The notion of hormesis and the dose–response theory: A unified approach

Obesity, type 2 diabetes, and other metabolic disorders have a large impact on global health, especially in Western countries. An important hallmark of metabolic disorders is chronic low-grade inflammation. A key player in chronic low-grade inflammation is dysmetabolism, which is defined as the inability to keep homeostasis resulting in loss of lipid control, oxidative stress, inflammation, and insulin resistance. Although often not yet detectable in the circulation, chronic low-grade inflammation can be present in one or multiple organs. The response to a metabolic challenge containing lipids may magnify dysfunctionalities at the tissue level, causing an overflow of inflammatory markers into the circulation and hence allow detection of early low-grade inflammation. Here, we summarize the evidence of successful application of metabolic challenge tests in type 2 diabetes, metabolic syndrome, obesity, and unhealthy aging. We also review how metabolic challenge tests have been successfully applied to evaluate nutritional intervention effects, including an “anti-inflammatory” mixture, dark chocolate, whole grain wheat and overfeeding. Additionally, we elaborate on future strategies to (re)gain inflammatory flexibility. Through epigenetic and metabolic regulation, the inflammatory response may be trained by regular mild and metabolic triggers, which can be understood from the perspective of trained immunity, hormesis and pro-resolution. New strategies to optimize dynamics of inflammation may become available.

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Current and Future Nutritional Strategies to Modulate Inflammatory Dynamics in Metabolic Disorders

Hormone replacement after menopause has in recent years been the subject of intense scientific debate and public interest and has sparked intense research efforts into the biological effects of estrogens and progestagens. However, there are reasons to believe that the doses used and plasma concentrations produced in a large number of studies casts doubt on important aspects of their validity. The concept of hormesis states that a substance can have diametrically different effects depending on the concentration. Even though estrogens and progestagens have proven prone to this kind of dose-response relation in a multitude of studies, the phenomenon remains clearly underappreciated as exemplified by the fact that it is common practice to only use one hormone dose in animal experiments. If care is not taken to adjust the concentrations of estrogens and progestagens to relevant biological conditions, the significance of the results may be questionable. Our aim is to review examples of female sexual steroids demonstrating bidirectional dose-response relations and to discuss this in the perspective of hormesis. Some examples are highlighted in detail, including the effects on cerebral ischemia, inflammation, cardiovascular diseases and anxiety. Hopefully, better understanding of the hormesis phenomenon may result in improved future designs of studies of female sexual steroids.

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Hormesis and Female Sex Hormones

Background: In the present work, we describe a group of anomalous dose-response (DR) profiles and develop a dynamic model that is able to explain them. Responses were obtained from conventional assays of three antimicrobial agents (nisin, pediocin and phenol) against two microorganisms (Carnobacterium piscicola and Leuconostoc mesenteroides). Results: Some of these anomalous profiles show biphasic trends which are usually attributed to hormetic responses. But they can also be explained as the result of the time-course of the response from a microbial population with a bimodal distribution of sensitivity to an effector, and there is evidence suggesting this last origin. In light of interest in the hormetic phenomenology and the possibility of confusing it with other phenomena, especially in the bioassay of complex materials we try to define some criteria which allow us to distinguish between sensu stricto hormesis and biphasic responses due to other causes. Finally, we discuss some problems concerning the metric of the dose in connection with the exposure time, and we make a cautionary suggestion about the use of bacteriocins as antimicrobial agents. Conclusions: The mathematical model proposed, which combines the basis of DR theory with microbial growth kinetics, can generate and explain all types of anomalous experimental profiles. These profiles could also be described in a simpler way by means of bisigmoidal equations. Such equations could be successfully used in a microbiology and toxicology context to discriminate between hormesis and other biphasic phenomena.

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Biphasic toxicodynamic features of some antimicrobial agents on microbial growth: a dynamic mathematical model and its implications on hormesis

Fractals are self-similar geometric patterns that are inherently embedded throughout nature. Their discovery and application have produced significant benefits across a wide variety of biomedical applications. Recently, complex physiological systems (e.g., neurological, respiratory, cardiovascular) have been shown to exhibit fractal dimensions that are capable of distinguishing among physiologic function versus dysfunction and, in turn, health versus disease. Additionally, fractal data suggest that the immune system operates under similar patterned relationships, and this is in keeping with the recent findings that immune-based diseases are organized according to specific patterns. This review considers the potential benefits of using fractal analysis along with considerations of nonlinearity, scaling, and chaos as calibration tools to obtain holistic information on immune–environment interactions. The potential uses of both synthetic and artificial immune systems for improved protection of the biological...

https://www.tandfonline.com/doi/pdf/10.3109/1547691X.2011.559951

Fractal immunology and immune patterning: Potential tools for immune protection and optimization

Linear-threshold and nonthreshold dose-response relationships have been of fundamental importance in toxicology risk assessment and regulation. However, many examples exist in the literature where immunologic and other data display inverted U-shaped (hormetic) dose-response curves. These data are characterized by stimulation of response at low doses but inhibition at higher doses (Calabrese and Baldwin, 2003). As an example, the nonsteroidal estrogenic compound diethylstilbestrol (DES) at physiologic doses stimulates mitogen-induced lymphocyte proliferation, while pharmacologic exposures inhibit this same response. Similar biphasic dose-response observations have been made for other bioassays that form the foundation of immunotoxicity testing—for example, antibody or cytokine production, macrophage phagocytosis, chemotaxis, or chemiluminescence; surface antigen expression; and ultimately, disease resistance. Dr. Calabrese effectively demonstrates that nonlinear doseresponse relationships are common in the immunology literature. He has reviewed an extraordinary number of references to support this idea. His abstract suggests that such biphasic immune responses have been little appreciated, which may not accurately represent researchers of the discipline. The several hundred graphs shown to support immunologic hormesis represent the work of immunologists, who then often discussed possible operating mechanisms behind the responses as well as potential clinical relevances. The authors of this review of the Calabrese review are among those who have shown nonlinear immunologic responses to immune modulating agents (Calemine et al., 2002), without describing these results as atypical or unexpected. Thus, at least from our perspective, the validity of many of these nonlinear immunologic dose responses is well accepted. We suggest that toxicologists in general have long recognized the existence of nonlinear dose-response curves, but may differently interpret their meaning or importance. David Eaton and

S. D. Holladay

Papers

Occurrence, Quantitative Features of the Dose Response, Mechanistic Foundations, and Clinical Implications