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OBJECTIVE: In this commentary I respond to points raised in the commentary by Mushak [Ad hoc and fast forward: the science and control of hormesis growth and development. Environ Health [...]

BACKGROUND: Hormesis is a binary response phenomenon with low-dose stimulation (or inhibition) of effects by substances producing opposite high-dose responses. Hormesis, after decades of obscurity, has undergone a renaissance in [...]

Epidemiological studies indicate that patients suffering from atherosclerosis are predisposed to develop osteoporosis. Atherogenic determinants such as oxidized low-density lipoprotein (oxLDL) particles have been shown both to stimulate the proliferation and promote apoptosis of bone-forming osteoblasts. Given such opposite responses, we characterized the oxLDL-induced hormesis-like effects in osteoblasts. Biphasic 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reductive activity responses were induced by oxLDL where low concentrations (10-50 [micro]g/ml) increased and high concentrations (from 150 [micro]g/ml) reduced the MTF activity. Cell proliferation stimulation by oxLDL partially accounted for the increased MTT activity. No alteration of mitochondria mass was noticed, whereas low concentrations of oxLDL induced mitochondria hyperpolarization and increased the cellular levels of reactive oxygen species (ROS). The oxLDL-induced MTT activity was not related to intracellular ROS levels. OxLDL increased NAD(P)H-associated cellular fluorescence and flavoenzyme inhibitor diphenyleneiodonium reduced basal and oxLDL-induced MTT activity, suggesting an enhancement of NAD(P)H-dependent cellular reduction potential. Low concentrations of oxLDL reduced cellular thiol content and increased metallothionein expression, suggesting the induction of compensatory mechanisms for the maintenance of cell redox state. These concentrations of oxLDL reduced osteoblast alkaline phosphatase activity and cell migration. Our results indicate that oxLDL particles cause hormesis-like response with the stimulation of both proliferation and cellular NAD(P)H-dependent reduction potential by low concentrations, whereas high concentrations lead to reduction of MTT activity associated with the cell death. Given the effects of low concentrations of oxLDL on osteoblast functions, oxLDL may contribute to the impairment of bone remodeling equilibrium. osteoblasts; atherosclerosis; oxysterol

The present assessment places hormetic dose responses within an historical context, documenting its origin, rejection by the biomedical community during the early decades of the 20th due to its close association with homeopathy and its revitalization during the later decades of the past century as the biomedical and toxicological communities became very interested in low dose effects of drugs and environmental agents. Particular attention is directed to assessing the quantitative features of the hormetic dose response, its underlying mechanisms and its implications for drug development and environmental risk assessment. Key words: Hormesis, biphasic, U-shaped, J-shaped, adaptive response, drug discovery, drug development,, INTRODUCTION Biphasic dose response relationships are commonly observed in the toxicological and pharmacological literature. Such dose response relationships have been typically observed as being a low dose stimulation while inhibition [...]

Single or multiple exposure to low doses of potentially harmful agents can have a variety of anti-aging and longevity-extending hormetic effects. These hormetic stressors include irradiation, physical activity, food limitation, heat, hypergravity, dietary components and reactive oxygen species. Molecular mechanisms facilitating the hormetic effects are being elucidated and comprise a cascade of stress response and maintenance and repair pathways. Although the extent of immediate hormetic effects after exposure to a particular stress may only be moderate, the chain of events following initial hormesis leads to biologically amplified effects that are much larger, synergistic and pleiotropic. A consequence of hormetic amplification is an increase in overall defence capacity of cells and organisms. Therefore, healthy aging may be achieved by hormesis through mild and periodic, but not severe or chronic, physical and mental challenges and by the use of dietary hormesis incorporating mild stress-inducing molecules called hormetins. However, prescribing a practical anti-aging hormetic regimen comprising physical, chemical, dietary and psychological stressors requires detailed information akin to that needed to develop personalized medicine. Key words: Aging, anti-aging, exercise, heat shock, homeostasis, homeodynamics, hormetin, longevity, stress, INTRODUCTION Biogerontological research has now established that the primary molecular phenotype of aging is the occurrence and accumulation of intra-cellular and intercellular molecular damage [1]. The main reason for the [...]

Hormesis refers to the ability of a chemical or physical agent to condition the physiological state of an organism to tolerate stress with low doses of otherwise harmful agents. Evolutionary evidence shows that the survival and longevity of species hinge on their optimal ability to resist stress challenge. Hormesis is a potent strategy to stimulate latent repair processes to tolerate a specific challenge. Examples of hormetic agent-mimetics, which induce at least partial physiological conditioning, activate known pathways of longevity determinants, i.e., genetic stability, altered metabolism, immunoregulation and stress resistance. Despite the diversity of age-related diseases, glucose and oxidation-mediated protein and DNA damage are common denominators. The associated physiological conditioning-benefits may trigger: 1) activation of latent stress resistance pathways of youthful DNA repair; 2) increased resistance to oxidizing pollutants; 3) improved protein structure and function; 4) improved immunity; 5) damaged tissue remodeling; 6) adjustments in central and peripheral nervous systems; 7) altered metabolism; and 8) delay or breaking of inappropriate protein cross-links. Hormetic mimetics have intervention potential in cancer, diabetes, age-related diseases, infectious diseases, heart and kidney failure, cardiovascular diseases and Alzheimer's disease. Small nucleotide SOS signals, dipeptides, ethanol, thiols, and metals and conserved peptide sequences found in sharks, frogs, woodchucks, and bears, can regulate cytokines, cellular immunity, and central and peripheral neuronal regulatory pathways to promote healthy blood pressure maintenance, heart rate, and metabolic pathways. disease sensitivity. Conserved stress mimetics are highlighted here that rejuvenate DNA and proteins repair and thus may intervene in aging, disease, and trauma. Hibernation Induction Trigger mimetics, Deltorphins, emerge as novel hormetic agents, effective both as pre and post exposure to physiological conditioners to tolerate stress, and prevent damage, and delay possibly aging. Hormesis mimetics offer powerful survival strategies, with better control over the beneficial dose response. Combinations of several mimetics may more closely mimic environmental challenges, which stimulate multiple stress responses. Key words: Mimetics, aging, radiation, diet restriction, hibernation, INTRODUCTION Hans Seyle emphasized that we must be guided by the principle to learn to imitate-and if necessary to correct and complement-the body's own molecular mechanisms used to combat the [...]

The mortality of a population reflects the combined effects of natural aging with environmental insults (e.g. toxicant exposure, caloric restriction, over feeding, infections, etc.). No single endpoint, such as carcinogenesis, completely describes toxicant-induced effects in laboratory animals. Mathematical models of mortality and time-dependent exposure to toxicants can yield indices of net injury from all causes. With careful manipulation of diet in control groups, the separate and combined effects of hormesis, caloric restriction and toxicity on mortality can be delineated. In particular, age-specific mortality rate analyses can characterize a) the temporal pattern of net injury from acute, short term and chronic environmental exposure, b) late-life effects, c) effects of fractional exposures and d) relative biological effectiveness. Changes in the design of toxicity studies and analyses of mortality data are suggested. Key words: Hormesis, caloric restriction, mortality, chronic toxicity, INTRODUCTION Hormesis and caloric restriction have been considered as related phenomena in laboratory rodents (see Human and Experimental Toxicology vol. 19 no 6, 2000). [1] Laboratory rodents are typically inbred [...]

The goals of this review were to identify methylene blue (MB) as a compound that follows hormetic behavior for a wide range of effects and to address the question of what is unique about MB that could account for its wide applicability and hormetic behavior as a drug. The MB hormetic doseresponse relationship is exemplified by an increase in various behavioral, physiological and biochemical responses with increasing dose, followed by a decrease in the same responses with an even higher dose, until the responses are equal to control responses. With MB doses increasing beyond the hormetic zone, the responses decrease even further, until they are below the control responses. At doses spanning its hormetic zone, MB can increase select responses until they are 130-160% of control. For example, low doses of MB produce maximum behavioral and biochemical responses with averages of approximately 140% of control. As MB dose is raised outside the hormetic zone the response decreases below the control response, as exemplified by MB's ability to increase cytochrome oxidase activity at intermediate doses, while decreasing cytochrome oxidase activity at higher doses. It is proposed that MB's autoxidizable chemical property may be responsible for its unique biological action as both a metabolic energy enhancer and antioxidant that is frequently characterized by hormetic dose-response relationships. Key words: Memory, cytochrome oxidase, redox, hormesis, biological stress, neuroprotection, INTRODUCTION Methylene blue (MB) is a remarkable compound in the history of pharmacology and chemotherapeutics. MB was the first phenothiazine compound developed and it has active biological properties which have [...]

Hormesis-like effects of immunity have been documented during tumor-growth experiments in mice, quantitatively large immune-reactions have inhibited while lesser quantities of the same specific immune-reactants have been stimulatory to the growth of implanted tumors. Likewise, carcinogenesis has been inhibited by a high quantities of immune reactants, but positively stimulated by lower levels of the same reactants. One observation suggests that malignant transformation may seldom, if ever, occur in vivo if there is no immune reaction against the incipient neoplasm. These and many similar observations suggest a real danger that some vaccines might stimulate rather than inhibit tumor growth. These hormesis-like effects may help to provide explanations for a number of otherwise perplexing observations such as the following: (1): The fact that immunodepression for heart or kidney allografting results in an increased incidence of some tumors, especially leukemias and skin tumors, while others, such as those of breast and rectum, show a decreased incidence in these immunodepressed patients, (2): The possible dependency of carcinogenesis on an immune reaction, (3): The fact that adult Down's syndrome patients are unexpectedly resistant to solid tumors, especially breast-carcinoma, but have a very high incidence of leukemia, (4): The fact that Kaposi's sarcoma in an AIDS-patient often tends to flare as the patient's disease is ameliorated, (5): The sneaking through phenomenon, (6): Lastly, some peculiarities in the metastatic patterns of tumors of various types. Key words: Carcinogenesis, tumor-immunostimulation, tumor-immunosurveillance, down-syndrome, kaposi's-sarcoma, INTRODUCTION Many toxins exhibit a nonlinear dosage effect called hormesis. This study is limited to a consideration of the hormetic-like effects of tumor-specific immunity on carcinogenesis and tumor growth, hormetic [...]

Contraction-induced production of reactive oxygen and nitrogen species has been shown to cause oxidative stress to skeletal muscle, heart and other organs. As an adaptive response, muscle antioxidant defense systems are upregulated in response to exercise to restore intracellular prooxidant-antioxidant homeostasis. Thus, both young and old animals and humans involved in regular exercise have shown reduced oxidative damage during acute physical exertion at accustomed or excessive intensity, or under oxidative challenges otherwise deemed detrimental. The current article provides a brief review of this exercise-induced hormesis with the emphasis on the role of redox sensitive signal transduction pathways (mainly nuclear factor kB and mitogen-activated protein kinase) that can activate the gene expression of antioxidant enzymes and proteins. Molecular mechanisms and gene targets for these signaling pathways, as well as the biological significance of the adaptations, are discussed. Key words: Antioxidant, exercise, oxidative stress, reactive oxygen species, signaling, INTRODUCTION Maintenance of oxidative -antioxidant homeostasis is critical for cell survival and normal function [1]. In the field of free radical biochemistry, one paradox continues to puzzle both researchers and [...]

An emerging concept of cancer chemotherapy is that of chemosensitization. Most often applied to the treatment of drug-resistance cancers, chemosensitization has utility when such cancers are rendered drug sensitive through treatment with the sensitizing agent. A particularly striking example of chemosensitization is that encountered with the synthetic isoflavene phenoxodiol where patients with taxane- and/or platinum-resistant ovarian carcinoma once again become sensitive to these drugs following treatment with phenoxodiol. The latter appears to be a true chemosensitization in that the phenoxodiol need not be co-administered with the taxane or platinum drugs. Sensitivity is retained many weeks after the phenoxodiol has been cleared from the system. The response appears to be mediated through the primary drug target of phenoxodiol, a cancer-specific cell surface ECTO-NOX or ENOX protein designated tNOX (ENOX2). The ENOX protein family has been previously recognized as a hormetic target. The hypothesis under investigation is that chemosensitization and low dose synergies are most obvious in the hormetic range of concentrations and that the two phenomena, hormesis and chemosensitization, may be related mechanistically. Key words: ECTO-NOX, NADH oxidase, cancer, phenoxodiol, sulforaphane, paclitaxel, cisplatin, HeLa cells, ovarian carcinoma, INTRODUCTION Hormesis is a dose-response phenomenon characterized by low-dose stimulation and a high-dose inhibition (Fig. 1) [1,2]. Hormesis is most often observed in the context of a dose-time-response framework where [...]

Polyphenols such as resveratrol and quercetin, which are produced by stressed plants, activate sirtuin enzymes and extend the lifespan of fungi and animals, ostensibly by mimicking the beneficial effects of caloric restriction. This observation raises an interesting question: Why should foreign molecules that are non-nutritive and seemingly unrelated to any endogenous molecule modulate the same biochemical pathways that mediate the response to an energy deficit? A possible explanation is that the sirtuin enzymes have evolved to respond to plant stress molecules as indicators of an impending deterioration of the environment. This idea has become known as the Xenohormesis Hypothesis, the name stemming from a combination of the prefix xeno-(for stranger) with hormesis (a protective response induced by mild stress). Here we review the evidence for xenohormesis in a broader context, taking into account the diverse spectrum of phytochemicals to which animals are exposed. We also consider alternative hypotheses that may explain some of the beneficial effects of plant-based foods. We suggest that xenohormesis, defined as an adaptive response in the physiology of an organism to molecular cues that are neither nutritive nor direct stressors, most likely occurs at some level. Whether this can fully or partially account for the beneficial effects of resveratrol and other phytochemicals remains to be seen. However, there is already sufficient cause to re-evaluate the relationship between complex organisms, including humans and their food. Key words: Hormesis, phytochemical, plant, resveratrol, polyphenol, INTRODUCTION It has long been appreciated that diets rich in fruits and vegetables promote health, reduce the risk of both cancer [1] and cardiovascular disease [2] and correlate with increased [...]

Classical monoamine oxidases and copper-containing semicarbazide-sensitive amine oxidases are drug targets for a variety of established and novel pharmaceuticals used to treat conditions such as depression, Parkinsonism and inflammatory disorders. Development of enzyme inhibitors, both historically and currently, assumes an underlying adherence of these enzymes to Michaelis-Menten kinetic principles. In this mini-review, we discuss historical data from several laboratories and novel data from our own laboratories which show clearly that such an assumption is invalid. Rather, these enzymes often display hormetic behaviour towards their substrates, resulting in bell-shaped kinetic plots. We outline possible underlying mechanisms which might account for this behaviour and show how novel reversible hormetic drugs may capitalise on these mechanisms to introduce a new dimension in selectivity. The potential future benefits for therapeutic modulation of amine oxidase activities are discussed. Key words: enzyme kinetics, amine oxidases, substrates, imidazolines, cations, INTRODUCTION Mammalian amine oxidase enzymes play critically important roles in physiological and pathological tissue development and function. These roles are, for the most part, directly related to the enzymatic capacity [...]

A number of chemicals including antioxidants, vitamins and hormones are widely advertised as anti-aging drugs (geroprotectors). It is usually believed that life-extending capacity of geroprotectors may be attributed to their specific anti-aging mechanisms, even without solid scientific evidence. The analysis of the survival data gathered by both anti-aging and hormetic interventions demonstrates that many essential similarities exist between them. The evidence that life-extending effects of anti-aging drugs may be due to hormetic-like response is discussed in this review. Key words: Anti-aging, geroprotectors, hormesis, longevity, INTRODUCTION One of the most important problems in modern gerontology is the development of means to extend healthy lifespan. Recently, a number of nutrients and chemicals have been widely advertised [...]

The potential of hormesis as the default model to assess and manage chemicals is considered in relation to micronutrients. It is pointed out that micronutrients, despite their well-known U-shaped dose-response curve, are assessed and managed only with excess-exposure in mind. Hereby a schism between health and safety is unjustifiably realized. This proves to be the conundrum of basically all chemicals regulation. It is proposed that hormesis could in principle address this conundrum. Key words: Hormesis, micronutrients, conundrum, INTRODUCTION Risk is an influential aspect of modern-day society. Terrorism, food-safety, climate change, to mention just three disparate subjects, dominate media and politics. But before we get bogged down into [...]

The aim of the present investigation was to assess neuroprotection exerted by GABA (100 nM-100 mM) in rat cortical brain slices subjected to oxygen-glucose deprivation and reoxygenation. Neuronal injury and neuroprotection were assessed by measuring the release of glutamate and lactate dehydrogenase and tissue water content. Results demonstrate that GABA exerted neuroprotective effects according to a U-shaped, hormetic-like, concentration-response curve, with an efficacy window of 10-100 [micro]M concentration. In order to verify whether GABA-neuroprotective effects were [GABA.sub.A]-or [GABA.sub.B]-mediated, Muscimol ([GABA.sub.A] agonist) and Baclofen ([GABA.sub.B] agonist) were tested. Results demonstrated that only Muscimol exerted neuroprotection according to a U-shaped, hormetic-like, concentration-response curve, while baclofen was ineffective. In conclusion, the hormetic response of GABA or [GABA.sub.A] agonists should be taken into consideration when designing experiments aimed at assessing neuroprotection by these agents against ischemia/reoxygenation injury. Key words: Brain ischemia, GABA, hormesis, GABA agonist/antagonist, neuroprotection, INTRODUCTION Ischemic injury to cerebral tissues triggers complex biochemical cascades that ultimately lead to neuronal death. Excessive excitatory neurotransmitter release occurs during this process, stimulating excitotoxic conditions that hasten depletion [...]

Many environmental stressors elicit biphasic effects from single cells. Such cellular hormesis may be interpreted in terms of (a) the superimposition of simple biochemical processes or (b) the non-specific behaviour of the cell. The latter approach is emphasized in this article and identified with the universal cell response (UCR); however, the importance of identifying molecular-level concomitants of the UCR is also acknowledged. One difficulty is that when the dose of ligand is very low, mass-action assumptions become invalid and reliable analysis of receptor-ligand interactions requires knowledge of the binding mechanism; this difficulty is discussed. The UCR (cellular hormesis) and its possible underlying mechanisms are considered in the framework of a general scheme of cell life, which logically implies cellular homeostasis or homeorhesis. This framework may be particularly helpful for elucidating and perhaps quantifying conditioning hormesis (adaptation to stressors). The findings of studies on the UCR cannot be extrapolated unequivocally to hormesis in whole organisms or populations and cellular-level hormesis cannot be inferred from whole-organism hormesis. Nevertheless, it has been argued that a better understanding of the underlying cellular mechanisms, i.e., of the UCR, may facilitate the analysis of whole-organism and population data. Key words: Universal cell response, cellular homeostasis, law of mass action, INTRODUCTION Failure to establish a credible mechanistic explanation of hormesis may partly explain why the scientific community remained sceptical about the phenomenon for so long, though there were other contributing [...]

In his letter, Mushak revisits his criticism (Mushak 2009) of previously reported hormesis frequency estimates (Calabrese and Baldwin 2001, 2003; Calabrese et al. 2006, 2008). In my commentary (Calabrese 2009). [...]

INTRODUCTION Hormesis is defined as 'a very low dose of a chemical agent [which] may trigger from an organism the opposite response to a very high dose' (Wikipedia, the free [...]

In his commentary in Environmental Health Perspectives, Calabrese (2009) offered a number of responses to my critique of hormesis methodology (Mushak 2009). Here I will provide a counterpoint to that [...]

HEALTH POLICY | The Precautionary Principle and Radiofrequency Exposures The precautionary principle may be roughly defined as the precept or belief that actions should be taken to avoid or reduce [...]