Hormetic effects of extremely diluted solutions on gene expression

This paper summarizes the results of investigations showing how molecular biological tools, such as DNA-microarrays, can provide useful suggestions about the behaviour of human organisms treated with microamounts of drugs or homeopathic medicines. The results reviewed here suggest firstly that the action of drugs is not quenched by ultra-high dilution and proceeds through modulation of gene expressions. The efficacy of drug solutions seems to be maintained in ultra-highly diluted preparations, a fact which constitutes a challenge to the dogma of quantization of matter.

The second and more important result is that the different gene expression profiles of cell systems treated with the same drugs at different dilutions suggest the existence of hormetic mechanisms. The gene expression profiles of cells treated with copper(II) sulfate, Gelsemium sempervirens and Apis mellifica, are characterized by the same common denominator of the concentration-dependent inversion of gene expression, which can justify at a molecular level the concept of simile adopted in homeopathy.

The main conclusion we draw from these results is that these procedures provide new kinds of information and a tool for disclosing the mechanisms involved in hormetic effects. The application of these effects to modern medicine may allow researchers to conceive unprecedented therapeutic applications or to optimize the currently used ones in the framework of a low-dose pharmacology based on a reliable experimental platform.

Key words

Gene expression - Hormesis - Microarray - Homeopathy - Low-dose pharmacology

• References

• 1 Calabrese E.J., Baldwin L.A. Defining Hormesis. Hum Exp Toxicol 2002; 21: 91-97.
• 2 Stebbing A.R.D. Hormesis: the stimulation of growth by low levels of inhibitors. Sci Total Environ 1982; 22: 213-234.
• 3 Maturana H., Varela F. Autopoiesis and Cognition. 1980. Reidel; Dordrecht.:
• 4 Calabrese E.J., Baldwin L.A. The dose determines the stimulation (and poison): development of a chemical hormesis database. Int J Toxicol 1997; 16: 545-559.
• 5 Calabrese E.J., Baldwin L.A. Chemical hormesis: its historical foundations as a biological hypothesis. Toxicol Pathol 1999; 27: 195-216.
• 6 Calabrese E.J., Baldwin L.A. The marginalization of hormesis. Hum Exp Toxicol 2000; 19: 32-40.
• 7 Calabrese E.J., Baldwin L.A. Hormesis: the dose-response revolution. Ann Rev Pharm Tox 2003; 43: 175-197.
• 8 Calabrese E.J. Hormesis: why it is important to toxicology and toxicologists. Environ Toxicol Chem 2008; 27: 1451-1474.
• 9 Calabrese E.J. Crit Rev Toxicol 2008; 38: 579-590.
• 10 Calabrese E.J. Hormesis and medicine. Br J Clin Pharmacol 2008; 66: 594-617.
• 11 Calabrese E.J. Biphasic dose responses in biology, toxicology and medicine: accounting for their generalizability and quantitative features. Environ Pollut 2013; (182) 2013: 452-460.
• 12 Calabrese E.J. Hormesis is central to toxicology, pharmacology and risk assessment. Hum Exp Toxicol 2010; 29: 249-261.
• 13 Calabrese E.J., Baldwin L.A. Toxicology rethinks its central belief. Nature 2003; 421: 691-692.
• 14 Weaver W. Science and complexity. Am Sci 1948; 36: 536.
• 15 Wiegant F.A.C., Spiecker N., van Wijk R. Stressor specific enhancement of hsp induction by low doses of stressors in condition of self- and cross-sensitization. Toxicology 1998; 127: 107-119.
• 16 Bond R.A. Is paradoxical pharmacology a strategy worth pursuing?. Trends Pharmacol Sci 2001; 22: 273-276.
• 17 Page C. Paradoxical pharmacology: turning our pharmacological models upside down. Trends Pharmacol Sci 2011; 32: 1263-1268.
• 18 Yun A.J. The intellectual lineage of paradoxical pharmacologystrategy. Med Hypotheses 2005; 65: 815.
• 19 Teixeira M.Z. ‘Paradoxical strategy for treating chronic diseases’: a therapeutic model used in homeopathy for more than two centuries. Homeopathy 2005; 94: 265-266.
• 20 Bernardini S., Dei A. Hormesis may provide a central concept for homeopathy development. Toxicol Appl Pharmacol 2006; 211: 84.
• 21 Calabrese E.J., Jonas W.B. Homeopathy: clarifying its relationship to hormesis. Hum Exp Toxicol 2010; 29: 531-536.
• 22 Van Wjik R., Wiegant F.A. Postconditioning hormesis and the homeopathic similia principle:molecular aspects. Hum Exp Tox 2010; 29: 561-565.
• 23 Bernardini S. Homeopathy clarifying its relationship to hormesis. Hum Exp Toxicol 2010; 29: 537-538.
• 24 Oberbaum M., Samuels N., Singer S.R. Hormesis is not homeopathy. Tox Appl Pharm 2005; 206: 365.
• 25 Fisher P. Does homeopathy have anything to contribute to hormesis?. Hum Exp Tox 2010; 29: 555.
• 26 Bellavite P., Chirumbolo S., Marzotto M. Hormesis and its relationship with homeopathy. Hum Exp Tox 2010; 29: 573-579.
• 27 Oberbaum M., Samuels N., Singer S.R. Hormesis and homeopathy: bridged over troubled waters. Hum Exp Tox 2010; 29: 567-571.
• 28 Oberbaum M., Samuels N., Singer S.R. Andrea Dei references published paper “Hormesis is not Homeopathy”. Tox Appl Pharm 2006; 211: 85-86.
• 29 Calabrese E., Iavicoli I., Calabrese V. Hormesis: Its impact on medicine and health. Hum Exp Toxicol 2013; (02) 2: 120-152.
• 30 Jonas W.B., Ives J.A. Should we explore the clinical utility of hormesis?. Hum Exp Toxicol 2008; 27: 123-127.
• 31 Lockhart D.J. Winzeler EA.Genomic, gene expression and DNA arrays. Nature 2000; 405: 827-836.
• 31a Suter L., Babiss L.E., Wheeldon E.B. Toxicogenomics in predictive toxicology in drug development. Chem Biol 2004; 11: 161-171.
• 31b Shalon D., Smith S.J., Brown P.O. A DNA microarray system for analyzing complex DNA samples using two-color fluorescent probe hybridization. Genome Res 1996; (07) 6: 639-645.
• 31c Churchill G.A. Fundamentals of experimental design for cDNA microarrays. Nature Genetics 2002; 32: 490-495.
• 32 Bigagli E., Luceri C., Bernardini S., Dei A., Dolara P. Extremely low copper concentrations affect gene expression profiles of human prostate epithelial cell lines. Chem Biol Interact 2010; 188: 214-219.
• 33 Khuda-Bukhsh A.R. Potentized homeopathic drugs act through regulation of gene expression: a hypothesis to explain their mechanism and pathways of action in vivo. Comp Ther Med 1997; 5: 43-46.
• 34 Khuda-Bukhsh A.R. Towards understanding molecular mechanisms of action of homeopathic drugs: an overview. Mol Cell Biochem 2003; 253: 339-345.
• 35 Thangapazham R.L., Gaddipati J.P., Rajeshkumar N.V. et al. Homeopathic medicines do not alter growth and gene expression in prostate and breast cancer cells in vitro. Integr Cancer Ther 2006; 5: 356-361.
• 36 Jonas W.B., Gaddipati J.P., Rajeshkumar N.V. et al. In vitro and in vivo Assessment of Homeopathic Treatment for Prostate Cancer. Paper Presented at: Society of Integrative Oncology First International Conference. New York, NY 2004. November 18,.
• 37 de Oliveira C.C., de Oliveira S.M., Goes V.M., Probst C.M., Krieger M.A., Buchi D.F. Gene expression profiling of macrophages following mice treatment with an immunomodulator medication. J Cell Biol 2008; 104: 1364-1377.
• 38 Saha S.K., Roy S., Khuda-Buksh A.R. Evidence in support of gene regulatory hypothesis: Gene expression profiling manifests homeopathy effects more than placebo. Int J High Dilution Res 2013; 12: 162-167.
• 39 Preethi K., Ellanghiyil S., Kuttan G., Kuttan R. Induction of apoptosis tumor cells by some potentiated homeopathic drugs: implications of mechanism of action. Integ Cancer Ther 2012; 11: 172-182.
• 40 Olioso D., Marzotto M., Moratti E., Brizzi M., Bellavite P. Effects of Gelsemium sempervirens L. on pathway-focused gene expression profiling in neuronal cells. J Ethnopharmacol 2014; 153: 535-539.
• 41 Marzotto M., Olioso D., Brizzi M., Tononi P., Cristofoletti M., Bellavite P. Extreme sensitivity of gene expression in human SH-SY5Y neurocytes to ultra-low doses of Gelsemium sempervirens . BMC Comp Alt Med 2014; 14: 104.
• 42 Bigagli E., Luceri C., Bernardini S., Dei A., Filippini A., Dolara P. Exploring the effects of homeopathic Apis mellifica preparations on human gene expression profiles. Homeopathy 2014; 103: 127-132.
• 43 Bell I.R., Koithan M. A model for homeopathic remedy effects: low dose nanoparticles, allostatic cross-adaptation, and timedependent sensitization in a complex adaptive system. BMC Complement Altern Med 2012; 12: 191.
• 44 Bellavite P., Marzotto M., Olioso D., Moratti M., Conforti A. High dilution effects revisited. 2. Pharmacodynamic mechanisms. Homeopathy 2014; 103: 22-43.
• 45 Boyd L.J. A Study of the Simile in Medicine. 1936. Boericke and Tafel; Philadelphia.:
• 46 Van Wijk R., Wiegant F.A. Postconditioning hormesis and similia principle. Front Biosci (Elite Ed.) 2011; 3: 1128-1138.
• 47 Lushchak V.I. Hormesis in biology and pharmacology. Biochem Pharmacol 2014; 3: e149.
• 48 Kyriazis M. Practical applications of chaos theory to the modulation of human ageing: Nature prefers chaos to regularity. Biogerontology 2003; 4: 75-90.
• 49 Radak Z., Chung H.Y., Koltai E., Taylor A.W., Goto S. Exercise, oxidative stress and hormesis. Ageing Res Rev 2008; 7: 34-42.
• 50 Rattan S.I. Principles and practice of hormetic treatment of aging and age-related diseases. Hum Exp Toxicol 2008; 27: 151.
• 51 Gems D., Partridge L. Stress-response hormesis and aging: “That which does not kill us makes us stronger”. Cell Metab 2008; 7: 200-203.
• 52 Ristow M., Zarse K. How increased oxidative stress promotes longevity and metabolic health: the concept of mitochondrial hormesis (mitohormesis). Exp Gerontol 2010; 45: 410-418.
• 53 Rattan S.I. Hormesis in aging. Ageing Res Rev 2008; 7: 63-78.
• 54 Pauli W. The Influence of Archetypal Ideas in the Scientific Theories of Kepler. 1993. Springer; Berlin Heidelberg.:
• 55 Kuratsu J., Kurino M., Fukunaga K., Miyamoto E., Ushio Y. Stimulatory effect of suramin on the proliferation of human glioma-cells. Anticancer Res 1995; 15: 1263-1268.