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Similarities between the Yin/Yang Doctrine and Hormesis in Toxicology and Pharmacology

2020; Elsevier BV; Volume: 41; Issue: 8 Linguagem: Inglês

10.1016/j.tips.2020.05.004

1873-3735

Haoyu Sun, Edward J. Calabrese, Zhifen Lin, Baoling Lian, Xiaoxian Zhang,

Effects of Radiation Exposure

Hormesis is a dose–response relationship characterized by stimulation at low dose and inhibition at high dose, and which is typically represented as a J-shaped or an inverted U-shaped curve.Hormesis exhibits generalizable features and has mechanistic explanations, but there is still much debate over this biphasic dose–response curve.However, hormesis is changing central beliefs in toxicology and pharmacology.To guide the debate on hormesis and further promote its acceptance and application, an improved biological framework to understand and interpret hormesis is needed.Yin/Yang doctrine, a traditional Chinese philosophy that has sound scientific foundations, can provide new insights into diverse biomedical problems, and provides an opportunity to re-recognize hormesis. Hormesis is a generalizable dose–response relationship characterized by low-dose stimulation and high-dose inhibition. Despite debate over this biphasic dose–response curve, hormesis is challenging central beliefs in the evaluation of chemicals or drugs and has influenced biological model selection, concentration range, study design, and hypothesis testing. We integrate the traditional Chinese philosophy – Yin/Yang doctrine – into the representation of the Western hormetic dose–response relationship and review the Yin/Yang historical philosophy contained in the hormesis concept, aiming to promote general acceptance and wider applications of hormesis. We suggest that the Yin/Yang doctrine embodies the hormetic dose–response, including the relationship between the opposing components, curve shape, and time-dependence, and may afford insights that clarify the hormetic dose–response relationship in toxicology and pharmacology. Hormesis is a generalizable dose–response relationship characterized by low-dose stimulation and high-dose inhibition. Despite debate over this biphasic dose–response curve, hormesis is challenging central beliefs in the evaluation of chemicals or drugs and has influenced biological model selection, concentration range, study design, and hypothesis testing. We integrate the traditional Chinese philosophy – Yin/Yang doctrine – into the representation of the Western hormetic dose–response relationship and review the Yin/Yang historical philosophy contained in the hormesis concept, aiming to promote general acceptance and wider applications of hormesis. We suggest that the Yin/Yang doctrine embodies the hormetic dose–response, including the relationship between the opposing components, curve shape, and time-dependence, and may afford insights that clarify the hormetic dose–response relationship in toxicology and pharmacology. Hormesis is a dose–response relationship characterized by stimulation at low dose and inhibition at high dose, and is typically represented as a J-shaped or inverted U-shaped curve (Figure 1A ) [1.Calabrese E.J. Baldwin L.A. Defining hormesis.Hum. Exp. Toxicol. 2002; 21: 91-97Crossref PubMed Scopus (644) Google Scholar]. Hormetic dose–response phenomena have generated considerable interest in the scientific community over several decades, and a large body of literature regarding hormetic phenomena has been published not only in toxicology and pharmacology but also in many other areas of biology (e.g., plant biology, microbiology, biogerontology) [2.Calabrese E.J. Hormesis: a fundamental concept in biology.Microb. Cell. 2014; 1: 145-149Crossref PubMed Scopus (127) Google Scholar,3.Calabrese E.J. Blain R.B. Hormesis and plant biology.Environ. Pollut. 2009; 157: 42-48Crossref PubMed Scopus (345) Google Scholar]. 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In addition, hormesis is increasingly recommended as a fundamental model because it more accurately reflects the actual dose–response at both low and high doses than do traditional threshold and linear non-threshold models [14.Calabrese E.J. Hormesis is central to toxicology, pharmacology and risk assessment.Hum. Exp. Toxicol. 2010; 29: 249-261Crossref PubMed Scopus (207) Google Scholar, 15.Calabrese E.J. Baldwin L.A. The hormetic dose–response model is more common than the threshold model in toxicology.Toxicol. Sci. 2003; 71: 246-250Crossref PubMed Scopus (372) Google Scholar, 16.Calabrese E.J. et al.Hormesis predicts low-dose responses better than threshold models.Int. J. Toxicol. 2008; 27: 369-378Crossref PubMed Scopus (101) Google Scholar, 17.Calabrese E.J. Baldwin L.A. Applications of hormesis in toxicology, risk assessment and chemotherapeutics.Trends Pharmacol. Sci. 2002; 23: 331-337Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar]. 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We introduce Yin/Yang doctrine into the re-exploration of hormesis, and establish the scientific concordance between hormesis and Yin/Yang doctrine by reviewing published hormetic dose–responses, including the stimulation/inhibition relationship, the time-dependent feature, and the fundamental meaning of the biphasic dose–response curve. Yin and Yang are two opposing but complementary parts (polarities or forces) [27.Jiang X. Chinese dialectical thinking – the Yin Yang model.Philos Compass. 2013; 8: 438-446Crossref Scopus (16) Google Scholar,37.Van Wijk R. et al.Human ultraweak photon emission and the Yin Yang concept of Chinese medicine.J. Acupunct. Meridian Stud. 2010; 3: 221-231Crossref PubMed Scopus (15) Google Scholar]. Ancient Chinese philosophy suggests that Yin and Yang work together to produce all things in the universe, where there are an infinite number of Yin/Yang pairs – such as Heaven and Earth, man and woman, hot and cool, high and low, large and small, and so on [27.Jiang X. Chinese dialectical thinking – the Yin Yang model.Philos Compass. 2013; 8: 438-446Crossref Scopus (16) Google Scholar]. Figure 1B depicts the classical Yin/Yang symbol. In general, whereas Yin refers to the essence and relatively immobile aspect of an entity, Yang represents its appearance and dynamic state. There are four types of relationships between Yin and Yang (Figure 1C), namely Yin/Yang containment, Yin/Yang consanguinity, Yin/Yang counterpoise, and Yin/Yang conversion; these so-called '4C' laws reflect the core concept of Yin/Yang doctrine [38.Baynes C.F. Wilhelm H. The I Ching: Or Book of Changes. Princeton University Press, 1967Google Scholar]. The 4C laws will be discussed later in more detail in the context of hormesis. Yin/Yang doctrine is a fundamental concept in traditional Chinese medicine (TCM) [39.Gong X. Sucher N.J. Stroke therapy in traditional Chinese medicine (TCM): prospects for drug discovery and development.Trends Pharmacol. Sci. 1999; 20: 191-196Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar], and this could be regarded as its earliest application in the biomedical field. TCM correlates the living system with health and disease using Yin/Yang [37.Van Wijk R. et al.Human ultraweak photon emission and the Yin Yang concept of Chinese medicine.J. Acupunct. Meridian Stud. 2010; 3: 221-231Crossref PubMed Scopus (15) Google Scholar]. Regarding the human body, the inner part is Yin whereas the outer part is Yang; for the trunk, the abdomen is Yin whereas the back is Yang; for the internal organs, the viscera are Yin and the bowels are Yang; the heart, liver, spleen, lung, and kidney are Yin, whereas the gallbladder, stomach, intestines, bladder, and San Jiao ('triple burner', a functional organ that does not have a physical structure) are Yang. In modern biomedicine, Yin/Yang doctrine was first used in 1975 to describe the antagonistic action between cAMP and cGMP in cellular regulation [40.Goldberg N.D. et al.The Yin Yang hypothesis of biological control: opposing influences of cyclic GMP and cyclic AMP in the regulation of cell proliferation and other biological processes.in: Clarkson B. Baserga R. Control of Proliferation in Animal Cells. Cold Spring Harbor Laboratory, 1974: 609-625Google Scholar]. 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In hormesis, stimulation and inhibition represent opposite and correlated polarities that make up the biphasic dose–response curve – that reflects the dual beneficial and adverse effects of an agent. Hence, stimulation/inhibition may be regarded as a typical Yin/Yang pair, and their relationship follows the 4C laws of Yin/Yang doctrine (Box 1 for an example), as summarized later.(i)Yin/Yang containment: based on the definition of hormesis, stimulation and inhibition in a biological context represent opposite endpoints induced by an agent relative to controls.(ii)Yin/Yang consanguinity: although stimulation and inhibition are opposing effects, they both derive from a biological response in which both stimulation and inhibition originate from the same root, and both stimulation and inhibition are indispensable components of the hormetic dose–response relationship.(iii)Yin/Yang counterpoise: Yin and Yang wax and wane with time before they finally achieve an equilibrium; in time-dependent hormesis, stimulation and inhibition always tend to be stable at the end of exposure time.(iv)Yin/Yang conversion: in time-dependent hormesis, the stimulatory effect (or inhibitory effect) of an agent at a given dose may change into an inhibitory effect (or stimulatory effect) with increased exposure time (points 'P' in Figure I in Box 1).Box 1An Example Where the Yin/Yang Doctrine Reflects Time-Dependent HormesisSun et al. found that sulfapyridine (SPY) triggers time-dependent hormesis in the bioluminescence of Aliivibrio fischeri (A. fischeri) over a period of 24 h (Figure I) [56.Sun H. et al.A swinging seesaw as a novel model mechanism for time-dependent hormesis under dose-dependent stimulatory and inhibitory effects: a case study on the toxicity of antibacterial chemicals to Aliivibrio fischeri.Chemosphere. 2018; 205: 15-23Crossref PubMed Scopus (29) Google Scholar]. (i) In the first stage (1–4 h), SPY has no influence on bioluminescence. (ii) In the second stage (5–9 h), there is only stimulation of bioluminescence, and the hourly maximum stimulatory rate first increases and then decreases. (iii) In the third stage (10–16 h), SPY begins to inhibit the bioluminescence at high doses, and the hourly maximum inhibitory rate increases while the hourly maximum stimulatory rate continues to decrease. (iv) In the fourth stage (17–24 h), the hourly maximum stimulatory and inhibitory rates both tend to stabilize.The changing feature of this typical time-dependent hormetic phenomenon conforms to the 4C laws of the Yin/Yang relationship.(i)In the first stage (1–4 h), SPY does not yet enter the cells and thus does not affect bioluminescence. The dose–response curve is a flat line (equivalent to Yin/Yang counterpoise).(ii)In the second and third stages (5–16 h), SPY acts on stimulatory and inhibitory signaling pathways to trigger stimulation and inhibition of bioluminescence, and these stimulatory and inhibitory actions are distinct in the different growth phases of A. fischeri; thus, SPY begins to trigger hermetic effects on the bioluminescence, and the basic parameters of dose–response curve vary with the increase of exposure time (equivalent to Yin/Yang containment and conversion).(iii)In the fourth stage (17–24 h), A. fischeri growth enters stationary phase in which the stimulatory and inhibitory actions of SPY on the bioluminescence stabilize (equivalent to Yin/Yang consanguinity and counterpoise).It should be noted that Yin/Yang is an integrated concept that describes all pairs of contrary and unified polarities. Specifically, Yin is not necessarily stimulation, and Yang is not necessarily inhibition: in some cases Yin may be inhibition and Yang may be stimulation. Sun et al. found that sulfapyridine (SPY) triggers time-dependent hormesis in the bioluminescence of Aliivibrio fischeri (A. fischeri) over a period of 24 h (Figure I) [56.Sun H. et al.A swinging seesaw as a novel model mechanism for time-dependent hormesis under dose-dependent stimulatory and inhibitory effects: a case study on the toxicity of antibacterial chemicals to Aliivibrio fischeri.Chemosphere. 2018; 205: 15-23Crossref PubMed Scopus (29) Google Scholar]. (i) In the first stage (1–4 h), SPY has no influence on bioluminescence. (ii) In the second stage (5–9 h), there is only stimulation of bioluminescence, and the hourly maximum stimulatory rate first increases and then decreases. (iii) In the third stage (10–16 h), SPY begins to inhibit the bioluminescence at high doses, and the hourly maximum inhibitory rate increases while the hourly maximum stimulatory rate continues to decrease. (iv) In the fourth stage (17–24 h), the hourly maximum stimulatory and inhibitory rates both tend to stabilize. The changing feature of this typical time-dependent hormetic phenomenon conforms to the 4C laws of the Yin/Yang relationship.(i)In the first stage (1–4 h), SPY does not yet enter the cells and thus does not affect bioluminescence. The dose–response curve is a flat line (equivalent to Yin/Yang counterpoise).(ii)In the second and third stages (5–16 h), SPY acts on stimulatory and inhibitory signaling pathways to trigger stimulation and inhibition of bioluminescence, and these stimulatory and inhibitory actions are distinct in the different growth phases of A. fischeri; thus, SPY begins to trigger hermetic effects on the bioluminescence, and the basic parameters of dose–response curve vary with the increase of exposure time (equivalent to Yin/Yang containment and conversion).(iii)In the fourth stage (17–24 h), A. fischeri growth enters stationary phase in which the stimulatory and inhibitory actions of SPY on the bioluminescence stabilize (equivalent to Yin/Yang consanguinity and counterpoise). It should be noted that Yin/Yang is an integrated concept that describes all pairs of contrary and unified polarities. Specifically, Yin is not necessarily stimulation, and Yang is not necessarily inhibition: in some cases Yin may be inhibition and Yang may be stimulation. Yin/Yang doctrine also casts light on the dose-dependence of stimulation/inhibition, namely the shape of the hormetic dose–response curve. If we plot the concentration or dose of an agent on the x axis, and the extent of inhibition on a test endpoint on the y axis, the hormetic dose–response (i.e., dose–inhibition) relationship inevitably exhibits a biphasic J-shaped curve (Figure 1A). It is intriguing that when the curve of the demarcation between Yin and Yan (in the classical Yin/Yang symbol) is rotated through 90° clockwise or anticlockwise, it strongly resembles the characteristic J-shaped hormetic dose–response curve (Figure 2A ). Indeed, some parameters quantitively follow the Yin/Yang demarcation curve – areas A and B in Figure 2B (left) represent the first and second regions delineated by the Yin/Yang curve and the x axis; m and n refer to the widths of areas A and B, respectively; and p and q are the heights of areas A and B, respectively. These parameters can have corresponding meanings in the hormetic dose–response curve (right): A and B then represent areas of stimulation and inhibition, respectively; m and n denote the stimulatory and inhibitory concentration ranges, respectively; and p and q denote the maximum and minimum extents of stimulation and inhibition, respectively (Figure 2B, right). Based on the opposing but complementary relationship between Yin and Yang, the area of region A should be equal to the area of region B; furthermore, m should be equal to n, and p should be equal to q. However, in actual J-shaped hormetic dose–response curves the stimulatory region usually differs from the inhibitory region in width, height, and area [57.Ge H.L. et al.Predicting hormesis effects of ionic liquid mixtures on luciferase activity using the concentration addition model.Environ. Sci. Technol. 2011; 45: 1623-1629Crossref PubMed Scopus (81) Google Scholar, 58.Puzzo D. et al.Hormetic effect of amyloid-beta peptide in synaptic plasticity and memory.Neurobiol. Aging. 2012; 33: 1484Crossref PubMed Scopus (94) Google Scholar, 59.Zhang Y. et al.The hormetic effect of cadmium on the activity of antioxidant enzymes in the earthworm Eisenia fetida.Environ. Pollut. 2009; 157: 3064-3068Crossref PubMed Scopus (106) Google Scholar], although this depends on the test organism, endpoint, concentration range, timepoint, and other parameters that influence the extent of both stimulation and inhibition. Moreover, the typical J-shaped hormetic dose–response curve is not exactly equivalent to the Yin/Yang curve: in detail, the extent of inhibition in the hormetic dose–response curve first decreases and then increases to a stable value (often approaching 100%, Figure 1A). We suggest that this depends on the test endpoint. The most commonly used endpoints in toxicology and pharmacology are qualitative, such as cell proliferation, cell vitality, or cell death [60.Berthois Y. et al.SR31747A is a sigma receptor ligand exhibiting antitumoural activity both in vitro and in vivo.Brit. J. Cancer. 2003; 88: 438-446Crossref PubMed Scopus (33) Google Scholar, 61.Coradini D. et al.Effects of toremifene and its main metabolites on growth of breast cancer cell lines.Anticancer Res. 1991; 11: 2191-2197PubMed Google Scholar, 62.Butler W.B. Fontana J.A. Responses to retinoic acid of tamoxifen-sensitive and -resistant sublines of human breast cancer cell line MCF-7.Cancer Res. 1992; 52: 6164-6167PubMed Google Scholar], which do not reflect the response of organism once the extent of inhibition reaches a maximum. We opine that the ideal J-shaped hormetic dose–response curve may display variations that themselves are similar to the Yin/Yang demarcation curve (Figure 2C), notably when the test endpoints reflect complex biological activities (e.g., bacterial bioluminescence; Box 1) rather than qualitative measures (e.g., cell proliferation), and when the organisms are exposed to wide dose range of agent (theoretically extending to an infinite dose). In such cases we speculate that the hormetic dose–response relationship may display undulations that reflect several successive Yin/Yang curves (Figure 2C). When the toxicity of an agent is tested at different time-points following exposure, the hormetic effects often vary with time, exhibiting time-dependent features [56.Sun H. et al.A swinging seesaw as a novel model mechanism for time-