RE: http://starbulletin.com/1999/11/19/news/story4.html
After searching the National Library of Medicine for a while I believe I've come upon a possible physiological basis for the indicated tofu-induced brain atrophy cited in my first post (URL above). It may be related to the fact that the main soy phytochemical genistein reduces DNA synthesis in the brain, and reduced DNA synthesis is associated with apoptosis, which is also know as "programmed cell death." This effect might be why genistein appears to cause cancer-cell death. Problem is your brain's not a cancer, and neither are a guy's balls (PubMed Search: http://www.ncbi.nlm.nih.gov/PubMed):
Biol Cell 1999 Sep;91(7):515-23
Cytotoxic potential of the phytochemical genistein isoflavone (4',5',7-trihydroxyisoflavone) and certain environmental chemical compounds on testicular cells.
Kumi-Diaka J, Nguyen V, Butler A
Florida Atlantic University, Department of Biology, College of Liberal Arts & Sciences, Davie 33314, USA.
[Medline record in process]
The effects of genistein (Gn), sodium azide (naz), and dexamethasone (dxm) on testicular cells TM3, TM4 and GC-1 spg were studied in vitro. First, a series of experiments were performed to assess the response of the cells to the exposure of Gn, naz, dxm, a combination of Gn with naz and Gn with dxm. Trypan blue exclusion assay was used to determine the percentage of viability, and LDH-cytotoxicity test was used to assess the degree of treatment-induced cytotoxicity on each cell type. A second series of experiments were performed to study cytomorphology and determine the type and percentage of treatment-induced cell death (apoptosis and necrosis) on each cell line, using fluorescent dye technique to detect apoptotic and necrotic cells, and tunnel assay to confirm apoptosis. The results from the data obtained demonstrated: i) that incubation of testis cells with each of the agents (Gn, dxm, naz) alone and in two combinations (Gn-dxm, and Gn-naz) induced significant testicular cell death; ii) that both genistein and dexamethasone mostly and significantly induced apoptotic cell death while sodium azide induced necrotic cell death; iii) that addition of dexamethasone to genistein demonstrated synergism in apoptosis on testis cells; and iv) that combination of naz with Gn demonstrated synergism in necrosis on testis cells even though Gn alone did not induce significant necrosis. It is concluded that the synergistic actions of genistein and dxm, and of genistein + sodium azide in induction of apoptosis and/or necrosis may be of clinical and pathophysiological research interest considering the chemopreventive and chemotherapeutic potential of genistein; and the clinico-pharmacological application of dexamethasone and sodium azide.
http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?uid=10572627&form=6&db=m
&Dopt=b
Some other related studies, search at PubMed recommended for more:
"Genistein decreased the DNA synthesis within less than 30 min."
Exp Neurol 1999 Sep;159(1):164-76
Early effects of protein kinase modulators on DNA synthesis in rat cerebral cortex.
Yakisich JS, Siden A, Vargas VI, Eneroth P, Cruz M
Applied Biochemistry, Clinical Research Center, Karolinska Institute, Novum, Huddinge University Hospital, Huddinge, S-141 86, Sweden.
By using tissue miniunits, protein kinase modulators, and
topoisomerase inhibitors in short-term incubation (0-90 min)
we studied (1) the role of protein phosphorylation in the
immediate control of DNA replication in the developing rat
cerebral cortex and (2) the mechanism of action for genisteinmediated
DNA synthesis inhibition. Genistein decreased the DNA
synthesis within less than 30 min. None of the other protein
kinase inhibitors examined (herbimycin A, staurosporine,
calphostin-C) or the protein phosphatase inhibitor sodium
orthovanadate inhibited DNA synthesis and they did not affect
the genistein-mediated inhibition. The selective topoisomerase
inhibitors camptothecin and etoposide decreased the DNA synthesis
to an extent similar to that of genistein and within less than
30 min. In addition, the effects of these substances on
topoisomerase I and II were studied. Etoposide and genistein
but not herbimycin A, staurosporine, or calphostin-C strongly
inhibited the activity of topoisomerase II. Our results (1)
strongly suggest that the net rate of DNA replication during
the S phase of the cell cycle is independent of protein
phosphorylation and (2) indicate that the early inhibitory
effect of genistein on DNA synthesis is mediated by
topoisomerase II inhibition rather than protein tyrosine
kinase inhibition.
Copyright 1999 Academic Press.
http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?uid=10486185&form=6&db=m
&Dopt=b
Acta Neuropathol (Berl) 1999 Jan;97(1):71-81
Age-related changes of DNA repair and mitochondrial DNA synthesis in the mouse brain.
Schmitz C, Axmacher B, Zunker U, Korr H
Department of Anatomy and Cell Biology, RWTH University of Aachen, Germany. cschmitz@alpha.imib.rwth-aachen,de
Using quantitative autoradiography, both nuclear DNA repair - measured as nuclear unscheduled DNA synthesis (UDS) - and mitochondrial (mt) DNA synthesis were evaluated in situ for several types of cells in the brains of untreated mice of various age. It was found that distinct types of neuronal cells showed a decline of both UDS and mtDNA synthesis with age, whereas - except for glial cells of the cerebral cortex - no glial or endothelial cells showed age-related alterations of UDS. Together with various data reported in the literature, these patterns of a cell type-specific decrease of UDS and mtDNA synthesis with age in the mouse brain lead to an improved understanding of the complex interrelationships between the molecular events associated with the phenomenon of aging as well as to a new idea regarding the cause of the specific distribution pattern of those cells in the human brain that are affected by the formation of paired helical filaments in Alzheimer's disease.
http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?uid=9930897&form=6&db=m& Dopt=b
Biochem Biophys Res Commun 1998 Feb 24;243(3):674-7
Early inhibition of DNA synthesis in the developing rat cerebral cortex by the purine analogues olomoucine and roscovitine.
Yakisich JS, Siden A, Idoyaga Vargas V, Eneroth P, Cruz M
Clinical Research Center, Karolinska Institute, Novum, Sweden.
The effects of the cyclin-dependent kinase (CDK) inhibitors olomoucine and roscovitine on DNA synthesis were studied using short time incubation (30-90 minutes). Both purine analogues at concentrations from 1-100 microM decreased the DNA synthesis of rat brain cortex in a dose-dependent manner and the maximum effect occurred within 30 min of incubation. Staurosporine, another potent CDK inhibitor did not affect the DNA synthesis in the concentration range 1-250 nM. These results indicate that olomoucine and roscovitine block DNA synthesis by a mechanism independent of CDK inhibition. We propose that the cellular effects of olomuocine and roscovitine on the cell cycle are at least in part due to this early inhibitory effect on DNA synthesis.
http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?uid=9500988&form=6&db=m& Dopt=b
Cancer Res 1999 Apr 15;59(8):1903-10
Roscovitine induces cell death and morphological changes indicative of apoptosis in MDA-MB-231 breast cancer cells.
Mgbonyebi OP, Russo J, Russo IH
Breast Cancer Research Laboratory, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
We have previously shown (Mgbonyebi et al., Anticancer Res., 18: 751-756, 1998) that roscovitine, an olomoucine-related purine analogue and a selective inhibitor of cyclin-dependent kinases, inhibited the proliferative activity of human breast epithelial cells in vitro. The purpose of the present study was to identify the cellular processes and targets affected by roscovitine treatment in the estrogen receptor-negative MDA-MB-231 human breast carcinoma cells. Treatment of the cells with 10 microg/ml roscovitine daily for a length of time ranging from 24 to 240 h revealed that the compound inhibited DNA synthesis, induced cell death, and irreversibly inhibited the proliferative activity of the cells. Morphological analysis of roscovitine-treated cells by light and fluorescence microscopy demonstrated that this cyclin-dependent kinase inhibitor induced cell shrinkage, chromatin condensation, reorganization of actin microfilament architecture, and extensive detachment of cells from the cell culture substratum. These cellular events are all known to be associated with apoptosis. Collectively, the data generated from this study suggest that roscovitine induced apoptosis in the estrogen receptor-negative MDA-MB-231 human breast cancer cells. Because the efficacy of many anticancer drugs depends on their ability to induce apoptotic cell death, modulation of this parameter by roscovitine may provide a new chemopreventive and chemotherapeutic strategy for the clinical management of hormone-resistant breast cancers.
http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?uid=10213499&form=6&db=m
&Dopt=b
Brain Res Mol Brain Res 1998 Oct 1;60(2):168-76
Changes in proliferating cell nuclear antigen, a protein involved in DNA repair, in vulnerable hippocampal neurons following global cerebral ischemia.
Tomasevic G, Kamme F, Wieloch T
Laboratory for Experimental Brain Research, Wallenberg Neuroscience Center, Lund University Hospital, S-221 85, Lund, Sweden. Gregor.Tomasevic@expbr.lu.se
Proliferating cell nuclear antigen (PCNA) is required for completion of the DNA synthesis step of DNA replication as well as nucleotide excision repair (NER) of damaged DNA. We investigated the expression of PCNA mRNA and the levels of PCNA protein in the adult rat hippocampus following normo- and hypothermic global forebrain ischemia. Hypothermia protected the CA1 neurons from ischemic damage. A constitutive expression of PCNA mRNA and protein was detected in all hippocampal subfields, as well as in other brain regions. During reperfusion, PCNA mRNA levels were up-regulated in the vulnerable CA1 subfield at 36 h following normothermic ischemia. In hypothermia, this induction appeared already after 18 h. Following normothermic ischemia, nuclear PCNA immunoreactivity was largely abolished during reperfusion in the vulnerable CA1 neurons, prior to cell death. In contrast, total PCNA protein content of this region, as measured by Western blotting, remained largely unchanged. In the CA3 region, a transient decrease in nuclear PCNA immunoreactivity was observed. In the dentate gyrus region, no down-regulation of nuclear or total PCNA protein was observed during reperfusion. Following hypothermic ischemia, the PCNA protein levels did not decrease in any of the hippocampal subregions. In contrast, no change in the levels of Ref-1, a protein involved in base excision DNA repair (BER), was observed following normo- or hypothermic ischemia. Our findings indicate an altered functional state of PCNA protein in the ischemia-sensitive CA1 neurons suggesting that DNA repair processes are affected in these post-mitotic cells following ischemia. Impaired DNA repair may play a role in the development of postischemic neuronal damage. Copyright 1998 Elsevier Science B.V.
http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?uid=9757027&form=6&db=m& Dopt=b
Synthesis, characterization and DNA modification induced by a novel Pt(IV)-bis(monoglutarate) complex which induces apoptosis in glioma cells.
Perez JM, Camazon M, Alvarez-Valdes A, Quiroga AG, Kelland LR, Alonso C, Navarro-Ranninger MC
Departamento de Quimica Inorganica, Facultad de Ciencias, Universidad Autonoma de Madrid, Cantoblanco, Spain.
Programmed cell death or apoptosis is a mechanism for the elimination of cells that occurs not only in physiological processes but also in drug-induced tumor cell death. Thus, because cisplatin, cis-diamminechloroplatinum (II), produces important damages on the DNA inducing apoptosis in several cell lines it has become a widely used antitumor drug. However, cisplatin possesses some dose-limiting toxicities mainly nephrotoxicity. Pt(IV) complexes, such as iproplatin, ormaplatin, and JM216 are a new class of platinum complexes that exhibits less toxicity than cisplatin. Some of these complexes have shown significant antitumor activity and a low cross-resistance to cisplatin. In the present paper, we have analyzed the DNA binding mode and the cytotoxicity of a novel Pt(IV)-bis (monoglutarate) complex. The data show that this novel complex produces DNA interstrand cross-links to a higher extent and with a faster kinetics than cisplatin. Also the Pt(IV)-bis (monoglutarate) complex kills glioma cells at drug concentrations significantly lower than those of cisplatin. Interestingly, this Pt(IV) complex produces in the glioma cells characteristic features of apoptosis such as 'DNA laddering' and fragmented nuclei. Moreover, the p53 protein accumulates early in glioma cells as a result of Pt(IV)-bis (monoglutarate) treatment. These data indicate that the Pt(IV)-bis (monoglutarate) complex induces apoptosis in glioma cells through a p53-dependent pathway.
http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?uid=10190571&form=6&db=m
&Dopt=b