Modulación por Passiflora edulis de triglicéridos y colesterol intracelulares en líneas celulares de cáncer colorrectal SW480 y sus derivadas metastásicas (SW620) / Modulation by Passiflora edulis of intracellular triglycerides and cholesterol in SW480 col orectal cancer cell lines and their metastatic derivatives (SW620)

Cancer cells modify lipid metabolism to proliferate, Passiflora edulis ( P. edulis ) fruit juice (ZuFru) has antitumor activity, but whether a mechanism is through modulation of cell lipids is unknown. T o establish if ZuFru modifies cholesterol and triglycerides in SW480 and SW620. ZuFru composition was studied by phytochemical march; antiproliferative activity by sulforhodamine B, cholesterol , and triglycerides by Folch method. Z ufru contains anthocyanins, flavonoids, alkaloids , and tannins. Cell lines showed differences in their growth rate ( p =0.049). At 39.6 µg/m L of ZuFru, cell viability was decreased: SW480 (45.6%) and SW620 (45.1%). In SW480, cholesterol (44.6%) and triglycerides (46.5%) decreased; In SW620, cholesterol decreased 14.8% and triglycerides increased 7%, with significant differences for both lines. A ntiproliferative activity of ZuFru could be associated with the inhibition of intracellular biosynthesis of cholesterol and triglycerides in SW480. Action mechanisms need to be further investigated.

Las células cancerosas modifican el metabolismo lipídico para proliferar; el zumo de fruta (ZuFru) de Passiflora edulis ( P. edulis ) tiene activida d antitumoral, sin embargo, se desconoce si se involucran los lípidos celulares. E stablecer si ZuFru modifica colesterol y triglicéridos en células SW480 y SW620. C omposición del ZuFru, actividad antiproliferativa, colesterol y triglicéridos. Se encontraro n antocianinas, flavonoides, alcaloides y taninos. Las líneas celulares mostraron diferencias en su tasa de crecimiento ( p =0 . 049); ZuFru 39,6 µg/ml se disminuyó la viabilidad celular; SW480 (45,6%) y SW620 (45,1%); en SW480 colesterol (44,6%) y triglicérid os (46,5%) en SW620, colesterol (14,8%) y los triglicéridos aumentaron 7%, con diferencias significativas para ambas líneas. La actividad antiproliferativa del ZuFru podría estar asociada a la inhibición de la biosíntesis intracelular de colesterol y de tr iglicéridos en SW480, pero no en SW620. Estos mecanismos de acción deben ser fuertemente investigados.

Enemies or Allies? Hormetic and Apparent Non-Dose-Dependent Effects of Natural Bioactive Antioxidants in the Treatment of Inflammation.

This review aims to analyze the emerging number of studies on biological media that describe the unexpected effects of different natural bioactive antioxidants. Hormetic effects, with a biphasic response depending on the dose, or activities that are apparently non-dose-dependent, have been described for compounds such as resveratrol, curcumin, ferulic acid or linoleic acid, among others. The analysis of the reported studies confirms the incidence of these types of effects, which should be taken into account by researchers, discarding initial interpretations of imprecise methodologies or measurements. The incidence of these types of effects should enhance research into the different mechanisms of action, particularly those studied in the field of basic research, that will help us understand the causes of these unusual behaviors, depending on the dose, such as the inactivation of the signaling pathways of the immune defense system. Antioxidative and anti-inflammatory activities in biological media should be addressed in ways that go beyond a mere statistical approach. In this work, some of the research pathways that may explain the understanding of these activities are revised, paying special attention to the ability of the selected bioactive compounds (curcumin, resveratrol, ferulic acid and linoleic acid) to form metal complexes and the activity of these complexes in biological media.

Hormetic Effect Caused by Sublethal Doses of Glyphosate on Toona ciliata M. Roem.

This study aimed to evaluate the response of Toona ciliata seedlings to sublethal doses of glyphosate. The increasing use of glyphosate in agriculture concerns the scientific community, as the drift of this pollutant into aquatic systems or atmospheric currents can affect non-target species. Therefore, we need to understand how non-target species respond to small doses of this herbicide. T. ciliata seedlings (clone BV-1110) were exposed to sublethal doses of glyphosate (0, 9.6, 19.2, 38.4, 76.8 g ae ha-1). Anatomical, physiological, and photochemical analyses were performed 60 days after herbicide application, and growth assessments were carried out after 160 days of cultivation. We found that sublethal doses of glyphosate above 19.2 g ae ha-1 induced toxicity symptoms in Toona ciliata leaves. These symptoms were mild in some cases, such as chlorosis, but severe in other cases, such as tissue necrosis. We observed a positive relationship between increased plant height and photochemical yield with plant exposure to sub-doses 9.6 and 19.2 g ae ha-1. A sublethal dose of 38.4 g ae ha-1 improved the photosynthetic rate and carboxylation efficiency. Thus, we confirmed the hypothesis of a hormetic effect when T. ciliata was exposed to sub-doses of glyphosate equal to or lower than 38.4 g ae ha-1. However, the sublethal dose of 76.8 g ae ha-1 must be considered toxic, impacting photosynthetic activity and, consequently, the height of T. ciliata. The stem diameter of T. ciliata responded positively to increasing glyphosate doses. This occurs to compensate for the negative effect of glyphosate on water absorption. Further research will provide valuable information for harnessing the potential benefits of hormesis to improve the productivity of T. ciliata.

Time-dependent hormetic dose responses of skin care product mixtures to Vibrio qinghaiensis sp.-Q67: Appearance and quantification.

Hormesis is a widely recognized and extensively studied phenomenon. However, few studies have described the quantitative characteristics of hormesis required for appropriate risk assessment. Although skin care product (SCP) mixtures and their active ingredients can induce the hormesis of Vibrio qinghaiensis sp.-Q67 (Q67), the quantitative characteristics of time-dependent hormetic dose responses in SCPs have not yet been investigated. In this study, 28 SCP mixtures were tested for luminescence toxicity against Q67 after five exposure durations (0.25, 3, 6, 9, and 12 h). With increasing exposure duration, the concentration response curves (CRCs) were classified as constant monotonic nonlinear (S-shaped) for four SCPs, S- to hormetic (J-shaped) for 13 SCPs, and constant J-shaped for 11 SCPs. Of 140 CRCs, 98 were J-shaped. An increased frequency of SCPs inducing hormesis was observed. The toxicity (pEC50) of the SCPs was independent of the exposure duration and product type. The maximum stimulatory effect (Emin) of the 12 SCPs increased with exposure duration. We proposed a modified parameter, the width of inhibition dose zone (WIDZ; EC50/EC10), to depict the width of inhibition dose zone. The WIDZ of S-shaped CRCs were significantly larger than that of J-shaped CRCs. In addition, the characteristic parameters reported in the general literature were analyzed. The good linear relationship between EC50 and the maximum stimulatory effective concentration (ECmin) indicated that toxicity may be transformed into stimulatory effects over exposure durations. The width of stimulation dose zone (WSDZ) and Emin of the seven SCPs had the same increasing trends with increasing exposure duration. The combination of WIDZ with other characteristic parameters (e.g., zero effective concentration point, ECmin, etc.) could better depict hormesis with low-dose stimulation and high-dose inhibition. The quantitative characteristics of the dose-responses of hormesis-inducing SCPs could provide reference basis for the risk assessment of SCP mixtures.

A study of long-term toxicity of multiple mixtures with hormetic effects by the characteristic parameter σ2(k∙ECx) and stepwise method.

A previous study found that the characteristic parameter σ2(k∙ECx) (the concentration ECx and slope k of the concentrationresponse curve (CRC) at the effect x %) can predict the acute combined toxicity of multiple mixtures with S-shaped CRCs. In this paper, the competence of σ2(k∙ECx) to predict the long-term toxicity of multiple mixtures with J-shaped CRCs was explored using the Aliivibrio fischeri as the test organism. The combined toxicity was evaluated by the independent action (IA) model and the effect ratio (ERx) model. The stepwise method was used to divide J-shaped CRC into ML and MR (SL and SR). The results showed that the σ2(k∙ECx) and ERx of each segment was in good agreement with the exponential function. A new type of mixture was added to the original type A and type B, whose rules of interaction were opposite to those of type B (named opposite B, OB). This paper improves the understanding and analysis of the J-shaped CRCs in environmental risk assessment.

Foliar application of lanthanum promotes growth and phytoremediation potential Solanum nigrum L.

The hormetic effect of rare earth elements (REEs) has been found in a variety of crops and has been promoting crop growth for decades. Spraying leaves with REEs can enhance the endocytosis of plant roots. The non-selectivity of endocytosis is conducive to the direct absorption of environmental pollutants. The hyperaccumulator Solanum nigrum L. (S. nigrum), as a plant with high biomass and heavy metal tolerance, is a good candidate for phytoremediation. La(III), as a typical light REE, also has an obvious hormetic effect on S. nigrum. At 10 µM La(III), the biomass of S. nigrum reached the maximum, which was 89% greater than the control, and La(III) concentration was much lower than the previously reported optimum of 56 µM for general plants. In the present study, enhanced endocytosis after foliar spraying of La(III) was firstly observed in the root cell of hyperaccumulation plants, and La(III) increased the biomass of S. nigrum by improving the photosynthetic system, and promoting nutrient uptake and root development. The antioxidant defense system improved by La(III) contributed to the tolerance of S. nigrum to heavy metals. Applying a reasonable range of La(III) is beneficial to improving S. nigrum growth and tolerance of heavy metals. Compared with spraying deionized water, the translocation factor and bioaccumulation factor value of S. nigrum to cadmium increased by 15% and 21% respectively when spraying 10 µM La(III). Our findings provide a reference for improving hyperaccumulator plant growth and biomass, which improves phytoremediation efficiency.

Hormetic activation of nano-sized rare earth element terbium on growth, PSII photochemistry, antioxidant status and phytohormone regulation in Lemnaminor.

Soils contaminated with rare earth elements (REEs) can damage agriculture by causing physiological disorders in plants which are evaluated as the main connection of the human food chain. A biphasic dose response with excitatory responses to low concentrations and inhibitory/harmful responses to high concentrations has been defined as hormesis. However, not much is clear about the ecological effects and potential risks of REEs to plants. For this purpose, here we showed the impacts of different concentrations of nano terbium (Tb) applications (5-10-25-50-100-250-500 mg L-1) on the accumulation of endogeneous certain ions and hormones, chlorophyll fluoresence, photochemical reaction capacity and antioxidant activity in duckweed (Lemna minor). Tb concentrations less than 100 mg L-1 increased the contents of nitrogen (N), phosphate (P), potassium (K+), calcium (Ca2+), magnesium (Mg2+), manganese (Mn2+) and iron (Fe2+). Chlorophyll fluorescence (Fv/Fm and Fv/Fo) was suppressed under 250-500 mg L-1 Tb. In addition, Tb toxicity affected the trapped energy adversely by the active reaction center of photosystem II (PSII) and led to accumulation of inactive reaction centers, thus lowering the detected level of electron transport from photosystem II (PSII) to photosystem I (PSI). On the other hand, 5-100 mg L-1 Tb enhanced the activities of superoxide dismutase (SOD), catalase (CAT), peroxidase (POX), NADPH oxidase (NOX), ascorbate peroxidase (APX), glutathione reductase (GR), monodehydroascorbate reductase (MDHAR), dehydroascorbate reductase (DHAR) and glutathione S-transferase (GST). Tb (5-50 mg L-1) supported the maintenance of cellular redox status by promoting antioxidant pathways involved in the ascorbate-glutathione (AsA-GSH) cycle. In addition to the antioxidant system, the contents of some hormones such as indole-3-acetic acid (IAA), gibberellic acid (GA), cytokinin (CK) and salicylic acid (SA) were also induced in the presence of 5-100 mg L-1 Tb. In addition, the levels of hydrogen peroxide (H2O2) and lipid peroxidation (TBARS) were controlled through ascorbate (AsA) regeneration and effective hormonal modulation in L. minor. However, this induction in the antioxidant system and phytohormone contents could not be resumed after applications higher than 250 mg L-1 Tb. TBARS and H2O2, which indicate the level of lipid peroxidation, increased. The results in this study showed that Tb at appropriate concentrations has great potential to confer tolerance of duckweed by supporting the antioxidant system, protecting the biochemical reactions of photosystems and improving hormonal regulation.

Plant-pest interactions under the microscope of chemical hormesis.

Low doses of contaminants and toxins can stimulate pests feeding on contaminated tissues of host plants and enhance herbivore activity and plant damage. These effects are opposite to those of high toxic doses, have largely been missed so far, and could compromise crop production. Thus, they deserve further consideration and study.

Evaluation of targeted oxidative stress induced by oxygen-ozone in vitro after ischemic induction.

Encephalic vascular accident, or stroke, is the most common pathology of the central nervous system in humans, the second leading cause of death and physical and cognitive disabilities, in developing countries. It presents as an ischemic (more common) or hemorrhagic form. Ozone therapy has been shown to be effective in neuromodulation, neuroprotection, and nerve regeneration. The present study aimed to evaluate the effect of targeted mild ozone after inducing cerebral ischemia in vitro. Neuroblastoma lineage cells (SH-SY5Y) and canine amniotic membrane stem cells were subjected to 24 hours of hypoxia in an incubator culture chamber. The cells were evaluated by MTT assay, colorimetric assay spectrophotometry, fluorescence microscopy, and flow cytometry. Treatment with low concentrations of ozone (2-10 µg/mL), indicated a possible neuroregenerative effect at low concentrations, correlated with lower levels of apoptosis and oxidative stress compared to cells not subjected to hypoxia. High concentrations of ozone (18-30 µg/mL) promoted an increase in rate of apoptosis and cell death. We developed a novel protocol that mimics ozone therapy for ischemic stroke, using ozonized culture medium after hypoxia induction. Although more studies are needed, we conclude that ozone has a dose-dependent hormetic effect and can reverse the effect of ischemia in vitro at low concentrations.

Hormetic Effects of Carbendazim on Mycelial Growth and Aggressiveness of Magnaporthe oryzae.

Rice blast caused by Magnaporthe oryzae is one of the most destructive fungal diseases of rice worldwide. Stimulatory effects of low doses of fungicides on pathogens are closely relevant to disease management. In the present study, in potato dextrose agar (PDA) amended with carbendazim at a dose range from 0.003 to 0.3 µg/mL, stimulatory effects on the mycelial growth of three isolates sensitive to carbendazim were tested. Carbendazim at concentrations from 0.003 to 0.1 µg/mL showed stimulatory effects on mycelial growth of isolates Guy11 and H08-1a, while carbendazim at concentrations from 0.003 to 0.03 µg/mL stimulated the growth of isolate P131. The maximum stimulation magnitudes were 11.84% for the three isolates tested. Mycelial colonies grown on PDA amended with different concentrations of carbendazim were incubated at 28 °C in darkness for 7 days as the pretreatment. Pretreatment mycelia were inoculated on fresh fungicide-free PDA and subsequent mycelia growth stimulations were still observed, and the maximum stimulation magnitudes were 9.15% for the three isolates tested. Pretreatment mycelia did not significantly change the tolerance to H2O2 and NaCl, except that the tolerance to H2O2 was increased significantly (p < 0.05) when the carbendazim was at 0.3 µg/mL. After five generations of mycelial transference on fungicide-free PDA, the transgenerational hormesis of mycelial were exhibited when transferred onto PDA supplemented with carbendazim at 0.3 µg/mL, and the maximum percent stimulation was 51.28%. The time course of infection indicated that the visible initial necrotic symptoms could be detected at 2 DPI on leaves treated with carbendazim at 0.03 µg/mL, whereas no necrotic symptom could be discerned for the control. Statistical results of lesion area and lesion type at 7 DPI showed that there was a significant stimulation (p < 0.05) on aggressiveness of M. oryzae isolate Guy11 on detached rice leaves at 0.03 µg/mL carbendazim. These results will advance our understanding of hormetic effects of fungicides and provide valuable information for judicious application of fungicides.

Toxicity and sublethal effects of diafenthiuron on life table parameters of Musca domestica L. (Diptera: Muscidae).

Housefly, Musca domestica L. (Diptera: Muscidae), is an important insect-pest owing to its disease transmitting capability in both humans and animals e.g. diarrhea, gastroenteritis diseases, lumpy skin disease, cholera. Residual insecticides are widely used to control houseflies that pose serious threat to human and animal health as well as to the environment. The population resurgence after insecticidal spray is also a common problem in many cases. Transgenerational studies can be very helpful to see the fate of insecticidal sprays. In the current study, we determined transgenerational effects of sublethal doses of diafenthiuron using Age-stage two-sex life table analysis, while focusing on potential use of diafenthiuron in baits. After treating adult flies with three different doses of diafenthiuron viz. LC10, LC20 and LC50, the progeny depicted significant changes regarding pre-adult duration (shorter in control), male and female longevity of their progeny were observed (more adult longevity in control). Additionally, population growth parameters viz. intrinsic rate of growth (r) (-0.03-0.12 per day), net reproductive rate (R0) (0.50-9.98), limiting rate of growth (λ) (0.96-1.13 per day) were also significantly reduced in the progeny of treated adults. Based on the decreased biotic potential i.e. intrinsic rate of growth and other population parameters, diafenthiuron can be recommended as an effective insecticide even at lower doses.

Low Levels of Contaminants Stimulate Harmful Algal Organisms and Enrich Their Toxins.

A widespread increase in intense phytoplankton blooms has been noted in lakes worldwide since the 1980s, with the summertime peak intensity amplifying in most lakes. Such blooms cause annual economic losses of multibillion USD and present a major challenge, affecting 11 out of the 17 United Nations Sustainable Development Goals. Here, we evaluate recent scientific evidence for hormetic effects of emerging contaminants and regulated pollutants on Microcystis sp., the most notorious cyanobacteria forming harmful algal blooms and releasing phycotoxins in eutrophic freshwater systems. This new evidence leads to the conclusion that pollution is linked to algal bloom intensification. Concentrations of contaminants that are considerably smaller than the threshold for toxicity enhance the formation of harmful colonies, increase the production of phycotoxins and their release into the environment, and lower the efficacy of algaecides to control algal blooms. The low-dose enhancement of microcystins is attributed to the up-regulation of a protein controlling microcystin release (McyH) and various microcystin synthetases in tandem with the global nitrogen regulator Ycf28, nonribosomal peptide synthetases, and several ATP-binding cassette transport proteins. Given that colony formation and phycotoxin production and release are enhanced by contaminant concentrations smaller than the toxicological threshold and are widely occurring in the environment, the effect of contaminants on harmful algal blooms is more prevalent than previously thought. Climate change and nutrient enrichment, known mechanisms underpinning algal blooms, are thus joined by low-level pollutants as another causal mechanism.

Antibiotic-Induced Changes in Pigment Accumulation, Photosystem II, and Membrane Permeability in a Model Cyanobacterium.

Fremyella diplosiphon is a well-studied a model cyanobacterium for photosynthesis due to its efficient light absorption potential and pigment accumulation. In the present study, the impact of ampicillin, tetracycline, kanamycin, and cefotaxime on pigment fluorescence and photosynthetic capacity in Fremyella diplosiphon strains B481-WT and B481-SD was investigated. Our results indicated that both strains exposed to kanamycin from 0.2 to 3.2 mg/L and tetracycline from 0.8 to 12.8 mg/L enhanced growth and pigment accumulation. Additionally, B481-SD treated with 0.2-51.2 mg/L ampicillin resulted in a significant enhancement of pigment fluorescence. A detrimental effect on growth and pigmentation in both the strains exposed to 6.4-102.5 mg/L kanamycin and 0.8-102.5 mg/L cefotaxime was observed. Detection of reactive oxygen species revealed highest levels of oxidative stress at 51.2 and 102.5 mg/L kanamycin for B481-SD and 102.5 mg/L for B481-WT. Membrane permeability detected by lactate dehydrogenase assay indicated maximal activity at 0.8 mg/L ampicillin, kanamycin, and tetracycline treatments on day 6. Abundant vacuolation, pyrophosphate, and cyanophycin granule formation were observed in treated cells as a response to antibiotic stress. These findings on the hormetic effect of antibiotics on F. diplosiphon indicate that optimal antibiotic concentrations induce cellular growth while high concentrations severely impact cellular functionality. Future studies will be aimed to enhance cellular lipid productivity at optimal antibiotic concentrations to disintegrate the cell wall, thus paving the way for clean bioenergy applications.

Zinc in soil-plant-human system: A data-analysis review.

Zinc (Zn) plays an important role in the physiology and biochemistry of plants due to its established essentiality and toxicity for living beings at certain Zn concentration i.e., deficient or toxic over the optimum range. Being a vital cofactor of important enzymes, Zn participates in plant metabolic processes therefore, alters the biophysicochemical processes mediated by Zn-related enzymes/proteins. Excess Zn can provoke oxidative damage by enhancing the levels of reactive radicals. Hence, it is imperative to monitor Zn levels and associated biophysicochemical roles, essential or toxic, in the soil-plant interactions. This data-analysis review has critically summarized the recent literature of (i) Zn mobility/phytoavailability in soil (ii) molecular understanding of Zn phytouptake, (iii) uptake and distribution in the plants, (iv) essential roles in plants, (v) phyto-deficiency and phytotoxicity, (vi) detoxification processes to scavenge Zn phytotoxicity inside plants, and (vii) associated health hazards. The review especially compares the essential, deficient and toxic roles of Zn in biophysicochemical and detoxification processes inside the plants. To conclude, this review recommends some Zn-related research perspectives. Overall, this review reveals a thorough representation of Zn bio-geo-physicochemical interactions in soil-plant system using recent data.

Differential effects of biogenic and chemically synthesized silver-nanoparticles application on physiological traits, antioxidative status and californidine content in California poppy (Eschscholzia californica Cham).

Silver nanoparticles (AgNPs) of both biologically and chemically origins trigger various physiological and metabolic processes through interaction with plant cells, exerting positive, negative and inconsequential effects. However, their impacts on plant systems must be critically investigated to guarantee their safe application in food chain. In this study, the effects of chemically synthesized (synthetic) AgNPs (sAgNPs) and biologically synthesized (biogenic) AgNPs (bAgNPs) on physiological and biochemical features of Eschscholzia californica Cham were evaluated at different concentrations (0, 10, 25, 50 and 100 mg L-1). Plants exposed to bAgNPs (at 10 and 25 mg L-1) and sAgNPs (at 10 mg L-1) displayed relatively uniform deposition of AgNPs on leaf surface, however, the higher concentration (100 mg L-1) was accompanied by aggregation of AgNPs, resulting in anatomical and physiological disorders. Foliar application of both AgNPs at lower concentrations resulted in significant (P < 0.01) improve in the content of photosynthetic pigments (chlorophylls a, b, a+b, and carotenoids) and total phenolics over the control in a dose-related manner. Leaf relative water content decreased steadily with increasing both sAgNPs and bAgNPs concentrations-with sAgNPs being more inhibitive. Both types of AgNPs at 100 mg L-1 significantly (P < 0.05) increased electrolyte leakage index, level of lipid peroxidation product (malondialdehyde), and leaf soluble sugar content when compared to controls. No significant difference was found on cell membrane stability index among the plants exposed to bAgNPs and sAgNPs at the lowest concentration over the control. Californidine content was significantly (P < 0.01, by 45.1%) increased upon all the bAgNPs treatments (with a peak at 25 mg L-1) relative to control. The obtained extracts from plants treated with bAgNPs at lower concentrations revealed a significant induction of antioxidant capacity (based on DPPH˙ free radical scavenging and ferrous ions-chelating activities) with lower IC50 values compared to the other treatments. Conclusively, bAgNPs at lower concentrations are potent elicitors of pharmaceutically active compounds biosynthesis, which enhance physiological efficiency of E. californica, but at higher concentrations bAgNPs are equally toxic as sAgNPs.

A gift from parent to offspring: transgenerational hormesis.

Hormesis is a biological phenomenon characterized by opposite effects between low and high doses of stresses that can result in stimulatory and adaptive benefits to individuals within a population. While evidence of hormesis is well established, two recent studies (Nogueira et al., Belz and Sinkkonen) suggest that hormesis can also offer transgenerational benefit.

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.

Natural variation in Caenorhabditis elegans responses to the anthelmintic emodepside.

Treatment of parasitic nematode infections depends primarily on the use of anthelmintics. However, this drug arsenal is limited, and resistance against most anthelmintics is widespread. Emodepside is a new anthelmintic drug effective against gastrointestinal and filarial nematodes. Nematodes that are resistant to other anthelmintic drug classes are susceptible to emodepside, indicating that the emodepside mode of action is distinct from previous anthelmintics. The laboratory-adapted Caenorhabditis elegans strain N2 is sensitive to emodepside, and genetic selection and in vitro experiments implicated slo-1, a large K+ conductance (BK) channel gene, in emodepside mode of action. In an effort to understand how natural populations will respond to emodepside, we measured brood sizes and developmental rates of wild C. elegans strains after exposure to the drug and found natural variation across the species. Some of the observed variation in C. elegans emodepside responses correlates with amino acid substitutions in slo-1, but genetic mechanisms other than slo-1 coding variants likely underlie emodepside resistance in wild C. elegans strains. Additionally, the assayed strains have higher offspring production in low concentrations of emodepside (a hormetic effect). We find that natural variation affects emodepside sensitivity, supporting the suitability of C. elegans as a model system to study emodepside responses across natural nematode populations.

Mechanisms underlying the hormetic effect of conjugated linoleic acid: Focus on Nrf2, mitochondria and NADPH oxidases.

Nuclear factor erythroid 2-related factor2 (Nrf2) is a redox-sensitive transcription factor. Its activation by low dietary intake of ligands leads to antioxidant effects (eustress), while pro-oxidant effects (oxidative distress) may be associated with high doses. NADPH oxidases (NOXs) and the mitochondrial electron transport chain are the main sources of intracellular ROS, but their involvement in the biphasic/hormetic activity elicited by Nrf2 ligands is not fully understood. In this study, we investigated the involvement of NOX expression and mitochondrial function in the hormetic properties of omega-3 typically present in fish oil (FO) and conjugated linoleic acid (CLA) in the mouse liver. Four-week administration of FO, at both low and high doses (L-FO and H-FO) improves Nrf2-activated cyto-protection (by phase 2 enzymes), while a significant increase in respiration efficiency occurs in the liver mitochondria of H-FO BALB/c mice. Eustress conditions elicited by low dose CLA (L-CLA) are associated with increased activity of phase 2 enzymes, and with higher NOX1-2, mitochondrial defences, mitochondrial uncoupling protein 2 (UCP2), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) expression, compared with controls. Steatogenic effects (lipid accumulation and alteration of lipid metabolism) elicited by high CLA (H-CLA) elicited that are associated with oxidative distress, increased mitochondrial complex I/III activity and reduced levels of phase 2 enzymes, in comparison with L-CLA-treated mice. Our results confirm the steatogenic activity of H-CLA and first demonstrate the role of NOX1 and NOX2 in the eustress conditions elicited by L-CLA. Notably, the negative association of the Nrf2/PGC-1α axis with the different CLA doses provides new insight into the mechanisms underlying the hormetic effect triggered by this Nrf2 ligand.

Hormetic dose-dependent response about typical antibiotics and their mixtures on plasmid conjugative transfer of Escherichia coli and its relationship with toxic effects on growth.

Bacterial resistance caused by the abuse of antibiotics has attracted worldwide attention. However, there are few studies exploring bacterial resistance under the environmental exposure condition of antibiotics that is featured by low-dose and mixture. In this study, sulfonamides (SAs), sulfonamide potentiators (SAPs) and tetracyclines (TCs) were used to determine the effects of antibiotics on plasmid RP4 conjugative transfer of Escherichia coli (E. coli) under single or combined exposure, and the relationship between the effects of antibiotics on conjugative transfer and growth was investigated. The results show that the effects of single or binary antibiotics on plasmid RP4 conjugative transfer all exhibit a hormetic phenomenon. The linear regression reveals that the concentrations of the three antibiotics promoting conjugative transfer are correlated with the concentrations promoting growth and the physicochemical properties of the compounds. The combined effects of SAs-SAPs and SAs-TCs on plasmid conjugative transfer are mainly synergistic and antagonistic. While SAPs provide more effective concentrations for the promotion of conjugative transfer in SAs-SAPs mixtures, SAs play a more important role in promoting conjugative transfer in SAs-TCs mixtures. Mechanism explanation shows that SAs, SAPs and TCs inhibit bacterial growth by acting on their target proteins DHPS, DHFR and 30S ribosomal subunit, respectively. This study indicates that toxic stress stimulates the occurrence of conjugative transfer and promotes the development of bacterial resistance, which will provide a reference for resistance risk assessment of antibiotic exposure.