Tuning the coordination properties of phenothiazine by regioselective introduction of diphenylphosphanyl groups.

The palladium and platinum complexes of the newly synthesized 1-(diphenylphosphino)-10-methyl-10H-phenothiazine (1) and the previously reported 3-(diphenylphosphino)-10-alkyl-10H-phenothiazine [alkyl = Me (2), Et (3)] and 4-(diphenylphosphino)-10-ethyl-10H-phenothiazine (4) were prepared. Density functional calculations were carried out to explain the electronic properties of compounds 1, 3 and 4. Compounds 1, 3 and 4 can interact with DNA, as was observed in agarose gel electrophoresis experiments. In addition, the cytotoxicity of the platinum complexes of ligands 2 and 4 towards breast, colorectal and hepatocarcinoma cell lines was studied.

Modulation of the pro-inflammatory cytokines and matrix metalloproteinases production in co-cultivated human keratinocytes and melanocytes.

The human epidermis exerts immunoregulatory functions through the variety of cytokines and other molecules elaborated by keratinocytes and melanocytes. Their constitutive production is very low; however, considerably increased upon stimulation. In vivo, keratinocytes and melanocytes have a typical exposure in the skin, referred as melanocyte epidermal unit. In the present study we co-cultivated these cells in vitro proposing to elucidate some communication links in close cell-to-cell association. We assessed the amounts of IL-6, IL-8, and matrix metalloproteinases (MMP-2 and MMP-9) in individually and co-cultured cells, exposed or not to UVB radiation. Normal human epidermal keratinocytes and melanocytes were grown in specific media and supplements. Cells were exposed to UVB radiation (100 mJ/cm(2)) to create comparable stress to the environmental one. Cytokines were determined with ELISA and confirmed with Western blot and metalloproteinases with gel zimography. Pure cultures of keratinocytes and melanocytes released low amounts of cytokines and metalloproteinases, these secretions being enhanced by UVB irradiation. In co-cultures, the cell-to-cell proximity triggered signals which markedly augmented the cytokines' secretions, whereas metalloproteinases were down-regulated. UVB irradiation did not influence either of these secretions in co-cultures. Concurrently with the highest levels of the pro-inflammatory cytokines, MMP-9 was up-regulated creating pro-inflammatory conditions and premises for changes in cellular survival, differentiation and phenotype. A complex network of interactions occurred between keratinocytes and melanocytes in co-cultures, resulting in modulated pro-inflammatory cytokines and metalloproteinases productions. Therefore, any disturbances in the microenvironmental signaling system and its molecular constituents may result in inflammation or even tumorigenesis in the epidermis.

Comparative study of two evaluation methods for the genotoxic effects of environmental heavy metals on normal cells.

Genetic modifications caused by chronic exposure to low levels of toxic metals may activate stress-signaling pathways, thus increasing cancer incidence among affected individuals. The aim of this study was to evaluate the relationship between exposure to heavy metals and the incidence of chromosomal aberrations and DNA lesions in a chronically exposed population by using specific biomarkers. The study included 156 subjects divided into two major groups: exposed individuals (in a heavy metal contaminated region, Maramures, Romania) and non-exposed population, as control group (Cluj, Romania). We compared the results of two cytogenetic methods for the detection and quantification of DNA lesions and chromosomal aberrations in normal human cells: Single Cell Gel Electrophoresis or Comet assay and Cytokinesis Block Micronucleus assay. The methods were performed on lymphocytes isolated from whole blood in density gradient. The basal DNA lesions and chromosomal aberrations were evaluated, as well as the repair capacity of the supplementary lesions induced by genotoxic agents such as ionizing radiations. Our results showed a great interindividual variability in the basal level of the DNA lesions and chromosomal aberrations, between and within the groups, the most affected being the heavy metals-exposed groups. Non-exposed subjects from rural area Cluj appeared to be more susceptible to the induction of supplementary DNA lesions and chromosomal aberrations by irradiation. The most efficient repair capacity of the radio-induced DNA lesions was observed in the non-exposed Cluj urban group. Both cytogenetic assays (as tools for detection of DNA lesions and chromosomal aberrations) may be used in human biomonitoring studies as indicators of early biological effects induced by exposure to heavy metals.

Photochemoprevention of cutaneous neoplasia through natural products.

Non-melanoma skin cancers such as squamous cell carcinoma and basal cell carcinoma are the most common types of human tumors, representing 30% of the new cases of malignancies diagnosed each year. Ultraviolet radiation (UV) from the sun is a major cause of non-melanoma skin cancer in humans. The prevention and mainly the photochemoprevention with natural products represent a simple but very effective strategy in the management of cutaneous neoplasia. Here we review the progress in the research of new and existing agents developed to protect the skin exposed to UV. We also discuss the current state of knowledge on their photosuppression mechanism in humans as well as in animal models, and efficiency in cancer prevention.