Hormesis, cellular stress response, and redox homeostasis in autism spectrum disorders.

In the United States, 1.1-1.5% of children have been diagnosed with autism spectrum disorders (ASD), corresponding to a 30% increase in incidence and prevalence. Social and communication impairments are the main signs and symptoms of ASD, and currently available medications have been ineffective in reducing these core deficits. Observational studies have indicated that children with ASD tend to show improved cognition and behavior after febrile illness, which is associated with alteration of metabolic pathways, leading to cellular stress responses and increased expression of heat shock proteins (Hsps). Sulforaphane and hydroxytyrosol, phytochemicals derived from cruciferous vegetables and extra virgin olive oil, respectively, can induce metabolic effects in cellular stress responses that are similar to those produced by fever. Thus, modulation of endogenous cellular defense mechanisms may be an innovative approach for therapeutic intervention in ASD and other disorders associated with neuroinflammation and neurodegeneration. This Review introduces the hormetic dose-response concept and presents possible mechanisms and applications for neuroprotection. We address the emerging role of Hsps in the neuroprotective network of redox stress-responsive mechanisms and propose the potential therapeutic utility of the nutritional antioxidants sulforaphane and hydroxytyrosol against particular signs and symptoms of ASD. We argue that such research findings must be approached with pragmatism and prudence. It is vital to capitalize on recent and ongoing investments in brain science research and to refine neuroscientific knowledge and capability for more accurate diagnosis and safe, effective, and ethically sound treatment of ASD and other neuropsychiatric spectrum disorders. © 2016 Wiley Periodicals, Inc.

Redox modulation of stress resilience by Crocus sativus L. for potential neuroprotective and anti-neuroinflammatory applications in brain disorders: From molecular basis to therapy.

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.

Radiotherapy treatment of human inflammatory diseases and conditions: Optimal dose.

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.

Funding trends in hormetic research.

The topic of hormesis research funding has been a focus of deliberation within the scientific community for several decades. A common assumption/belief is that most hormesis research is funded by the private sector. With this assumption may emerge questions revolving around potential bias of such research. To provide some clarification to this issue, all hormesis research articles were obtained through online databases for 5-year increments starting with 1995 and ending with 2015 and were subsequently categorized by their funding source. A total of 710 articles were found for those years and 383 of those reported information on funding sources. Reporting funding is not required by law and until more recently was not encouraged or required by funders, research institutions, and/or scientific publishers. The analysis revealed that the assumption that the majority of hormesis research has been privately funded was not supported, with the public sector (i.e. federal and state governmental agencies) exclusively contributing to 78% of the reported research funding. Going forward, funding transparency for scientific research as a whole is essential within the scientific community as it may affect how research may be perceived, accepted, and applied.

Originator of the hormesis concept: Rudolf Virchow or Hugo Schulz.

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.

Low doses of dietary lead are associated with a profound reduction in the time to the onset of puberty in female mice.

We report results from a replication in second and third generation female mice of accelerated time to puberty associated with low Pb exposure levels . Mice in the 2nd generation study are offspring of mice from the initial study; the 3rd generation mice are offspring from mice in the 2nd generation study. For each generation the time to puberty onset was markedly influenced by exposure to dietary lead. Modest increases in blood lead concentration from a normal background of 2-3 to 8-13 micro g/dl delayed the onset of puberty by 10-20% from a normal of 33-35 days to about 40-43 days; reducing blood lead from 2-3 to 0.7 micro g/dl was associated with profound acceleration of puberty to 21 days, an enhancement by over 30%. This dose-response relationship, which replicates previous novel findings, has possible ecological as well as public health significance and indicates that lead is able to induce biologically significant changes at blood lead levels previously thought to be without effect.

Adaptive preconditioning in neurological diseases - therapeutic insights from proteostatic perturbations.

In neurological disorders, both acute and chronic neural stress can disrupt cellular proteostasis, resulting in the generation of pathological protein. However in most cases, neurons adapt to these proteostatic perturbations by activating a range of cellular protective and repair responses, thus maintaining cell function. These interconnected adaptive mechanisms comprise a 'proteostasis network' and include the unfolded protein response, the ubiquitin proteasome system and autophagy. Interestingly, several recent studies have shown that these adaptive responses can be stimulated by preconditioning treatments, which confer resistance to a subsequent toxic challenge - the phenomenon known as hormesis. In this review we discuss the impact of adaptive stress responses stimulated in diverse human neuropathologies including Parkinson׳s disease, Wolfram syndrome, brain ischemia, and brain cancer. Further, we examine how these responses and the molecular pathways they recruit might be exploited for therapeutic gain. This article is part of a Special Issue entitled SI:ER stress.

Hormesis: U-shaped dose responses and their centrality in toxicology.

The fundamental nature of the dose response is neither linear or threshold, but rather U-shaped. When studies are properly designed to evaluate biological activity below the traditional toxicological threshold, low-dose stimulatory responses are observed with high frequency and display specific quantitative features. With a few exceptions, the low-dose stimulatory response is usually not more than twofold greater than the control response, with a stimulatory zone that is more variable, ranging from less than tenfold to more than several orders of magnitude of the dose. Considerable mechanistic evidence indicates that hormetic effects represent overcompensation in response to disruptions in homeostasis that are mediated by agonist concentration gradients with different affinities for stimulatory and inhibitory regulatory pathways.

Superoxide dismutase: its role in xenobiotic detoxification.

Since the discovery of superoxide dismutase in 1969, the role of this enzyme in modulating cellular toxicity of superoxide has been well established. Experimentally, cellular damage from compounds or exposures which produce superoxide extracellularly can be prevented or modified by pretreating a cell or organ system with SOD. Likewise, induction of intracellular SOD by exposing the cell system to various types of nonlethal stress will impart resistance or tolerance to further exposures to oxidant and nonoxidant stresses which would normally be toxic. The differences in intracellular SOD activity based on species, age, and organ variability can have a major impact on the interpretation of toxicology data, particularly extrapolation to human toxicology. An awareness of the importance of SOD to the toxicity of xenobiotics which produce superoxide, either directly or indirectly, will enable those conducting toxicology studies to better understand and interpret their results.

Catalase: its role in xenobiotic detoxification.

Catalase activity is found primarily in peroxisomes although in some species and in some organ systems, cytosolic catalase also may be involved in intracellular oxidant stress protection. Toxicology studies with repeat exposures to xenobiotics producing hydrogen peroxide either directly or indirectly generally indicate that the organisms develop resistance to the toxin (adaptation). This adaptation would result from induction of catalase activity in most target organs. The induction of hepatic peroxisomes accompanied by less than compensatory increase in catalase activity is now recognized as suggesting a potential for hepatotoxic and hepatocarcinogenic effects. Although these effects seem to also require mobilization of fatty acids, it is not clear if such mobilization is an absolute requirement. As would be expected, there are great differences among species in catalase activity thus making animal-human extrapolations difficult. Finally, with the exception of premature and neonatal animals, age-related variations in catalase activity do not seem to be large enough to have toxicological relevance. However, in old animals, their apparent inability to replace lost catalase activity after repeated stress may have major significance in explaining observed young-old differences in toxicity resulting from oxidant stress.

Historical blunders: how toxicology got the dose-response relationship half right.

Substantial evidence indicates that reliable examples of hormetic dose responses in the toxicological literature are common and generalizable across biological model, endpoint measured and chemical class. Further evaluation revealed that the hormetic dose response model is more common than the threshold dose response model in objective, head-to-head comparisons. Nonetheless, the field of toxicology made a profound error by rejecting the use of the hormetic dose response model in its teaching, research, risk assessment and regulatory activities over nearly the past century. This paper argues that the hormetic dose response model (formerly called the Arndt-Schulz Law) was rejected principally because of its close historical association with the medical practice of homeopathy as a result of the prolonged and bitter feud between traditional medicine and homeopathy. Opponents of the concept of hormesis, making use of strong appeals to authority, were successful in their misrepresentation of the scientific foundations of hormesis and in their unfair association of it with segments of the homeopathic movement with extreme and discreditable views. These misrepresentations became established and integrated within the pharmacology and toxicology communities as a result of their origins in and continuities with traditional medicine and subsequently profoundly impacted a broad range of governmental risk assessment activities further consolidating the rejection of hormesis. This error of judgment was reinforced by toxicological hazard assessment methods using only high and few doses that were unable to assess hormetic responses, statistical modeling processes that were constrained to deny the possibility of hormetic dose response relationships and by the modest nature of the hormetic stimulatory response itself, which required more rigorous study designs to evaluate possible hormetic responses.

Analytical approaches to the diagnosis and treatment of aging and aging-related disease: redox status and proteomics.

Basal levels of oxidants are indispensible for redox signaling to produce adaptive cellular responses such as vitagenes linked to cell survival; however, at higher levels, they are detrimental to cells, contributing to aging and to the pathogenesis of numerous age-related diseases. Aging is a complex systemic process and the major gap in aging research reminds the insufficient knowledge about pathways shifting from normal "healthy" aging to disease-associated pathological aging. The major complication of normal "healthy" aging is in fact the increasing risk of age-related diseases such as cardiovascular diseases, diabetes mellitus, and neurodegenerative pathologies that can adversely affect the quality of life in general, with enhanced incidences of comorbidities and mortality. In this context, global "omics" approaches may help to dissect and fully study the cellular and molecular mechanisms of aging and age-associated processes. The proteome, being more close to the phenotype than the transcriptome and more stable than the metabolome, represents the most promising "omics" field in aging research. In the present study, we exploit recent advances in the redox biology of aging and discuss the potential of proteomics approaches as innovative tools for monitoring at the proteome level the extent of protein oxidative insult and related modifications with the identification of targeted proteins.

Comparative biology of test species.

This paper assesses the capacity of animal models to predict human response to carcinogenic agents with consideration for the heterogeneity of humans. It is widely accepted that human susceptibility to toxic substances, including carcinogens, is highly variable. Conventional rodent models are usually highly inbred and valued for their ability to display characteristic homogeneity. Current practice assumes that the homogeneity of response to toxic agents, including carcinogens, in the rodent model will be representative of humans. The issue then becomes, To which of the broad spectrum of human responses are specific animal models likely to be related? This paper examines the extent of human heterogeneity over a broad range of biochemical characteristics (e.g., aryl hydrocarbon hydroxylase activity, epoxide hydrase activity, beta-glucuronidase activity, debrisoquine hydroxylation, DNA-adduct formation) with emphasis on those biochemical characteristics that affect responses to carcinogens. Examples are presented to compare the heterogeneity of selected animal models for these biochemical characteristics as they relate to the spectrum of human responses noted above. The paper presents a theoretical perspective for determining to which part of the human population response spectrum common animal models are most likely to be extrapolated.

Expanded operational concept of high risk groups and its role in standard setting.

The role of the knowledge of high risk groups in the standard-setting process is examined. The overall conclusion is that many potential high risk segments of the population have not been studied adequately and that this deficiency in our knowledge markedly reduces the ability of decision makers to derive appropriate regulatory decisions by either ignoring the potential health effects or applying potentially excessive and expensive safety factors.

Role of epidemiologic studies in deriving drinking water standards for metals.

Epidemiological investigations are shown to have contributed in a significant way to our understanding of the potential adverse health effects of drinking water with elevated levels of several metals. Particular emphasis is given to an assessment of the epidemiological investigations concerned with characterizing the health effects of exposure to elevated levels of arsenic and sodium in drinking water.

Toxicological effects of chlorite in the mouse.

When exposed to a maximum level of 100 ppm chlorine dioxide in their drinking water, neither A/J or C57L/J mice exhibited any hematologic changes. Chlorite exposure under similar conditions produced increases for red blood cells in osmotic fragility, mean corpuscular volume, and glucose-6-phosphate dehydrogenase activity for both strains. Chlorite exposure of pregnant A/J mice resulted in a significant decrease in the weight of pups at weaning and a lower average birth to weaning growth rate. Mice exposed to as much as 100 ppm sodium chlorite (NaClO2) in their drinking water for up to 120 days failed to demonstrate any histopathological changes in kidney structure.

Age as a function in the development of sodium-related hypertension.

The populations of the developed nations of the world exhibit an increase in blood pressure with age, while in primitive societies blood pressure remains relatively constant throughout adult life. Hypertension may be a complex of diseases all having the same clinical manifestations but not being caused necessarily by the same factors. A possible common denominator in the development of any chronic elevation of blood pressure is the need for the kidney to increase urine volume to promote sodium excretion and, thereby, prevent a chronically expanded extracellular fluid (ECF). Hypertension may be viewed as a maladaptation of the body in its attempt to maintain homeostasis of the ECF. Man evolved under conditions of relative scarcity of salt and even now can maintain normal body function with an intake of less than 2 g/day. The high risk person appears to have a hereditary predisposition to a rise in blood pressure in the presence of a high sodium (NaCl) intake. Actually, the degree of rise in blood pressure may be an interaction between the amount of genetic predisposition and the level of sodium and its relation to potassium intake. Recent work in two Massachusetts communities supports this interpretation and suggests that differences in blood pressure distribution may increase with age between a higher and lower sodium community.

Hormesis as a biological hypothesis.

A comprehensive effort was undertaken to identify articles demonstrating chemical hormesis. Nearly 4000 potentially relevant articles were retrieved from preliminary computer database searches by using various key word descriptors and extensive cross-referencing. A priori evaluation criteria were established including study design features (e.g., number of doses, dose range), statistical analysis, and reproducibility of results. Evidence of chemical hormesis was judged to have occurred in approximately 350 of the 4000 studies evaluated. Chemical hormesis was observed in a wide range of taxonomic groups and involved agents representing highly diverse chemical classes, many of potential environmental relevance. Numerous biological end points were assessed; growth responses were the most prevalent, followed by metabolic effects, longevity, reproductive responses, and survival. Hormetic responses were generally observed to be of limited magnitude. The average low-dose maximum stimulation was approximately 50% greater than controls. The hormetic dose-response range was generally limited to about one order of magnitude, with the upper end of the hormetic curve approaching the estimated no observable effect level for the particular end point. Based on the evaluation criteria, high to moderate evidence of hormesis was observed in studies comprised of > 6 doses; with > 3 doses in the hormetic zone. The present analysis suggests that chemical hormesis is a reproducible and relatively common biological phenomenon. A quantitative scheme is presented for future application to the database.

Resolving intertracer inconsistencies in soil ingestion estimation.

In this article we explore sources and magnitude of positive and negative error in soil ingestion estimates for children on a subject-week and trace element basis. Errors varied among trace elements. Yttrium and zirconium displayed predominantly negative error; titanium and vanadium usually displayed positive error. These factors lead to underestimation of soil ingestion estimates by yttrium and zirconium and a large overestimation by vanadium. The most reliable tracers for soil ingestion estimates were aluminum, silicon, and yttrium. However, the most reliable trace element for a specific subject-day (or week) would be the element with the least error during that time period. The present analysis replaces our previous recommendations that zirconium and titanium are the most reliable trace elements in estimating soil ingestion by children. This report identifies limitations in applying the biostatistical model based on data for adults to data for children. The adult-based model used data less susceptible to negative bias and more susceptible to source error (positive bias) for titanium and vanadium than the data for children. These factors contributed significantly to inconsistencies in model predictions of soil ingestion rates for children. Correction for error at the subject-day level provides a foundation for generation of subject-specific daily soil ingestion distributions and for linking behavior to soil ingestion.

Daily estimates of soil ingestion in children.

Soil ingestion estimates play an important role in risk assessment of contaminated sites, and estimates of soil ingestion in children are of special interest. Current estimates of soil ingestion are trace-element specific and vary widely among elements. Although expressed as daily estimates, the actual estimates have been constructed by averaging soil ingestion over a study period of several days. The wide variability has resulted in uncertainty as to which method of estimation of soil ingestion is best. We developed a methodology for calculating a single estimate of soil ingestion for each subject for each day. Because the daily soil ingestion estimate represents the median estimate of eligible daily trace-element-specific soil ingestion estimates for each child, this median estimate is not trace-element specific. Summary estimates for individuals and weeks are calculated using these daily estimates. Using this methodology, the median daily soil ingestion estimate for 64 children participating in the 1989 Amherst soil ingestion study is 13 mg/day or less for 50% of the children and 138 mg/day or less for 95% of the children. Mean soil ingestion estimates (for up to an 8-day period) were 45 mg/day or less for 50% of the children, whereas 95% of the children reported a mean soil ingestion of 208 mg/day or less. Daily soil ingestion estimates were used subsequently to estimate the mean and variance in soil ingestion for each child and to extrapolate a soil ingestion distribution over a year, assuming that soil ingestion followed a log-normal distribution.