Trace Toxins: The Key Component of a Healthful Diet.

Although it is well established that a vegetable-rich (Mediterranean) diet is associated with health benefits in later life, the mechanisms and biological origins of this benefit are not well established. This review seeks to identify the components a healthful diet that reduce the individual's suffering from non-communicable disease and extend longevity. We note the difference between the claims made for an essential diet (that prevents deficiency syndromes) and those argued for a diet that also prevents or delays non-communicable diseases and ask: what chemicals in our food induce this added resilience, which is effective against cardiovascular and neurodegenerative diseases, diabetes and even cancer? Working in the framework of acquired resilience (tissue resilience induced by a range of stresses), we arguethat the toxins evolved by plants as part of allelopathy (the competition between plant species) are key in making the 'healthful difference'. We further suggest the recognition of a category of micronutrients additional to the established 'micro' categories of vitamins and trace elements and suggest also that the new category be called 'trace toxins'. Implications of these suggestions are discussed.

Promotion of tumor angiogenesis and growth induced by low-dose antineoplastic agents via bone-marrow-derived cells in tumor tissues.

Background: More research is needed to solidify the basis for reasonable metronomic chemotherapy regimens due to the inconsistent clinical outcomes from studies on metronomic chemotherapy with antineoplastic agents, along with signs of a nonlinear dose-response relationship at low doses. The present study therefore explored the dose-response relationships of representative antineoplastic agents in low dose ranges and their underlying mechanisms. Methods: Cyclophosphamide (CPA) and 5-fluorouracil (5-Fu) were employed to observe the effects of the frequent administration of low-dose antineoplastic agents on tumor growth, tumor angiogenesis, and bone-marrow-derived cell (BMDC) mobilization in mouse models. The effects of antineoplastic agents on tumor and endothelial cell functions with or without BMDCs were analyzed in vitro. Results: Tumor growth and metastasis were significantly promoted after the administration of CPA or 5-Fu at certain low dose ranges, and were accompanied by enhanced tumor angiogenesis and proangiogenic factor expression in tumor tissues, increased proangiogenic BMDC release in the circulating blood, and augmented proangiogenic BMDC retention in tumor tissues. Low concentrations of CPA or 5-Fu were found to significantly promote tumor cell migration and invasion, and enhance BMDC adhesion to endothelial cells in vitro. Conclusion: These results suggest that there are risks in empirical metronomic chemotherapy using low-dose antineoplastic agents and the optimal dosage and administration schedule of antineoplastic agents need to be determined through further research.

Translational insights into the hormetic potential of carbon dioxide: from physiological mechanisms to innovative adjunct therapeutic potential for cancer.

Background: Carbon dioxide (CO2), traditionally viewed as a mere byproduct of cellular respiration, plays a multifaceted role in human physiology beyond simple elimination through respiration. CO2 may regulate the tumor microenvironment by significantly affecting the release of oxygen (O2) to tissues through the Bohr effect and by modulating blood pH and vasodilation. Previous studies suggest hypercapnia (elevated CO2 levels) might trigger optimized cellular mechanisms with potential therapeutic benefits. The role of CO2 in cellular stress conditions within tumor environments and its impact on O2 utilization offers a new investigative area in oncology. Objectives: This study aims to explore CO2's role in the tumor environment, particularly how its physiological properties and adaptive responses can influence therapeutic strategies. Methods: By applying a structured translational approach using the Work Breakdown Structure method, the study divided the analysis into six interconnected work packages to comprehensively analyze the interactions between carbon dioxide and the tumor microenvironment. Methods included systematic literature reviews, data analyses, data integration for identifying critical success factors and exploring extracellular environment modulation. The research used SMART criteria for assessing innovation and the applicability of results. Results: The research revealed that the human body's adaptability to hypercapnic conditions could potentially inform innovative strategies for manipulating the tumor microenvironment. This could enhance O2 utilization efficiency and manage adaptive responses to cellular stress. The study proposed that carbon dioxide's hormetic potential could induce beneficial responses in the tumor microenvironment, prompting clinical protocols for experimental validation. The research underscored the importance of pH regulation, emphasizing CO2 and carbonic acid's role in modulating metabolic and signaling pathways related to cancer. Conclusion: The study underscores CO2 as vital to our physiology and suggests potential therapeutic uses within the tumor microenvironment. pH modulation and cellular oxygenation optimization via CO2 manipulation could offer innovative strategies to enhance existing cancer therapies. These findings encourage further exploration of CO2's therapeutic potential. Future research should focus on experimental validation and exploration of clinical applications, emphasizing the need for interdisciplinary and collaborative approaches to tackle current challenges in cancer treatment.

The interplay between temperature and an insecticide mixture modulates the stimulatory response of sublethally exposed Myzus persicae.

Temperature can interact with chemical pesticides and modulate their toxicity. Sublethal exposure to pesticides is known to trigger hormetic responses in pests. However, the simultaneous effects of temperature and sublethal exposure to single or mixture-based insecticides on the insects' stimulatory responses are not frequently considered in toxicological studies. Here we investigated the combined effects of temperature on the lethal and sublethal responses of the green peach aphid Myzus persicae after exposure to commercial formulations of a neonicotinoid (thiamethoxam) and a pyrethroid (lambda-cyhalothrin) and their mixture. Firstly, the concentration-response curves of the insecticides were determined under four temperatures (15 °C, 20 °C, 25 °C, and 28 °C) by the leaf dipping method. Subsequently, the sublethal concentrations C0, CL1, CL5, CL10, CL15, CL20, and CL30 were selected to assess sublethal effects on aphids' longevity and reproduction under the same temperatures. The results showed that the mixture of thiamethoxam + lambda-cyhalothrin caused greater toxicity to aphids compared to the formulations with each active ingredient alone and that the toxicity was higher at elevated temperatures. Furthermore, the exposure to low concentrations of the mixture (thiamethoxam + lambda-cyhalothrin) and the separated insecticides induced stimulatory responses in the longevity and fecundity of exposed aphid females, but the occurrence of such hormetic responses depended on the insecticide type, its sublethal concentration, and the temperature as well as their interactions.

Reversible ON- and OFF-switch receptors Clec4G and Rab1A reveal the hormetic effects of a pectin polysaccharide in Aralia elata (Miq.) Seem.

BACKGROUND: Numerous studies indicate that natural polysaccharides have immune-enhancing effects as a host defense potentiator. Few reports are available on hormetic effects of natural polysaccharides, and the underlying mechanisms remain unclear. PURPOSE: AELP-B6 (arabinose- and galactose-rich pectin polysaccharide) from Aralia elata (Miq.) Seem was taken as a case study to clarify the potential mechanism of hormetic effects of natural polysaccharides. METHODS: The pharmacodynamic effect of AELP-B6 was verified by constructing the CTX-immunosuppressive mouse model. The hormetic effects were explored by TMT-labeled proteomics, energy metabolism analysis, flow cytometry and western blot. The core-affinity target of AELP-B6 was determined by pull down, nanoLC-nanoESI+-MS, CETSA, immunoblot and SPR assay. The RAW264.7Clec4G-RFP and RAW264.7Rab1A-RFP cell lines were simultaneously constructed to determine the affinity difference between AELP-B6 and targets by confocal laser scanning live-cell imaging. Antibody blocking assays were further used to verify the mechanism of hormetic effects. RESULTS: AELP-B6 at low and medium doses may maintain the structural integrity of thymus and spleen, increase the concentrations of TNF-α, IFN-γ, IL-3 and IL-8, and alleviate CTX-induced reduction of immune cell viability in vivo. Proteomics and energy metabolism analysis revealed that AELP-B6 regulate HIF-1α-mediated metabolic programming, causing Warburg effects in macrophages. AELP-B6 at low and medium doses promoted the release of intracellular immune factors, and driving M1-like polarization of macrophages. As a contrast, AELP-B6 at high dose enhanced the expression levels of apoptosis related proteins, indicating activation of the intrinsic apoptotic cascade. Two highly expressed transmembrane proteins in macrophages, Clec4G and Rab1A, were identified as the primary binding targets of AELP-B6 which co-localized with the cell membrane and directly impacted with immune cell activation and apoptosis. AELP-B6 exhibits affinity differences with Clec4G and Rab1A, which is the key to the hormetic effects. CONCLUSION: We observed hormesis of natural polysaccharide (AELP-B6) for the first time, and AELP-B6 mediates the hormetic effects through two dose-related targets. Low dose of AELP-B6 targets Clec4G, thereby driving the M1-like polarization via regulating NF-κB signaling pathway and HIF-1α-mediated metabolic programming, whereas high dose of AELP-B6 targets Rab1A, leading to mitochondria-dependent apoptosis.

Biological resilience in health and disease.

All living organisms - from single-celled prokaryotes through to invertebrates and humans - are frequently exposed to numerous challenges during their lifetime, which could damage their molecular and cellular contents and threaten their survival. Nevertheless, these diverse organisms are, on the whole, remarkably resilient to potential threats. Recent years have seen rapid advances in our mechanistic understanding of this emerging phenomenon of biological resilience, which enables cells, tissues and whole organisms to bounce back from challenges or stress. In this At a Glance article, I discuss current knowledge on the diverse molecular mechanisms driving biological resilience across scales, with particular focus on its dynamic and adaptive nature. I highlight emerging evidence that loss of biological resilience could underly numerous pathologies, including age-related frailty and degenerative disease. Finally, I present the multi-disciplinary experimental approaches that are helping to unravel the causal mechanisms of resilience and how this emerging knowledge could be harnessed therapeutically in the clinic.

Histone H3.3 chaperone HIRA renders stress-responsive genes poised for prospective lethal stresses in acquired tolerance.

Appropriate responses to environmental challenges are imperative for the survival of all living organisms. Exposure to low-dose stresses is recognized to yield increased cellular fitness, a phenomenon termed hormesis. However, our molecular understanding of how cells respond to low-dose stress remains profoundly limited. Here we report that histone variant H3.3-specific chaperone, HIRA, is required for acquired tolerance, where low-dose heat stress exposure confers resistance to subsequent lethal heat stress. We found that human HIRA activates stress-responsive genes, including HSP70, by depositing histone H3.3 following low-dose stresses. These genes are also marked with histone H3 Lys-4 trimethylation and H3 Lys-9 acetylation, both active chromatin markers. Moreover, depletion of HIRA greatly diminished acquired tolerance, both in normal diploid fibroblasts and in HeLa cells. Collectively, our study revealed that HIRA is required for eliciting adaptive stress responses under environmental fluctuations and is a master regulator of stress tolerance.

Hormesis and synergistic effects of disinfectants chloroxylenol and benzethonium chloride on highly efficient heterotrophic nitrification-aerobic denitrification functional strain: From performance to mechanism.

The heterotrophic nitrification-aerobic denitrification (HNAD) strain Exiguobacterium H1 (H1) was isolated in this study. The changes in nitrogen metabolism functions of H1 strain were discussed in presence of disinfectants chloroxylenol (PCMX) and benzethonium chloride (BEC) alone and combined pollution (PCMX+BEC). The H1 strain could use NH4+-N, NO2--N and NO3--N as nitrogen sources and had good nitrogen removal performance under conditions of C/N ratio 25, pH 5-8, 25-35 oC and sodium acetate as carbon. PCMX and BEC alone exhibited hormesis effects on H1 strain which promoted the growth of H1 strain at low concentrations but inhibited it at high concentrations, and combined pollution showed synergistic inhibitory on H1 strain. H1 strain owned a full nitrogen metabolic pathway according to functional genes quantification. PCMX encouraged nitrification process of H1, while BEC and combined pollution mostly blocked nitrogen removal. PCMX, but not BEC, mainly led to the enrichment of resistance genes. These findings will aid in systematic assessment of contaminant tolerance characteristics of HNAD strain and its application prospects.

Transgenerational hormesis in healthy aging and antiaging medicine from bench to clinics: Role of food components.

Neurodegenerative diseases have multifactorial pathogenesis, mainly involving neuroinflammatory processes. Finding drugs able to treat these diseases, expecially because for most of these diseases there are no effective drugs, and the current drugs cause undesired side effects, represent a crucial point. Most in vivo and in vitro studies have been concentrated on various aspects related to neurons (e.g. neuroprotection), however, there has not been focus on the prevention of early stages involving glial cell activation and neuroinflammation. Recently, it has been demonstrated that nutritional phytochemicals including polyphenols, the main active constituents of the Mediterranean diet, maintain redox balance and neuroprotection through the activation of hormetic vitagene pathway. Recent lipidomics data from our laboratory indicate mushrooms as strong nutritional neuronutrients with strongly activity against neuroinflammation in Meniere' diseaseas, a model of cochleovestibular neural degeneration, as well as in animal model of traumatic brain injury, or rotenone induced parkinson's disease. Moreover, Hidrox®, an aqueous extract of olive containing hydroxytyrosol, and Boswellia, acting as Nrf2 activators, promote resilience by enhancing the redox potential, and thus, regulate through hormetic mechanisms, cellular stress response mechanisms., Thus, modulation of cellular stress pathways, in particular vitagenes system, may be an innovative approach for therapeutic intervention in neurodegenerative disorders.

Age-dependent heat shock hormesis to HSF-1 deficiency suggests a compensatory mechanism mediated by the unfolded protein response and innate immunity in young Caenorhabditis elegans.

The transcription factor HSF-1 (heat shock factor 1) acts as a master regulator of heat shock response in eukaryotic cells to maintain cellular proteostasis. The protein has a protective role in preventing cells from undergoing ageing, and neurodegeneration, and also mediates tumorigenesis. Thus, modulating HSF-1 activity in humans has a promising therapeutic potential for treating these pathologies. Loss of HSF-1 function is usually associated with impaired stress tolerance. Contrary to this conventional knowledge, we show here that inactivation of HSF-1 in the nematode Caenorhabditis elegans results in increased thermotolerance at young adult stages, whereas HSF-1 deficiency in animals passing early adult stages indeed leads to decreased thermotolerance, as compared to wild-type. Furthermore, a gene expression analysis supports that in young adults, distinct cellular stress response and immunity-related signaling pathways become induced upon HSF-1 deficiency. We also demonstrate that increased tolerance to proteotoxic stress in HSF-1-depleted young worms requires the activity of the unfolded protein response of the endoplasmic reticulum and the SKN-1/Nrf2-mediated oxidative stress response pathway, as well as an innate immunity-related pathway, suggesting a mutual compensatory interaction between HSF-1 and these conserved stress response systems. A similar compensatory molecular network is likely to also operate in higher animal taxa, raising the possibility of an unexpected outcome when HSF-1 activity is manipulated in humans.

Investigating hormesis, aging, and neurodegeneration: From bench to clinics.

Mitochondria-derived reactive oxygen species production at a moderate physiological level plays a fundamental role in the anti-aging signaling, due to their action as redox-active sensors for the maintenance of optimal mitochondrial balance between intracellular energy status and hormetic nutrients. Iron regulatory protein dysregulation, systematically increased iron levels, mitochondrial dysfunction, and the consequent oxidative stress are recognized to underlie the pathogenesis of multiple neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. Central to their pathogenesis, Nrf2 signaling dysfunction occurs with disruption of metabolic homeostasis. We highlight the potential therapeutic importance of nutritional polyphenols as substantive regulators of the Nrf2 pathway. Here, we discuss the common mechanisms targeting the Nrf2/vitagene pathway, as novel therapeutic strategies to minimize consequences of oxidative stress and neuroinflammation, generally associated to cognitive dysfunction, and demonstrate its key neuroprotective and anti-neuroinflammatory properties, summarizing pharmacotherapeutic aspects relevant to brain pathophysiology.

Frankincense: A neuronutrient to approach Parkinson's disease treatment.

Parkinson's disease (PD), characterized by tremor, slowness of movement, stiffness, and poor balance, is due to a significant loss of dopaminergic neurons in the substantia nigra pars compacta and dopaminergic nerve terminals in the striatum with deficit of dopamine. To date the mechanisms sustaining PD pathogenesis are under investigation; however, a solid body of experimental evidence involves neuroinflammation, mitochondrial dysfunction, oxidative stress, and apoptotic cell death as the crucial factors operating in the pathogenesis of PD. Nutrition is known to modulate neuroinflammatory processes implicated in the pathogenesis and progression of this neurodegenerative disorder. Consistent with this notion, the Burseraceae family, which includes the genera Boswellia and Commiphora, are attracting emerging interest in the treatment of a wide range of pathological conditions, including neuroinflammation and cognitive decline. Bioactive components present in these species have been shown to improve cognitive function and to protect neurons from degeneration in in vitro, animal, as well as clinical research. These effects are mediated through the anti-inflammatory, antiamyloidogenic, anti-apoptotic, and antioxidative properties of bioactive components. Although many studies have exploited possible therapeutic approaches, data from human studies are lacking and their neuroprotective potential makes them a promising option for preventing and treating major neurodegenerative disorders.

The current insights of mitochondrial hormesis in the occurrence and treatment of bone and cartilage degeneration.

It is widely acknowledged that aging, mitochondrial dysfunction, and cellular phenotypic abnormalities are intricately associated with the degeneration of bone and cartilage. Consequently, gaining a comprehensive understanding of the regulatory patterns governing mitochondrial function and its underlying mechanisms holds promise for mitigating the progression of osteoarthritis, intervertebral disc degeneration, and osteoporosis. Mitochondrial hormesis, referred to as mitohormesis, represents a cellular adaptive stress response mechanism wherein mitochondria restore homeostasis and augment resistance capabilities against stimuli by generating reactive oxygen species (ROS), orchestrating unfolded protein reactions (UPRmt), inducing mitochondrial-derived peptides (MDP), instigating mitochondrial dynamic changes, and activating mitophagy, all prompted by low doses of stressors. The varying nature, intensity, and duration of stimulus sources elicit divergent degrees of mitochondrial stress responses, subsequently activating one or more signaling pathways to initiate mitohormesis. This review focuses specifically on the effector molecules and regulatory networks associated with mitohormesis, while also scrutinizing extant mechanisms of mitochondrial dysfunction contributing to bone and cartilage degeneration through oxidative stress damage. Additionally, it underscores the potential of mechanical stimulation, intermittent dietary restrictions, hypoxic preconditioning, and low-dose toxic compounds to trigger mitohormesis, thereby alleviating bone and cartilage degeneration.

Recent discoveries on the historical foundations of cancer risk assessment: Shedding light on the limits of LNT.

Within the past three years there has been a spate of historical discoveries by our research team on various different facets of the historical foundations of cancer risk assessment. This series of discoveries was stimulated by the creation of a 22-episode documentary of the historical foundations of cancer risk assessment by the US Health Physics Society and the need to provide documentation. This process yielded nearly two dozen distinct historical findings which have been published in numerous papers in the peer-reviewed literature. These discoveries are itemized and summarized in the present paper, along with the significance of each discovery within the historical context of ionizing radiation research and cancer risk assessment.

Exploring the co-exposure effects of environmentally relevant microplastics and an estrogenic mixture on the metabolome of the Sydney rock oyster.

In aquatic environments the concurrent exposure of molluscs to microplastics (MPs) and estrogens is common, as these pollutants are frequently released by wastewater treatment plants into estuaries. Therefore, this study aimed to evaluate the independent and co-exposure impacts of polyethylene microplastics (PE-MPs) and estrogenic endocrine-disrupting chemicals (EEDCs) at environmentally relevant concentrations on polar metabolites and morphological parameters of the Sydney rock oyster. A seven-day acute exposure revealed no discernible differences in morphology; however, significant variations in polar metabolites were observed across oyster tissues. The altered metabolites were mostly amino acids, carbohydrates and intermediates of the Kreb's cycle. The perturbation of metabolites were tissue and sex-specific. All treatments generally showed an increase of metabolites relative to controls - a possible stimulatory and/or a potential hormetic response. The presence of MPs impeded the exposure of adsorbed and free EEDCs potentially due to the selective feeding behaviour of oysters to microplastics, favouring algae over similar-sized PE-MPs, and the formation of an eco/bio-corona involving faeces, pseudo-faeces, natural organic matter, and algae.

Redox regulation of UPR signalling and mitochondrial ER contact sites.

Mitochondria and the endoplasmic reticulum (ER) have a synergistic relationship and are key regulatory hubs in maintaining cell homeostasis. Communication between these organelles is mediated by mitochondria ER contact sites (MERCS), allowing the exchange of material and information, modulating calcium homeostasis, redox signalling, lipid transfer and the regulation of mitochondrial dynamics. MERCS are dynamic structures that allow cells to respond to changes in the intracellular environment under normal homeostatic conditions, while their assembly/disassembly are affected by pathophysiological conditions such as ageing and disease. Disruption of protein folding in the ER lumen can activate the Unfolded Protein Response (UPR), promoting the remodelling of ER membranes and MERCS formation. The UPR stress receptor kinases PERK and IRE1, are located at or close to MERCS. UPR signalling can be adaptive or maladaptive, depending on whether the disruption in protein folding or ER stress is transient or sustained. Adaptive UPR signalling via MERCS can increase mitochondrial calcium import, metabolism and dynamics, while maladaptive UPR signalling can result in excessive calcium import and activation of apoptotic pathways. Targeting UPR signalling and the assembly of MERCS is an attractive therapeutic approach for a range of age-related conditions such as neurodegeneration and sarcopenia. This review highlights the emerging evidence related to the role of redox mediated UPR activation in orchestrating inter-organelle communication between the ER and mitochondria, and ultimately the determination of cell function and fate.

Facilitating the End of the Linear No-Threshold Model Era.

The linear no-threshold (LNT) model, which asserts that any level of ionizing radiation increases cancer risk, has been the basis of global radiation protection policies since the 1950s. Despite ongoing endorsements, a growing body of evidence challenges the LNT model, suggesting instead that low-level radiation exposure might reduce cancer risk, a concept known as radiation hormesis. This editorial examines the persistence of the LNT model despite evidence favoring radiation hormesis and proposes a solution: a public, online debate between proponents of the LNT model and advocates of radiation hormesis. This debate, organized by a government agency like Medicare, would be transparent and thorough, potentially leading to a shift in radiation protection policies. Acceptance of radiation hormesis could significantly reduce cancer mortality rates and streamline radiation safety regulations, fostering medical innovation and economic growth.

Time Is Ripe for Targeting Per- and Polyfluoroalkyl Substances-Induced Hormesis: Global Aquatic Hotspots and Implications for Ecological Risk Assessment.

Globally implemented ecological risk assessment (ERA) guidelines marginalize hormesis, a biphasic dose-response relationship characterized by low-dose stimulation and high-dose inhibition. The present study illuminated the promise of hormesis as a scientific dose-response model for ERA of per- and polyfluoroalkyl substances (PFAS) represented by perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS). A total of 266 hormetic dose-response relationships were recompiled from 1237 observations, covering 30 species from nine representative taxonomic groups. The standardized hormetic amplitudes followed the log-normal probability distribution, being subject to the limits of biological plasticity but independent of stress inducers. The SHapley Additive exPlanations algorithm revealed that the target endpoint was the most important variable explaining the hormetic amplitudes. Subsequently, quantitative frameworks were established to incorporate hormesis into the predicted no-effect concentration levels, with a lower induction dose and a zero-equivalent point but a broader hormetic zone for PFOS. Realistically, 10,117 observed concentrations of PFOA and PFOS were gathered worldwide, 4% of which fell within hormetic zones, highlighting the environmental relevance of hormesis. Additionally, the hormesis induction potential was identified in other legacy and emerging PFAS as well as their alternatives and mixtures. Collectively, it is time to incorporate the hormesis concept into PFAS studies to facilitate more realistic risk characterizations.

Physical Activity and Oxidative Stress in Aging.

Biological aging, characterized by changes in metabolism and physicochemical properties of cells, has an impact on public health. Environment and lifestyle, including factors like diet and physical activity, seem to play a key role in healthy aging. Several studies have shown that regular physical activity can enhance antioxidant defense mechanisms, including the activity of enzymes such as superoxide dismutase (SOD), catalase, and glutathione peroxidase. However, intense or prolonged exercise can also lead to an increase in reactive oxygen species (ROS) production temporarily, resulting in oxidative stress. This phenomenon is referred to as "exercise-induced oxidative stress". The relationship between physical activity and oxidative stress in aging is complex and depends on various factors such as the type, intensity, duration, and frequency of exercise, as well as individual differences in antioxidant capacity and adaptation to exercise. In this review, we analyzed what is reported by several authors regarding the role of physical activity on oxidative stress in the aging process as well as the role of hormesis and physical exercise as tools for the prevention and treatment of sarcopenia, an aging-related disease. Finally, we reported what has recently been studied in relation to the effect of physical activity and sport on aging in women.