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Pesticide resistance increases and threatens crop production sustainability. Chemical contamination contributes to the development of pest resistance to pesticides, in part by causing stimulatory effects on pests at low sub-toxic doses and facilitating the spread of resistance genes. This article discusses hormesis and low-dose biological stimulation and their relevance to crop pest resistance. It highlights that a holistic approach is needed to tackle pest resistance to pesticides and reduce imbalance in accessing food and improving food security in accordance with the UN's Sustainable Development Goals. Among others, the effects of sub-toxic doses of pesticides should be considered when assessing the impact of synthetic and natural pesticides, while the promotion of alternative agronomical practices is needed to decrease the use of agrochemicals. Potential alternative solutions include camo-cropping, exogenous application of phytochemicals that are pest-suppressing or -repelling and/or attractive to carnivorous arthropods and other pest natural enemies, and nano-technological innovations. Moreover, to facilitate tackling of pesticide resistance in poorer countries, less technology-demanding and low-cost practices are needed. These include mixed cropping systems, diversification of cultures, use of ‘push-pull cropping’, incorporation of flower strips into cultivations, modification of microenvironment, and application of beneficial microorganisms and insects. However, there are still numerous open questions, and more research is needed to address the ecological and environmental effects of many of these potential solutions, with special reference to trophic webs.

Supplemental Material, Supplementary-material for Does Green Tea Induce Hormesis? by Edward J. Calabrese, Aristidis Tsatsakis, Evgenios Agathokleous, James Giordano and Vittorio Calabrese in Dose-Response

Background This paper assesses possible reasons why Hermann J. Muller avoided peer-review of data that became the basis of his Nobel Prize award for producing gene mutations in male Drosophila by X-rays. Methods Extensive correspondence between Muller and close associates and other materials were obtained from preserved papers to compliment extensive publications by and about Muller in the open literature. These were evaluated for potential historical insights that clarify why he avoided peer-review of his Nobel Prize findings. Results This paper clarifies the basis of Muller’s (Muller HJ, Sci 66 84-87, 1927c) belief that he produced X-ray induced “gene” mutations in Drosophila. It then shows his belief was contemporaneously challenged by his longtime friend/confidant and Drosophila geneticist, Edgar Altenburg. Altenburg insisted that Muller may have simply poked large holes in chromosomes with massive doses of X-rays, and needed to provide proof of gene “point” mutations. Given the daunting and uncertain task to experimentally address this criticism, especially within the context of trying to become first to produce gene mutations, it is proposed that Muller purposely avoided peer-review while rushing to publish his paper in Science to claim discovery primacy without showing any data. The present paper also explores ethical issues surrounding these actions, including those of the editor of Science, James McKeen Catell and Altenburg, and their subsequent impact on the scientific and regulatory communities. Conclusion This historical analysis suggests that Muller deliberately avoided peer-review on his most significant findings because he was extremely troubled by the insightful and serious criticism of Altenburg, which suggested he had not produced gene mutations as he claimed. Nonetheless, Muller manipulated this situation (i.e., publishing a discussion within Science with no data, publishing a poorly written non-peer reviewed conference proceedings with no methods and materials, and no references) due to both the widespread euphoria over his claim of gene mutation and confidence that Altenburg would not publically challenge him. This situation permitted Muller to achieve his goal to be the first to produce gene mutations while buying him time to later try to experimentally address Altenburg’s criticisms, and a possible way to avoid discovery of his questionable actions.

Abnormal redox homeostasis and oxidative stress have been proposed to play a role in the etiology of several neuropsychiatric spectrum disorders. Emerging interest has recently focused on markers of oxidative stress and neuroinflammation in schizophrenic spectrum disorders, at least in particular subgroups of patients. Altered expression of genes related to oxidative stress, oxidative damage to DNA, protein and lipids, as well as reduced glutathione levels in central and peripheral tissues could act synergistically, and contribute to the course of the disease. Herein, we discuss cellular mechanisms that may be operative in neuroinflammation and contributory to schizophrenia. We address modulation of endogenous cellular defense mechanisms as a potentially innovative approach to therapeutics for schizophrenia, and other neuropsychiatric conditions that are associated with neuroinflammation. Specifically, we discuss the emerging role of heme oxygenase as prominent member of neuroprotective network in redox stress responsive mechanisms, as well as the importance of glutathione relevant in schizophrenia pathophysiology. Finally we introduce the hormetic dose response concept as relevant and important to neuroprotection, and review hormetic mechanisms as possible approaches to manipulation of neuroinflammatory targets that may be viable for treating schizophrenia spectrum disorders. © 2016 Wiley Periodicals, Inc.

The scientific community, recently, has focused notable attention on the chemopreventive and therapeutic effects of dietary polyphenols for human health. Emerging evidence demonstrates that polyphenols, flavonoids and vitamins counteract and neutralize genetic and environmental stressors, particularly oxidative stress and inflammatory process closely connected to cancer initiation, promotion and progression. Interestingly, polyphenols can exert antioxidant or pro-oxidant cytotoxic effects depending on their endogenous concentration. Notably, polyphenols at high dose act as pro-oxidants in a wide type of cancer cells by inhibiting Nrf2 pathway and the expression of antioxidant vitagenes, such as NAD(P)H-quinone oxidoreductase (NQO1), glutathione transferase (GT), GPx, heme oxygenase-1 (HO-1), sirtuin-1 (Sirt1) and thioredoxin (Trx) system which play an essential role in the metabolism of reactive oxygen species (ROS), detoxification of xenobiotics and inhibition of cancer progression, by inducing apoptosis and cell cycle arrest according to the hormesis approach. Importantly, mutagenesis of Nrf2 pathway can exacerbate its "dark side" role, representing a crucial event in the initiation stage of carcinogenesis. Herein, we review the hormetic effects of polyphenols and nanoincapsulated-polyphenols in chemoprevention and treatment of brain tumors via activation or inhibition of Nrf2/vitagenes to suppress carcinogenesis in the early stages, and thus inhibit its progression. Lastly, we discuss innovative preclinical approaches through mini-brain tumor organoids to study human carcinogenesis, from basic cancer research to clinical practice, as promising tools to recapitulate the arrangement of structural neuronal tissues and biological functions of the human brain, as well as test drug toxicity and drive personalized and precision medicine in brain cancer.

Age-related changes in the brain reflect a dynamic interaction of genetic, epigenetic, phenotypic, and environmental factors that can be temporally restricted or more longitudinally present throughout the lifespan. Fundamental to these mechanisms is the capacity for physiological adaptation through modulation of diverse molecular and biochemical signaling occurring from the intracellular to the network-systemic level throughout the brain. A number of agents that affect the onset and progression of Parkinson's disease (PD)-like effects in experimental models exhibit temporal features, and mechanisms of hormetic dose responses. These findings have particular significance since the hormetic dose response describes the amplitude and range of potential therapeutic effects, thereby affecting the design and conduct of studies of interventions against PD (and other neurodegenerative diseases), and may also be important to a broader consideration of hormetic processes in resilient adaptive responses that might afford protection against the onset and/or progression of PD and related disorders.

In order to better understand the pathogenesis of Parkinson's Disease (PD) it is important to consider possible contributory factors inherent to the aging process, as age-related changes in a number of physiological systems (perhaps incurred within particular environments) appear to influence the onset and progression of neurodegenerative disorders. Accordingly, we posit that a principal mechanism underlying PD is inflammaging, i.e. the chronic inflammatory process characterized by an imbalance of pro- and anti-inflammatory mechanisms which has been recognized as operative in several age-related, and notably neurodegenerative diseases. Recent conceptualization suggests that inflammaging is part of the complex adaptive mechanisms (“re-modeling”) that are ongoing through the lifespan, and which function to prevent or mitigate endogenous processes of tissue disruption and degenerative change(s). The absence of an adequate anti-inflammatory response can fuel inflammaging, which propagates on both local (i.e.- from cell to cell) and systemic levels (e.g.- via exosomes and other molecules present in the blood). In general, this scenario is compatible with the hypothesis that inflammaging represents a hormetic or hormetic-like effect, in which low levels of inflammatory stress may prompt induction of anti-inflammatory mediators and mechanisms, while sustained pro-inflammatory stress incurs higher and more durable levels of inflammatory substances, which, in turn prompt a local-to-systemic effect and more diverse inflammatory response(s). Given this perspective, new treatments of PD may be envisioned that strategically are aimed at exerting hormetic effects to sustain anti-inflammatory responses, inclusive perhaps, of modulating the inflammatory influence of the gut microbiota.

The concept of hormesis, as an adaptive response of biological systems to moderate environmental challenges, has raised considerable nano-toxicological interests in view of the rapid pace of production and application of even more innovative nanomaterials and the expected increasing likelihood of environmental and human exposure to low-dose concentrations. Therefore, the aim of this review is to provide an update of the current knowledge concerning the biphasic dose-responses induced by nanoparticle exposure. The evidence presented confirmed and extended our previous findings, showing that hormesis is a generalized adaptive response which may be further generalized to nanoscale xenobiotic challenges. Nanoparticle physico-chemical properties emerged as possible features affecting biphasic relationships, although the molecular mechanisms underlining such influences remain to be fully understood, especially in experimental settings resembling long-term and low-dose realistic environmental exposure scenarios. Further investigation is necessary to achieve helpful information for a suitable assessment of nanomaterial risks at the low-dose range for both the ecosystem function and the human health.

This paper provides a broad overview of hormesis, a specific type of biphasic dose response, its historical and scientific foundations as well as its biomedical applications, especially with respect to aging. Hormesis is a fundamental component of adaptability, neutralizing many endogenous and environmental challenges by toxic agents, thereby enhancing survival. Hormesis is highly conserved, broadly generalizable, and pleiotrophic, being independent of biological model, endpoint measured, inducing agent, level of biological organization and mechanism. The low dose stimulatory hormetic response has specific characteristics which defines both the quantitative features of biological plasticity and the potential for maximum biological performance, thereby estimating the limits to which numerous medical and pharmacological interventions may affect humans. The substantial degrading of some hormetic processes in the aged may profoundly reduce the capacity to respond effectively to numerous environmental/ischemic and other stressors leading to compromised health, disease and, ultimately, defining the bounds of longevity.

Quantitative changes in different cytokines were determined in serum of female Wistar rats exposed to Rhodium (III) chloride hydrate to evaluate its early effects on the immune system. Findings revealed an inhibitory effect of Rh salt since each cytokine, with the exceptions of IL-1α and IL-2 levels observed at the highest doses of exposure, was reduced compared to the controls and interestingly, the lowest doses induced the greatest inhibition. This generalized decrease of cytokine levels was not related to a specific cytokine pathway, and may suggest an anti-inflammatory role of Rh salt.

This paper offers a broad assessment of the hormetic dose response and its relevance to biogerontology. The paper provides detailed background information on the historical foundations of hormesis, its quantitative features, mechanistic foundations, as well as how the hormesis concept could be further applied in the development of new therapeutic advances in the treatment of age-related diseases. The concept of hormesis has direct application to biogerontology not only affecting the quality of the aging process but also experimental attempts to extend longevity.

Understanding mechanisms of aging and determinants of life span will help to reduce age-related morbidity and facilitate healthy aging. Average lifespan has increased over the last centuries, as a consequence of medical and environmental factors, but maximal life span remains unchanged. Extension of maximal life span is currently possible in animal models with measures such as genetic manipulations and caloric restriction (CR). CR appears to prolong life by reducing reactive oxygen species (ROS)-mediated oxidative damage. But ROS formation, which is positively implicated in cellular stress response mechanisms, is a highly regulated process controlled by a complex network of intracellular signaling pathways. By sensing the intracellular nutrient and energy status, the functional state of mitochondria, and the concentration of ROS produced in mitochondria, the longevity network regulates life span across species by co-ordinating information flow along its convergent, divergent and multiply branched signaling pathways, including vitagenes which are genes involved in preserving cellular homeostasis during stressful conditions. Vitagenes encode for heat shock proteins (Hsp) Hsp32, Hsp70, the thioredoxin and the sirtuin protein systems. Dietary antioxidants, such as carnosine, carnitines or polyphenols, have recently been demonstrated to be neuroprotective through the activation of hormetic pathways, including vitagenes. The hormetic dose-response, challenges long-standing beliefs about the nature of the dose-response in a lowdose zone, having the potential to affect significantly the design of pre-clinical studies and clinical trials as well as strategies for optimal patient dosing in the treatment of numerous diseases. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing stress responses. In this review we discuss the most current and up to date understanding of the possible signaling mechanisms by which caloric restriction, as well hormetic caloric restriction-mimetics compounds by activating vitagenes can enhance defensive systems involved in bioenergetic and stress resistance homeostasis with consequent impact on longevity processes.

Despite the widespread use of iridium (Ir) in catalytic converters for improved capacity for reducing carbon monoxide (CO), hydrocarbon (HC) and nitrogen oxide (NO(x)) emissions, there is a lack of studies that have assessed possible toxicological hazards of exposure to Ir. The present investigation indicates that female Wistar rats exposed to Ir in the drinking water for 90 days displayed renal toxicity based on the elevated urinary retinol binding protein (RBP) and albumin. The RBP was more sensitive to albumin, showing significant increases at 0.01 mg/L.

Nanoparticles are particles with lengths that range from 1 to 100 nm. They are increasingly being manufactured and used for commercial purpose because of their novel and unique physicochemical properties. Although nanotechnology-based products are generally thought to be at a pre-competitive stage, an increasing number of products and materials are becoming commercially available. Human exposure to nanoparticles is therefore inevitable as they become more widely used and, as a result, nanotoxicology research is now gaining attention. However, there are many uncertainties as to whether the unique properties of nanoparticles also pose occupational health risks. These uncertainties arise because of gaps in knowledge about the factors that are essential for predicting health risks such as routes of exposure, distribution, accumulation, excretion and dose-response relationship of the nanoparticles. In particular, uncertainty remains with regard to the nature of the dose-response curve at low level exposures below the toxic threshold. In fact, in the literature, some studies that investigated the biological effects of nanoparticles, observed a hormetic dose-response. However, currently available data regarding this topic are extremely limited and fragmentary. It therefore seems clear that future studies need to focus on this issue by studying the potential adverse health effects caused by low-level exposures to nanoparticles.