Article -S
Regulation
of ischemia cell death by the
lipoic acid-palladium complex, Poly-MVA, in Gerbils
Experimental Neurology
May 3, 2004
Article -R
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DNA Tunnel Diode Behavior
205th Meeting- Electrochemical
Society, May 2004, San Antonio
Merrill Garnett and C.V.Krishnan
Garnett McKeen Lab. Inc.
150 Islip Ave., Ste 6, Islip, New York 11751 USA
We reported that at controlled positive potentials on the mercury electrode, with trace peroxide in sodium acetate
solution, DNA (ct) exhibits a reversing impedance plot extending smoothly through the upper left quadrant of the
complex plane (1,2). The narrow band positive potential produces a dopant mercury ion. This impedance has an equivalent
circuit fit similar to a transmission line (3) but with a negative value for the resistance in the second (RC)
unit : R(RC)(RC)(RC). The plot is produced from high to low frequencies but not from low to high. This resembles
rectification. The loading (L) and discharging (D) portions of the curve are indicated (fig.1).
Fig. 1
Three properties point to tunnel diode behavior
: negative resistance, transmission line circuit fit, and rectification.
Now we show that DNA (ct, 5.0 mg/mL) with trace peroxide in 0.1 M NaCl can be dried on a glass slide in a magnetic
field to reveal a microscopic crystal array (fig.2,3, and 4).
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Fig. 2
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Fig. 3
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Fig. 4
The array resembles strings of tetrahedra following
the field lines.
We propose this crystal structure is the basis of the diode properties. In fig.4 the lines of crystals seem to
converge at magnetic poles. The convergence recalls the vortex state in which magnetic lines thread through thin
films, mixed states, and magnetized type II superconductors (4). Here the lines converge with the packing geometry
of liquid crystals in water. The peroxide paramagnetic requirement for DNA negative impedance, repeats the palladium
paramagnetic effect shown in our work on palladium lipoic acid complex (5). We believe distributed paramagnetism
lowers the resistance in liquid crystal hydration lattices. The diode type charge transfer in the DNA hydration
layer does not minimize the pi charge transfer through the gene bases. Together they raise the possibility of an
efficient twisted pair cable configuration with mutual inductance. The magnitudes of the two conduction routes
are under study.
References :
1. M.Garnett, and C.V.Krishnan, 204th
Meeting ECS, Abs. 1377, Orlando, 2003
2. M.Garnett, and C.V.Krishnan, 204th
Meeting ECS, Abs. 1379, Orlando, 2003
3. M.E.G.Lyons (ed.), Electroactive
Polymer Electrochemistry, Part 1,
Fundamentals, Plenum Press,
1994
4. C.Kittel, Introduction to Solid State
Physics, Wiley, 1986
5. C.V.Krishnan, M. Garnett, and
J.L.Remo, 203d Meeting ECS, Abs.
2703, Paris, 2003
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Article -Q
Abs. 739, 205th Meeting, May 2004-
In Print
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STATE-SOLVENT INTERACTIONS
FROM IMPEDANCE MEASUREMENTS: CONCENTRATION DEPENDENCE OF DNA
The unique nature of impedance
data exhibited by palladium lipoic acid (1:1) complex (1), a chemotherapy agent developed in our laboratory, prompted
us to investigate in detail the impedance of alkali chlorides (2) as well as the most important biological molecule
DNA (3), The alkali chloride data revealed frequency and potential dependent orientation effects of the water molecule.
DNA impedance data was subtly dependent on the nature of the alkali metal iron. This prompted us to study further
the concentration dependence of DNA impedance without any added electrolyte. The electrochemical literature date
of nucleic acids (4) is at very low concentrations of DNA and at negative potentials of the mercury electrode.
The present investigation was intended to gain information on the influence of orientation of solvent molecules,
packing, and dopant ions on the impedance. Therefore concentrations of 0.1, 1.0, 5.0, and 10.0 mg/ml. Calf-Thymus
double stranded DNA (Type 1, sodium salt, pH 7.5) were used at potentials positive enough to produce dopant ions
of mercury.
Typical admittance plots(Figures
1 and 2) indicate that solvent
orientation and DNA conformation effects are more dominant (with four peaks) at higher concentrations of DNA than
at lower concentrations (two peaks). The effects are also enhanced at lower frequencies. Mott-Schottky plots indicate
dominant p-type behavior. Double layer capacitance plots exhibit two peaks at positive potentials. At potentials
between 0.2 and 0.3 V, the impedance plot (Figure 3) and
especially the phase angle plot (Figure
4) indicate that the double
layer is altered. Unlike alkali halides, the double layer DNA concentration... Low frequency effects are dominant
during this changeover of double layer structure.
For all concentrations of DNA, the impedance date at -1.5, -1.0, -0.6, -0.3, 0.0, 0.1, 0.2, and 0.3 V could be
fitted with the equivalent electronic circuit of R (RC)(RC)(RC). This circuit suggests a transmission line model
for DNA conductance.
References
1. C.V.Krishnan, and M. Garnett, 1st Spring Meeting of ISE, Abs. P06, Spain 2003
2. 2. C.V. Krishnan, and M. Garnett, 226th ACS National Meeting, Abs. Inor. 0028, NY 2003
3. C.V. Krishnan, and M. Garnett, 204th Meeting of ECS, Abs. 1378, Orlando 2003.
4. E. Palecek, M.Fojta, F.Jelen, and V. Vetterl in Bioelectrochemistry, Vol. 9 Chapter 12, p365, Edited by George
S. Wilson, Wiley-VCH, Weinheim, 2.
Figure
1
Figure 2
Figure 3
Figure 4
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Article - P
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"The Effects of a Lipoic
Acid/Palladium Complex
on Hippocampal Progenitor Cells"
F.J. Antonawich*. S.M. Fiore and J.N. Davis.
SUNY at Stony Brook,
Stony Brook, NY 11794.
The Lipoic acid/pallacium complex, DNA reductase, appears to be an effective anti-glioblastoma agent in clinical
preliminary studies. The present experiments were aimed to elucidating DNA reductase's effects on CNS cells still
undergoing neurogenesis. We studied the AP31 hippocampal progenitor cell line and 3T3 fibroblasts. The cells were
cultured in DMEM/F12 supplemented with N2 and FGF (20ng/ml). Within 18 hours there was a significant decrease in
the number of progenitor cells on poly-L-ornithine (PORN)/lamine coated plates exposed to DNA reductase (8µM),
however 3T3 cells, on plastic, were unaffected by even the highest tested concentrations. Plating of 3T3 cells
on coverslips further augments the effects on DNA reductase (40µM). Cervical carcinoma cells (HeLa) have
been shown to have this same sensitivity to this glass substrate. Low quality glass, such as coverslip, is highly
charged due to the presence of heavily charged silicates. Poly-L-ornithine promotes cell attachment by positively
charging the surface Therefore, our results suggest that highly charged matrices (e.g. plastic, PORN), normally
seen in growth and in tumor formation, facilitate the effects of DNA reductase, while more neutral surfaces (e.g.
plastic) appear protective. (Supported by Garnett McKeen Laboratories Inc.)
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Article - O
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"DNA Reductase: A Synthetic
Enzyme with Opportunist
Clinical Activity Against Radiation Sickness"
(Garnett and Remo, International Symposium on
Applications of Enzymes in Chemistry, 2001)
INTERNATIONAL SYMPOSIUM ON APPLICATIONS OF ENZYMES IN CHEMICAL AND BIOLOGICAL DEFENSE.
May 2001
Plenary Session Abstracts
DNA Reductase: A Synthetic Enzyme with Opportunistic Clinical Activity Against Radiation Sickness
Merrill Garnett and John L. Remo
Garnett McKeen Laboratory, Inc., Islip, New York
DNA reductase(Poly MVA-Supplement Name), a stable synthetic enzyme, gives protection against radiation illness. During oral administration of this material in the emergency treatment of certain
brain tumors, it was found that patients receiving concurrent radiation did not develop the usual signs of radiation toxicity such as nausea, exhaustion,
disorientation, and depression.
This compound is a liquid crystal polymer composed of palladium and lipoic acid. It has been reported to show DNA
electronic reducing activity by cyclic voltammetry (1). A charge transfer from membrane phospholipid to DNA is
the presumptive mechanism whereby certain tumors, protozoa, and yeasts, are inhibited by this complex. The subcellular
site of destruction has been shown to be the membrane (2). The functional catalytic group incriminated by ESR spectroscopy
is a sequestered peroxide within the polymer, which unlike solvated peroxide, does not form superoxide. We believe
this sequestered peroxide is the charge carrier site. This charge carrier is able to discharge into tumor membranes
during cellular migration of the complex. The electronic reduction denatures the polar disulfide groups binding
peptides together and compromises the integrity of the membrane.
Fluorescent probes delineate the increase in cell voltage, and the membrane rupture. This is seen in the facultative
protozoan Tetrahymena. While Tetrahymena tolerates DNA reductase under aerobic conditions, it suffers membrane
rupture in a similar challenge under anaerobic conditions.
Another illustration of this principle occurs when sea urchins are exposed to DNA reductase. Only those cells in
the anaerobic archenteron are destroyed. This produces sea urchins without a gastro-intestinal system. In normal
cells, the absence of side effects is attributed to the process by which reducing equivalents are rapidly engaged
in electron transfer sequences which terminate in oxygen.
This textbook metabolic differential protects
the host organism and its energy competent cells from electrocution.
This is the proposed explanation as to why formal studies in mice, and twenty documented human cases testify to
the safety of synthetic DNA reductase(Poly MVA). It was during the emergency clinical use of orally administered
DNA reductase that we learned of its protection against the side effects of radiation. There was both prevention
and relief from radiation sickness occurring in patients receiving radiation therapy. Subsequent questioning in
more radiated patients indicated this protection was reproducible. We believe the mechanism of the radiation protection
by DNA reductase will be found in studies of the vector addition radiative and non-radiative charge transfer at
the level of its liquid crystal structure.
While radiation protection was not the original therapeutic design for DNA reductase, it appears that quantitative
animal and human studies in this are warranted.
Critical assays of the dose relationships can develop this material for applications in radiation risk environments
in civilian utilities, and military sites. Such studies can lead to commercial development and an advance in public
safety procedures.
References:
1. Garnett, M., U.S. Patent no. 5,463,093, Oct. 31, 1995.
2. Garnett, M., J. Inorg. Biochem. 59: nos. 2&3, C48, p.231, Elsevier, 1995.
Other Scientific Research References
"Synthetic DNA Reductase"
(Garnett), J. Bioinorg. Chem. V. 59, P. 231 Aug. '95, Lubeck
"Charge Relay from Molybdate Oxyradicals to Palladium Lipoic Complex to DNA" (Garnett and Garnett, Conference
on Oxygen Intermediates in Nonheme Metallobiochemistry, 1996)
"Developmental Electronic Pathways and Carcinogenesis"(Garnett, Remo, and Krishnan, Sixth International
Conference of Bioenergetic Medicine, 2002)
"Increased Pseudoinductance in Paired Mixtures of Biopolymers is a Model for Twin Wire Mutual Inductance in
RNA and DNA"(Garnett and Remo, 198th Meeting of Electrochemical Society, Abstract 1152, Phoenix 2000)
"Impedance Spectroscopy of DNA"(Garnett and Garnett, Journal of Inorganic Biochemistry, V.74, 1999)
"Mesophase Interactions Between Biological Polymers"(Garnett and Remo, 200th Meeting of Electrochemical
Society, Abstract 1132, 2002)
"Pulsed Electrospinning of Biopolymers"(Garnett and Krishnan, 201st Meeting of Electrochemical Society,
Abstract 78, Philadelphia 2002).
"Soluble Sensors of Telephonic
Signals" (Garnett and Remo, 200th Meeting of Electrochemical Society, Abstract 185, 2000)
"Synthetic DNA Reductase"(Garnett, Journal of Inorganic Biochemistry, V.59, C48, p.231, 1995)
"Dissipative Impedance in a Doped Liquid Crystal"(Krishnan and Garnett, 1st Spring Meeting of the International
Society of Electrochemistry, Abstract P06, Spain 2003)
"Dopant Catalyzed Charge Dissipation in a Liquid Crystal" (Krishnan and Garnett, 203rd Meeting of Electrochemical
Society, Abstract 2703, Paris 2003)
"Duplex semiconductor behavior of mercury electrode in aqueous solutions" (Krishnan and Garnett, 226th
American Chemical Society National Meeting, Abstract Inor.0028, New York 2003)
"A New Model for DNA Charge Transfer: Variable Electronic Circuitry" (Garnett and Krishnan, 204th Meeting
of Electrochemical Society, Abstract 1377, Orlando 2003)
"Modulation of Impedance in DNA Solutions by Ions and Molecules: 1. Effect of Alkali Metal Ions" (Krishnan
and Garnett, 204th Meeting of Electrochemical Society, Abstract 1378, Orlando 2003)
"Peroxide Doping of DNA Enables Dissipative Impedance" (Garnett and Krishnan, 204th Meeting of Electrochemical
Society, Abstract 1379, Orlando 2003)
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