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.

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.

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.

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.

Sex hormonal regulation and hormesis in aging and longevity: role of vitagenes.

Aging process is accompanied by hormonal changes characterized by an imbalance between catabolic hormones, such as cortisol and thyroid hormones which remain stable and hormones with anabolic effects (testosterone, insulin like growth factor-1 (IGF-1) and dehydroepiandrosterone sulphate (DHEAS), that decrease with age. Deficiencies in multiple anabolic hormones have been shown to predict health status and longevity in older persons.Unlike female menopause, which is accompanied by an abrupt and permanent cessation of ovarian function (both folliculogenesis and estradiol production), male aging does not result in either cessation of testosterone production nor infertility. Although the circulating serum testosterone concentration does decline with aging, in most men this decrease is small, resulting in levels that are generally within the normal range. Hormone therapy (HT) trials have caused both apprehension and confusion about the overall risks and benefits associated with HT treatment. Stress-response hormesis from a molecular genetic perspective corresponds to the induction by stressors of an adaptive, defensive response, particularly through alteration of gene expression. Increased longevity can be associated with greater resistance to a range of stressors. During aging, a gradual decline in potency of the heat shock response occur and this may prevent repair of protein damage. Conversely, thermal stress or pharmacological agents capable of inducing stress responses, by promoting increased expression of heat-shock proteins, confer protection against denaturation of proteins and restoration of proteome function. If induction of stress resistance increases life span and hormesis induces stress resistance, hormesis most likely result in increased life span. Hormesis describes an adaptive response to continuous cellular stresses, representing a phenomenon where exposure to a mild stressor confers resistance to subsequent, otherwise harmful, conditions of increased stress. This biphasic dose-response relationship, displaying low-dose stimulation and a high-dose inhibition, as adaptive response to detrimental lifestyle factors determines the extent of protection from progression to metabolic diseases such as diabetes and more in general to hormonal dysregulation and age-related pathologies. Integrated responses exist to detect and control diverse forms of stress. This is accomplished by a complex network of the so-called longevity assurance processes, which are composed of several genes termed vitagenes. Vitagenes encode for heat shock proteins (Hsps), thioredoxin and sirtuin protein systems. Nutritional antioxidants, have recently been demonstrated to be neuroprotective through the activation of hormetic pathways under control of Vitagene protein network. Here we focus on possible signaling mechanisms involved in the activation of vitagenes resulting in enhanced defense against functional defects leading to degeneration and cell death with consequent impact on longevity processes.

Historical use of x-rays: treatment of inner ear infections and prevention of deafness.

PURPOSE: This article provides an historical assessment of the role of radiotherapy in the treatment of inner ear infections. MATERIALS AND METHODS: The research utilized a literature-based evaluation of the use of x-rays during the first half of the 20th century on the treatment of otitis media (OM), mastoiditis, and cervical adenitis and their impact on the occurrence of deafness. RESULTS: X-Rays were consistently found to be effective as a treatment modality at relatively low doses, in the range of 10-20% of the skin erythema dose, rapidly reducing inflammation, and accelerating the healing process. The mechanistic basis of the clinical successes, while addressed by contemporary researchers, is evaluated in the present article in light of current molecular biology advances, which indicate that clinically effective low doses of ionizing radiation act via the creation of an anti-inflammatory phenotype in highly inflamed tissue. CONCLUSIONS: X-Ray treatment of OM, mastoiditis, and cervical adenitis was widely accepted in the first half of the 20th century by clinicians as an effective treatment when administered within an appropriate dosage range.

Hormesis: its impact on medicine and health.

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.

Hormesis: improving predictions in the low-dose zone.

This chapter explores the historical foundations of hormesis, including the underlying reasons for its marginalization during most of the twentieth century and factors that are contributing to its resurgence and acceptance within the toxicological and pharmacological communities. Special consideration is given to the quantitative features of the hormetic dose response, as well as its capacity for generalization. Based on subsequent comparisons with other leading dose-response models, the hormesis dose response consistently provides more accurate predictions in the below threshold zone. It is expected that the hormetic dose response will become progressively more useful to the fields of toxicology, pharmacology, risk assessment, and the life sciences in general, especially where low-dose effects are of interest.

The hormetic role of dietary antioxidants in free radical-related diseases.

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.

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.

Below background levels of blood lead impact cytokine levels in male and female mice.

A number of studies have documented that Pb exerts immunotoxic effects on T lymphocytes. In studies designed to explore this general response over a broad dose range, female Swiss mice were administered six different diets containing Pb acetate 1 day after mating. During lactation, the mothers received the same feed given during pregnancy, and the same diets were administered to the offspring for 9 months after weaning. At the end of exposure, blood Pb level in the offspring was determined, and possible changes in two type 1 cytokines (IL-2, INF-gamma) and one type 2 cytokine (IL-4) in the serum were measured. At higher dietary Pb levels (40 and 400 ppm), a significant increase in IL-4 production was associated with a profound decrease in INF-gamma and IL-2 production. At the lowest Pb diet level (0.02 ppm), which resulted in a blood lead level of (0.8 microg/dL), which is below background (2-3 microg/dL) values in humans, increases in INF-gamma and IL-2 production along with a significant decrease in IL-4 production were observed. The findings provide evidence of a reversal of lead-induced cytokine skewing depending on the blood lead concentration. As blood lead concentration increases, there is a notable skewing toward Th2, while the pattern is reversed favoring Th1 development at lower blood lead values. The present findings are also notable since they indicate the potential for dietary Pb to have significant biological effects below normal background concentrations.

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.

Effects of low doses of dietary lead on puberty onset in female mice.

Female Swiss mice typically display signs of puberty at about 33-37 days of age. In the present investigation (96 female mice tested in 8 Pb exposure levels, n=12 per exposure level), the time to puberty onset was markedly influenced by exposure to dietary lead. While modest increases in blood lead concentrations from a normal background of 2-3 to 13.2 microg/dl delayed the onset of puberty by 15-20% to about 40-43 days, reducing blood lead from 2-3 to 0.7 microg/dl was associated with an acceleration of puberty to 21 days, an enhancement by over 30%. This dose-response relationship represents novel findings of 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.

Effects of low doses of dietary lead on red blood cell production in male and female mice.

The effect of lead (Pb) ingestion on hematological parameters in male and female Swiss mice was assessed. Eight different doses of Pb were administered through preparation of different feeds. The levels of Pb in the diet were designed to provide exposure below (0.6 to <2.0 microg/dl) and above (>2.0-13 microg/dl) normal background. One litter of mice was exposed to each Pb dose, with the mother given the feed 1 day after mating, and the mother and offspring continuing to receive the feed until the litter was 90 days old. Male and female mice receiving below normal background levels of dietary Pb displayed enhanced red blood cell (RBC) production as measured by increased numbers of RBC and increased hemoglobin and hematocrit values. However, as the blood Pb levels approached 10 microg/dl there was a marked decrease in RBC production. These findings are significant since Pb was biologically active in a stimulating manner below typical background levels (2.0 microg/dl) while adversely effecting red cell synthesis at above background levels (7.0-13 microg/dl) encountered in the environment by humans.

Defining hormesis.

Much confusion surrounds the concept of hormesis and what its biological meaning represents. This paper provides a definition of hormesis that addresses its historical foundations, quantitative features, and underlying evolutionary and toxicologically based mechanistic strategies. Hormesis should be considered an adaptive response characterized by biphasic dose responses of generally similar quantitative features with respect to amplitude and range of the stimulatory response that are either directly induced or the result of compensatory biological processes following an initial disruption in homeostasis. Given the limited magnitude of the stimulatory response (i.e., usually 30-60% greater than controls at maximum), heightened study design and replication requirements are often necessary to ensure reliable judgments on causality. Even though hormesis is considered an adaptive response, the issue of beneficial/harmful effects should not be part of the definition of hormesis, but reserved to a subsequent evaluation of the biological and ecological context of the response.

Effects of per os lead acetate administration on mouse hepatocyte survival.

Previously published studies indicate that hepatotoxicity is associated with high blood lead (Pb) levels in animal models and humans. The present investigation evaluated the effects of in vivo Pb exposure via drinking water on mouse hepatocyte survival in vitro when blood Pb concentrations reflected those seen in children in urban and rural settings (2-15 microg/dl). The findings indicated a biphasic dose-response with low concentrations associated with a modest decrease in hepatocyte survival, while at the highest concentration, survival was significantly enhanced (60%). Since these responses were associated with concentrations normally encountered by children, follow-up investigations are warranted.

Hormesis: a generalizable and unifying hypothesis.

The present article represents a comprehensive effort to assess the hypothesis that hormesis is a highly generalizable biological phenomenon independent of environmental stressor, biological endpoint, and experimental model system. The evaluative methodology and complementary approaches employed to assess this question are (1) evolutionary biology-based theoretical paradigm; (2) evaluation of > 20,000 toxicology articles using a priori entry and evaluative criteria; (3) evaluation of 17 large-scale studies each providing data on numerous agents tested in the same experimental model by the same research team; (4) the assimilation of experimental pharmacological data on 24 receptor systems in which biphasic dose responses have been established reproducibly along with hormetic mechanism elucidation; and (5) assessment of the original hormesis database with 1600 dose-response relationships demonstrating evidence consistent with the hormesis hypothesis. The complementary approaches for assessing hormesis provided strong support for its credibility as a central biological theory based on its high frequency of occurrence and quantitative features of expression within microbe, plant, and invertebrate and vertebrate animal systems. The findings suggest that hormetic effects represent evolutionary-based adaptive responses to environmentally induced disruptions in homeostasis. Such adaptive responses, which are incorporated into organismal integrative physiological systems and now clarified at the mechanistic level for more than two dozen receptor systems, provide a cogent basis for the application of hormetic mechanisms in the elucidation of fundamental evolutionary-based biological processes and in the development of novel clinical modalities.