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

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

Quorum-sensing gene regulates hormetic effects induced by sulfonamides in Comamonadaceae.

IMPORTANCE: Antibiotics can induce dose-dependent hormetic effects on bacterial cell proliferation, i.e., low-dose stimulation and high-dose inhibition. However, the underlying molecular basis has yet to be clarified. Here, we showed that sulfonamides play dual roles as a weapon and signal against Comamonas testosteroni that can modulate cell physiology and phenotype. Subsequently, through investigating the hormesis mechanism, we proposed a comprehensive regulatory pathway for the hormetic effects of Comamonas testosteroni low-level sulfonamides and determined the generality of the observed regulatory model in the Comamonadaceae family. Considering the prevalence of Comamonadaceae in human guts and environmental ecosystems, we provide critical insights into the health and ecological effects of antibiotics.

Dosage impact of submerged plants extracts on Microcystis aeruginosa growth: From hormesis to inhibition.

Allelopathy has been demonstrated to be an environmentally friendly way to control harmful algal blooms. Allelochemicals of submerged plants have attracted extensive research due to their bioavailability. The dose-response of submerged plant extracts on algae growth is worth further study to improve the efficiency of bioremediation. In this study, the ultrasonic-enzymatic assistance method was utilized to extract allelochemicals from Ceratophyllum, Myriophyllum spicatum, and Vallisneria. The effects of low-dosage and high-dosage extracts on the growth of Microcystis aeruginosa were compared based on cell biomass and morphology, photosynthetic parameters, reactive oxygen species (ROS), superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) levels. The results showed that the three submerged plant extracts exhibited hormetic effects at low dosages and inhibitory effects at high dosages on algal growth. Within 48 h of cultivation, the enzymatic activities of Microcystis aeruginosa fluctuated, suggesting that the extracts of the three submerged plants induced different oxidative reactions. After 120 h of cultivation with high-dosage extracts, the physiological and biochemical reactions of Microcystis aeruginosa significantly decreased, indicating the effectiveness of the allelopathy of Ceratophyllum, Myriophyllum spicatum, and Vallisneria extracts in controlling algal blooms. The phenomenon of hormesis and inhibition effect confirmed a significant dose-response relationship between the allelochemicals of submerged plant extracts and Microcystis aeruginosa, which could be attributed to the composition and content of allelochemicals. These findings highlight the importance of the relative concentration of the biological algaecide and will benefit other researchers in determining the safe dosage of plant allelochemicals when used in water.

Polyamines and hormesis: Making sense of a dose response dichotomy.

The diverse biological effects of polyamines (putrescine, spermidine and spermine) were reviewed in the context of hormesis in an integrative manner for the first time. The findings illustrate that each of these polyamines commonly induces hormetic dose responses in a wide range of biological models and types of cells for multiple endpoints in numerous plant species and animal models. Plant research emphasized preconditioning experimental studies in which the respective polyamines conferred some protection against the damaging effects of a broad range of environmental stressors such as drought, salinity, cold/heat, heavy metals and UV-damage in an hormetic manner. Polyamine-based animal hormesis studies emphasized biomedical endpoints such as longevity and neuroprotection. These findings have important biological and biomedical implications and should guide experimental designs of low dose investigations.

Hormesis of glyphosate on ferulic acid metabolism and antifungal volatile production in rice root biocontrol endophyte Burkholderia cepacia LS-044.

Glyphosate (GP, N-phosphonomethyl glycine) is one of the most popular organophosphate herbicides widely used in agricultural practices worldwide. There have been extensive reports on the biohazard attributes and hormetic impacts of GP on plant and animal systems. However, the effects of GP on plant growth-promoting microbes and its ecological relevance remain unknown. Here, we show that GP does exert a hormetic impact on Burkholderia cepacia LS-044, a rice (Oryza sativa ssp. japonica cv. Tainung 71) root endophytic isolate. We used increasing doses of ferulic acid (FA, 1-25 mM) and GP (0.5-5 mM) to test the growth and antifungal volatile production in LS-044 by electrochemical, liquid chromatographic, gas chromatographic and spectrophotometric means. GP treatment at a low dose (0.5 mM) increased FA utilization and significantly (P < 0.0001) enhanced antifungal volatile activity in LS-044. Although FA (1 mM) was rapidly utilized by LS-044, no chromatographically detectable utilization of GP was observed at tested doses (0.5-5 mM). LS-044 emitted predominant amounts of tropone in addition to moderate-to-minor amounts of diverse ketones and/or their derivatives (acetone, acetophenone, 2-butanone, 1-propanone, 1-(2-furanyl-ethanone, 1-phenyl-1-propanone and 1-(3-pyridinyl)-1-propanone), d-menthol, 2-methoxy-3-(1-methylethyl)-pyrazine, dimethyl disulfide, pyridine and ammonium carbamate when grown under GP supplement. GP hormesis on LS-044 induced phenotypic variations in O. sativa ssp. japonica cv. Tainan 11 as evident through seed germination assay. Genes involved in the transformation of FA, and a key gene encoding 5-enolpyruvylshikimate 3-phosphate synthase (EPSPS) with Gly-94 and Tyr-95 residues localized at active site most likely rendering EPSPS sensitivity to GP, were detected in LS-044. This is the first report on the GP hormesis influencing morphological and metabolic aspects including volatile emission in a biocontrol bacterium that could modulate rice plant phenotype.

Hormetic dose responses induced by nickel oxide nanoparticles (NiONPs) on growth, biochemical, and antioxidant defense systems of Dracocephalum kotschyi.

The application of nickel oxide nanoparticles (NiONPs) in various fields leads to their release into soil and water and, consequently, interaction with plants. Unlike its bulk counterpart, the phytotoxic potential of NiONPs is relatively less studied, particularly in a hormesis framework. Hormesis is an interesting phenomenon characterized by low-dose stimulation and high-dose inhibition. Therefore, this study demonstrates the stimulatory and inhibitory effects of NiONPs on Dracocephalum kotschyi Boiss as a medicinal plant cultivated in a pot experiment carried out in a greenhouse for 3 weeks. High bioaccumulation of nickel (Ni) in roots of treated plants relative to shoots indicates higher oxidative damage. NiONPs induced hormetic effects on photosynthetic pigments, as at low concentration of 50 mg/L stimulated chlorophyll (2.8-46.7%), carotenoid (16%), and anthocyanin (5.9%) contents and at higher concentrations inhibited the content of these pigments. A hormetic response was observed in growth parameters, i.e., NiONPs induced shoot height (7.2%) and weight (33%) at 100 mg/L, while inhibited shoot and root length (14.5-16.1% and 28.7-42.7%) and weight (46.8-48.1% and 37-40.6%), respectively, at 1000 and 2500 mg/L. The treated plants declined the toxic effects and oxidative stress caused by NiONPs by activating non-enzymatic antioxidants (phenolic compounds and proline) and enzymatic antioxidants, i.e., increasing the levels of SOD, POD, CAT, and APX. Therefore, the present study investigated for the first time the different mechanisms and responses of D. kotschyi plants to NiONPs in a wide range of concentrations. The results suggest that NiONPs may act as an elicitor at lower concentrations in medicinal plants according to specific conditions. However, these NPs at higher concentrations induce oxidative stress and harmful effects on plants, so their use poses serious risks to human health and the environment.

Rhodiola rosea and salidroside commonly induce hormesis, with particular focus on longevity and neuroprotection.

The biological effects of Rhodiola rosea extracts and one of its major constituents, salidroside, were evaluated for their capacity to induce hormesis/hormetic effects. The findings indicate that the Rhodiola rosea extracts and salidroside commonly induce hormetic dose responses within a broad range of biological models, cell types and across a broad range of endpoints, with particular emphasis on longevity and neuroprotective endpoints. This paper represents the first integrative documentation and assessment of Rhodiola rosea extracts and salidroside induction of hormetic effects. These findings have important biomedical applications and should have an important impact with respect to critical study design, dose selection and other experimental features.

Protective effects of alpha lipoic acid (ALA) are mediated by hormetic mechanisms.

The endogenous and dietary agent, alpha lipoic acid (ALA), is evaluated for its capacity to induce a broad spectrum of adaptive responses via hormetic dose responses and their underlying mechanisms. ALA was shown to induce hormetic effects in a wide range of experimental models within in vitro and in vivo experimental settings which included direct exposure and pre- and post-conditioning experimental protocols. The hormetic effects occur in a broad range of organ systems, including the brain, heart, kidney and other tissues, with possible public health and clinical/therapeutic applications linked to reducing the onset and progression of neurogenerative diseases and also in the preservation of sperm health and functionality during cryopreservation. This paper provides the first integrated assessment of ALA-induced hormetic dose responses. Underlying mechanisms that mediated the occurrence of ALA-induced hormetic effects involved the induction of low levels of ROS that activate key cell signaling antioxidant (e.g. Nrf2) pathways.

Cellular Stress Response (Hormesis) in Response to Bioactive Nutraceuticals with Relevance to Alzheimer Disease.

Significance: Alzheimer's disease (AD) is the most common form of dementia associated with aging. As the large Baby Boomer population ages, risk of developing AD increases significantly, and this portion of the population will increase significantly over the next several decades. Recent Advances: Research suggests that a delay in the age of onset by 5 years can dramatically decrease both the incidence and cost of AD. In this review, the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in AD is examined in the context of heme oxygenase-1 (HO-1) and biliverdin reductase-A (BVR-A) and the beneficial potential of selected bioactive nutraceuticals. Critical Issues: Nrf2, a transcription factor that binds to enhancer sequences in antioxidant response elements (ARE) of DNA, is significantly decreased in AD brain. Downstream targets of Nrf2 include, among other proteins, HO-1. BVR-A is activated when biliverdin is produced. Both HO-1 and BVR-A also are oxidatively or nitrosatively modified in AD brain and in its earlier stage, amnestic mild cognitive impairment (MCI), contributing to the oxidative stress, altered insulin signaling, and cellular damage observed in the pathogenesis and progression of AD. Bioactive nutraceuticals exhibit anti-inflammatory, antioxidant, and neuroprotective properties and are potential topics of future clinical research. Specifically, ferulic acid ethyl ester, sulforaphane, epigallocatechin-3-gallate, and resveratrol target Nrf2 and have shown potential to delay the progression of AD in animal models and in some studies involving MCI patients. Future Directions: Understanding the regulation of Nrf2 and its downstream targets can potentially elucidate therapeutic options for delaying the progression of AD. Antioxid. Redox Signal. 38, 643-669.

Physiological and microbiological hormesis in sedge Eleocharis palustris induced by crude oil in phytoremediation of flooded clay soil.

Soil contamination with petroleum hydrocarbons affects plants and rhizospheric microorganisms. Microbial activity participates in important biochemical processes that stimulate, together with plants, the modification of toxic compounds for organisms. A nine-month experiment was set up to study the effect over time of oil on plant height (cm), formation of new plants, plant matter production (gravimetry), and population of rhizospheric microorganisms (serial dilution) in the sedge Eleocharis palustris. Removal of total petroleum hydrocarbons (soxhlet and gravimetry) from the soil was also evaluated. The means of the evaluated variables registered significant statistical differences (Duncan, p < 0.05) regarding the age of the plant and the amount of crude oil. There was a high correlation between oil and plant height (0.848) and with new plants (0.994). 60 mg oil dose promoted the greatest statistical difference in the amounts of roots and plant biomass (p < 0.05). E. palustris exposed to 60 and 75 mg of oil stimulated high densities of microalgae, actinomycetes, fungi, hydrocarbonoclastic bacteria and Pseudomonas spp; the overall ratio was 2:1 relative to natural attenuation. Plant and microorganism variables evaluated registered physiological and microbiological hormetic indices ≥1, showing a positive linear relationship. Natural attenuation was more efficient in removing crude oil. We conclude that E. palustris is tolerant to oil exposure. It is suggested to combine it with natural attenuation for the optimization of soils contaminated with crude oil.

Hormesis: wound healing and fibroblasts.

Hormetic dose responses are reported here to occur commonly in the dermal wound healing process, with the particular focus on cell viability, proliferation, migration and collagen deposition of human and murine fibroblasts with in vitro studies. Hormetic responses were induced by a wide range of substances, including endogenous agents, pharmaceutical preparations, plant-derived extracts including many well-known dietary supplements, as well as physical stressor agents such as low-level laser treatments. Detailed mechanistic studies have identified common signaling pathways and their cross-pathway communications that mediate the hormetic dose responses. These findings complement and extend a similar comprehensive assessment concerning the occurrence of hormetic dose responses in keratinocytes. These findings demonstrate the generality of the hormetic dose response for key wound healing endpoints, suggesting that the hormesis concept has a fundamental role in wound healing, with respect to guiding strategies for experimental evaluation as well as therapeutic applications.

Enhancing health span: muscle stem cells and hormesis.

Sarcopenia is a significant public health and medical concern confronting the elderly. Considerable research is being directed to identify ways in which the onset and severity of sarcopenia may be delayed/minimized. This paper provides a detailed identification and assessment of hormetic dose responses in animal model muscle stem cells, with particular emphasis on cell proliferation, differentiation, and enhancing resilience to inflammatory stresses and how this information may be useful in preventing sarcopenia. Hormetic dose responses were observed following administration of a broad range of agents, including dietary supplements (e.g., resveratrol), pharmaceuticals (e.g., dexamethasone), endogenous ligands (e.g., tumor necrosis factor α), environmental contaminants (e.g., cadmium) and physical agents (e.g., low level laser). The paper assesses both putative mechanisms of hormetic responses in muscle stem cells, and potential therapeutic implications and application(s) of hormetic frameworks for slowing muscle loss and reduced functionality during the aging process.

Human dental pulp stem cells and hormesis.

This paper represents the first assessment of hormetic dose responses by human dental pulp stem cells (hDPSCs) with particular emphasis on cell renewal (proliferation) and differentiation. Hormetic dose responses were commonly reported in this model, encompassing a broad range of chemicals, including principally pharmaceuticals (e.g., metformin and artemisinin), dietary supplements/extracts from medicinal plants (e.g., berberine, N-acetyl-L-cysteine, and ginsenoside Rg1) and endogenous agents (e.g., ATP, TNF-α). The paper assesses mechanistic foundations of the hDPSCs hormetic dose responses for both cell proliferation and cell differentiation, study design considerations, and therapeutic implications.

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.

Uptake, translocation, phytotoxicity, and hormetic effects of titanium dioxide nanoparticles (TiO2NPs) in Nigella arvensis L.

The extensive application of titanium dioxide nanoparticles (TiO2NPs) in agro-industrial practices leads to their high accumulation in the environment or agricultural soils. However, their threshold and ecotoxicological impacts on plants are still poorly understood. In this study, the hormetic effects of TiO2NPs at a concentration range of 0-2500 mg/L on the growth, and biochemical and physiological behaviors of Nigella arvensis in a hydroponic system were examined for three weeks. The translocation of TiO2NPs in plant tissues was characterized through scanning and transmission electron microscopy (SEM and TEM). The bioaccumulation of total titanium (Ti) was quantified by inductively coupled plasma atomic emission spectroscopy (ICP-AES). Briefly, the elongation of roots and shoots and the total biomass growth were significantly promoted at 100 mg/L TiO2NPs. As the results indicated, TiO2NPs had a hormesis effect on the proline content, i.e., a stimulating effect at the low concentrations of 50 and 100 mg/L and an inhibiting effect in the highest concentration of 2500 mg/L. A biphasic dose-response was observed against TiO2NPs in shoot soluble sugar and protein contents. The inhibitory effects were detected at ≥1000 mg/L TiO2NPs, where the synthesis of chlorophylls and carotenoid was reduced. At 1000 mg/ L, TiO2NPs significantly promoted the cellular H2O2 generation, and increased the activities of antioxidant enzymes such as superoxide dismutase (SOD), ascorbate peroxidase (APX), and catalase (CAT). Furthermore, it enhanced the total antioxidant content (TAC), total iridoid content (TIC), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity. Overall, the study revealed the physiological and biochemical alterations in a medicinal plant affected by TiO2NPs, which can help to use these NPs beneficially by eliminating their harmful effects.

Hormesis and embryonic stem cells.

This paper provides an identification and detailed assessment of hormetic dose responses of embryonic stem cells (ESCs) with particular emphasis on cell renewal (proliferation) and differentiation, underlying mechanistic foundations and potential therapeutic implications. Hormetic dose responses were commonly reported, being induced by a broad range of chemicals, including pharmaceuticals (e.g., atorvastatin, isoproterenol, lithium, nicotine, ouabain), dietary supplements (e.g., curcumin, multiple ginsenosides, resveratrol), endogenous agents (e.g., estrogen, hydrogen peroxide, melatonin), and physical stressor agents (e.g., hypoxia, ionizing radiation). ESC-hormetic dose responses are similar for other stem cell types (e.g., adipose-derived stem cells, apical papilla, bone marrow stem cells, dental pulp stem cells, endothelial stem cells, muscle stem cells, periodontal ligament stem cells, neural stem cells), indicating a high degree of generality for the hormetic-stem cells response. The widespread occurrence of hormetic dose responses shown by ESCs and other stem cells suggests that the hormetic dose response may represent a fundamental and highly conserved evolutionary strategy.

Hormesis and neural stem cells.

This paper provides a detailed identification and assessment of hormetic dose responses in neural stem cells (NSCs) as identified in a number of animal models and human tissues, with particular emphasis on cell proliferation and differentiation. Hormetic dose responses were commonly observed following administration of a number of agents, including dietary supplements [e.g., berberine, curcumin, (-)-epigallocatechin-3-gallate (EGCG), Ginkgo Biloba, resveratrol], pharmaceuticals (e.g., lithium, lovastatin, melatonin), endogenous ligands [e.g., hydrogen sulfide (H2S), magnesium, progesterone, taurine], environmental contaminants (e.g., arsenic, rotenone) and physical agents [e.g., hypoxia, ionizing radiation, electromagnetic radiation (EMF)]. These data indicate that numerous agents can induce hormetic dose responses to upregulate key functions of such as cell proliferation and differentiation in NSCs, and enhance resilience to inflammatory stresses. The paper assesses both putative mechanisms of hormetic responses in NSCs, and the potential therapeutic implications and application(s) of hormetic frameworks in clinical approaches to neurological injury and disease.

Cadmium-induced hormesis effect in medicinal herbs improves the efficiency of safe utilization for low cadmium-contaminated farmland soil.

Compared to other soil remediation technologies, Cd-contaminated farmland soil with low cadmium accumulation (LCA) plant-based safe utilization is more catered to developing countries with food in high demand. Hormesis, which describes the fortification of plant growth performance by a low level of environmental stress, can be innovatively used to achieve increases in crop yield and plant functional components, thus amplifying the safe utilization efficiency of low Cd-contaminated soil by LCA plants. In the present study, the growth and physiological responses of Polygonatum sibiricum, a traditional Chinese medicinal herb, were investigated under laboratory conditions of gradient Cd dosage concentrations and times. As a result, the growth performance of P. sibiricum reached the peak of an inverse U-shaped curve of hormesis under e0 mg kg-1 and 9 months of Cd stress, with elevations in tuber biomass (medicinal part), plant height and polysaccharide content (medicinal components) of 143%, 25% and 90%, respectively. Meanwhile, trace Cd accumulation (0.41 mg kg-1) in the tuber guaranteed medicinal edible safety. In addition, Cd-induced hormesis in P. sibiricum was verified to be overcompensated by antioxidation systems. In conclusion, such 'win-win' results, including low Cd accumulation and enhancement of plant pharmaceutical value, provided medicinal herbs with a possibility for safe soil utilization.

Periodical UV-B radiation hormesis in biosynthesis of kale sprouts nutraceuticals.

The objective of the present study was to evaluate the periodical UV-B radiation hormesis during kale seeds germination in their main content of secondary metabolite compounds (phenols; glucosinolates; total antioxidant capacity -TAC-) and their changes during a refrigerated shelf-life. The total UV-B doses received were 0, 5, 10, and 15 kJ m-2 (CTRL, UVB5, UVB10, and UVB15) in where the 25% was applied on the 3rd, 5th, 7th, and 10th sprouting day. UV radiation did not affect the morphological development of the sprouts. UVB10 and UVB15 treatments increased their phenolic content (>30%). Likewise, TAC was increased by UV-B lighting ~10% (DPPH) and ~20% (FRAP). The hydroxycinnamic acid content in UVB15-treated sprouts increased by 52%, while UVB5 reported an increase of 34% in the kaempferol-3,7-di-O-glucoside concentration, compared to CTRL. After 10 d at 4 °C of shelf-life, content of gallic acid hexoside I and gallic acid increased by 55 and 78% compared to UV-untreated kale sprouts, respectively. Glucoraphanin was the main glucosinolate found in kale sprouts and seeds, followed by 4-hydroxy-glucobrassicin, whose biosynthesis was enhanced by UVB10 (~24 and ~27%) and UVB15 (~36 and ~30%), respectively, compared to CTRL. In conclusion, periodical low UV-B illumination represents a useful tool to stimulate phytochemicals biosynthesis in kale sprouts as an important source of bioactive compounds with potential health benefits.

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.