Association Between Neighborhood Opportunity, Allostatic Load, and All-Cause Mortality in Patients With Breast Cancer.

PURPOSE: Adverse neighborhood contextual factors may affect breast cancer outcomes through environmental, psychosocial, and biological pathways. The objective of this study is to examine the relationship between allostatic load (AL), neighborhood opportunity, and all-cause mortality among patients with breast cancer. METHODS: Women age 18 years and older with newly diagnosed stage I-III breast cancer who received surgical treatment between January 1, 2012, and December 31, 2020, at a National Cancer Institute Comprehensive Cancer Center were identified. Neighborhood opportunity was operationalized using the 2014-2018 Ohio Opportunity Index (OOI), a composite measure derived from neighborhood level transportation, education, employment, health, housing, crime, and environment. Logistic and Cox regression models tested associations between the OOI, AL, and all-cause mortality. RESULTS: The study cohort included 4,089 patients. Residence in neighborhoods with low OOI was associated with high AL (adjusted odds ratio, 1.21 [95% CI, 1.05 to 1.40]). On adjusted analysis, low OOI was associated with greater risk of all-cause mortality (adjusted hazard ratio [aHR], 1.45 [95% CI, 1.11 to 1.89]). Relative to the highest (99th percentile) level of opportunity, risk of all-cause mortality steeply increased up to the 70th percentile, at which point the rate of increase plateaued. There was no interaction between the composite OOI and AL on all-cause mortality (P = .12). However, there was a higher mortality risk among patients with high AL residing in lower-opportunity environments (aHR, 1.96), but not in higher-opportunity environments (aHR, 1.02; P interaction = .02). CONCLUSION: Lower neighborhood opportunity was associated with higher AL and greater risk of all-cause mortality among patients with breast cancer. Additionally, environmental factors and AL interacted to influence all-cause mortality. Future studies should focus on interventions at the neighborhood and individual level to address socioeconomically based disparities in breast cancer.

Stress and Allostatic Load in Patients With Primary Open Angle Glaucoma.

PRCIS: This study evaluated the allostatic load (AL) in primary open angle glaucoma (POAG) patients and reported that the AL score was significantly higher in glaucoma patients compared with age-matched controls. PURPOSE: To evaluate the AL in patients with POAG. METHODS: This case-control study comprised 50 POAG (glaucoma patients) and 50 age-matched controls without glaucoma (controls). AL was estimated based on 13 variables: systolic blood pressure (BP), diastolic BP, homocysteine, triglycerides, total cholesterol, high-density lipoprotein, low-density lipoprotein, body mass index, serum cortisol, glycosylated hemoglobin, albumin, creatinine clearance, and C-reactive protein. High-risk thresholds were determined based on biological cutoffs of each biomarker. One point was assigned for each biomarker reading above cutoff and were summated to obtain AL score; score ≥4 was considered high. RESULTS: Mean age of glaucoma patients was 60.82±6.26 and 60.14±6.72 years in controls ( P =0.602). All components of AL score (except C-reactive protein) had higher values in glaucoma patients. There was a statistically significant difference in homocysteine ( P =0.001), total cholesterol ( P =0.037), high-density lipoprotein ( P =0.005), and glycosylated hemoglobin ( P =0.003). Mean AL score was 4.68±2.09 in glaucoma patients and 3.32±1.34 in controls ( P <0.001). There was significant association of high AL score with older age ( P =0.006), low socioeconomic status ( P =0.020), and glaucoma severity ( P =0.001). Negative correlation was seen between AL and retinal nerve fiber layer thickness (Right Eye: r =-0.37, P <0.001; Left Eye: r =-0.298, P <0.001) and visual field mean deviation (Right Eye: r =-0.469, P <0.001; Left Eye: r =-0.520, P <0.001). CONCLUSIONS: Glaucoma patients exhibited allostatic overload indicating physiological dysregulation to chronic stress although additional research is required to establish causality. A holistic approach with lifestyle modifications to reduce chronic stress should be an integral part of managing glaucoma patients as it would serve both to possibly reduce or prevent disease progression and improve overall health outcomes.

Association of Allostatic Load With All-Cause Mortality in Patients With Breast Cancer.

Importance: Elevated allostatic load (AL) has been associated with adverse socioenvironmental stressors and tumor characteristics that convey poor prognosis in patients with breast cancer. Currently, the association between AL and all-cause mortality in patients with breast cancer is unknown. Objective: To examine the association between AL and all-cause mortality in patients with breast cancer. Design, Setting, and Participants: This cohort study used data from an institutional electronic medical record and cancer registry at the National Cancer Institute Comprehensive Cancer Center. Participants were patients with breast cancer diagnoses (stage I-III) between January 1, 2012, through December 31, 2020. Data were analyzed from April 2022 through November 2022. Exposure: AL was expressed as a summary score calculated by assigning 1 point for biomarkers in the worst sample quartile. High AL was defined as AL greater than the median. Main Outcomes and Measures: The main outcome was all-cause mortality. A Cox proportional hazard models with robust variance tested the association between AL and all-cause mortality. Results: There were 4459 patients (median [IQR] age, 59 [49-67] years) with an ethnoracial distribution of 3 Hispanic Black patients (0.1%), 381 non-Hispanic Black patients (8.5%), 23 Hispanic White patients (0.5%), 3861 non-Hispanic White patients (86.6%), 27 Hispanic patients with other race (0.6%), and 164 non-Hispanic patients with other race (3.7%). The mean (SD) AL was 2.6 (1.7). Black patients (adjusted relative ratio [aRR], those with 1.11; 95% CI, 1.04-1.18), single marital status (aRR, 1.06; 95% CI, 1.00-1.12), and those with government-supplied insured (Medicaid aRR, 1.14; 95% CI, 1.07-1.21; Medicare aRR, 1.11; 95% CI, 1.03-1.19) had a higher adjusted mean AL than those who were White, married/living as married, or privately insured, respectively. Adjusting for sociodemographic, clinical, and treatment factors, high AL was associated with a 46% increase in mortality risk (hazard ratio [HR], 1.46; 95% CI, 1.11-1.93) over low AL. Similarly, compared with patients in the first AL quartile, those in the third quartile (HR, 1.53; 95% CI, 1.07-2.18) and the fourth quartile (HR, 1.79; 95% CI, 1.16-2.75) had significantly increased risks of mortality. There was a significant dose-dependent association between increased AL and a higher risk of all-cause mortality. Furthermore, AL remained significantly associated with higher all-cause mortality after adjusting for the Charlson Comorbidity Index. Conclusions and Relevance: These findings suggest increased AL is reflective of socioeconomic marginalization and associated with all-cause mortality in patients with breast cancer.

Allostasis and metastasis: The yin and yang of childhood self-regulation.

Most research has studied self-regulation by presenting experimenter-controlled test stimuli and measuring change between baseline and stimulus. In the real world, however, stressors do not flash on and off in a predetermined sequence, and there is no experimenter controlling things. Rather, the real world is continuous and stressful events can occur through self-sustaining interactive chain reactions. Self-regulation is an active process through which we adaptively select which aspects of the social environment we attend to from one moment to the next. Here, we describe this dynamic interactive process by contrasting two mechanisms that underpin it: the "yin" and "yang" of self-regulation. The first mechanism is allostasis, the dynamical principle underlying self-regulation, through which we compensate for change to maintain homeostasis. This involves upregulating in some situations and downregulating in others. The second mechanism is metastasis, the dynamical principle underling dysregulation. Through metastasis, small initial perturbations can become progressively amplified over time. We contrast these processes at the individual level (i.e., examining moment-to-moment change in one child, considered independently) and also at the inter-personal level (i.e., examining change across a dyad, such as a parent-child dyad). Finally, we discuss practical implications of this approach in improving the self-regulation of emotion and cognition, in typical development and psychopathology.

Association of Allostatic Load With Overall Mortality Among Patients With Metastatic Non-Small Cell Lung Cancer.

Importance: Adverse social determinants of health (SDHs) (eg, poverty) are associated with poor oncologic outcomes among patients with lung cancer. However, no studies have evaluated biological correlates of adverse SDHs, operationalized as allostatic load (AL), with mortality due to lung cancer. Objective: To examine the association among AL, SDHs, and mortality among patients with metastatic non-small cell lung cancer (NSCLC). Design, Setting, and Participants: This cross-sectional study of an observational cohort was performed at a National Cancer Institute-designated comprehensive cancer center with data accrued from June 1, 2017, to August 31, 2019. Patients with metastatic (stage IV) NSCLC enrolled at diagnosis into a prospective observational cohort study were included in the present analysis if they had all the biomarkers to calculate an AL score (N = 143). Follow-up was completed on August 31, 2021, and data were analyzed from July 1 to September 30, 2021. Exposures: Social determinants of health. Main Outcomes and Measures: Overall mortality and AL. Results: A total of 143 patients met the study criteria with a median age of 63 (IQR, 55-71) years (89 men [62.2%] and 54 women [37.8%]). In terms of race and ethnicity, 1 patient (0.7%) was Asian, 7 (4.9%) were Black, 117 (81.8%) were White, 17 (11.9%) were of multiple races, and 1 (0.7%) was of other race or ethnicity. The mean (SD) AL was 2.90 (1.37). Elevated AL covaried with lower educational level (r = -0.26; P = .002), male sex (r = 0.19; P = .02), limited mobility (r = 0.19; P = .04), worsening self-care (r = 0.30; P < .001), problems engaging in usual activities (r = 0.21; P = .01), depressive symptoms (r = 0.23; P = .005), and a high number of stressful life events (r = 0.30; P < .001). Multivariable analysis found only increasing difficulty with mobility (r = 0.37 [95% CI, 0.13-0.60]; P = .002) and male sex (r = 0.63 [95% CI, 0.19-1.08]; P = .005) associated with higher AL. On adjusted analysis, elevated AL (hazard ratio, 1.43 [95% CI, 1.16-1.79]; P = .001) and low educational level (hazard ratio, 2.11 [95% CI, 1.03-4.34]; P = .04) were associated with worse overall mortality. Conclusions and Relevance: The findings of this cross-sectional study suggest that higher AL was associated with adverse SDHs and worse overall mortality among patients with advanced NSCLC. These results provide a framework for replication and further studies of AL as a biological correlate for SDH and future prognostic marker.

Neurofeedback and neural self-regulation: a new perspective based on allostasis.

The field of neurofeedback training (NFT) has seen growing interest and an expansion of scope, resulting in a steadily increasing number of publications addressing different aspects of NFT. This development has been accompanied by a debate about the underlying mechanisms and expected outcomes. Recent developments in the understanding of psychophysiological regulation have cast doubt on the validity of control systems theory, the principal framework traditionally used to characterize NFT. The present article reviews the theoretical and empirical aspects of NFT and proposes a predictive framework based on the concept of allostasis. Specifically, we conceptualize NFT as an adaptation to changing contingencies. In an allostasis four-stage model, NFT involves (a) perceiving relations between demands and set-points, (b) learning to apply collected patterns (experience) to predict future output, (c) determining efficient set-points, and (d) adapting brain activity to the desired ("set") state. This model also identifies boundaries for what changes can be expected from a neurofeedback intervention and outlines a time frame for such changes to occur.

Combined Effect of Lead Exposure and Allostatic Load on Cardiovascular Disease Mortality-A Preliminary Study.

This study explores the combined effect of lead (Pb) exposure and an index of chronic physiological stress on cardiovascular disease mortality using data from the National Health and Nutrition Examination Survey (NHANES) 1999-2008 linked to 1999-2014 National Death Index data. Chronic physiological stress was measured using the allostatic load (AL) index, which was formed by analyzing markers from the cardiovascular, inflammatory, and metabolic systems, with Pb levels, assessed using blood lead levels (BLL). The dataset was analyzed with statistical techniques to explore (a) the relationship between Pb exposure and AL, and (b) the combined role of Pb and AL on cardiovascular disease mortality. Results indicated that AL was more elevated in those with BLLs above the 50th percentile in the US population and that those with elevated AL were more likely to have high BLL. Finally, the interaction of AL and BLL significantly increased the likelihood of cardiovascular disease mortality. These findings highlight the need for considering the totality of exposures experienced by populations to build holistic programs to prevent Pb exposure and reduce stressors to promote optimal health outcomes and reduce cardiovascular mortality risk.

Cancer and stress: NextGen strategies.

Chronic stress is well-known to cause physiological distress that leads to body balance perturbations by altering signaling pathways in the neuroendocrine and sympathetic nervous systems. This increases allostatic load, which is the cost of physiological fluctuations that are required to cope with psychological challenges as well as changes in the physical environment. Recent studies have enriched our knowledge about the role of chronic stress in disease development, especially carcinogenesis. Stress stimulates the hypothalamic-pituitaryadrenal (HPA) axis and the sympathetic nervous system (SNS), resulting in an abnormal release of hormones. These activate signaling pathways that elevate expression of downstream oncogenes. This occurs by activation of specific receptors that promote numerous cancer biological processes, including proliferation, genomic instability, angiogenesis, metastasis, immune evasion and metabolic disorders. Moreover, accumulating evidence has revealed that ß-adrenergic receptor (ADRB) antagonists and downstream target inhibitors exhibit remarkable anti-tumor effects. Psychosomatic behavioral interventions (PBI) and traditional Chinese medicine (TCM) also effectively relieve the impact of stress in cancer patients. In this review, we discuss recent advances in the underlying mechanisms that are responsible for stress in promoting malignancies. Collectively, these data provide approaches for NextGen pharmacological therapies, PBI and TCM to reduce the burden of tumorigenesis.

Reflections on Bruce S. McEwen's contributions to stress neurobiology and so much more.

The authors highlight, from a firsthand perspective, Bruce S. McEwen's seminal influence on the field of stress neurobiology and beyond, and how these investigations have yielded important insights, principles and critical questions that continue to guide stress research today. Featured are discussion of: 1) the important inverted-U relationship between stress/glucocorticoids and optimal physiological function, 2) stress adaptation and the role of adaptive stress responses, 3) mechanisms by which the short-term stress response promotes heightened immune function and immunity, and 4) the far reaching impact of the theoretical framework of allostasis and allostatic load-concepts that have created new bridges between stress physiology, biomedical sciences, health psychology and sociology.

Perspectives on tissue adaptation related to allostatic load: Scoping review and integrative hypothesis with a focus on osteopathic palpation.

INTRODUCTION: Osteopathic care may support an individual's adaptive capacity, including allostatic regulation and tissue changes in both health and disease. The palpatory findings which osteopaths claim are related to tissue changes may be linked to allostatic load. However, this putative link has not been formally investigated. METHODS: We conducted a scoping review to critically appraise the relevant literature on the relationship between allostatic processes and tissue alterations. This review evaluates the use and relevance of palpatory findings in osteopathic care. We searched on PubMed, EMBASE, Cochrane library for research exploring the links between tissue adaptation, allostasis and osteopathic palpatory findings (OPF). RESULTS: Recent studies provide insights into the role of allostatic regulation on body systems' responses related to tissue alterations. These results provide new insights into the relevance of OPF to clinical practice. DISCUSSION: We build upon the findings of our review to propose a putative model for OPF in clinical practice. CONCLUSION: Although the clinical phenomena associated with OPF may be biologically plausible, it lacks the necessary underpinning research evidence. Arguably, the classical focus on the diagnosis of palpable tissue changes fails to integrate biological, social and neuropsychological aspects such as stress responses. Tissue alterations related to stress and allostatic load markers have been less studied. Tissue changes involved in the adaptive process may be useful to practitioners in the field of manual therapy, particularly in osteopathy. We propose that OPF are one of the multidimensional aspects that may inform osteopathic decision-making. However, they should be considered within a biopsychosocial perspective and taking into account concepts of allostatic load and regulation.

Choroid Plexus Enlargement and Allostatic Load in Schizophrenia.

Although schizophrenia is a brain disorder, increasing evidence suggests that there may be body-wide involvement in this illness. However, direct evidence of brain structures involved in the presumed peripheral-central interaction in schizophrenia is still unclear. Seventy-nine previously treatment-naïve first-episode schizophrenia patients who were within 2-week antipsychotics initial stabilization, and 41 age- and sex-matched healthy controls were enrolled in the study. Group differences in subcortical brain regional structures measured by MRI and the subclinical cardiovascular, metabolic, immune, and neuroendocrine biomarkers as indexed by allostatic load, and their associations were explored. Compared with controls, patients with schizophrenia had significantly higher allostatic load (P = .001). Lateral ventricle (P < .001), choroid plexus (P < .001), and thalamus volumes (P < .001) were significantly larger, whereas amygdala volume (P = .001) was significantly smaller in patients. The choroid plexus alone was significantly correlated with higher allostatic load after age, sex, education level, and the total intracranial volume were taken into account (t = 3.60, P < .001). Allostatic load was also significantly correlated with PANSS positive (r = 0.28, P = .016) and negative (r = -0.31, P = .008) symptoms, but in opposite directions. The peripheral multisystemic and central nervous system abnormalities in schizophrenia may interact through the choroid plexus during the early stage of the illness. The choroid plexus might provide a sensitive structural biomarker to study the treatment and prevention of brain-periphery interaction abnormalities in schizophrenia.

The role of the brain-gut-microbiota axis in psychology: The importance of considering gut microbiota in the development, perpetuation, and treatment of psychological disorders.

INTRODUCTION: The prevalence of psychological disorders remains stable despite steady increases in pharmacological treatments suggesting the need for auxiliary treatment options. Consideration of the brain-gut-microbiota axis (BGMA) has made inroads into reconceptualizing psychological illness from a more holistic perspective. While our understanding of the precise role of gut microbiota (GM) in psychological illness is in its infancy, it represents an attractive target for novel interventions. METHOD: An extensive review of relevant literature was undertaken. RESULTS: Gut microbiota are proposed to directly and indirectly influence mood, cognition, and behavior which are key components of mental health. This paper outlines how GM may be implicated in psychological disorders from etiology through to treatment and prevention using the Four P model of case formulation. CONCLUSION: Moving forward, integration of GM into the conceptualization and treatment of psychological illness will require the discipline of psychology to undergo a significant paradigm shift. While the importance of the GM in psychological well-being must be respected, it is not proposed to be a panacea, but instead, an additional arm to a multidisciplinary approach to treatment and prevention.

Osteopathic Manipulative Treatment for Allostatic Load Lowering.

CONTEXT: Limited research has been done to examine osteopathic manipulative treatment (OMT) effects on modulating a compilation of allostatic load (AL) biomarkers that work to measure the body's multisystem response to homeostatic deviation. OBJECTIVE: To examine the efficacy of OMT on graduate students' overall health through an objective index of representative AL biomarkers. METHODS: A within-subject pre- and postintervention study was conducted at Touro University College of Osteopathic Medicine in California during the fall 2017 semester. Graduate students enrolled in the Masters of Science in Medical Health Sciences program volunteered to participate in the study and received treatment by an osteopathic physician. The participants were evaluated using the following measures: Trier Inventory for the Assessment of Chronic Stress; diurnal urine cortisol and catecholamines; dried blood glycated hemoglobin, dehydroepiandrosterone, high-density lipoprotein, and high-sensitivity C-reactive protein; blood pressure, body mass index, and waist-to-hip ratio before (preintervention) and after (postintervention) OMT. RESULTS: The study consisted of 1 man (participant 1) and 1 woman (participant 2) aged 23 and 22 years, respectively. Participants were enrolled in the same academic program and received 3 OMT sessions in 7 weeks. Analysis of AL biomarkers revealed a decrease in overall AL scores from preintervention to postintervention in participant 1 (from 7 to 4) and participant 2 (from 9 to 7). Analysis of Trier Inventory for the Assessment of Chronic Stress scores revealed a decrease in self-perceived stress from preintervention to postintervention in participant 1 (from 18 to 15) and in participant 2 (from 40 to 13). CONCLUSION: The OMT protocol used in the current study decreased measures of overall AL and self-perceived stress in both participants. This finding suggests that OMT may represent a reasonable modality to reduce AL and self-perceived stress in graduate students. Since the current study is limited by its small sample size, further research is warranted.

Allostasis: A Brain-Centered, Predictive Mode of Physiological Regulation.

Although the concept of allostasis was proposed some 30 years ago, doubts persist about its precise meaning and whether it is useful. Here we review the concept in the context of recent studies as a strategy to efficiently regulate physiology and behavior. The brain, sensing the internal and external milieu, and consulting its database, predicts what is likely to be needed; then, it computes the best response. The brain rewards a better-than-predicted result with a pulse of dopamine, thereby encouraging the organism to learn effective regulatory behaviors. The brain, by prioritizing behaviors and dynamically adjusting the flows of energy and nutrients, reduces costly errors and exploits more opportunities. Despite significant costs of computation, allostasis pays off and can now be recognized as a core principle of organismal design.

The Biological Measurements of Mindfulness-based Stress Reduction: A Systematic Review.

BACKGROUND: Chronic Stress disrupts homeostasis, resulting in adverse physiologic and psychologic sequela. Research on the effects of mindfulness-based stress reduction (MBSR) have primarily used self-report measures or biological measurements of a single body system. There has been no attempt to synthesize the literature of the biological measurements of MBSR. OBJECTIVE: The objectives of this systematic review were to: (1) identify the biological markers of mindfulness-based stress reduction (MBSR) and (2) determine if the identified markers support the theories of allostasis and top-down, bottom-up processes. DATA SOURCES: Seven databases, Pubmed/Medline, Embase, Psychinfo, Cochrane database, CINAHL, Medline/Web of Science and OVID from 1985 to May 2018 were searched for relevant studies. STUDY SELECTION: Mindfulness-based stress reduction studies were selected that used biomarkers or neuroimaging in adult clinical and non-clinical populations. Excluded studies were conference papers, abstracts, studies with no biological measurements, other mindfulness interventions, editorial articles, and feasibility studies DATA EXTRACTION: Sixty-seven studies from 11 articles were reviewed. Fifteen biological measurements were identified including autonomic, immune, inflammatory and neurobiological markers DATA SYNTHESIS AND CONCLUSIONS: The identified biological markers demonstrate preliminary support for the theories of allostasis and top-down, bottom-up processes. Recommendations for future research are discussed.

From serendipity to clinical relevance: How clinical psychology and neuroscience converged to illuminate psychoneuroendocrinology.

Dirk Hellhammer and his colleagues have played a major role in creating the field of psychoneuroendocrinology from their roots in psychology. In this review, using examples from the history of the McEwen laboratory and neuroscience and neuroendocrinology colleagues, I summarize my own perspective as to how the fields of neuroscience and neuroendocrinology have contributed to psychoneuroendocrinology and how they converged with the contributions from Dirk Hellhammer and his colleagues.

Chronic Stress protection for postnatal dEpREssioN prEvention (SERENE): a protocol for an exploratory study.

INTRODUCTION: The prevalence of postnatal depression (PND) is significant: reaching up to 20% in the general population. In mechanistic terms, the risk of PND lies in an interaction between a maternal psychophysiological vulnerability and a chronic environmental context of stress. On the one hand, repetition of stressor during pregnancy mimics a chronic stress model that is relevant to the study of the allostatic load and the adaptive mechanisms. On the other hand, vulnerability factors reflect a psychological profile mirroring mindfulness functioning (psychological quality that involves bringing one's complete and non-judgemental attention to the present experience on a moment-to-moment basis). This psychological resource is linked to protective and resilient psychic functioning. Thus, PND appears to be a relevant model for studying the mechanisms of chronic stress and vulnerability to psychopathologies.In this article, we present the protocol of an ongoing study (started in May 2017). METHODS AND ANALYSIS: The study is being carried out in five maternities and will involve 260 women. We aim to determine the predictive psychobiological factors for PND emergence and to provide a better insight into the mechanisms involved in chronic stress during pregnancy. We use a multidisciplinary approach that encompasses psychological resources and biophysiological and genetic profiles in order to detect relevant vulnerability biomarkers for chronic stress and the development of PND. To do so, each woman will be involved in the study from her first trimester of pregnancy until 12 months postdelivery. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Ile de France III Ethics Committee, France (2016-A00887-44). We aim to disseminate the findings through international conferences and international peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03088319; Pre-results.

Water-Related Mechanisms Proposed for Storing and Transmitting Homeopathic Information: Putative Links with Biological Responses.

INTRODUCTION: There are two critical pillars of homeopathy that contrast with the dominant scientific approach: the similitude principle and the potentization of serial dilutions. Three main hypotheses about the mechanisms of action are in discussion: nanobubbles-related hormesis; vehicle-related electric resonance; and quantum non-locality. OBJECTIVES: The aim of this paper is to review and discuss some key points of such properties: the imprint of supramolecular structures based on the nanoparticle-allostatic, cross-adaptation-sensitization (NPCAS) model; the theory of non-molecular electromagnetic transfer of information, based on the coherent water domains model, and relying (like the NPCAS model) on the idea of local interactions; and the hypothesis of quantum entanglement, based on the concept of non-locality. RESULTS AND DISCUSSION: The nanoparticles hypothesis has been considered since 2010, after the demonstration of suspended metal nanoparticles even in very highly diluted remedies: their actual action on biological structures is still under scrutiny. The second hypothesis considers the idea of electric resonance mechanisms between living systems (including intracellular water) and homeopathic medicines: recent findings about potency-related physical properties corroborate it. Finally, quantum theory of 'non-local' phenomena inspires the idea of an 'entanglement' process among patient, practitioner and the remedy: that quantic phenomena could occur in supra-atomic structures remains speculative however. CONCLUSION: Further studies are needed to ascertain whether and which of these hypotheses may be related to potential cellular effects of homeopathic preparations, such as organization of metabolic pathways or selective gene expression.