[Show abstract][Hide abstract] ABSTRACT: Pesticides used in agriculture are designed to protect crops against unwanted species, such as weeds, insects, and fungus. Many compounds target the nervous system of insect pests. Because of the similarity in brain biochemistry, such pesticides may also be neurotoxic to humans. Concerns have been raised that the developing brain may be particularly vulnerable to adverse effects of neurotoxic pesticides. Current requirements for safety testing do not include developmental neurotoxicity. We therefore undertook a systematic evaluation of published evidence on neurotoxicity of pesticides in current use, with specific emphasis on risks during early development. Epidemiologic studies show associations with neurodevelopmental deficits, but mainly deal with mixed exposures to pesticides. Laboratory experimental studies using model compounds suggest that many pesticides currently used in Europe--including organophosphates, carbamates, pyrethroids, ethylenebisdithiocarbamates, and chlorophenoxy herbicides--can cause neurodevelopmental toxicity. Adverse effects on brain development can be severe and irreversible. Prevention should therefore be a public health priority. The occurrence of residues in food and other types of human exposures should be prevented with regard to the pesticide groups that are known to be neurotoxic. For other substances, given their widespread use and the unique vulnerability of the developing brain, the general lack of data on developmental neurotoxicity calls for investment in targeted research. While awaiting more definite evidence, existing uncertainties should be considered in light of the need for precautionary action to protect brain development.
Full-text · Article · Nov 2008 · Environmental Health
[Show abstract][Hide abstract] ABSTRACT: The development of selective cell-permeable inhibitors of protein kinases whose aberrant activation contributes to cell transformation is a promising approach in cancer treatment. Emodin is a natural anthraquinone derivative that exhibits anti-proliferative effects in various cancer cell lines by efficient induction of apoptosis. The phosphoinositide 3-kinase (PI3K)/AKT pathway has been shown to be central in the promotion of cell survival since the alteration of this signalling cascade is a frequent event in human malignancies. Previous published results indicated that treatment of cells with inhibitors of protein kinase CK2, such as emodin, induces apoptosis and that the anti-apoptotic effect of CK2 is partially mediated by target phosphorylation and up-regulation of AKT by CK2. In the present study, a screening with selected CK2 inhibitors induced a variable response with respect to AKT down-regulation, emodin being the most effective, suggesting that other mechanisms other than the inhibition of CK2 were responsible for the emodin-mediated modulation of AKT. We found that emodin does not directly affect AKT kinase. Furthermore, we show that the down-regulation of AKT is due to the emodin-mediated target inhibition of components of the PI3K pathway, which directly or indirectly affect AKT activity, i.e. the mammalian target of rapamycin and the phosphatase and tensin homolog deleted on chromosome 10, but not the phosphoinositide-dependent kinase 1. Taken together, our results highlight a new mechanism by which emodin exerts anti-cancer activity and suggest the further investigation of plant polyphenols, such as emodin, as therapeutic and preventive agents for cancer therapy.
No preview · Article · Feb 2007 · The International Journal of Biochemistry & Cell Biology
[Show abstract][Hide abstract] ABSTRACT: The 'regulatory' beta-subunit of protein kinase CK2 has previously been shown to interact with protein kinases such as A-Raf, c-Mos, Lyn and Chk1 in addition to the catalytic subunit of CK2. Sequence alignments suggest that these interactions have a structural basis, and hence other protein kinases harboring corresponding sequences may be potential interaction partners for CK2beta. We show here that Chk2 specifically interacts with CK2beta in vitro and in cultured cells, and that activation of Chk2 leads to a reduction of this interaction. Additionally, we show that the presence of the CK2beta-subunit significantly reduces the Chk2-catalysed phosphorylation of p53 in vitro. These findings support the notion that CK2beta can act as a general modulator of remote docking sites in protein kinase--substrate interactions.
[Show abstract][Hide abstract] ABSTRACT: By GST pull downs and co-immunoprecipitation analyses we found that recombinant Chk2 and HDM2 can form stable complexes in vitro. Chk2/HDM2 complexes were also detected in transfected Cos-1 cells over-expressing both proteins. Furthermore, we show that HDM2, as would be expected, severely affects the Chk2-catalyzed phosphorylation of p53. HDM2 itself is only slightly phosphorylated by Chk2. However, whereas HDM2 inhibits the Chk2-catalyzed p53 phosphorylation, HDM2 phosphorylation by Chk2 doubles in the presence of p53. The significance of the HDM2 phosphorylation is unknown, but it is possible that it might influence the stability of the HDM2/p53 complex.
[Show abstract][Hide abstract] ABSTRACT: The Fas-associated factor 1, FAF1, is a protein, which was first identified as an interaction partner of the death receptor Fas. Not much is known about the function of FAF1, but it has been found that it is able to potentiate Fas-induced apoptosis in cell lines. To clarify the role of FAF1 in human cancer, a number of tumors from different organs were screened for expression of the protein, and it was only found reduced in gastric carcinoma tissue. Thus, 58 human gastric carcinomas were collected, and the expression of FAF1 was analyzed by Western blotting and in a few cases also by immunohistochemistry. The hypothesis was that since FAF1 is able to potentiate apoptosis, it would likely be reduced in the gastric carcinomas in order for them to escape apoptosis. We found that FAF1 was reduced in 50% (29/58) of the gastric carcinomas analyzed as compared to non-neoplastic gastric mucosa from the same patients. 26 of the investigated carcinomas contained signet ring cells, and FAF1 was significantly reduced in 69% of these (p=0.017), whereas it was only reduced in 34% of the carcinomas without signet ring cells. The observed reduction of FAF1 was predominantly caused by proteolytic cleavage of the protein. Additionally, 31 colorectal carcinomas were analyzed for expression of FAF1. Here, FAF1 was only reduced in 16% of the carcinomas when compared to non-neoplastic colorectal mucosa. Our findings support the hypothesis that FAF1 is reduced in gastric carcinomas compared to non-neoplastic tissue, and there was a significant relation between FAF1 reduction and content of signet ring cells in the gastric carcinomas. Also, the reduction of FAF1 is likely to be specific for gastric cancer, which might be due to the fact that signet ring cells are most frequently found in gastric cancers.
No preview · Article · Nov 2003 · International Journal of Oncology
[Show abstract][Hide abstract] ABSTRACT: Alterations in gene expression during apoptosis in HL-60 cells were identified by a cDNA based array analysis. Apoptosis was induced in the human promyelocytic leukemia cell line, HL-60, by incubation with 30 microM etoposide for 5 hours. Changes in gene expression occurring during apoptosis in these cells were detected using the "ATLAS cDNA Expression Array" technique. 40 genes were identified as differentially expressed in the apoptotic cells by at least a factor of two. 30 of these genes were down-regulated during apoptosis. Many of the down-regulated genes reflected decreased proliferative activity in the cells as well as decreased activity of survival pathways. Most of the genes, which were up-regulated during apoptosis, were genes involved in pathways leading to cell death and suppression of proliferation. Based on the up-regulations observed at the mRNA level, it is speculated that etoposide-induced apoptosis in the HL-60 cells proceeds via pathways involving factors such as TNFalpha, IGFBP3, SAPK1, AP-1 and GADD153/CHOP10. Four genes, which showed changes at the mRNA level, were also analyzed by Western blotting in order to confirm the observed differences at the protein level.