly asynchronous division of nuclei, premature chromosome condensation and formation of telophase-like nuclei were observed in polykaryons. In the period of the second wave (14-20 h), mitoses were mainly synchronous and completed with cytokinesis. Micronuclei were formed frequently as a result of such mitoses. After the first wave of mitoses the number of polykaryons with pycnotic chromosomes sharply increased, and after the second wave of mitoses the number of polykaryons with pycnotic nuclei increased. The results obtained allow to conclude that heterophasic condition of the fused cells is one of the causes of pathological mitosis of polykaryons and of their death.     

Hypopigmenting agents: an updated review on biological, chemical and clinical aspects

An overview of agents causing hypopigmentation in human skin is presented. The review is organized to put forward groups of biological and chemical agents. Their mechanisms of action cover (i) tyrosinase inhibition, maturation and enhancement of its degradation; (ii) Mitf inhibition; (iii) downregulation of MC1R activity; (iv) interference with melanosome maturation and transfer; (v) melanocyte loss, desquamation and chemical peeling. Tyrosinase inhibition is the most common approach to achieve skin hypopigmentation as this enzyme catalyses the rate-limiting step of pigmentation. Despite the large number of tyrosinase inhibitors in vitro, only a few are able to induce effects in clinical trials. The gap between in-vitro and in-vivo studies suggests that innovative strategies are needed for validating their efficacy and safety. Successful treatments need the combination of two or more agents acting on different mechanisms to achieve a synergistic effect. In addition to tyrosinase inhibition, other parameters related to cytotoxicity, solubility, cutaneous absorption, penetration and stability of the agents should be considered. The screening test system is also very important as keratinocytes play an active role in modulating melanogenesis within melanocytes. Mammalian skin or at least keratinocytes/melanocytes co-cultures should be preferred rather than pure melanocyte cultures or soluble tyrosinase.     

Quantitative studies on the arrangement of human metaphase chromosomes

Summary The association pattern was studied in 1182 mitoses of 21 patients with trisomy 13 and in a control group. In addition, 173 trisomic mitoses were compared with the same number of diploid mitoses in a case of mosaicism.The number of mitoses with associations was no higher in the trisomic cells than in cells with normal karyotypes. Some differences were observed in the frequency of associations per cell and of the types of associations in the patient group and in the trisomic cells of the mosaic case. The number of associations in which more than two acrocentric chromosomes were involved was unexpectedly low in the cells with a supernumerary chromosome 13.The result are interpreted as suggesting the existence of a compensatory mechanism activated by the additional acrocentric chromosome.Parts of this work are included in the doctoral (MD) thesis of DM     

Synergistic actions of disulfide-reducing agents on 1-methyladenine-induced oocyte maturation in starfish

Several disulfide-reducing agents, such as dithiothreitol, 2,3-dimercapto-1-propanol, cysteine ethyl ester, and cysteine methyl ester enhanced the effectiveness of 1-methyladenine (1-MeAde) to induce oocyte maturation in the starfish Asterina pectinifera. This enhancement occurred at relatively low concentrations at which these agents by themselves were ineffective in inducing oocyte maturation. The agents caused a marked (about twofold) increase in specific [1-3H]MeAde binding. The binding increased directly in relation to the potency of the agents in enhancing 1-MeAde action. Scatchard analysis indicated that dithiothreitol increased the Bmax without affecting the affinity of 1-MeAde binding. These results strongly suggest that disulfide-reducing agents enhance the maturational action of 1-MeAde by increasing the number of 1-MeAde binding sites in oocyte cortices.     

Stimulation of DNA synthesis in cultures of mouse embryo fibroblast-like cells

Stimulation of the DNA synthesis and mitoses in stationary cultures of mouse embryo fibroblast-like cells was induced by various agents such as ribonuclease, digitonin, fresh medium and commercial preparations of hyaluronidases. Time sequence of stimulation was similar in experiments with all these agents. Cells were activated to enter S phase from GI phase. The rise of the number of DNA-synthesizing cells was preceded by a latent period of about 8–12 hours with the maximal number of DNA-synthesizing cells being observed at 16–24 hours. Mitotic wave was observed after the wave of DNA synthesis. Stimulation of DNA synthesis and mitosis was not preceded by any significant decrease of an average cell density in the culture. The progeny of activated cells had no greater chance than other cells to be activated again when stimulation was repeated. It is concluded that similar proliferative reactions can be induced in stationary cultures by a variety of diverse agents. Possible role of cell surface changes in the induction of these reactions is discussed.     

Modification of Combined Effect of Radiation and Sodium Chloride on Microorganisms by Chemical Agents during Irradiation

Effects of various chemical agents on the synergistic action of NaCl to the radiation inactivation of bacteria and yeast were studied. The remarkable modification of the radiation lethal effect by some reagents is considered to be a strong evidence for an indirect nature of NaCl synergistic action during irradiation. Most of these modification effects were restricted to the actions during irradiation, supporting the free radical hypothesis in which the short-life active species formed by radiation were considered to attack bacterial cells. Furthermore, pre-irradiation effects under various conditions suggest that the enhancement of radiation lethal effect by NaCl may involve the intracellular events.     

Endocrine disruptors: Revisiting concepts and dogma in toxicology

During the last decades, a large number of observations have shown that some exogenous substances could interfere with hormone levels or hormone action and could induce toxic effects. This has led to the identification of endocrine disruptors more than 25 years ago as a new class of toxic agents (Zoeller et al., 2014). Those widely used agents correspond to a variety of chemical classes, are not identified by their chemical structure or by a specific type of usage, but rather by their mechanisms of action; this is not unprecedented in toxicology since genotoxicants have also been identified by their mechanism of action, i.e. their ability to alter DNA structure and function.     

Effects of the plant steroidal hormone, 24-epibrassinolide, on the mitotic index and growth of onion (Allium cepa) root tips

The purpose of the present study was to determine the effects of the steroidal plant hormone, 24-epibrassinolide (BL), on the mitotic index and growth of onion (Allium cepa) root tips. The classical Allium test was used to gather and quantify data on the rate of root growth, the stages of mitosis, and the number of mitoses in control and BL-treated groups of onions. Low doses of BL (0.005 ppm) nearly doubled the mean root length and the number of mitoses over that of controls. Intermediate doses of BL (0.05 ppm) also produced mean root lengths and number of mitoses that were significantly greater than those of the controls. The highest dose of BL (0.5 ppm) produced mean root lengths and number of mitoses that were less than control values, but the differences were not statistically significant. Examination of longitudinally sectioned root tips produced relatively similar results. This study confirms the suppositions of previous authors who have claimed that exogenously applied BL can increase the number of mitoses in plants, but failed to show cytogenetic data. This is the first report detailing the effects of BL on chromosomes and the cell cycle.     

Nycthemeral variations of mitotic activity in the adrenal cortex of the rat]

Working on histologic sections 7 microns thick in the equatorial part of male rat adrenal cortex, we found two high mitotic activity periods. The first one stays at midnight and shows an average number of 42 mitoses per section; the second one occurs at 5 a.m. with an average number of mitoses of 70,1 per section. If we except these particular points, the mitotic activity is low, the average number of mitoses being 13,2 per section.     

A comparative investigation of the antimitotic action of 2-mercaptoethanol and colcemid on V-79 Chinese hamster cells

Abstract. The current study was performed to characterize the antimitotic action of 2-mercaptoethanol (MET) on mammalian cells.
At concentrations of 2.5 × 10^-2 M, MET arrests V-79 Chinese hamster cells in metaphase. Smaller concentrations (from 5 × 10^-3 M) only produce a mitotic block after several hours, only arresting those mitoses which have gone through one cell cycle in the presence of MET. The accumulation of mitoses by MET is smaller in comparison with colcemid, explained by an effect reducing the number of cells which enter mitosis. In contrast to colcemid, MET-concentrations which do not lead to a mitotic block cause a delay in proliferation. It was shown, by means of the BUdR-labelling method that cells in the presence of colcemid concentrations which arrest mitosis again enter interphase and become polyploid, whereas MET leads to an irreversible arrest of mitosis and does not produce polyploidy in V-79 cells.     

An evaluation of the mutagenic, carcinogenic and teratogenic potential of microwaves

A notable proportion of the population is exposed to an increasing number of devices emitting microwaves, a form of non-ionizing electromagnetic radiation in the range 300-30000 mHz. The activation energy of microwave radiations is too small to directly modify any chemical bonds in the irradiated matter. At microwave frequencies the macroscopic dielectric properties of tissues are strongly determined by their water content. Tissues like muscle, brain, skin, with a high water content, have higher permittivity and conductivity values than bone or fat with low water contents. Owing to the energy transfer, to living tissues, by a dipolar relaxation mechanism of water molecules, the penetration of microwaves is limited and one observes a fast and very efficient heat-loss production. A review of the available literature shows that most results on the mutagenicity of microwaves are negative or can often be explained by a temperature enhancement. If microwaves are apparently unable to damage DNA at sub-thermal exposure levels, some results indicate, however, that they might easily potentiate the damaging action of other DNA antagonist agents such as UV or chemicals.