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.

Critical insights into the Hormesis of antibiotic resistome in saline soil: Implications from salinity regulation.

Soil is recognized as an important reservoir of antibiotic resistance genes (ARGs). However, the effect of salinity on the antibiotic resistome in saline soils remains largely misunderstood. In this study, high-throughput qPCR was used to investigate the impact of low-variable salinity levels on the occurrence, health risks, driving factors, and assembly processes of the antibiotic resistome. The results revealed 206 subtype ARGs across 10 categories, with medium-salinity soil exhibiting the highest abundance and number of ARGs. Among them, high-risk ARGs were enriched in medium-salinity soil. Further exploration showed that bacterial interaction favored the proliferation of ARGs. Meanwhile, functional genes related to reactive oxygen species production, membrane permeability, and adenosine triphosphate synthesis were upregulated by 6.9%, 2.9%, and 18.0%, respectively, at medium salinity compared to those at low salinity. With increasing salinity, the driver of ARGs in saline soils shifts from bacterial community to mobile gene elements, and energy supply contributed 28.2% to the ARGs at extreme salinity. As indicated by the neutral community model, stochastic processes shaped the assembly of ARGs communities in saline soils. This work emphasizes the importance of salinity on antibiotic resistome, and provides advanced insights into the fate and dissemination of ARGs in saline soils.

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.

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.

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.

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.

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.

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.

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.

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.

Cereal grass juice in wound healing: hormesis and cell-survival in normal fibroblasts, in contrast to toxic events in cancer cells.

Natural products and traditional medicines are of great importance. Recent studies have demonstrated, that cereal grass juice improves wound healing, however the cellular and molecular mechanisms underlying these processes have not been fully characterized. Also, the full phytochemical characteristics of freshly squeezed juices obtained from cereal grasses is still missing. Thus, in this study a multi-dimensional analysis of juice parameters like refraction value, pH, chlorophyll and flavonoids content as well as antioxidant properties was performed. The results demonstrate that the effect induced by freshly squeezed cereal juices is strictly cell type-dependent. In this study, it is shown for the first time, that in normal fibroblasts (BJ cells) low dose cereal grass juices exhibit strong adaptive response through hormetic mechanism mediated by NF-κB/HO-1 and insulin/IGF-1 anti-oxidant pathways. As consequence, the process of wound healing is significantly upregulated. In cancer cells (ES-2 cells), despite anti-oxidant defense mechanism activation, levels of ROS and RNS are elevated. This leads to enhanced O-GlcNAcylation, DNA damage and cell cycle arrest, and as a result impaired wound healing. This study provides insights into the underlying mechanisms through which cereal grass juices activate hermetic adaptation response in normal fibroblasts, and induce cytotoxic and genotoxic events in cancer cells.

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.

Hormesis effect of hydrogen peroxide on the promoter activity of neuropeptide receptor PAC1-R.

Pituitary adenylate cyclase-activating polypeptide (PACAP) receptor 1 (PAC1-R) is the neuropeptide PACAP-preferring receptor-mediating neuroprotective activity. In order to clarify the biological mechanism of its expression, we cloned the 2,526 bp promoter fragment from -2,500 to +26 of the transcription initiation site of human ADCYAP1R1 gene and constructed the novel promotor reporter system named pYr-PromDetect-PAC1p. It was found in SH-SY5Y cells low concentration (<10 nM) of hydrogen peroxide (H2 O2 ) significantly promoted the activity of PAC1-R promoter in dose-dependent way, which was significantly inhibited by the transcription factor specificity protein 1 (SP1) inhibitor mithramycin A and was further confirmed in the deletion mutation of the predicted SP1 binding sites. Moreover, higher concentration of H2 O2 (>10 nM) inhibited the activity of PAC1-R in dose-dependent way. The hormesis effect of H2 O2 on PAC1-R promoter would help to further clarify the physiological effect of low-dose reactive oxygen on nervous system. PRACTICAL APPLICATIONS: PAC1-R mediates well-known neuroprotective, neurotrophic, and neurogenesis effects, which is an important drug target for neurodegenerative diseases. The hormesis effects of oxidative stress on PAC1-R expression not only help to explain the hormesis effects of oxidative stress on nerve system, but also offer a novel strategy to increase the expression of PAC1-R for the nerve protection or nerve generation. For example, taking advantage of low degree of oxidative stress to increases the expression of PAC1-R might help prevent subsequent surgical serious injury on the nervous system. The activation of PAC1-R promoter by low concentration of H2 O2 would help to further clarify the physiological effect of low-dose reactive oxygen on nervous system.

Employing multi-omics to elucidate the hormetic response against oxidative stress exerted by nC60 on Daphnia pulex.

This study evaluated hormetic effect of oxidative stress exerted by fullerene crystals (nC60) on Daphnia pulex, employing transcriptomics and metabolomics. D. pulex were exposed to various concentrations of nC60 for 21 days. Hormetic effect of oxidative stress was most evident after 7 days, with markedly increased L-Glutathione (GSH) concentration and Superoxide Dismutase (SOD) activity at low doses of nC60 exposure, and oppositely at high doses. The transcriptomics and metabolomics were used to elucidate the molecular mechanism underlying the hormesis in oxidative stress. There were significant alterations in major pathways involving oxidative stress and energy metabolism in D. pulex. Some important intermediates and the expression of their regulatory genes coincided with each other with first up-regulated and then down-regulated with the concentration increased, consistent with the hormesis description. The nC60 interfered the TCA cycle of D. pulex. The synthesis of L-cysteine and glutamate was directly affected, and further disturbed the synthesis of GSH. This work is of great significance to provide the molecular-level evidence into the hormetic effect in oxidative stress of D. pulex exposed to nC60.

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.

Hydroxyurea attenuates oxidative, metabolic, and excitotoxic stress in rat hippocampal neurons and improves spatial memory in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by accumulation of amyloid ß-peptide (Aß) plaques in the brain and decreased cognitive function leading to dementia. We tested if hydroxyurea (HU), a ribonucleotide reductase inhibitor known to activate adaptive cellular stress responses and ameliorate abnormalities associated with several genetic disorders, could protect rat hippocampal neurons against oxidative-, excitatory-, mitochondrial-, and Aß-induced stress and if HU treatment could improve learning and memory in the APP/PS1 mouse model of AD. HU treatment attenuated the loss of cell viability induced by treatment of hippocampal neurons with hydrogen peroxide, glutamate, rotenone, and Aß1-42. HU treatment attenuated reductions of mitochondrial reserve capacity, maximal respiration, and cellular adenosine triphosphate content induced by hydrogen peroxide treatment. In vivo, treatment of APP/PS1 mice with HU (45 mg/kg/d) improved spatial memory performance in the hippocampus-dependent Morris water maze task without reducing Aß levels. HU provides neuroprotection against toxic insults including Aß, improves mitochondrial bioenergetics, and improves spatial memory in an AD mouse model. HU may offer a new therapeutic approach to delay cognitive decline in AD.

Hormetic dose response to L-ascorbic acid as an anti-cancer drug in colorectal cancer cell lines according to SVCT-2 expression.

L-Ascorbic acid (vitamin C, AA) exhibits anti-cancer effects with high-dose treatment through the generation of reactive oxygen species (ROS) and selective damage to cancer cells. The anti-cancer effects of L-ascorbic acid are determined by sodium-dependent vitamin C transporter 2 (SVCT-2), a transporter of L-ascorbic acid. In this study, we demonstrate that L-ascorbic acid treatment showed efficient anti-cancer activity in cell lines with high expression levels of SVCT-2 for a gradient concentration of L-ascorbic acid from 10 µM -2 mM. However, in low SVCT-2 expressing cell lines, high-dose L-ascorbic acid (>1 mM) showed anti-cancer effects but low-dose (<10 µM) treatment induced cell proliferation. Such conflicting results that depend on the concentration are called a hormetic dose response. A hormetic dose response to low-dose L-ascorbic acid was also observed in high SVCT-2 expressing cell lines in the presence of a SVCT family inhibitor. Insufficient uptake of L-ascorbic acid in low SVCT-2 expressing cancer cell lines cannot generate sufficient ROS to kill cancer cells, resulting in the hormetic response. Molecular analysis confirmed the increased expression of cancer proliferation markers in the hormetic dose response. These results suggest that L-ascorbic exhibits a biphasic effect in cancer cells depending on SVCT-2 expression.

Silver nanoparticle-induced hormesis of astroglioma cells: A Mu-2-related death-inducing protein-orchestrated modus operandi.

Hormesis is a dose-response phenomenon that, when applied to nanomaterial-biological interactions, refers to growth stimulation at low doses and growth inhibition at high doses. MUDENG (Mu-2-related death-inducing gene, MuD) is involved in cell death signaling. Astrocytes, the major glial cell type in the central nervous system, are a major source of brain tumors. In this study, we investigated whether silver nanoparticles (AgNPs) induce hormesis in astroglioma cells and the possible involvement of MuD in AgNP-induced hormesis. AgNPs exhibited cytotoxic effects on cell proliferation in a dose-dependent manner and increased MuD expression was observed during AgNP-induced astroglioma hormesis. Studies using MuD-knockout cells and MuD siRNA transfection showed that MuD might influence cell viability upon AgNP treatment. In addition, apoptotic cell population and production of reactive oxygen species in the absence of MuD were significantly increased. The phosphorylation of two mitogen-activated protein kinases, p38 and extracellular signal-regulated kinase (ERK), but not c-Jun N-terminal kinases (JNK), was observed upon AgNP stimulation. In summary, AgNPs at low doses induced hormesis of human astroglioma cells, and MuD and p38/ERK mediators are involved in AgNP-induced astroglioma hormesis, resulting in beneficial effects from the cellular point of view.