Subscribe to RSS
Metal nanoparticle induced hormetic activation: a novel mechanism of homeopathic medicines
Received09 April 2017
accepted19 June 2017
02 January 2018 (online)
Background: High-potency homeopathic remedies, 30c and 200c have enormous dilution factors of 1060 and 10400 respectively. Therefore, the presence of physical entities in them is inconceivable. As a result, their efficacy is highly debated and often dismissed as a placebo. Despite several hypotheses postulated to explain the claimed homeopathic efficacy, none have satisfactorily answered the qualms of the sceptics. Against all beliefs and principles of conventional dilution, we have shown that nanoparticles (NPs) of the starting metals are unequivocally found in the 30c and 200c remedies at concentrations of a few pg/ml. In this paper, our aim was to answer the important question of whether such negligible metal concentrations elicit a biological response.
Methods: Metal-based homeopathic medicines (30c and 200c) were analysed at doses between 0.003%v/v and 10%v/v in in-vitro HepG2 cell-line. Upon treatment, cell response was estimated by MTT assay, FACS and total intracellular protein. Experiments were performed to discern whether the hormesis was a cell-activation or a proliferation effect.
Results: Remedies at doses containing a few femtograms/ml levels of the starting metals induced a proliferation-independent hormetic activation by increasing the intracellular protein synthesis. The metal concentrations (at fg/ml) were a billion-fold lower than the studies with synthetic NPs (at μg/ml). Further, we also highlight a few plausible mechanisms initiating a hormetic response at a billion-fold lower dose.
Conclusions: Hormetic activation has been shown for the first time with standard homeopathic high-potency remedies. These findings should have a profound effect in understanding these extreme dilutions from a biological perspective.
- 1 Davenas E., Beauvais F., Amara J. et al. Human basophil degranulation triggered by very dilute antiserum against IgE. Nature 1988; 333: 816-818.
- 2 Chaplin M.F. The memory of water: an overview. Homeopathy 2007; 96: 143-150.
- 3 Teixeira J. Can water possibly have a memory? A sceptical view. Homeopathy 2007; 96: 158-162.
- 4 Anagnostatos G.S. Small water clusters (clathrates) in the homeopathic preparation process. In: Endler P.C., Schulte J. (eds). Ultra High Dilution – Physiology and Physics. 1994. The Netherlands: Kluwer Academic Publishers; 121-128.
- 5 Anagnostatos G.S. On the structure of high dilutions according to the clathrate model. In: Taddei-Ferretti C., Marotta P. (eds). High Dilution Effects on Cells and Integrated Systems. 1998. Singapore: World Scientific Publishing Co. Pte. Ltd.; 305-312.
- 6 Rao M.L., Roy R., Bell I.R., Hoover R. The defining role of structure (including epitaxy) in the plausibility of homeopathy. Homeopathy 2007; 96: 175-182.
- 7 Davydov A.S. Energy and electron transport in biological systems. In: Ho M.W., Popp F.A., Warnke U. (eds). Bioelectrodynamics and Biocommunication. 1994. Singapore: World Scientific Publishing Co. Pte. Ltd.; 411-430.
- 8 Anick D.J., Ives J.A. The silica hypothesis for homeopathy: physical chemistry. Homeopathy 2007; 96: 189-195.
- 9 Chikramane P.S., Suresh A.K., Bellare J.R., Kane S.G. Extreme homeopathic dilutions retain starting materials: a nanoparticulate perspective. Homeopathy 2010; 99: 231-242.
- 10 Chikramane P.S., Kalita D., Suresh A.K., Kane S.G., Bellare J.R. Why extreme dilutions reach non-zero asymptotes: a nanoparticulate hypothesis of based on froth flotation. Langmuir 2012; 28: 15864-15875.
- 11 Stebbing A.R.D. Hormesis – the stimulation of growth by low levels of inhibitors. Sci Total Environ 1982; 22: 213-234.
- 12 Calabrese E.J., Baldwin L.A. Defining hormesis. Hum Exp Toxicol 2002; 21: 91-97.
- 13 Mattson M.P. Hormesis defined. Ageing Res Rev 2008; 7: 1-7.
- 14 Calabrese E.J., Jonas W.B. Homeopathy: clarifying its relationship to hormesis. Hum Exp Toxicol 2010; 29: 531-536.
- 15 Calabrese E.J., Baldwin L.A. Hormesis – the dose-response revolution. Annu Rev Pharmacol Toxicol 2003; 43: 175-197.
- 16 Calabrese E.J., Baldwin L.A. Hormesis as a biological hypothesis. Environ Health Persp 1998; 106: 357-362.
- 17 Calabrese E.J., Blain R. Metals and hormesis. J Environ Monit 2004; 6: 14N-19N.
- 18 Calabrese E.J. Evidence that hormesis represents an overcompensation response due to disruption in homeostasis. Ecotox Environ Safe 1999; 42: 135-137.
- 19 Mushak P. Hormesis and its place in non-monotonic dose-response relationships: some scientific reality checks. Environ Health Persp 2007; 115: 500-506.
- 20 Agutter P.S. Elucidating the mechanisms of hormesis at the cellular level: the universal cell response. Am J Pharmacol Toxicol 2008; 3: 97-107.
- 21 Calabrese E.J. Hormesis and medicine. Br J Clin Pharmacol 2008; 66: 594-617.
- 22 Arthur P.G., Lim S.C.C., Meloni B.P., Munns S.E., Chan A., Knuckey N.W. The protective effect of hypoxic preconditioning on cortical neuronal cultures is associated with increases in the activity of several antioxidant enzymes. Brain Res 2004; 1017: 146-154.
- 23 Fisher P. Homeopathy, hormesis, nanoparticles and nanostructures. Homeopathy 2015; 104: 67-68.
- 24 Bell I.R., Schwartz G.E. Enhancement of adaptive biological effects by nanotechnology preparation methods in homeopathic medicines. Homeopathy 2015; 104: 123-138.
- 25 Calabrese E.J. Hormesis: principles and applications. Homeopathy 2015; 104: 69-82.
- 26 Dei A., Bernardini S. Hormetic effects of extremely diluted solutions on gene expression. Homeopathy 2015; 104: 116-122.
- 27 Oberbaum M., Gropp C. Update on hormesis and its relation to homeopathy. Homeopathy 2015; 104: 227-233.
- 28 Mastrangelo D. Hormesis, epitaxy, the structure of liquid water and the science of homeopathy. Med Sci Monit 2007; 13: SR1-8.
- 29 Damelin L.H., Vokes S., Whitcutt J.N., Damelin S.B., Alexander J.J. Hormesis: a stress response in cells exposed to low levels of heavy metals. Hum Exp Toxicol 2000; 19: 420-430.
- 30 Damelin L.H., Alexander J.J. Metal-induced hormesis requires cPKC-dependent glucose transport and lowered respiration. Hum Exp Toxicol 2001; 20: 347-358.
- 31 Mantha M., Jumarie C. Cadmium-induced hormetic effect in differentiated Caco-2 cells: ERK and p38 activation without cell proliferation stimulation. J Cell Physiol 2010; 224: 250-261.
- 32 Calabrese E.J., Baldwin L.A. Ethanol and hormesis. Crit Rev Toxicol 2003; 33: 407-424.
- 33 Boericke W. Argentum metallicum. In: Pocket Manual of Homoeopathic Materia Medica – With Indian Medicine and Repertory. 2007. New Delhi, India: Indian books and periodicals publishers; 71-72.
- 34 Boericke W. Stannum metallicum. In: Pocket Manual of Homoeopathic Materia Medica – With Indian Medicine and Repertory. 2007. New Delhi, India: Indian books and periodicals publishers; 605-607.
- 35 Boericke W. Zincum metallicum. In: Pocket Manual of Homoeopathic Materia Medica – With Indian Medicine and Repertory. 2007. New Delhi, India: Indian books and periodicals publishers; 683-687.
- 36 Boericke W. Plumbum metallicum. In: Pocket Manual of Homoeopathic Materia Medica – With Indian Medicine and Repertory. 2007. New Delhi, India: Indian books and periodicals publishers; 524-526.
- 37 Boericke W. Aurum metallicum. In: Pocket Manual of Homoeopathic Materia Medica – With Indian Medicine and Repertory. 2007. New Delhi, India: Indian books and periodicals publishers; 96-99.
- 38 Braydich-Stolle L., Hussain S., Schlager J.J., Hoffmann M.C. In vitro cytotoxicity of nanoparticles in mammalian germline stem cells. Toxicol Sci 2005; 88: 412-441.
- 39 Shin S.H., Ye M.K., Kim H.S., Kang H.S. The effects of nano-silver on the proliferation and cytokine expression by peripheral blood mononuclear cells. Int Immunopharmacol 2007; 7: 1813-1818.
- 40 Kawata K., Osawa M., Okabe S. In vitro toxicity of silver nanoparticles at noncytotoxic doses to HepG2 human hepatoma cells. Environ Sci Technol 2009; 43: 6046-6051.
- 41 Lin D., Xing B. Phytotoxicity of nanoparticles: inhibition of seed germination and root growth. Environ Pollut 2007; 150: 243-250.
- 42 Chen B., Lutker K., Raju S.V. et al. Texture of nanocrystalline nickel: Probing the lower size limit of dislocation activity. Science 2012; 338: 1448-1451.
- 43 Piot L., Le Floch S., Cornier T., Daniele S., Machon D. Amorphization in nanoparticles. J Phys Chem C 2013; 117: 11133-11140.
- 44 Sharma S.M., Sikka S.K. Pressure induced amorphization of materials. Prog Mater Sci 1996; 40: 1-77.
- 45 Dong Y. Mechanically-driven amorphization in metallic systems. J Mater Sci Technol 1993; 9: 161-166.
- 46 Nel A.E., Mädler L., Velegol D. et al. Understanding biophysicochemical interactions at the nano-bio interface. Nat Mater 2009; 8: 543-557.
- 47 Truong V.K., Lapovok R., Estrin Y.S. et al. The influence of nano-scale surface roughness on bacterial adhesion on ultrafine-grained titanium. Biomaterials 2010; 31: 3674-3683.
- 48 Petros R.A., DeSimone J.M. Strategies in the design of nanoparticles for therapeutic applications. Nat Rev 2010; 9: 615-627.
- 49 Gratton S.E.A., Ropp P.A., Pohlhaus P.D. et al. The effect of particle design on cellular internalization pathways. Proc Natl Acad Sci USA 2008; 105: 11613-11618.
- 50 Geng Y., Dalhaimer P., Cai S. et al. Shape effects of filaments versus spherical particles in flow and drug delivery. Nat Nanotechnol 2007; 2: 249-255.
- 51 Nishiyama N. Nanomedicine: nanocarriers shape up for long life. Nat Nanotechnol 2007; 2: 203-204.
- 52 Pal S., Tak Y.K., Song J.M. Does the antibacterial activity of silver nanoparticles depend on the shape of the nanoparticle? A study of the gram-negative bacterium Escherichia coli . Appl Environ Microbiol 2007; 73: 1712-1720.
- 53 Champion J.A., Katare Y.K., Mitragotri S. Particle shape: a new design parameter for micro- and nanoscale drug delivery carriers. J Control Release 2007; 121: 3-9.
- 54 Euliss L.E., DuPont J.A., Gratton S., DeSimone J. Imparting size, shape and composition control of materials for nanomedicine. Chem Soc Rev 2006; 35: 1095-1104.
- 55 Barua S., Yoo J.W., Kolhar P., Wakankar A., Gokarn Y.R., Mitragotri S. Particle shape enhances specificity of antibody-displaying nanoparticles. Proc Natl Acad Sci USA 2013 http://dx.doi.org/10.1073/pnas.1216893110. Early edition www.pnas.org/cgi/.
- 56 Canelas D.A., Herlihy K.P., DeSimone J.M. Top-down particle fabrication: control of size and shape for diagnostic imaging and drug delivery. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2009; 1: 391-404.
- 57 Albanese A., Tang P.S., Chan W.C.W. The effect of nanoparticle size, shape and surface chemistry on biological systems. Annu Rev Biomed Eng 2012; 14: 1-16.