Low-dose zinc oxide nanoparticles trigger the growth and biofilm formation of Pseudomonas aeruginosa: a hormetic response.

INTRODUCTION: Hormesis describes an inverse dose-response relationship, whereby a high dose of a toxic compound is inhibitory, and a low dose is stimulatory. This study explores the hormetic response of low concentrations of zinc oxide nanoparticles (ZnO NPs) toward Pseudomonas aeruginosa. METHOD: Samples of P. aeruginosa, i.e. the reference strain, ATCC 27,853, together with six strains recovered from patients with cystic fibrosis, were exposed to ten decreasing ZnO NPs doses (0.78-400 µg/mL). The ZnO NPs were manufactured from Peganum harmala using a chemical green synthesis approach, and their properties were verified utilizing X-ray diffraction and scanning electron microscopy. A microtiter plate technique was employed to investigate the impact of ZnO NPs on the growth, biofilm formation and metabolic activity of P. aeruginosa. Real-time polymerase chain reactions were performed to determine the effect of ZnO NPs on the expression of seven biofilm-encoding genes. RESULT: The ZnO NPs demonstrated concentration-dependent bactericidal and antibiofilm efficiency at concentrations of 100-400 µg/mL. However, growth was significantly stimulated at ZnO NPs concentration of 25 µg/mL (ATCC 27853, Pa 3 and Pa 4) and at 12.5 µg/mL and 6.25 µg/mL (ATCC 27853, Pa 2, Pa 4 and Pa 5). No significant positive growth was detected at dilutions < 6.25 µg/mL. similarly, biofilm formation was stimulated at concentration of 12.5 µg/mL (ATCC 27853 and Pa 1) and at 6.25 µg/mL (Pa 4). At concentration of 12.5 µg/mL, ZnO NPs upregulated the expression of LasB ( ATCC 27853, Pa 1 and Pa 4) and LasR and LasI (ATCC 27853 and Pa 1) as well as RhII expression (ATCC 27853, Pa 2 and Pa 4). CONCLUSION: When exposed to low ZnO NPs concentrations, P. aeruginosa behaves in a hormetic manner, undergoing positive growth and biofilm formation. These results highlight the importance of understanding the response of P. aeruginosa following exposure to low ZnO NPs concentrations.

Hormetic dose response induced by sublethal-dose sulfoxaflor leads to reproductive stimulation of Aphis gossypii.

Aphis gossypii Glover is one of the most agriculturally important phloem-feeding economic pests, causing tremendous loss in crop yield annually. The hormesis is an important cause of A. gossypii resistance formation, population resurgence, and re-outbreak. However, whether the hormesises induced by different insecticides interact mutually remain largely unclear. In the study, four-generation A. gossypii experiment found that the 24-h sublethal-dose (LC20) sulfoxaflor treatment on G0 significantly increased the net reproductive rate (R0) and fecundity of G1 and G2 generation A. gossypii, but it did not significantly affect the fecundity of G3 and G4 individuals. Transcriptomic analyses revealed that the insecticide-induced significant up-regulation of pathways ribosome, energy metabolism, and the DNA replication and reparation might be responsible for the enhancement of fecundity in G1 and G2 A. gossypii. Notably, G0 exposure to LC20 sulfoxaflor followed by G1 exposure to LC30 deltamethrin resulted in a stronger reproductive stimulation than sulfoxaflor or deltamethrin exposure alone. Our findings provide valuable reference for optimizing sulfoxaflor application in integrated pest management strategies.

The phytoprotective agent sulforaphane prevents inflammatory degenerative diseases and age-related pathologies via Nrf2-mediated hormesis.

In numerous experimental models, sulforaphane (SFN) is shown herein to induce hormetic dose responses that are not only common but display endpoints of biomedical and clinical relevance. These hormetic responses are mediated via the activation of nuclear factor erythroid- derived 2 (Nrf2) antioxidant response elements (AREs) and, as such, are characteristically biphasic, well integrated, concentration/dose dependent, and specific with regard to the targeted cell type and the temporal profile of response. In experimental disease models, the SFN-induced hormetic activation of Nrf2 was shown to effectively reduce the occurrence and severity of a wide range of human-related pathologies, including Parkinson's disease, Alzheimer's disease, stroke, age-related ocular damage, chemically induced brain damage, and renal nephropathy, amongst others, while also enhancing stem cell proliferation. Although SFN was broadly chemoprotective within an hormetic dose-response context, it also enhanced cell proliferation/cell viability at low concentrations in multiple tumor cell lines. Although the implications of the findings in tumor cells are largely uncertain at this time and warrant further consideration, the potential utility of SFN in cancer treatment has not been precluded. This assessment of SFN complements recent reports of similar hormesis-based chemoprotections by other widely used dietary supplements, such as curcumin, ginkgo biloba, ginseng, green tea, and resveratrol. Interestingly, the mechanistic profile of SFN is similar to that of numerous other hormetic agents, indicating that activation of the Nrf2/ARE pathway is probably a central, integrative, and underlying mechanism of hormesis itself. The Nrf2/ARE pathway provides an explanation for how large numbers of agents that both display hormetic dose responses and activate Nrf2 can function to limit age-related damage, the progression of numerous disease processes, and chemical- and radiation- induced toxicities. These findings extend the generality of the hormetic dose response to include SFN and many other chemical activators of Nrf2 that are cited in the biomedical literature and therefore have potentially important public health and clinical implications.

The hormetic dose-response mechanism: Nrf2 activation.

A generalized mechanism for hormetic dose responses is proposed that is based on the redox-activated transcription factor (TF), Nrf2, and its upregulation of an integrative system of endogenous anti-oxidant and anti-inflammatory adaptive responses. Nrf2 can be activated by numerous oxidative stressors (e.g., exercise, caloric restriction/intermittent fasting) and by exposures to synthetic, naturally occurring and endogenous chemicals, to non-ionizing (e.g., low-level light) and ionizing radiation, and to low-to-moderate stress from aging processes, among others. Nrf2 conducts crosstalk with other TFs to further integrate and enhance the effectiveness of adaptive metabolic strategies that produce acquired resilience. This adaptive mechanism of Nrf2 accounts for the generality and ubiquity of hormetic dose responses and supports the fundamental hormetic characteristic of protecting biological systems. At the same time, Nrf2 is highly evolutionarily conserved and quantitatively constrained in response (i.e., modest stimulatory response), further conserving biological resources and enhancing metabolic efficiencies. The notion that Nrf2 may serve as an hormetic mediator not only provides a regulatory-based evolutionary understanding of temporal acquired resilience and adaptive homeostasis but also causally integrates toxicological and pharmacological detoxification processes that are central to ecological and human risk assessments as well as to the development of drugs and therapeutics. These findings can also account for considerable inter-individual variation in susceptibility to toxic substances, the differential effectiveness of numerous therapeutic agents, and the variation in onset and severity of numerous age-related illnesses, such as type II diabetes.

Hormesis Effect of Berberine against Klebsiella pneumoniae Is Mediated by Up-Regulation of the Efflux Pump KmrA.

Berberine (BBR) is an effective drug for human intestinal inflammation by preventing intestinal adhesion of bacterial pathogens, while its antibacterial activity is ineffective. Although the antimicrobial mechanisms of BBR are intensively studied at high concentrations, the response of pathogens to its low concentrations remains poorly understood. Here we demonstrated that low concentrations of BBR (3 and 6 µg/mL) conferred by hormesis accelerated cell growth of an important Gram-negative pathogen, Klebsiella pneumoniae, in vitro, while higher concentrations (25 and 50 µg/mL) resulted in the opposite. Transcriptome analysis of K. pneumoniae revealed the up-regulated expression of the KmrA efflux pump and further confirmed it was hypersensitive to BBR stress. Strikingly, when cultivated in tetracycline, the growth-promoting effect of BBR became more significant, while this effect was reversed in the presence of the efflux pump inhibitor cyanide-m-chlorophenylhydrazone. The hormesis was also found in Enterobacter cloacae and Acinetobacter baumannii. More importantly, the presence of BBR at low concentrations resulted in higher minimal inhibitory concentrations of efflux-related antibiotics such as rifampicin and azithromycin. Overall, our data demonstrated the hormesis of BBR and revealed the potential risk of its applications against Gram-negative pathogens at low concentrations.

Hormesis in plants: Physiological and biochemical responses.

Hormesis is a favorable response to low level exposures to substance or to adverse conditions. This phenomenon has become a target to achieve greater crop productivity. This review aimed to address the physiological mechanisms for the induction of hormesis in plants. Some herbicides present a hormetic dose response. Among them, those with active ingredients glyphosate, 2,4-D and paraquat. The application of glyphosate as a hormesis promoter is therefore showing promess . Glyphosate has prominent role in shikimic acid pathway, decreasing lignin synthesis resulting in improved growth and productivity of several crops. Further studies are still needed to estimate optimal doses for other herbicides of crops or agricultural interest. Biostimulants are also important, since they promote effects on secondary metabolic pathways and production of reactive oxygen species (ROS). When ROS are produced, hydrogen peroxide act as a signaling molecule that promote cell walls malleability allowing inward water transport causing cell expansion. . Plants'ability to overcome several abiotic stress conditions is desirable to avoid losses in crop productivity and economic losses. This review compiles information on how hormesis in plants can be used to achieve new production levels.

The Hormetic Effect of Metformin: "Less Is More"?

Metformin (MTF) is the first-line therapy for type 2 diabetes (T2DM). The euglycemic effect of MTF is due to the inhibition of hepatic glucose production. Literature reports that the principal molecular mechanism of MTF is the activation of 5'-AMP-activated protein kinase (AMPK) due to the decrement of ATP intracellular content consequent to the inhibition of Complex I, although this effect is obtained only at millimolar concentrations. Conversely, micromolar MTF seems to activate the mitochondrial electron transport chain, increasing ATP production and limiting oxidative stress. This evidence sustains the idea that MTF exerts a hormetic effect based on its concentration in the target tissue. Therefore, in this review we describe the effects of MTF on T2DM on the principal target organs, such as liver, gut, adipose tissue, endothelium, heart, and skeletal muscle. In particular, data indicate that all organs, except the gut, accumulate MTF in the micromolar range when administered in therapeutic doses, unmasking molecular mechanisms that do not depend on Complex I inhibition.

Toluene induces hormetic response of soil alkaline phosphatase and the potential enzyme kinetic mechanism.

Hormesis of soil enzyme that involved in heavy metal has been attracting much more attention for risk assessment of heavy metal toxicity, but insufficient studies were conducted to define the hormetic responses induced by toluene or other organic pollutions. The objectives of this study were to investigate the hormetic responses of soil enzyme induced by toluene and explore the potential enzyme kinetic mechanism. Soil alkaline phosphatase (ALP) activity was regarded as the endpoint to explore the hormetic responses under different doses of toluene (0.0, 0.1, 0.5, 1.0, 2.0, 3.0, 5.0, 10.0, 50.0 and 100.0 µL g-1). Subsequently, we conducted the experiments of enzymatic reaction kinetics and pure enzyme to further verify the potential mechanisms of soil ALP's hormesis. Results showed that ALP activities at 0.1-1.0 µL g-1 toluene were significantly increased in contrast to the control (0 µL g-1 toluene) (P < 0.05) at the exposure time of 30, 36, 48 and 54 h, with the maximum stimulation magnitudes of 24-43%. ALP activities were almost not affected by toluene (2-100 µL L-1) in the whole experimental period (6-54 h). Meanwhile, the values of catalytic efficiency (the radio Vmax/Km, Vmax: maximum reaction velocity and Km: Michaelis constant) and Vmax significantly increased compared with the control, but the value of Km decreased from 2.5 to 1.6. Overall, low dose toluene can induce hormesis of soil ALP. The potential reason is that low-dose toluene could enhance the combination of soil ALP and substrates. We believe that this study will provide a new viewpoint for ecological risk assessment of toluene contaminated soils.

Luteolin protects microglia against rotenone-induced toxicity in a hormetic manner through targeting oxidative stress response, genes associated with Parkinson's disease and inflammatory pathways.

Rotenone, an environmental toxin, triggers Parkinson's disease (PD)-like pathology through microglia-mediated neuronal death. The effects and molecular mechanisms of flavonoid luteolin against rotenone-induced toxicity was assessed in microglial BV2 cells. Cells were pretreated with luteolin (1-50 µM) for 12 h and then was co-treated with 20 µM of rotenone for an additional 12 h in the presence of luteolin. The viability (MTT), IL-1ß and TNF-α levels and lactate dehydrogenase (LDH) release (ELISA), and Park2, Lrrk2, Pink1, Nrf2 and Trx1 mRNA levels (qRT-PCR) were measured. In rotenone exposed microglia, luteolin increased viability significantly at lower concentrations (1-5 µM) compared to higher concentrations (25-50 µM). Rotenone increased LDH release and IL-1ß levels in a dose-dependent manner (1-20 µM). Luteolin inhibited rotenone-induced LDH release, however the activity decreased in concentration-dependent manner Neither rotenone nor luteolin altered TNF-α levels, but luteolin reduced IL-1ß levels in a concentration dependent manner in rotenone exposed cells. The mRNA levels of Nrf2 and Trx1, which are the master regulators of redox state, were increased by rotenone, as well as by luteolin, which exhibited an inverse relationship between its concentration and effect (1-20 µM). Park2 mRNA levels increased by luteolin, but decreased by rotenone. Pink1 mRNA levels was not altered by rotenone or luteolin. Lrrk2 mRNA levels reduced by luteolin, while it was increased by rotenone. Results suggest that luteolin have favorable effects on regulation of oxidative stress response, genes associated with PD and inflammatory pathways, hence protects microglia against rotenone toxicity in a hormetic manner.

The Soluble Adenylyl Cyclase Inhibitor LRE1 Prevents Hepatic Ischemia/Reperfusion Damage Through Improvement of Mitochondrial Function.

Hepatic ischemia/reperfusion (I/R) injury is a leading cause of organ dysfunction and failure in numerous pathological and surgical settings. At the core of this issue lies mitochondrial dysfunction. Hence, strategies that prime mitochondria towards damage resilience might prove applicable in a clinical setting. A promising approach has been to induce a mitohormetic response, removing less capable organelles, and replacing them with more competent ones, in preparation for an insult. Recently, a soluble form of adenylyl cyclase (sAC) has been shown to exist within mitochondria, the activation of which improved mitochondrial function. Here, we sought to understand if inhibiting mitochondrial sAC would elicit mitohormesis and protect the liver from I/R injury. Wistar male rats were pretreated with LRE1, a specific sAC inhibitor, prior to the induction of hepatic I/R injury, after which mitochondria were collected and their metabolic function was assessed. We find LRE1 to be an effective inducer of a mitohormetic response based on all parameters tested, a phenomenon that appears to require the activity of the NAD+-dependent sirtuin deacylase (SirT3) and the subsequent deacetylation of mitochondrial proteins. We conclude that LRE1 pretreatment leads to a mitohormetic response that protects mitochondrial function during I/R injury.

Hormesis in Plants: The Role of Oxidative Stress, Auxins and Photosynthesis in Corn Treated with Cd or Pb.

Hormesis, which describes the stimulatory effect of low doses of toxic substances on growth, is a well-known phenomenon in the plant and animal kingdoms. However, the mechanisms that are involved in this phenomenon are still poorly understood. We performed preliminary studies on corn coleoptile sections, which showed a positive correlation between the stimulation of growth by Cd or Pb and an increase in the auxin and H2O2 content in the coleoptile sections. Subsequently, we grew corn seedlings in hydroponic culture and tested a wide range of Cd or Pb concentrations in order to determine hormetic growth stimulation. In these seedlings the gas exchange and the chlorophyll a fluorescence, as well as the content of chlorophyll, flavonol, auxin and hydrogen peroxide, were measured. We found that during the hormetic stimulation of growth, the response of the photosynthetic apparatus to Cd and Pb differed significantly. While the application of Cd mostly caused a decrease in various photosynthetic parameters, the application of Pb stimulated some of them. Nevertheless, we discovered that the common features of the hormetic stimulation of shoot growth by heavy metals are an increase in the auxin and flavonol content and the maintenance of hydrogen peroxide at the same level as the control plants.

Tolerance of Facultative Metallophyte Carlina acaulis to Cadmium Relies on Chelating and Antioxidative Metabolites.

The impact of long-term chronic cadmium stress (ChS, 0.1 µM Cd, 85 days) or short-term acute cadmium stress (AS, 10 µM Cd, 4 days) on Carlina acaulis (Asteraceae) metabolites was compared to identify specific traits. The content of Cd was higher under AS in all organs in comparison with ChS (130 vs. 16 µg·g-1 DW, 7.9 vs. 3.2 µg·g-1 DW, and 11.5 vs. 2.4 µg·g-1 DW in roots, leaves, and trichomes, respectively) while shoot bioaccumulation factor under ChS (ca. 280) indicates efficient Cd accumulation. High content of Cd in the trichomes from the AS treatment may be an anatomical adaptation mechanism. ChS evoked an increase in root biomass (hormesis), while the impact on shoot biomass was not significant in any treatment. The amounts of ascorbic acid and sum of phytochelatins were higher in the shoots but organic (malic and citric) acids dominated in the roots of plants from the ChS treatment. Chlorogenic acid, but not ursolic and oleanolic acids, was elevated by ChS. These data indicate that both chelation and enhancement of antioxidative power contribute to protection of plants exposed to long-term (chronic) Cd presence with subsequent hormetic effect.

Isoliquiritigenin Pretreatment Induces Endoplasmic Reticulum Stress-Mediated Hormesis and Attenuates Cisplatin-Induced Oxidative Stress and Damage in LLC-PK1 Cells.

Isoliquiritigenin (IsoLQ) is a flavonoid with antioxidant properties and inducer of endoplasmic reticulum (ER) stress. In vitro and in vivo studies show that ER stress-mediated hormesis is cytoprotective; therefore, natural antioxidants and ER stress inducers have been used to prevent renal injury. Oxidative stress and ER stress are some of the mechanisms of damage involved in cisplatin (CP)-induced nephrotoxicity. This study aims to explore whether IsoLQ pretreatment induces ER stress and produces hormesis to protect against CP-induced nephrotoxicity in Lilly Laboratories Cell-Porcine Kidney 1 (LLC-PK1) cells. During the first stage of this study, both IsoLQ protective concentration and pretreatment time against CP-induced toxicity were determined by cell viability. At the second stage, the effect of IsoLQ pretreatment on cell viability, ER stress, and oxidative stress were evaluated. IsoLQ pretreatment in CP-treated cells induces expression of glucose-related proteins 78 and 94 kDa (GRP78 and GRP94, respectively), attenuates CP-induced cell death, decreases reactive oxygen species (ROS) production, and prevents the decrease in glutathione/glutathione disulfide (GSH/GSSG) ratio, free thiols levels, and glutathione reductase (GR) activity. These data suggest that IsoLQ pretreatment has a moderately protective effect on CP-induced toxicity in LLC-PK1 cells, through ER stress-mediated hormesis, as well as by the antioxidant properties of IsoLQ.

In Vitro Hormetic Effect Investigation of Thymol on Human Fibroblast and Gastric Adenocarcinoma Cells.

The concept of hormesis includes a biphasic cellular dose-response to a xenobiotic stimulus defined by low dose beneficial and high dose inhibitory or toxic effects. In the present study, an attempt has been made to help elucidate the beneficial and detrimental effects of thymol on different cell types by evaluating and comparing the impact of various thymol doses on cancerous (AGS) and healthy (WS-1) cells. Cytotoxic, genotoxic, and apoptotic effects, as well as levels of reactive oxygen species and glutathione were studied in both cell lines exposed to thymol (0-600 µM) for 24 h. The results showed significant differences in cell viability of AGS compared to WS-1 cells exposed to thymol. The differences observed were statistically significant at all doses applied (P ≤ 0.001) and revealed hormetic thymol effects on WS-1 cells, whereas toxic effects on AGS cells were detectable at all thymol concentrations. Thymol at low concentrations provides antioxidative protection to WS-1 cells in vitro while already inducing toxic effects in AGS cells. In that sense, the findings of the present study suggest that thymol exerts a dose-dependent hormetic impact on different cell types, thereby providing crucial information for future in vivo studies investigating the therapeutic potential of thymol.

Hormetic effect of glyphosate on Urochloa decumbens plants.

Urochloa decumbens plants may be reached by herbicide drift from applications of glyphosate from neighboring areas or by variations during applications. Considering the different phenological stages and size of plants in these areas, the amount of active ingredient that reaches the plants probably varies. The objective of this study was to evaluate the effects of the application of different doses of glyphosate on U. decumbens plants. Two greenhouse experiments were conducted with two replications at different times. The first experiment evaluated the biological response of U. decumbens plants to glyphosate doses (0, 2.81, 5.63, 11.25, 22.5, 45, 90, 180, 360, 720, and 1,440 g a.e. ha-1), with six replications. The second experiment evaluated the response of U. decumbens plants to the application of a selected low dose of 11.25 g a.e. ha-1. Evaluations of injury were performed at 0, 7, 14, and 21 days after application, and dry weight of plants was determined for each evaluation period. U. decumbens plants increased in dry weight when using the glyphosate dose of 11.25 g a.e. ha-1. However, plants had different responses to the application of this low dose. It can promote both stimulation and inhibition of plant growth.

Effect of Graphene Oxide on Growth of Wheat Seedlings: Insights from Oxidative Stress and Physiological Flux.

In this study, the responses of wheat seedlings to graphene oxide (GO) were investigated at a wide concentration range of 0-1000 mg L-1, including oxidative stress, real-time membrane potential as well as proton and calcium ion fluxes. The results show that GO induced a hormesis effect on root growth (low concentration (100 mg L-1) promotion and high concentration (1000 mg L-1) inhibition. Oxidative stress was responsible for the growth inhibition at GO concentration of 1000 mg L-1, as suggested from great stimulation in the activities of antioxidant enzymes and MDA content in roots or leaves. Superoxide dismutase (SOD), catalase (CAT), peroxidase (POD) activities were highly correlated with MDA levels (r2 = 0.963, 0.984, and 0.960, respectively). GO exposure caused significant concentration-dependent membrane depolarization in roots, and significantly inhibited H+ efflux and extracellular Ca2+ influx in root cap.

Hormesis of methylmercury-human serum albumin conjugate on N9 microglia via ERK/MAPKs and STAT3 signaling pathways.

Methylmercury (MeHg+) is an extremely toxic organomercury cation that can induce severe neurological damage. Once it enters the body, methylmercury binds to amino acids or proteins containing free sulfhydryl groups. In particular, methylmercury is known to bind with human serum albumin (HSA) in human plasma; however, the effects of methylmercury-HSA conjugate (MeHg-HSA) on the central nervous system (CNS) are not fully understood. In the present study, we used the microglial cell line N9 as the target cells to evaluate the effect of MeHg-HSA on physiological function of the CNS preliminarily. The various factors in the cell culture were monitored by MTT assay, total lactate dehydrogenase assay, ELISA, qPCR, Western blot and flow cytometry techniques. The results showed that low-dose treatment with MeHg-HSA activated N9 cells, promoting cell proliferation and total cell number, enhancing NO and intracellular Ca2+ levels, and suppressing the release of TNFα and IL1ß without cytotoxic effects; while high-dose MeHg-HSA exhibited cytotoxic effects on N9 cells, including promoting cell death and increasing the secretion of TNFα and IL1ß. These results indicate that MeHg-HSA causes hormesis in microglia N9 cells. Furthermore, ERK/MAPKs and STAT3 signaling pathways related to the hormesis of MeHg-HSA on N9 cells. In addition, low dose of MeHg-HSA might be viewed as something very close to a lowest observed adverse effect level (LOAEL) for N9 cells. These findings will be useful for investigating the hormesis mechanism of MeHg+ and exploring the specific functions of MeHg-sulfhydryl conjugates on the central nervous system.

A quantitative assessment of hormetic responses of plants to ozone.

Evaluations of ozone effects on vegetation across the globe over the last seven decades have mostly incorporated exposure levels that were multi-fold the preindustrial concentrations. As such, global risk assessments and derivation of critical levels for protecting plants and food supplies were based on extrapolation from high to low exposure levels. These were developed in an era when it was thought that stress biology is framed around a linear dose-response. However, it has recently emerged that stress biology commonly displays non-linear, hormetic processes. The current biological understanding highlights that the strategy of extrapolating from high to low exposure levels may lead to biased estimates. Here, we analyzed a diverse sample of published empirical data of approximately 500 stimulatory, hormetic-like dose-responses induced by ozone in plants. The median value of the maximum stimulatory responses induced by elevated ozone was 124%, and commonly <150%, of the background response (control), independently of species and response variable. The maximum stimulatory response to ozone was similar among types of response variables and major plant species. It was also similar among clades, between herbaceous and woody plants, between deciduous and evergreen trees, and between annual and perennial herbaceous plants. There were modest differences in the stimulatory response between genera and between families which may reflect different experimental designs and conditions among studies. The responses varied significantly upon type of exposure system, with open-top chambers (OTCs) underestimating the maximum stimulatory response compared to free-air ozone-concentration enrichment (FACE) systems. These findings suggest that plants show a generalized hormetic stimulation by ozone which is constrained within certain limits of biological plasticity, being highly generalizable, evolutionarily based, and maintained over ecological scales. They further highlight that non-linear responses should be taken into account when assessing the ozone effects on plants.

Bt-induced hormesis in Bt-resistant insects: Theoretical possibility or factual concern?

The biphasic dose-response of a stressor where low amounts of a toxicant may stimulate some biological processes is a recent focus of attention in insecticide ecotoxicology. Nonetheless, the importance and management consequences of this phenomenon of pesticide-induced hormesis remain largely unrecognized. Curiously, the potential induction of hormesis by insecticidal proteins such as Bacillus thuringiensis toxins (i.e., Bt toxins), a major agriculture pest management tool of widespread use, has been wholly neglected. Thus, we aimed to circumvent this shortcoming while assessing the potential occurrence of hormesis induced by the Bt toxin Cry1Fa in its main target pest species - the fall armyworm Spodoptera frugiperda. Concentration-response bioassays were carried out in a Bt-susceptible and a Bt-resistant population providing the purified Cry1Fa toxin in artificial diet and recording the insect demographic parameters. As significant hormetic effect was detected in both populations with a significant increase in the net reproductive rate and the intrinsic rate of population growth, the potential occurrence of Bt-induced hormesis was subsequently tested providing the insects with leaves from transgenic Bt maize expressing the toxic protein. The performance of the Bt-resistant insects was not different in both maize genotypes, indicating that the leaf expression of the Bt protein did not promote hormesis in the resistant insects. Thus, despite the Bt-induced hormesis detected in the purified protein bioassays, the phenomenon was not detected with current levels of Bt expression in maize minimizing the risk of this additional efficacy constraint besides that of field occurrence of Bt resistance.

Low concentrations of FA exhibits the Hormesis effect by affecting cell division and the Warburg effect.

Formaldehyde (FA), a ubiquitous indoor environmental pollutant, has been classified as a carcinogen. There are many studies showed that low levels of FA could promote cell proliferation, however, little is known about the signal pathways. To determine the potential molecular mechanisms, human chronic myeloid leukemia cells (K562 cells) and human bronchial epithelial cells (16HBE cells) were exposed to different concentrations of FA. The data showed that FA at 0-125 µM or 0-60 µM promoted the proliferation of K562 cells or 16HBE cells respectively, indicating that FA did have the Hormesis effect. FA at 75 µM (K562 cells) and 40 µM (16HBE cells) significantly promoted cell proliferation, increased intracellular reactive oxygen species (ROS) levels, and decreased glutathione (GSH) content. At the same time, FA treatment induced a marked increase in the key molecules of cell division like CyclinD-cdk4 and E2F1. In addition, pyruvate kinase isozyme M2 (PKM2), glucose, glucose transporter 1 (GLUT1), lactic acid and lactate dehydrogenase A (LDHA) content in the Warburg effect were increased. Administering Vitamin E (VE), significantly disrupted cell division and disturbed the Warburg effect, effectively indicating the decrease of cell activity. Conclusively, these findings suggested that low concentrations of FA could promote cell proliferation by accelerating cell division process or enhancing the Warburg effect to embody the Hormesis effect.