Hormesis Calabrese, EJ; Iavicoli, I; Calabrese, V
Human & experimental toxicology,
02/2013, Letnik:
32, Številka:
2
Journal Article
Recenzirano
This article offers a broad assessment of the hormetic dose response and its relevance to biomedical researchers, physicians, the pharmaceutical industry, and public health scientists. This article ...contains a series of 61 questions followed by relatively brief but referenced responses that provides support for the conclusion that hormesis is a reproducible phenomenon, commonly observed, with a frequency far greater than other dose–response models such as the threshold and linear nonthreshold dose–response models. The article provides a detailed background information on the historical foundations of hormesis, its quantitative features, mechanistic foundations, as well as how hormesis is currently being used within medicine and identifying how this concept could be further applied in the development of new therapeutic advances and in improved public health practices.
A relational retrieval database has been developed compiling toxicological studies assessing the occurrence of hormetic dose responses and their quantitative characteristics. This database permits an ...evaluation of these studies over numerous parameters, including study design and dose–response features and physical/chemical properties of the agents. The database contains approximately 5600 dose–response relationships satisfying evaluative criteria for hormesis across over approximately 900 agents from a broadly diversified spectrum of chemical classes and physical agents. The assessment reveals that hormetic dose–response relationships occur in males and females of numerous animal models in all principal age groups as well as across species displaying a broad range of differential susceptibilities to toxic agents. The biological models are extensive, including plants, viruses, bacteria, fungi, insects, fish, birds, rodents, and primates, including humans. The spectrum of endpoints displaying hormetic dose responses is also broad being inclusive of growth, longevity, numerous metabolic parameters, disease incidences (including cancer), various performance endpoints such as cognitive functions, immune responses among others. Quantitative features of the hormetic dose response reveal that the vast majority of cases display a maximum stimulatory response less than two-fold greater than the control while the width of the stimulatory response is typically less than 100-fold in dose range immediately contiguous with the toxicological NO(A)EL. The database also contains a quantitative evaluation component that differentiates among the various dose responses concerning the strength of the evidence supporting a hormetic conclusion based on study design features, magnitude of the stimulatory response, statistical significance, and reproducibility of findings.
During the early part of the past century, hundreds of clinical studies involving more than 37,000 patients were conducted that showed radiotherapy (RT) to be a successful and safe alternative to ...drug therapy for the treatment of many diverse inflammatory conditions and diseases (e.g. tendonitis, bursitis, arthritis, and serious inflammatory lung conditions). Data from these studies were collected and analyzed with the intent of estimating an optimal dosing range for RT that would induce an efficacious treatment response. RT was reported to be frequently effective after only a single treatment, with a rapid (within 24 h) and often long-lasting (from months to years) relief from symptoms. Over a two-decade span from the 1920s to the 1940s, the therapeutic responses to a single RT treatment consistently improved as the dosing for multiple ailments decreased over time to between 30 roentgen (r) and 100 r. These findings are significant and in agreement with a number of contemporary reports from Germany where RT has been commonly and successfully employed in treating ailments with an inflammatory origin. A proposed mechanism by which RT mitigates inflammation and facilitates healing is via the polarization of macrophages to an anti-inflammatory or M2 phenotype.
Measurements of cosmic microwave background (CMB) anisotropies provide strong evidence for the existence of dark matter and dark energy. They can also test its composition, probing the energy density ...and particle mass of different dark-matter and dark-energy components. CMB data have already shown that ultralight axions (ULAs) with mass in the range 10−32 eV→10−26 eV compose a fraction ≲0.01 of the cosmological critical density. The next Stage-IV CMB experiment (CMB-S4) (assuming a 1 arcmin beam and ∼1 μK−arcmin noise levels over a sky fraction of 0.4) to the density of ULAs and other dark-sector components is assessed. CMB-S4 data should be ∼10 times more sensitive to the ULA energy density than Planck data alone, across a wide range of ULA masses 10−32≲ma≲10−23 eV, and will probe axion decay constants of fa≈1016 GeV, at the grand unified scale. CMB-S4 could improve the CMB lower bound on the ULA mass from ∼10−25 eV to 10−23 eV, nearing the mass range probed by dwarf galaxy abundances and dark-matter halo density profiles. These improvements will allow for a multi-σ detection of percent-level departures from CDM over a wide range of masses. Much of this improvement is driven by the effects of weak gravitational lensing on the CMB, which breaks degeneracies between ULAs and neutrinos. We also find that the addition of ULA parameters does not significantly degrade the sensitivity of the CMB to neutrino masses. These results were obtained using the axionCAMB code (a modification to the CAMB Boltzmann code), presented here for public use.
Regular consumption of cruciferous vegetables or spices is associated with a reduced incidence of cancer and reduction of markers for neurodegenerative damage. Furthermore, greater health benefit may ...be obtained from raw as opposed to cooked vegetables. Nutritional interventions, by increasing dietary intake of fruits and vegetables, can retard and even reverse age-related declines in brain function and cognitive performance. The mechanisms through which dietary supplementation with antioxidants may be useful to prevent free radical-related diseases is related to their ability to counteract toxic production of both reactive oxygen and nitrogen species, along with the up-regulation of vitagenes, such as members of the heat shock protein (Hsp) family heme oxygenase-1 and Hsp70. The most prominent dietary factor that affects the risk of many different chronic diseases is energy intake - excessive calorie intake increases the risk. Reducing energy intake by controlled caloric restriction or intermittent fasting increases lifespan and protects various tissues against diseases, in part, by hormetic mechanisms that increase cellular stress resistance. This biphasic dose-response relationship, referred to here as hormesis, display low-dose stimulation and a high-dose inhibition. Despite the current interest in hormesis by the toxicology community, quantitatively similar U-shaped dose responses have long been recognized by researchers to be involved with factors affecting memory, learning, and performance, as well as nutritional antioxidants and oxidative stress-mediated degenerative reactions. Dietary polyphenols present strong cytoprotective effects, however under uncontrolled nutritional supplementation gene induction effects and the interaction with detoxification responses can have negative consequences through the generation of more reactive and harmful intermediates.
The threshold dose-response model is widely viewed as the most dominant model in toxicology. The present study was designed to test the validity of the threshold model by assessing the responses of ...doses below the toxicological NOAEL (no observed adverse effect level) in relationship to the control response (i.e., unexposed group). Nearly 1800 doses below the NOAEL, from 664 dose-response relationships derived from a previously published database that satisfied a priori entry criteria, were evaluated. While the threshold model predicts a 1:1 ratio of responses “greater than” to “less than” the control response (i.e., a random distribution), a 2.5:1 ratio (i.e., 1171:464) was observed, reflecting 31% more responses above the control value than expected (p < 0.0001). The mean response (calculated as % control response) of doses below the NOAEL was 115.0% ± 1.5 standard error of the mean (SEM). These findings challenge the long-standing belief in the primacy of the threshold model in toxicology (and other areas of biology involving dose-response relationships) and provide strong support for the hormetic-like biphasic dose-response model characterized by a low-dose stimulation and a high-dose inhibition. These findings may affect numerous aspects of toxicological and biological/biomedical research related to dose-response relationships, including study design, risk assessment, as well as chemotherapeutic strategies.
Hormesis has been defined as a dose-response relationship in which there is a stimulatory response at low doses, but an inhibitory response at high doses, resulting in a U- or inverted U-shaped dose ...response. To assess the proportion of studies satisfying criteria for evidence of hormesis, a database was created from published toxicological literature using rigorous a priori entry and evaluative criteria. One percent (195 out of 20,285) of the published articles contained 668 dose-response relationships that met the entry criteria. Subsequent application of evaluative criteria revealed that 245 (37% of 668) dose-response relationships from 86 articles (0.4% of 20,285) satisfied requirements for evidence of hormesis. Quantitative evaluation of false-positive and false-negative responses indicated that the data were not very susceptible to such influences. A complementary analysis of all dose responses assessed by hypothesis testing or distributional analyses, where the units of comparison were treatment doses below the NOAEL, revealed that of 1089 doses below the NOAEL, 213 (19.5%) satisfied statistical significance or distributional data evaluative criteria for hormesis, 869 (80%) did not differ from the control, and 7 (0.6%) displayed evidence of false-positive values. The 32.5-fold (19.5% vs 0.6%) greater occurrence of hormetic responses than a response of similar magnitude in the opposite (negative) direction strongly supports the nonrandom nature of hormetic responses. This study, which provides the first documentation of a data-derived frequency of hormetic responses in the toxicologically oriented literature, indicates that when the study design satisfies a priori criteria (i.e., a well-defined NOAEL, ≥ 2 doses below the NOAEL, and the end point measured has the capacity to display either stimulatory or inhibitory responses), hormesis is frequently encountered and is broadly represented according to agent, model, and end point. These findings have broad-based implications for study design, risk assessment methods, and the establishment of optimal drug doses and suggest important evolutionarily adaptive strategies for dose-response relationships.
Recent evidence demonstrates that Crocus sativus L. (saffron) counteracts oxidative stress, mitochondrial dysfunction and neuroinflammation, closely linked to initiation and progression of major ...brain pathologies. Interestingly, saffron constituents such as crocin, crocetin and safranal can exert antioxidant or toxic effects depending on their endogenous concentration. According to the hormesis principles, at low dose they act as antioxidants in a wide range of brain diseases by upregulating Nrf2 signaling pathway and the expression of vitagenes, such as NAD(P)H-quinone oxidoreductase (NQO1), glutathione transferase (GT), heme oxygenase-1 (HO-1), sirtuin-1 (Sirt1) and thioredoxin (Trx) system. Importantly, neuronal dysregulation of Nrf2 pathway can be a prominent cause of selective susceptibility, under neuroinflammatory conditions, due to the high vulnerability of brain cells to oxidative stress. Here we discuss natural inducers from saffron targeting Nrf2/vitagene pathway for development of new therapeutical strategies to suppress oxidative stress and neuroinflammation and consequently cognitive dysfunction. In this review we also focus on the hormetic effect of saffron active constituents, summarizing their neuroprotective and anti-neuroinflammatory properties, as well as pharmacological perspectives in brain disorders.
•Saffron and its active constituents exert anti-inflammatory and antioxidants effects acting via transcription of vitagenes.•Saffron preparations are promising agents for therapeutic applications in the treatment of neurodegenerative disorders.•The dose-response pattern of saffron within a hormetic response is able to modulate oxidative stress.
In 2006, Henschler disputed the claim of Calabrese and Baldwin that Hugo Schulz should be considered the originator of the hormesis concept. Henschler cited an 1854 paper by Rudolf Virchow on the ...effects of two agents on the beating of cilia, which showed a hormetic–biphasic dose response. The interpretation of Henschler became broadly accepted over the past decade based on citations in the literature. However, a recent translation of the Virchow paper from German into English reveals that the claims of Henschler are not supported by the article.
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