*Corresponding author email: ibell@email.arizona.edu Symbiosis Group Symbiosis www.symbiosisonline.org www.symbiosisonlinepublishing.com Extending the Adaptive Network Nanomedicine Model for Homeopathic Medicines: Nanostructures as Salient Cell Danger Signals for Adaptation Iris R. Bell 1-4 * Gary E. Schwartz 5 , Joyce Frye 6 , Barbara Sarter 7 , and Leanna J. Standish 4 1 Department of Family and Community Medicine, University of Arizona College of Medicine, Tucson, AZ, USA 2 Arizona Center for Integrative Medicine (Department of Medicine), University of Arizona College of Medicine, Tucson, AZ, USA 3 University of Arizona College of Nursing, University of Arizona, Tucson, AZ, USA 4 Bastyr Integrative Oncology Research Center, Bastyr University, Kenmore, WA 98028, USA 5 Department of Psychology, University of Arizona, Tucson, AZ, USA 6 Fusion Medicine Collaborative, Philadelphia, PA, USA 7 Bastyr University -San Diego, CA, USA Nanoscience & Technology: Open Access Open Access Research Article Abbreviations HSPs: Heat Shock Proteins; AMPs: Antimicrobial Peptides; D-cells: Dendritic Cells; ERVs: Endogenous Retroviruses; LINEs: Long Interspersed Nuclear Elements; meDNA: Methylated DNA; dNTPs: Deoxynucleoside Triphosphates; CNS: Central Nervous System; HMs: Homeopathic Medicines; NPs: Nanoparticles; DAMP: Danger-Associated Molecular Patterns Introduction This paper articulates and expands upon a model based on the biological implications of the discovery of source and silica nanostructures in Homeopathic Medicines (HMs). The paper summarizes growing data on the nanotechnology aspects and findings for nanostructures in HMs and discusses ways in which these agents can act at the nanoscale in the body [1,2]. Substantial evidence indicates that nanomaterials possess unique capacities for triggering size-, shape-, and surface property- dependent biological responses, even at very low concentrations [3-7] (Table1). The present model may also have more general implications for exploring novel therapeutic mechanisms such as hormesis [7,8] for the field of nanomedicine and perhaps for evaluating effects of environmentally-relevant, low level nanomaterials in nanotoxicology [9-11]. Homeopathy is a traditional, albeit controversial, system of Complementary and Alternative Medicine (CAM) used worldwide, notably in India, Latin America, the United Kingdom, and Europe. The nature and mechanisms of action of HMs have stirred intense debate throughout the more than 200-year history of homeopathy’s existence as a natural product-based system of CAM [12]. Preparation of HMs involves serial steps of dilution of plant, animal, or mineral source materials in dry lactose, ethanol/ Abstract This paper examines the growing evidence supporting the adaptive network nanomedicine model for Homeopathic Medicines (HMs) and their actions. Multiple laboratories have identified nanostructures in homeopathically-manufactured medicines at low and high potencies. Replicated studies in mainstream pharmaceutical research and in homeopathy have also demonstrated elevated levels of elemental silicon and/or bioactive silica Nanoparticles (NPs) released from glassware during agitation or multiple homeopathic succussions. The model suggests that (a) very low potency HMs are complex mixtures of bulk, micro- and nanoscale forms of the medicine’s natural source material made by prolonged mechanical grinding (trituration) in dry lactose; (b) low and higher potency liquid HMs made in glass containers are nanocomposite materials formed from source NPs, nanosilica-coated source NPs, adjuvant nanosilica and source-doped, coated, seeded or template nanosilica in colloidal solutions that can survive drying. We hypothesize that HMs include hybrid nanostructures of various sources, small sizes, shapes, surface defects, zeta potentials, and surface reactivity. HMs serves as individually-salient, sub toxic virus-like foreign danger signals. Nanosilica would help carry and amplify the fingerprint signal of co-occurring and adsorbed source material on its surfaces at higher liquid potencies. Cell Defense Response (CDR) network constituents that HMs modulate involve gene expression, cytokine release, cell signaling, and cell stress mediators. Once triggered, nonlinear endogenous amplification processes facilitate evolution of the therapeutic response over time. Keywords: Homeopathy; Nanoparticles; Silica; Adsorption; Surface chemistry; Protein corona; Cell danger response; Danger- Associated Molecular Patterns (DAMP); Biological signaling; Adaptation; Hormesis; Inflammasome; Heat shock proteins; Oxidative stress; Cell stress; Cell signaling; Cytokines; Gene expression Received: May 14, 2015; Accepted: June 14, 2015; Published: June 26, 2015 *Corresponding author: Iris R. Bell, Department of Family and Community Medicine, University of Arizona College of Medicine, 1450 N Cherry, MS 245052, Tucson, AZ 85719, USA, Tel: +520-906-6767; Fax: +520-626-2030; E-mail: ibell@email.arizona.edu