From: Ian Goddard (Ian@goddard.net)
Date: Sat Nov 27 1999 - 03:24:24 MST
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):
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Soy-phytochemical genistein "induced significant testicular cell death."
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:
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"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 genistein-
mediated 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
============================================================
Reduce DNA synthesis associated with aging
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
===============================================================
The DNA-synthesis-blocking effect of roscovitine is indicated
to be the cause of the cellular effects of roscovitine, which
the next study shows includes causing cell death (apoptosis):
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
===================================================================
"the [roscovitine] compound inhibited DNA synthesis, induced cell
death, and irreversibly inhibited the proliferative activity of the cells."
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
================================================================
"Impaired DNA repair may play a role in the
development of postischemic neuronal damage"
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
===============================================================
Chem Biol Interact 1999 Jan 29;117(2):99-115
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
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