Hormesis and bone marrow stem cells: Enhancing cell proliferation, differentiation and resilience to inflammatory stress.

This paper identifies and provides the first detailed assessment of hormetic dose responses by bone marrow stem cells (BMSCs) from a broad range of animal models and humans with particular emphasis on cell renewal (proliferation), cell differentiation and enhancing resilience to inflammatory stress. Such hormetic dose responses are commonly reported, being induced by a broad range of chemicals, including pharmaceuticals (e.g., caffeine, dexamethasone, nicotine), dietary supplements (e.g., curcumin, Ginkgo biloba, green tea extracts. resveratrol, sulforaphane), endogenous agents (e.g., hydrogen sulfide, interleukin 10), environmental contaminants (e.g., arsenic, PFOS) and physical stressor agents (e.g., EMF, shockwaves). Hormetic dose responses reported here for BMSCs are similar to those induced with other stem cell types [e.g., adipose-derived stem cells (ADSCs), dental pulp stem cells (DPSCs), periodontal ligament stem cells (PDLSCs), neuro stem cells (NSCs), embryonic stem cells (ESCs)], indicating a substantial degree of generality for hormetic responses in stem cells. The paper assesses both the underlying mechanistic foundations of BMSC hormetic responses and their potential therapeutic implications.

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.

Induction of hormesis in plants by urban trace metal pollution.

Hormesis is a dose-response phenomenon observed in numerous living organisms, caused by low levels of a large number of stressors, among which metal ions. In cities, metal levels are usually below toxicity limits for most plant species, however, it is of primary importance to understand whether urban metal pollution can threaten plant survival, or, conversely, be beneficial by triggering hormesis. The effects of Cd, Cr and Pb urban concentrations were tested in hydroponics on three annual plants, Cardamine hirsuta L., Poa annua L. and Stellaria media (L.) Vill., commonly growing in cities. Results highlighted for the first time that average urban trace metal concentrations do not hinder plant growth but cause instead hormesis, leading to a considerable increase in plant performance (e.g., two to five-fold higher shoot biomass with Cd and Cr). The present findings, show that city habitats are more suitable for plants than previously assumed, and that what is generally considered to be detrimental to plants, such as trace metals, could instead be exactly the plus factor allowing urban plants to thrive.

Ferulic acid and hormesis: Biomedical and environmental implications.

The present paper provides the first systematic assessment of the capacity of ferulic acid to induce hormetic dose responses in biological systems. Ferulic acid induced hormetic effects in a broad range of animal models, affecting numerous biological endpoints, with particular focus on neuroprotective effects. Emerging evidence in multiple biomedical systems indicates that the hormetic effects of ferulic acid depend upon the activation of the transcription factor Nrf2. Ferulic acid was also shown to have an important role in ecological settings, being routinely released into the environment by numerous plant species, acting as an allelopathic agent affecting the growth of neighboring species via hormetic dose responses. These findings demonstrate the potential ecological and biomedical importance of ferulic acid effects and that these effects are commonly expressed via the hormetic dose response, suggesting complex multisystem evolutionary regulatory strategies.

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.

Phenolic acid metabolites of polyphenols act as inductors for hormesis in C. elegans.

INTRODUCTION: Aging represents a major risk factors for metabolic diseases, such as diabetes, obesity, or neurodegeneration. Polyphenols and their metabolites, especially simple phenolic acids, gained growing attention as a preventive strategy against age-related, non-communicable diseases, due to their hormetic potential. Using Caenorhabditis elegans (C. elegans) we investigate the effect of protocatechuic, gallic, and vanillic acid on mitochondrial function, health parameters, and the induction of potential hormetic pathways. METHODS: Lifespan, heat-stress resistance and chemotaxis of C. elegans strain P X 627, a specific model for aging, were assessed in 2-day and 10-day old nematodes. Mitochondrial membrane potential (ΔΨm) and ATP generation were measured. mRNA expression levels of longevity and energy metabolism-related genes were determined using qRT-PCR. RESULTS: All phenolic acids were able to significantly increase the nematodes lifespan, heat-stress resistance and chemotaxis at micromolar concentrations. While ΔΨm was only affected by age, vanillic acid (VA) significantly decreased ATP concentrations in aged nematodes. Longevity pathways, were activated by all phenolic acids, while VA also induced glycolytic activity and response to cold. CONCLUSION: While life- and health span parameters are positively affected by the investigated phenolic acids, the concentrations applied were unable to affect mitochondrial performance. Therefore we suggest a hormetic mode of action, especially by activation of the sirtuin-pathway.

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 of low-dose inhibition of pAkt1 (Ser473) followed by a great increase of proline-rich inositol polyphosphate 5-phosphatase (PIPP) level in oocytes.

Hormesis describes a biphasic dose-response relationship generally characterized by a low-dose excitement and a high-dose inhibition. This phenomenon has been observed in the regulation of cell, organ, and organismic level. However, hormesis has not reported in oocytes. In this study, we observed, for the first time, hormetic responses of PIPP levels in oocytes by inhibitor of Akt1 or PKCδ. The expression of PIPP was detected by qPCR, immunofluorescent (IF), and Western Blot (WB). To observe the changes of PIPP levels, we used the inhibitors against pAkt1 (Ser473) or PKCδ, SH-6 or sotrastaurin with low and/or high-dose, treated GV oocytes and cultured for 4 h, respectively. The results showed that PIPP expression was significantly enhanced when oocytes were treated with SH-6 or sotrastaurin 10 µM, but decreased with SH-6 or sotrastaurin 100 µM. We also examined the changes of PIPP levels when GV oocytes were treated with exogenous PtdIns(3,4,5)P3 or LY294002 for 4 h. Our results showed that PIPP level was enhanced much higher under the treatment of 0.1 µM PtdIns(3,4,5)P3 than that of 1 µM PtdIns(3,4,5)P3, which is consistent with the changes of PIPP when oocytes were treated with inhibitors of pAkt1 (Ser473) or PKCδ. In addition, with PIPP siRNA, we detected that down-regulated PIPP may affect distributions of Akt, Cdc25, and pCdc2 (Tyr15). Taken together, these results show that the relationships between PIPP and Akt may follow the principle of hormesis and play a key role during release of diplotene arrest in mouse oocytes.

Putative hormetic mechanisms and effects of atypical antipsychotic agents: Implications for study design and clinical psychopharmacotherapeutics.

This paper addresses a novel putative mechanism by which atypical antipsychotic agents induce clinically significant neuroprotective effects that may be viable in the treatment of schizophrenia - and perhaps other neuropsychiatric disorders. Based upon experimental studies with multiple in vitro models (i.e., PC 12 cells, NSC-34 hybrid cells, SH-SY5Y cells, the immune cell line U-937) and several rodent in vivo models, six atypical antipsychotic drugs, within direct experimental comparisons and/or preconditioning protocol studies with six different stressor/toxic agents (i.e. rotenone, hydrogen peroxide, MPP+, serum withdrawal, beta-amyloid, and corticosterone) were demonstrated to induce neuroprotective effects with consistently hormetic dose response patterns. These findings suggest that some of the reported neuroprotective effects of atypical human antipsychotic agents are likely to be mediated by hormetic mechanisms. These findings may have important implications for both experimental study design and clinical therapeutics.

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.

Dual role of eugenol on chronic gastric ulcer in rats: Low-dose healing efficacy and the worsening gastric lesion in high doses.

This study evaluated the gastric healing activity of eugenol, the main bioactive compound from clove (Syzygium aromaticun) essential oil. Five groups of female Wistar rats were submitted to acetic acid-induced ulcer model and treated with Vehicle (1 mL/kg, p.o.), eugenol (1, 10 or 100 mg/kg, p.o) or omeprazole (20 mg/kg, p.o), twice a day, by seven or fourteen days. Macroscopic, microscopic and biochemical analyses were performed in the ulcerated site. Eugenol (1 mg/kg, p.o) administered by 7 or 14 days accelerated the gastric healing process by 33% and 52%, respectively. The healing actions of eugenol were accompanied by the rescue on the histological architecture and the normalization of the superoxide dismutase and catalase activity. Moreover, eugenol (1 mg/kg, p.o) reduced the gastric mucosal myeloperoxidase activity and increased the mucin secretion. In contrast, eugenol at a dose of 100 mg/kg administered by 7 days enhanced 49% the ulcerated area, but at 10 mg/kg did not change the ulcer area after 7 or 14 days of treatment. Thus, despite the undesirable results due to the worsening of the gastric lesion with the use of eugenol in high doses, the antiulcer potential of this compound is evident and manageable in an adequate dose.

On an extended understanding of the term "hormesis" for denoting alternating directions of the organism's response to increasing adverse exposures.

The authors propose to consider as hormesis phenomenon not only a realization of the Arndt-Schulze rule but any non-monotonic dose-response relationship for a certain outcome that is characterized by changing direction of a response between adjacent ranges of doses of an initiator of this response, the number of such ranges being two or more. This approach is illustrated with results of several in vitro experiments on different established cell lines exposed to CdS or PbS nanoparticles.

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.

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.

Nanoparticle treatment of maize analyzed through the metatranscriptome: compromised nitrogen cycling, possible phytopathogen selection, and plant hormesis.

BACKGROUND: The beneficial use of nanoparticle silver or nanosilver may be confounded when its potent antimicrobial properties impact non-target members of natural microbiomes such as those present in soil or the plant rhizosphere. Agricultural soils are a likely sink for nanosilver due to its presence in agrochemicals and land-applied biosolids, but a complete assessment of nanosilver's effects on this environment is lacking because the impact on the natural soil microbiome is not known. In a study assessing the use of nanosilver for phytopathogen control with maize, we analyzed the metatranscriptome of the maize rhizosphere and observed multiple unintended effects of exposure to 100 mg kg-1 nanosilver in soil during a growth period of 117 days. RESULTS: We found several unintended effects of nanosilver which could interfere with agricultural systems in the long term. Firstly, the archaea community was negatively impacted with a more than 30% decrease in relative abundance, and as such, their involvement in nitrogen cycling and specifically, nitrification, was compromised. Secondly, certain potentially phytopathogenic fungal groups showed significantly increased abundances, possibly due to the negative effects of nanosilver on bacteria exerting natural biocontrol against these fungi as indicated by negative interactions in a network analysis. Up to 5-fold increases in relative abundance have been observed for certain possibly phytopathogenic fungal genera. Lastly, nanosilver exposure also caused a direct physiological impact on maize as illustrated by increased transcript abundance of aquaporin and phytohormone genes, overall resulting in a stress level with the potential to yield hormetically stimulated plant root growth. CONCLUSIONS: This study indicates the occurrence of significant unintended effects of nanosilver use on corn, which could turn out to be negative to crop productivity and ecosystem health in the long term. We therefore highlight the need to include the microbiome when assessing the risk associated with nano-enabled agriculture. Video Abstract.

Root Microbiome Modulates Plant Growth Promotion Induced by Low Doses of Glyphosate.

Glyphosate is a commonly used herbicide with a broad action spectrum. However, at sublethal doses, glyphosate can induce plant growth, a phenomenon known as hormesis. Most glyphosate hormesis studies have been performed under microbe-free or reduced-microbial-diversity conditions; only a few were performed in open systems or agricultural fields, which include a higher diversity of soil microorganisms. Here, we investigated how microbes affect the hormesis induced by low doses of glyphosate. To this end, we used Arabidopsis thaliana and a well-characterized synthetic bacterial community of 185 strains (SynCom) that mimics the root-associated microbiome of Arabidopsis We found that a dose of 3.6 × 10-6 g acid equivalent/liter (low dose of glyphosate, or LDG) produced an ∼14% increase in the shoot dry weight (i.e., hormesis) of uninoculated plants. Unexpectedly, in plants inoculated with the SynCom, LDG reduced shoot dry weight by ∼17%. We found that LDG enriched two Firmicutes and two Burkholderia strains in the roots. These specific strains are known to act as root growth inhibitors (RGI) in monoassociation assays. We tested the link between RGI and shoot dry weight reduction in LDG by assembling a new synthetic community lacking RGI strains. Dropping RGI strains out of the community restored growth induction by LDG. Finally, we showed that individual RGI strains from a few specific phyla were sufficient to switch the response to LDG from growth promotion to growth inhibition. Our results indicate that glyphosate hormesis was completely dependent on the root microbiome composition, specifically on the presence of root growth inhibitor strains.IMPORTANCE Since the introduction of glyphosate-resistant crops, glyphosate has become the most common and widely used herbicide around the world. Due to its intensive use and ability to bind to soil particles, it can be found at low concentrations in the environment. The effect of these remnants of glyphosate in plants has not been broadly studied; however, glyphosate 1,000 to 100,000 times less concentrated than the recommended field dose promoted growth in several species in laboratory and greenhouse experiments. However, this effect is rarely observed in agricultural fields, where complex communities of microbes have a central role in the way plants respond to external cues. Our study reveals how root-associated bacteria modulate the responses of Arabidopsis to low doses of glyphosate, shifting between growth promotion and growth 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.

Insights into the role of energy source in hormesis through diauxic growth of bacteria in mixed cultivation systems.

Hormesis, a biphasic dose-response relationship characterized by low-dose stimulation and high-dose inhibition, has been reported to be closely related to energy sources in cultivation systems. However, few studies have clarified how the energy source influences hormesis. In this study, based on the typical diauxic patterns of Escherichia coli (E. coli) growth in mixed cultivation media containing 1.0 g L-1 glucose and Luria-Bertani broth, the hormetic response of sulfonamides (SAs) to E. coli growth was investigated under this diauxic growth condition to thoroughly explain the close relationship between hormesis and energy sources in cultivation systems. The results indicated that SAs trigger time-dependent hormetic effects on E. coli growth over the span of 24 h, in which the biphasic dose-response occurs only during the second lag and the earlier stage of the second log phase of diauxic growth. Mechanistic exploration reveals that SAs can bind with adenylate cyclase at a low dose and dihydropteroate synthase at a high dose, respectively, activating the stimulatory and inhibitory signaling pathway to influence carbon catabolite repression in diauxic growth, which can interfere with the metabolism of tryptone and yeast extract to ultimately trigger hormesis. Moreover, the stimulatory and inhibitory effects of SAs are changed by the variations in metabolic status at different growth phases, resulting in time-dependent hormesis. This study proposes an induced mechanistic explanation of hormesis in mixed cultivation media based on the energy source's metabolism, which may not only reflect the generalizability of hormesis but also further promote its application in production activities.

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.