Molecular mechanisms involved in the production of chromosomal aberrations

Chinese hamster ovary cells (CHO cells) and mouse fibroblasts (PG 19) were permeabilized with inactivated Sendai virus, treated with different types of restriction endonucleases (Eco RV, Pvu II, Bam HI, Sma I, Asu III, Nun II), and studied for the occurrence of chromosomal aberrations at different times following treatment. The pattern of chromosomal aberrations observed was similar to that induced by ionizing radiations. Restriction endonucleases that induce blunt double-strand breaks (Eco RV, Pvu II) were more efficient in inducing chromosomal aberrations than those that induce breaks with cohesive ends (Bam HI, Nun II, Asu III). Ring types were very frequent among the aberrations induced by restriction enzymes. Cytosine arabinoside, an inhibitor of DNA repair, was found to increase the frequencies of aberrations induced by restriction enzymes, indicating its effect on ligation of double-strand breaks. The relevance of these results to the understanding of the mechanisms of chromosomal aberration formation following treatment with ionizing radiations is discussed.     

Interaction between X-ray- and restriction endonuclease-induced lesions in the formation of chromosomal aberrations

Experiments were performed to analyze the possible interaction between lesions induced by X-rays and restriction endonucleases in the production of chromosome-type exchanges. A stronger interaction was found between X-rays and the AluI-induced 'blunt termini' lesions than between X-rays and the BamHI-induced 'cohesive termini' lesions.     

Molecular mechanisms of memory formation

Studies with neonate chicks, trained on a passive avoidance task, suggest that at least two shorter-term memory stages precede long-term, protein synthesis-dependent memory consolidation. Posttetanic neuronal hyperpolarization arising from two distinct mechanisms is postulated to underlie formation of these two early memory stages. Maintenance of the second of these stages may involve a prolonged period of hyperpolarization brought about by phosphorylation of particular proteins. A triggering mechanism for long-term consolidation is postulated to occur at a specific time during the second stage, and may involve reinforcement-contingent release of neuronal noradrenaline stimulating cAMP-dependent intracellular processes. The possibility that astroglia may have a critical role to play in these early stages of memory processing is raised.     

Kinetics of micronucleus formation in relation to chromosomal aberrations in mouse bone marrow

A simulation analysis of the kinetics of micronucleus formation in polychromatic erythrocytes in mouse bone marrow was performed after a single administration of 3 chemicals--mitomycin C (MMC), 6-mercaptopurine (6-MP) and 1-beta-D-arabinofuranosylcytosine (Ara-C)--with different modes of action. The time-response patterns in the incidence of chromosomal aberrations and micronuclei after treatment with each chemical were compared and subjected to the simulation study with 3 parameters. Two of them, the time between the final mitotic metaphase of the erythroid series and nucleus expulsion (T1), and the duration of the polychromatic erythrocyte (PCE) stage in the bone marrow (T2), were almost identical for the 3 chemicals. However, the coefficients of formation rate of micronucleated cells resulting from cells with chromosomal aberration(s) (k) differed: Ara-C differed from the other two. These results indicate that chromosomal aberrations, especially chromatid breaks and probably gaps, induced by this chemical, effectively contribute to micronucleus formation. The DNA content of micronuclei was also compared to the length of acentric fragments induced by Ara-C and it was found that their distributions were comparable. These findings strongly suggest that chromosomal aberrations induced by chemicals are essential events for the induction of micronuclei in the PCE of bone marrow.     

Molecular mechanisms of inflammatory bone damage: emerging targets for therapy

Chronic inflammatory bone diseases, such as rheumatoid arthritis (RA), ankylosing spondylitis and periodontal disease, demonstrate the major impact of chronic inflammation on both bone metabolism and bone architecture. During the past decade, scientists have gained increasing insight into the link between inflammation and bone. As a result of new discoveries about the molecular mechanisms of inflammatory bone loss, several molecules have been identified that are attractive and novel targets for the treatment of inflammatory bone loss. These novel therapeutic approaches include anti-tumor necrosis factor (TNF)-alpha blocking agents, neutralizing antibodies against certain pro-inflammatory cytokines, such as interleukin (IL)-6 and IL-17, and a set of other promising targets that still require extensive research, such as the Wnt signaling network.     

Molecular mechanisms of COPII vesicle formation

The first step in protein secretion from eukaryotic cells is mediated by COPII vesicles, known for the cytoplasmic coat proteins that are the minimal machinery required to generate these small transport carriers. The five COPII coat components coordinate to create a vesicle by locally generating membrane curvature and populating the incipient bud with the appropriate cargo. This review describes the molecular details of how the COPII coat sculpts vesicles from the endoplasmic reticulum and highlights some unresolved questions regarding the regulation of this process in the complex environment of the eukaryotic cell.     

Molecular mechanisms in chronic obstructive pulmonary disease: potential targets for therapy

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease associated with progressive airflow obstruction. Tobacco smoking is the main risk factor worldwide. In contrast to asthma, antiinflammatory therapies are rather ineffective in improving chronic symptoms and reducing inflammation, lung function decline, and airway remodeling. Specific drugs that are directed against the remodeling and chronic inflammation, thereby preventing lung tissue damage and progressive lung function decline, must be developed. Experimental models and expression studies suggest that anti-vascular endothelial growth factor (VEGF) receptor strategies may be of use in patients with emphysema, whereas anti-HER1-directed strategies may be more useful in patients with pulmonary mucus hypersecretion, as seen in chronic bronchitis and asthma. Growth factors and cytokines including VEGF, fibroblast growth factors, transforming growth factor-beta, tumor necrosis factor-alpha, CXCL1, CXCL8, and CCL2, and signal transduction proteins such as mitogen-activated protein kinase p38 and nuclear factor-kappaB, seem to be important pathogenetic molecules in COPD. Specific antagonists for these proteins may be effective for different inflammatory diseases. However, their efficacy for COPD therapy has not yet been demonstrated. Finally, other drugs such as retinoic acids may provide restoration of lung tissue structure. Such approaches, however, must await the first results of growth factor or cytokine antagonist therapy in chronic lung diseases.     

The role of autophagy in liver cancer: Molecular mechanisms and potential therapeutic targets

Autophagy is an evolutionarily conserved pathway for degradation of cytoplasmic proteins and organelles via lysosome. Proteins coded by the autophagy-related genes (Atgs) are the core molecular machinery in control of autophagy. Among the various biological functions of autophagy identified so far, the link between autophagy and cancer is probably among the most extensively studied and is often viewed as controversial. Autophagy might exert a dual role in cancer development: autophagy can serve as an anti-tumor mechanism, as defective autophagy (e.g., heterozygous knockdown Beclin 1 and Atg7 in mice) promotes the malignant transformation and spontaneous tumors. On the other hand, autophagy functions as a protective or survival mechanism in cancer cells against cellular stress (e.g., nutrient deprivation, hypoxia and DNA damage) and hence promotes tumorigenesis and causes resistance to therapeutic agents. Liver cancer is one of the common cancers with well-established etiological factors including hepatitis virus infection and environmental carcinogens such as aflatoxin and alcohol exposure. In recent years, the involvement of autophagy in liver cancer has been increasingly studied. Here, we aim to provide a systematic review on the close cross-talks between autophagy and liver cancer, and summarize the current status in development of novel liver cancer therapeutic approaches by targeting autophagy. It is believed that understanding the molecular mechanisms underlying the autophagy modulation and liver cancer development may provoke the translational studies that ultimately lead to new therapeutic strategies for liver cancer.     

Somatic chromosomal aberrations and male infertility

A significant correlation was found between the frequency of chromosomally aberrant peripheral lymphocytes and a low frequency of morphologically normal spermatozoa in men. No correlation was found between increased chromosomal breakage, other sperm parameters and density, motility or agglutination of spermatozoa. Smokers had significantly more cells with aberrations than nonsmokers. The significance of induced lesions in peripheral lymphocytes and their relationship to reproduction was discussed.     

Homozygous chromosomal aberrations in Anopheles stephensi

Homozygotes for six autosomal paracentric inversions, an inserted paracentric inversion, an autosomal translocation, and two X-chromosome-chromosome 3 translocations in Anopheles stephensi are described. Three of these aberrations are being maintained in pure strains without the necessity of selection.     

Occupational styrene exposure and chromosomal aberrations

Results from a study on the clastogenicity of styrene in vivo are reported. The chromosomes in cultured blood lymphocytes from ten men occupationally exposed to styrene and 5 controls were examined. Styrene-exposed men showed an increase in the rate of chromosomal aberrations. The incidence of aberrant cells ranged from 11 to 26% in the lymphocytes of the exposed subjects and was 3% or less in those of the control group.