Aluminium-induced Entropy in Biological Systems

presented by

Robert M. Davidson M.D. Ph.D.PhyNet, Inc.

Longview, Texas, USAEmail: patrons99@yahoo.com

The Eleventh Keele Meeting on Aluminium 28 Feb - 4 Mar 2015

Lille, France

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Acknowledgement of Co-Authors

Christopher A. Shaw Stephanie Seneff Stephen D. Kette Lucija Tomljenovic John W. Oller Jr. Robert M. Davidson

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Shaw, C.A., Seneff, S., Kette, S.D., Tomljenovic, L., Oller, J.W. and Davidson, R.M. (2014). Aluminum-Induced Entropy in Biological Systems: Implications for Neurological Disease. Journal of Toxicology, 2014, 27.

Summary Graphic

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Al Impacts Water Dynamics and Biosemiotic Systems Globally

• Al negatively impacts the central nervous system in all species that have been studied, including humans.

• CNS disorders in humans are sensitive indicators of the Al toxicants to which we are being exposed.

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Common Al/Al3+ Sources and Their Immune-Neuro-Toxicologic Effects

• Oral• Parenteral• Inhaled• Topical

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Stellachi’s Lysosome-Enhanced Trojan Horse (LETH) Mechanism

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Source: Sabella, S., Carney, R.P., Brunetti, V., Malvindi, M.A., Al-Juffali, N., Vecchio, G., Janes, S.M., Bakr, O.M., Cingolani, R., Stellacci, F. and Pompa, P.P. (2014). A general mechanism for intracellular toxicity of metal-containing nanoparticles. Nanoscale, 6, 7052-7061.

Aluminium Nanoparticles versus Aluminium Aquo Cations

Structure of octahedral metal aquo complexes

Source: Chemistry 445 Lecture 10 Hydrolysis of Metal Ions

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The Inner and Outer Sphere of Waters around a Metal Ion in Solution

• Inner-sphere of waters coordinated to the metal ion via M-O bonds

• Outer-sphere of more structured waters held to the inner-sphere by H-bonding and electrostatic attraction

SOURCE: Chemistry 445 Lecture 10 Hydrolysis of Metal Ions 8

Metal Ions in Aqueous Solution (Aquo Cations) Behave as Lewis Acids

SOURCE: M. Pilkington Lecture 21 www.mpilkington.com/Lecture_21.pdf

The rate of hydrolysis of metal or acidity of a hydrated cation increases with increasing charge and decreasing radii.

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• The exchange rates for [Na(H2O6]+ and [Al(H2O)6]3+ differ by a factor of 109.

• [M(H2O)n]z+ + H2O* [M(H2O)n-1(H2O*)]z+ + H2O

• Electron configuration is also a major factor, illustrated by the fact that the rates of water exchange for [Al(H2O)6]3+ and [Ir(H2O)6]3+ differ by a factor of 109 also.

• Water exchange usually follows a dissociative substitution pathway, so the rate constants indicate first order reactions.

• Acid-base reactions: Solutions of metal aquo complexes are acidic owing to the ionization of protons from the water ligands.

• The hydrolyzed species often exhibit very different properties from the precursor hexa-aquo complex. For example, water exchange in [Al(H2O)5OH]2+ is some 20000 times faster than in [Al(H2O)6]3+.

SOURCES:(1) Helm, L. and Merbach, A.E. (2005). Inorganic and Bioinorganic Solvent Exchange Mechanisms. Chemical Reviews, 105, 1923-1960.(2) http://en.wikipedia.org/wiki/Metal_aquo_complex 10

Water Exchange Rates and Acid-Base Reactions

Ascorbate versus Aluminium –A Tale of Good versus Evil

Pro-Oxidative Stress

Mitigates Oxidative Stress

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SOURCE:Yousef, M.I., El-Morsy, A.M.A. and Hassan, M.S. (2005). Aluminium-induced deterioration in reproductive performance and seminal plasma biochemistry of male rabbits: Protective role of ascorbic acid. Toxicology, 215, 97-107.

SOURCE:Mujika, J.I., Ruipérez, F., Infante, I., Ugalde, J.M., Exley, C. and Lopez, X. (2011). Pro-oxidant Activity of Aluminum: Stabilization of the Aluminum Superoxide Radical Ion. The Journal of Physical Chemistry A, 115, 6717-6723.

Prof. Exley’s Model of Al3+ Superoxide

SOURCE:Mujika, J.I., Ruipérez, F., Infante, I., Ugalde, J.M., Exley, C. and Lopez, X. (2011). Pro-oxidant Activity of Aluminum: Stabilization of the Aluminum Superoxide Radical Ion.The Journal of Physical Chemistry A, 115, 6717-6723.

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Water Exchange Enhancement on Al3+

“Water exchange on Al3+ is also progressively enhanced by several orders of magnitude in substituting first shell water molecules by F-, malonate, methylmalonate, or salicylate (Table 4) and for H2O exchange on polycations.”

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SOURCE:Helm, L. and Merbach, A.E. (2005). Inorganic and Bioinorganic Solvent Exchange Mechanisms. Chemical Reviews, 105, 1923-1960.

• Neurotropic is an adjective used in medicine defined as (of a virus, toxin, or chemical) tending to attack or affect the nervous system preferentially.

• Aluminium has a propensity for tissue of ectodermal origin.

• Embryological envelopment of tissue layers is biophysically-driven by gradients of interfacial tension, under Brodland’s Differential Interfacial Tension Hypothesis (DITH).

• The neurotoxicant properties of Al are biophysically-based, supramolecular, epigenetic, and begin in utero. Germ cells, stem cells, and all blood cell lines are highly sensitive to Al-induced EIWS.

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Aluminium is Neurotropic

The Problem of Aluminium Speciation in Biology

Source:Mujika, J.I., Rezabal, E., Mercero, J.M., Ruipérez, F., Costa, D., Ugalde, J.M. and Lopez, X. (2014). Aluminium in Biological Environments: A Computational Approach. Computational and Structural Biotechnology Journal, 9, e201403002.

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Semi-rigid versus Locked-in Solvation

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SOURCES:(1) K. J. Tielrooij, N. Garcia-Araez, M. Bonn, and H. J. Bakker, “Cooperativity in ion hydration,” Science, vol. 328, no. 5981, pp. 1006–1009, 2010.

(2) Tielrooij, K.J., van der Post, S.T., Hunger, J., Bonn, M. and Bakker, H.J. (2011). Anisotropic Water Reorientation around Ions. The Journal of Physical Chemistry B, 115, 12638-12647

Redox Stress and/or Interfacial Water Stress

• The redox potential of water is pH dependent.

• “Free radicals” are often associated with vortices, helices, and spirals in liquid-crystalline environments.

• Dynamical vortices of water with variable helical twisting power (HTP) and interfacial tension.

• Magnetohydrodynamics is largely non-thermal (not diffusion-limited).

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Disruption of Biosemiotic Coherence = Biosemiotic Entropy

• We need to do everything in our power to evade decoherence of our biological water.

• A combination of EMT and orthomolecular medical intervention is urgently needed.

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Al-induced EIWS is Pleiotropic in the Biophysical Sense

• Under Exogenous Interfacial Water Stress (EIWS) theory, long range dynamical gradients of interfacial water tension are necessary for cytokinesis, allostery, and chemotaxis.

• Al-induced EIWS promotes locked-in kinetics, broken symmetry, and loss of anisotropy

• Al-induced EIWS promotes both pro-oxidative and pro-coagulant effects in vivo

• Molecular motors are “driven” in part by non-metabolic ELF EM energy from the environment which is trapped and transduced by interfacial water

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SOURCES:(1) Hannan, K.L., Berg, D.E., Baumzweiger, W., Harrison, H.H., Berg, L.H., Ramirez, R. and Nichols, D. (2000). Activation of the coagulation system in Gulf War Illness: a potential pathophysiologic link with chronic fatigue syndrome. A laboratory approach to diagnosis. Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis, 11, 673-678.

(2) Widdas, W.F. (2008). A reconsideration of the link between the energetics of water and of ATP hydrolysis energy in the power strokes of molecular motors in protein structures. Int J Mol Sci, 9, 1730-1752.

(3) Widdas, W.F. and Baker, G.F. (2001). The surface energy of water: the largest but forgotten source of energy in biological systems. Cytobios, 106, 7-54.

Al-induced EIWS Disrupts Stem Cell Function in All Age Groups

• Stem cell niches (“fractones”) in the heart, brain, gut, and RES/marrow are likely to be disrupted.

• “Pericytes” are pluripotent vascular stem cells: highest density is in the brain.

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SOURCES:Song, H.J., Stevens, C.F. and Gage, F.H. (2002). Neural stem cells from adult hippocampus develop essential properties of functional CNS neurons. Nature neuroscience, 5, 438-445.

Hochman-Mendez C, Cantini M, Moratal D, Salmeron-Sanchez M, Coelho-Sampaio T (2014) A Fractal Nature for Polymerized Laminin. PLoS ONE 9(10): e109388. doi:10.1371/journal.pone.0109388

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THANK YOU !