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.

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.

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.

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.

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.

A low dose of curcumin-PDA nanoparticles improves viability and proliferation in endoneurial fibroblasts and Schwann cell cultures.

Curcumin is a polyphenol extracted from Curcuma longa's roots. Low doses of curcumin are related to anti-inflammatory, antioxidant, and neuroprotective effects, while high doses are used for their lethality. This diversity of behaviors allows us to understand curcumin as a compound with hormetic action. Due to its strongly hydrophobic character, curcumin is often solubilized in organic compounds. In this way, we have recently reported the undesirable and occasionally irreversible effects of alcohol and DMSO on the viability of primary Schwann cell cultures. In this scenario, the use of nanoparticles as delivery systems has become a successful alternative strategy for these compounds. In the present work, we describe the structure of Polydopamine (PDA) nanoparticles, loaded with a low dose of curcumin (Curc-PDA) without the use of additional organic solvents. We analyzed the curcumin released, and we found two different forms of curcumin. Small increased cell viability and proliferation were observed in endoneurial fibroblast and Schwann cell primary cultures when Curc-PDA was steadily supplied for 5 days. The increased bioavailability of this natural compound and the impact on cells in culture not only confirm the properties of curcumin at very low doses but also provide a glimpse of a possible therapeutic alternative for PNS conditions in which SCs are involved.

Enhancing the human health and lifespan: a targeted strategy emphasizing statins.

There has been substantial research interest in finding activities/agents that slow the onset and reduce the severity of numerous age-related diseases/conditions. This assessment indicates that the most studied agent intended to promote health in human population investigations for a broad spectrum of diseases are the statins, with large-scale epidemiological studies addressing numerous health endpoints. The key findings are that statin treatment consistently reduces the occurrence and attenuates the course of numerous non-communicable and contagious pathologies and numerous types of cancer with high mortality rates by about 20-50%. That one agent could affect such a broad based and consistently positive trends in epidemiological studies is unexpected and impressive, along with consistent cell and animal model research. Underlying mechanisms have been proposed that significantly contribute to the spectrum of salutary effects of statins, especially the capacity to activate Nrf2 showing hormetic dose responses in multiple organs and cell types, due to its bioavailability and broad tissue distribution. The widespread use of statins, which has the capacity to enhance human health span, should be considered for experimental exploration as a novel public health strategy that includes practical approaches for reduction of the most common adverse effects of this class of drugs including myalgia/myopathy and transaminitis.

Dynamic model of changes in the trophic structure of an ecosystem affected by chronic radiation exposure.

The conceptual dynamic ecosystem model was developed to evaluate the self-organization of trophic structure in ecosystems during the course of biogenic succession. This model was applied to analyze the possible changes in the ecosystem under impact of the anthropogenic physical stressor - chronic exposure to ionizing irradiation. The model predicts that amount of the limiting biogenic nutrient in the environment can modify the ecological effects of ionizing radiation. Negative effects of the chronic exposure are less significant in ecosystems with high food supply. The model does not show presence of any ecological effect of radiation at the exposure rates less than the derived consideration reference levels, obtained by International Commission on Radiological Protection for individual nature organisms. If the dose rates are higher than those levels, radiation exposure can affect ecological interactions between species. The model shows that environmental hormesis can exist in the ecosystems, impacted by the chronic radiation exposure. The reason of this effect is change of the ecological coefficients (for example, decrease of the predation rate), which in the certain range of parameters leads to the increase of biomasses of all species at the same amount of the limiting biogenic nutrient in ecosystem. Trigger regimes exist in the model ecosystem with mixed-feeding consumers. Within the trigger area, the realization of a particular trophic structure depends on initial species biomasses. A hysteresis phenomenon exists in such ecosystems, which means that the successive changes in the trophic structures realized following the increase of the influencing factor are not reproduced in the same order if the influencing factor was gradually decreased back to its previous values. The model predicts for this case, that the radioactively contaminated ecosystem does not necessarily return to its initial trophic structure, despite the dose rate decreases to the initial levels.

Tetraniliprole risk assessment: Unveiling a hidden threat for managing a generalist herbivore.

Insecticide resistance poses a significant challenge in managing generalist herbivores such as the tobacco cutworm (TCW), Spodoptera litura. This study investigates the potential risks associated with using the novel diamide insecticide tetraniliprole to control TCW. A tetraniliprole-resistant strain was developed through twelve generations of laboratory selection, indicating an intermediate risk of resistance development. Field monitoring in China revealed a significant incidence of resistance, particularly in the Nanchang (NC) population (>100-fold). Tetraniliprole showed moderate to high cross-resistance to multiple insecticides and was autosomally inherited with incomplete dominance, controlled by multiple genes, some of which belong to the cytochrome P450 family associated with enhanced detoxification. Life table studies indicated transgenerational hormesis, stimulating TCW female fecundity and increasing population net reproduction rates (R0). These findings suggest a potential for pest resurgence under tetraniliprole use. The integrated risk assessment provides a basis for the sustainable management of TCW using tetraniliprole.

Photodynamic treatment increases the lifespan and oxidative stress resistance of Caenorhabditis elegans.

Photodynamic therapy is a noninvasive treatment in which specific photosensitizers and light are used to produce high amounts of reactive oxygen species (ROS), which can be employed for targeted tissue destruction in cancer treatment or antimicrobial therapy. However, it remains unknown whether lower amounts of ROS produced by mild photodynamic therapy increase lifespan and stress resistance at the organism level. Here, we introduce a novel photodynamic treatment (PDTr) that uses 20 µM hypericin, a photosensitizer that originates from Hypericum perforatum, and orange light (590 nm, 5.4 W/m2, 1 min) to induce intracellular ROS formation (ROS), thereby resulting in lifespan extension and improved stress resistance in C. elegans. The PDTr-induced increase in longevity was abrogated by N-acetyl cysteine, suggesting the hormetic response was driven by prooxidative mechanisms. PDTr activated the translocation of SKN-1/NRF-2 and DAF-16/FOXO, leading to elevated expression of downstream oxidative stress-responsive genes, including ctl-1, gst-4, and sod-3. In summary, our findings suggest a novel PDTr method that extends the lifespan of C. elegans under both normal and oxidative stress conditions through the activation of SKN-1 and DAF-16 via the involvement of many antioxidant genes.

Investigation of biological-rhythm patterns: physiological and biochemical effects in herbaceous plants exposed to low-level chronic radiation - part 1: nonirradiated seeds.

HYPOTHESIS: Because reactive oxygen species are involved in the regulation of biological rhythms, we hypothesized that intra-annual variability of seed progeny quality at low doses of ionizing radiation (LDIRs) would differ from that of background plants. MATERIALS AND METHODS: We conducted 12 consecutive experiments using the roll culture method by germinating seeds (monthly for 3 weeks) of six herbaceous plant species (Bromus inermis, Geum aleppicum, Plantago major, Rumex confertus, Silene latifolia, and Taraxacum officinale) growing under conditions of chronic radiation in the East Ural Radioactive Trace (EURT). We assessed physiological (seed viability and abnormality frequency) and biochemical (low-molecular-weight antioxidants, LMWAs) parameters of seedlings. RESULTS: Total absorbed dose rates of maternal plants (TADRplants) and seed embryos (TADRseeds) in the EURT exceeded background levels by 1-3 and 1-2 orders of magnitude, respectively. Nonlinear dependencies on TADR were mainly characteristic of physiological and biochemical parameters. For most populations of the studied species (B. inermis, G. aleppicum, R. confertus, and S. latifolia), seedling survival and root length decreased in the autumn-winter period, while the frequency of abnormal seedlings increased. The content of LMWAs could be ranked as R. confertus > B. inermis > G. aleppicum > S. latifolia, in good agreement with the presence of anthocyanin pigmentation in the plants. The lowest synthesis of antioxidants in seedlings was observed in winter. A high LMWA content promoted growth and reduced the frequency of abnormal seedlings. CONCLUSIONS: These results underscore a multistage nature of the impact of LDIRs on intra-annual biological rhythms in plants. High heterogeneity in reference group 'wild grasses' and diversity of their radiobiological effects should help to develop methods of radiation protection for natural ecosystems and facilitate approaches used by the International Commission on Radiological Protection.HighlightsAbsorbed dose rates for six plant species in the East Ural Radioactive Trace (EURT) area range from 0.11 to 73.89 µGy h-s (plants) and 0.11 to 6.88 µGy h-s (seed embryos).Intra-annual rhythms of physiological and biochemical parameters in the EURT zone differ from those in background seedlings.Plants in the EURT area exhibit a wide range of trait variability, asynchrony of the manifestation of the effects, nonlinear dose-response relations, and hormesis.A high content of low-molecular-weight antioxidants (LMWAs) is associated with low frequency of developmental abnormalities and high viability of seed progeny.

Alzheimer's disease and low-dose radiation therapy: A new hope.

The concept of low-dose radiation (LDR)-induced hormetic responses was initially observed approximately 70 years ago and systematically reviewed along with the discovery of LDR-induced adaptive responses in a cytogenetic in vitro study in 1980s. By the end of the 1990s, discussions regarding the potential applications of LDR-induced hormesis and adaptive responses for preventing or treating chronic diseases, such as Alzheimer's disease (AD) had taken place. Until 2016, reports on radiotherapy for the subjects with AD and for genetic AD model mice were published. Subsequently, several preclinical studies with animal models of AD and clinical studies in AD subjects were conducted. A significant milestone was achieved with the online availability of a new Systematic Review based on qualified publications from these preclinical and clinical studies. This mini-review provides a concise historical introduction to LDR-induced hormesis and adaptive responses with discussion of AD radiotherapy with either LDR or relatively high dose radiation. Highlights of this Systematic Review cover promising outcomes, challenges, and new questions, followed by discussion of potential mechanisms.

Hormetic Nutrition and Redox Regulation in Gut-Brain Axis Disorders.

The antioxidant and anti-inflammatory effects of hormetic nutrition for enhancing stress resilience and overall human health have received much attention. Recently, the gut-brain axis has attracted prominent interest for preventing and therapeutically impacting neuropathologies and gastrointestinal diseases. Polyphenols and polyphenol-combined nanoparticles in synergy with probiotics have shown to improve gut bioavailability and blood-brain barrier (BBB) permeability, thus inhibiting the oxidative stress, metabolic dysfunction and inflammation linked to gut dysbiosis and ultimately the onset and progression of central nervous system (CNS) disorders. In accordance with hormesis, polyphenols display biphasic dose-response effects by activating at a low dose the Nrf2 pathway resulting in the upregulation of antioxidant vitagenes, as in the case of heme oxygenase-1 upregulated by hidrox® or curcumin and sirtuin-1 activated by resveratrol to inhibit reactive oxygen species (ROS) overproduction, microbiota dysfunction and neurotoxic damage. Importantly, modulation of the composition and function of the gut microbiota through polyphenols and/or probiotics enhances the abundance of beneficial bacteria and can prevent and treat Alzheimer's disease and other neurological disorders. Interestingly, dysregulation of the Nrf2 pathway in the gut and the brain can exacerbate selective susceptibility under neuroinflammatory conditions to CNS disorders due to the high vulnerability of vagal sensory neurons to oxidative stress. Herein, we aimed to discuss hormetic nutrients, including polyphenols and/or probiotics, targeting the Nrf2 pathway and vitagenes for the development of promising neuroprotective and therapeutic strategies to suppress oxidative stress, inflammation and microbiota deregulation, and consequently improve cognitive performance and brain health. In this review, we also explore interactions of the gut-brain axis based on sophisticated and cutting-edge technologies for novel anti-neuroinflammatory approaches and personalized nutritional therapies.

Physiology of deep closed circuit rebreather mixed gas diving: vascular gas emboli and biological changes during a week-long liveaboard safari.

Introduction: Diving decompression theory hypothesizes inflammatory processes as a source of micronuclei which could increase related risks. Therefore, we tested 10 healthy, male divers. They performed 6-8 dives with a maximum of two dives per day at depths ranging from 21 to 122 msw with CCR mixed gas diving. Methods: Post-dive VGE were counted by echocardiography. Saliva and urine samples were taken before and after each dive to evaluate inflammation: ROS production, lipid peroxidation (8-iso-PGF2), DNA damage (8-OH-dG), cytokines (TNF-α, IL-6, and neopterin). Results: VGE exhibits a progressive reduction followed by an increase (p < 0.0001) which parallels inflammation responses. Indeed, ROS, 8-iso-PGF2, IL-6 and neopterin increases from 0.19 ± 0.02 to 1.13 ± 0.09 µmol.min-1 (p < 0.001); 199.8 ± 55.9 to 632.7 ± 73.3 ng.mg-1 creatinine (p < 0.0001); 2.35 ± 0.54 to 19.5 ± 2.96 pg.mL-1 (p < 0.001); and 93.7 ± 11.2 to 299 ± 25.9 µmol·mol-1 creatinine (p = 0.005), respectively. The variation after each dive was held constant around 158.3% ± 6.9% (p = 0.021); 151.4% ± 5.7% (p < 0.0001); 176.3% ± 11.9% (p < 0.0001); and 160.1% ± 5.6% (p < 0.001), respectively. Discussion: When oxy-inflammation reaches a certain level, it exceeds hormetic coping mechanisms allowing second-generation micronuclei substantiated by an increase of VGE after an initial continuous decrease consistent with a depletion of "first generation" pre-existing micronuclei.

Bioorthogonal microglia-inspired mesenchymal stem cell bioengineering system creates livable niches for enhancing ischemic stroke recovery via the hormesis.

Mesenchymal stem cells (MSCs) experience substantial viability issues in the stroke infarct region, limiting their therapeutic efficacy and clinical translation. High levels of deadly reactive oxygen radicals (ROS) and proinflammatory cytokines (PC) in the infarct milieu kill transplanted MSCs, whereas low levels of beneficial ROS and PC stimulate and improve engrafted MSCs' viability. Based on the intrinsic hormesis effects in cellular biology, we built a microglia-inspired MSC bioengineering system to transform detrimental high-level ROS and PC into vitality enhancers for strengthening MSC therapy. This system is achieved by bioorthogonally arming metabolic glycoengineered MSCs with microglial membrane-coated nanoparticles and an antioxidative extracellular protective layer. In this system, extracellular ROS-scavenging and PC-absorbing layers effectively buffer the deleterious effects and establish a micro-livable niche at the level of a single MSC for transplantation. Meanwhile, the infarct's inanimate milieu is transformed at the tissue level into a new living niche to facilitate healing. The engineered MSCs achieved viability five times higher than natural MSCs at seven days after transplantation and exhibited a superior therapeutic effect for stroke recovery up to 28 days. This vitality-augmented system demonstrates the potential to accelerate the clinical translation of MSC treatment and boost stroke recovery.

Hypothesis: Cancer Hormesis and Its Potential for Cancer Therapeutics.

Primary tumors can inhibit the growth of secondary lesions, particularly metastases, in a phenomenon termed "concomitant resistance". Several mechanisms have been proposed for this effect, each supported by experimental data. In this paper, we hypothesize that concomitant resistance is a form of hormesis, a biphasic dose response in which a stimulus has a positive and/or stimulatory effect at low dosages and a negative, inhibitory, and/or toxic effect at higher dosages. When this paradigm applies to tumorigenesis, it is referred to as "cancer hormesis". Thus, low numbers of benign neoplastic cells or less tumorigenic malignant cells may result in resistance to the development of malignant neoplasms, including metastases. A host containing a number of (less tumorigenic) neoplastic cells may exhibit greater protection against more tumorigenic malignant neoplasms than a host who lacks neoplastic cells, or who has too few neoplastic cells to stimulate a protective response. As a theoretical endeavor, this paper also proposes that cancer hormesis can be leveraged for therapeutic purposes, by the implantation of safely controlled, benign artificial tumors in high-risk patients. These tumors would prevent the development of endogenous malignant neoplasms by creating an inhibitory environment for such growth. Strategies for testing the hypothesis are proposed.

Reassessing the role of phytochemicals in cancer chemoprevention.

In this comprehensive review we tried to reassess the role of phytochemicals in cancer chemoprevention. The exploration of the "synergistic effect" concept, advocating combined chemopreventive agents, faces challenges like low bioavailability. The review incorporates personal, occasionally controversial, viewpoints on natural compounds' cancer preventive capabilities, delving into mechanisms. Prioritizing significant contributions within the vast research domain, we aim stimulating discussion to provide a comprehensive insight into the evolving role of phytochemicals in cancer prevention. While early years downplayed the role of phytochemicals, the late nineties witnessed a shift, with leaders exploring their potential alongside synthetic compounds. Challenges faced by chemoprevention, such as limited pharmaceutical interest and cost-effectiveness issues, persist despite successful drugs. Recent studies, including the EPIC study, provide nuanced insights, indicating a modest risk reduction for increased fruit and vegetable intake. Phytochemicals, once attributed to antioxidant effects, face scrutiny due to low bioavailability and conflicting evidence. The Nrf2-EpRE signaling pathway and microbiota-mediated metabolism emerge as potential mechanisms, highlighting the complexity of understanding phytochemical mechanisms in cancer chemoprevention.

Are Supra-Physiological Plant-Based Antioxidants Ready for the Clinic? A Scoping Review of Hormetic Influences Driving Positive Clinical Outcomes.

Background: A pro-inflammatory metabolic state is key to the chronic disease epidemic. Clinicians' ability to use nutrients to balance inflammation via oxidant homeostasis depends on the quality of antioxidants research. Understanding the intersection of two prominent theories for how antioxidants quell inflammation-nutritional hormesis and oxidant scavenging-will enable therapeutic antioxidant use in clinical practice. Purpose: We sought to survey the literature to answer the question: has the hormetic response of exogenous antioxidants been studied in humans and if so, what is its effect Research Design: This review investigates the less well-established theory, nutritional hormesis. To understand the state of hormetic response research, we conducted a literature review describing the relationship between exogenous antioxidants, hormesis, and chronic disease. We used an adaptive search strategy (PubMed and Scopus), retrieving 343 articles, of which 218 were unique. Most studies reviewed the hormetic response in plant and cell models (73.6%) while only 2.2% were in humans. Results: Given the limited robust evidence, clinicians lack research-based guidance on the appropriate therapeutic dose of exogenous antioxidants or, more concerning, supra-physiological dosing via supplements. A critical hurdle in searching the literature is the lack of standardized nomenclature describing the hormetic effect, challenging the ability of clinicians to make informed decisions. Conclusion: Non-human research shows a biphasic, hormetic relationship with antioxidants but observational studies have yet to translate this into the complexities of human biochemistry and physiology. Therefore, we cannot accurately translate this into clinical care. To remedy this insufficiency, we suggest: (1) Improved data collection quality: controlled diet, standardized antioxidant measurements, bioavailability assessed via biomarkers; (2) Larger, harmonized datasets: research subject transparency, keyword standardization, consensus on a hormesis definition.

Unlocking hormesis and toxic effects induced by cadmium in Polygonatum cyrtonema Hua based on morphology, physiology and metabolomics.

Traditional Chinese medicine materials (TCMMs) are widely planted and used, while cadmium (Cd) is a widespread pollutant that poses a potential risk to plant growth and human health. However, studies on the influences of Cd on TCMMs have been limited. Our study aims to reveal the antioxidation-related detoxification mechanism of Polygonatum cyrtonema Hua under Cd stress based on physiology and metabolomics. The results showed that Cd0.5 (total Cd: 0.91 mg/kg; effective Cd: 0.45 mg/kg) induced hormesis on the biomass of roots, tubers and aboveground parts with increases of 22.88%, 27.12% and 17.02%, respectively, and significantly increased the flavonoids content by 57.45%. Additionally, the metabolism of caffeine, glutamine, arginine and purine was upregulated to induce hormesis in Cd0.5, which enhanced the synthesis of resistant substances such as spermidine, choline, IAA and saponins. Under Cd2 stress, choline and IAA decreased, and fatty acid metabolites (such as peanut acid and linoleic acid) and 8-hydroxyguanosine increased in response to oxidative damage, resulting in a significant biomass decrease. Our findings further reveal the metabolic process of detoxification by antioxidants and excessive Cd damage in TCMMs, deepen the understanding of detoxification mechanisms related to antioxidation, and enrich the relevant theories of hormesis induced by Cd.