Inter-animal signaling from irradiated to non-irradiated organisms has been demonstrated for whole body irradiated mice and also for fish. The aim of the current study was to look at radiotherapy style limited exposure to part of the body using doses relevant in preclinical therapy. High dose homogenous field irradiation and the use of irradiation in the microbeam radiation therapy mode at the European Synchrotron Radiation Facility (ESRF) at Grenoble was tested by giving high doses to the right brain hemisphere of the rat. The right and left cerebral hemispheres and the urinary bladder were later removed to determine whether abscopal effects could be produced in the animals and also whether effects occurred in cage mates housed with them. The results show strong bystander signal production in the contra-lateral brain hemisphere and weaker effects in the distant bladder of the irradiated rats. Signal strength was similar or greater in each tissue in the cage mates housed for 48hrs with the irradiated rats. Our results support the hypothesis that proximity to an irradiated animal induces signalling changes in an unirradiated partner. If similar signaling occurs between humans, the results could have implications for caregivers and hospital staff treating radiotherapy patients.
P53 protein has an intrinsic role in modulating the cellular response against DNA radioinduced damages and has been pointed out as an indirect indicator of individual radiosensitivity. The rate of cell proliferation is also a parameter that has been related to tissue sensitivity to radiation. However, this feature is yet understudied. In this context, the aim of this work was to employ Flow Cytometry (FC) for simultaneously assessing of p53 protein expression levels together with cellular proliferation rate of irradiated human lymphocytes. From in vitro irradiated human blood samples, mononuclear cells were isolated and labeled with Carboxylfluorescein Diacetate Succinimidyl Ester (CFSE) prior to phytohaemagglutinin (PHA) stimulation in culture for 96 hours. Cells were also labeled with anti-p53 monoclonal antibody PE-conjugated in order to analyze either proliferation rate or p53 expression levels by FC. It was verified a reduction in the proliferation rate of irradiated lymphocytes and, in parallel, a rise in the p53 expression levels, similar for quiescent and proliferating lymphocytes. The results emphasize the importance of the use of CFSE-stained lymphocytes in assays associated to proliferation rate and the use of this methodology in several studies, such as for evaluating individual radiosensitivity.
P53 protein; Proliferation rate; Flow cytometry; CFSE; Radiosensitivity
Although severe stress can elicit toxicity, mild stress often elicits adaptations. Here we review the literature on stress-induced adaptations versus stress sensitization in models of neurodegenerative diseases. We also describe our recent findings that chronic proteotoxic stress can elicit adaptations if the dose is low but that high-dose proteotoxic stress sensitizes cells to subsequent challenges. In these experiments, long-term, low-dose proteasome inhibition elicited protection in a superoxide dismutase-dependent manner. In contrast, acute, high-dose proteotoxic stress sensitized cells to subsequent proteotoxic challenges by eliciting catastrophic loss of glutathione. However, even in the latter model of synergistic toxicity, several defensive proteins were upregulated by severe proteotoxicity. This led us to wonder whether high-dose proteotoxic stress can elicit protection against subsequent challenges in astrocytes, a cell type well known for their resilience. In support of this new hypothesis, we found that the astrocytes that survived severe proteotoxicity became harder to kill. The adaptive mechanism was glutathione dependent. If these findings can be generalized to the human brain, similar endogenous adaptations may help explain why neurodegenerative diseases are so delayed in appearance and so slow to progress. In contrast, sensitization to severe stress may explain why defenses eventually collapse in vulnerable neurons.
dual hit; two hit; Parkinson’s disease; Alzheimer’s disease; preconditioning; hormesis; U-shaped
Synthetic oleanane triterpenoids are multifunctional drugs being developed for the prevention and treatment of a variety of chronic diseases driven by inflammation and oxidative stress. Low nanomolar concentrations of triterpenoids inhibit the induction of inflammatory cytokines, and these drugs are potent activators of the Nrf2 cytoprotective pathway. In contrast, low micromolar concentrations of triterpenoids increased the production of ROS and induced apoptosis in a dose-dependent manner in malignant MCF10 CA1a breast cancer cells. Because cancer cells respond differently to ROS than normal cells, it should be possible to exploit these differences therapeutically. In an experimental model of lung cancer, the triterpenoids activated the Nrf2 pathway, as seen by induction of the cytoprotective enzyme NQO1, and reduced the toxicity of carboplatin and paclitaxel. The induction of the Nrf2 pathway in the lung did not suppress the efficacy of treatment with carboplatin and paclitaxel, as the average tumor burden in the group treated with the combination of CDDO-Me and carboplatin/paclitaxel decreased by 90% (P < 0.05 vs. the controls and both single treatment groups). Understanding the dose response of triterpenoids and related drugs will help provide the proper context for optimizing their potential clinical utility.
triterpenoid; CDDO-Methyl ester; reactive oxygen species; Nrf2; carboplatin toxicity; lung cancer
Chlorophyll and carotenoid content (ChCar), lipid peroxidation (LP) and growth parameters (GP) in plants are often used for environmental pollution estimation. However, the nonmonotonic dose–response dependences (hormesis and paradoxical effects) of these indices are insufficiently explored following exposure to different pollutants. In this experiment, we studied nonmonotonic changes in ChCar, LP, GP in wheat seedlings (Triticum aestivum L.) upon exposure to lead, cadmium, copper, manganese, formaldehyde, the herbicide glyphosate, and sodium chloride in a wide range from sublethal concentration to 102–105 times lower concentrations. 85.7% of dose–response dependences were nonmonotonic (of these, 5.5% were hormesis and paradoxical effects comprised 94.5%). Multiphasic dependences were the most widespread type of paradoxical effect. Hormesis was a part of some multiphasic responses (i.e. paradoxical effects), which indicates a relationship between these phenomena. Sublethal pollutant concentrations significantly increased LP (to 2.0–2.4 times, except for manganese and glyphosate) and decreased GP (to 2.1–36.6 times, except for glyphosate), while ChCar was reduced insignificantly, normalized or even increased. Lower pollutant concentrations caused a moderate deviation in all parameters from the control (not more than 62%) for hormesis and paradoxical effects. The seedling parameters could have different types of nonmonotonic responses upon exposure to the same pollutant.
Triticum aestivum L.; dose–response dependences; physiological parameters; environmental pollutants; plant hormesis; plant paradoxical effects
Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of hospital- and community-associated infections. The formation of adherent clusters of cells known as biofilms is an important virulence factor in MRSA pathogenesis. Previous studies showed that subminimal inhibitory (sub-MIC) concentrations of methicillin induce biofilm formation in the community-associated MRSA strain LAC. In this study we measured the ability sub-MIC concentrations of eight other β-lactam antibiotics and six non-β-lactam antibiotics to induce LAC biofilm. All eight β-lactam antibiotics, but none of the non-β-lactam antibiotics, induced LAC biofilm. The dose-response effects of the eight β-lactam antibiotics on LAC biofilm varied from biphasic and bimodal to near-linear. We also found that sub-MIC methicillin induced biofilm in 33 out of 39 additional MRSA clinical isolates, which also exhibited biphasic, bimodal and linear dose-response curves. The amount of biofilm formation induced by sub-MIC methicillin was inversely proportional to the susceptibility of each strain to methicillin. Our results demonstrate that induction of biofilm by sub-MIC antibiotics is a common phenotype among MRSA clinical strains and is specific for β-lactam antibiotics. These findings may have relevance to the use of β-lactam antibiotics in clinical and agricultural settings.
antibiotic; bimodal; biofilm; biphasic; MRSA; Staphylococcus aureus; subminimal inhibitory
Low capacity runner (LCR) rats have been developed by divergent artificial selection for treadmill endurance capacity to explore an aerobic biology-disease connection. The beneficial effects of resveratrol supplementation have been demonstrated in endurance running. In this study it was examined whether 12 weeks of treadmill exercise training and/or resveratrol can retrieve the low running performance of the LCR and impact mitochondrial biogenesis and quality control. Resveratrol regressed running performance in trained LCR (p<0.05). Surprisingly, exercise and resveratrol treatments significantly decreased pAMPK/AMPK, SIRT1, SIRT4, forkhead transcription factor 1 (FOXO1) and mitochondrial transcription factor A (TFAM) levels in these animals (p<0.05). Mitochondrial fusion protein, HSP78 and polynucleotide phosphorylase were significantly induced in LCR-trained, LCR-resveratrol treated, LCR-trained and resveratol treated groups compared to LCR-controls. The data indicate that the AMPK-SIRT1-NAMPT-FOXO1 axis could be important to the limited aerobic endurance capacity of low running capacity rats. Resveratrol supplementation was not beneficial in terms of aerobic endurance performance, mitochondrial biogenesis, or quality control.
Resveratrol; Exercise; Sirtuins; Adaptation; Free Radicals
Concentration-dependent effects of aqueous extract from R. rosea root on long-term survival and stress resistance of budding yeast Saccharomyces cerevisiae were studied. At low concentrations, R. rosea aqueous extract extended yeast chronological lifespan, enhanced oxidative stress resistance of stationary-phase cells and resistance to number stressors in exponentially growing cultures. At high concentrations, R. rosea extract sensitized yeast cells to stresses and shortened yeast lifespan. These biphasic concentration-responses describe a common hormetic phenomenon characterized by a low-dose stimulation and a high-dose inhibition. Yeast pretreatment with low doses of R. rosea extract enhanced yeast survival and prevented protein oxidation under H2O2-induced oxidative stress. Positive effect of R. rosea extract on yeast survival under heat shock exposure was not accompanied with changes in antioxidant enzyme activities and levels of oxidized proteins. The deficiency in transcriptional regulators, Msn2/Msn4 and Yap1, abolished the positive effect of low doses of R. rosea extract on yeast viability under stress challenges. Potential involvement of Msn2/Msn4 and Yap1 regulatory proteins in realization of R. rosea beneficial effects is discussed.
Saccharomyces cerevisiae; Rhodiola rosea; lifespan; stress resistance; Yap1p; Msn2/Msn4p
Targeted radiotherapy is a potentially useful treatment for some cancers and may be potentiated by bystander effects. However, without estimation of absorbed dose, it is difficult to compare the effects with conventional external radiation treatment. Methods: Using the Vynckier – Wambersie dose point kernel, a model for dose rate evaluation was created allowing for calculation of absorbed dose values to two cell lines transfected with the noradrenaline transporter (NAT) gene and treated with [131I]MIBG. Results: The mean doses required to decrease surviving fractions of UVW/NAT and EJ138/NAT cells, which received medium from [131I]MIBG-treated cells, to 25 – 30% were 1.6 and 1.7 Gy respectively. The maximum mean dose rates achieved during [131I]MIBG treatment were 0.09 – 0.75 Gy/h for UVW/NAT and 0.07 – 0.78 Gy/h for EJ138/NAT. These were significantly lower than the external beam gamma radiation dose rate of 15 Gy/h. In the case of control lines which were incapable of [131I]MIBG uptake the mean absorbed doses following radiopharmaceutical were 0.03 – 0.23 Gy for UVW and 0.03 – 0.32 Gy for EJ138. Conclusion: [131I]MIBG treatment for ICCM production elicited a bystander dose-response profile similar to that generated by external beam gamma irradiation but with significantly greater cell death.
radiation bystander effect; MIBG; gene therapy; targeted radiotherapy; Vynckier-Wambersie
Hormesis is a biphasic dose-response relationship, occurring when low concentrations of toxic agents elicit apparent improvements. In this work, the ability of sub-inhibitory concentrations of Tetracycline to induce hormetic response in a model organism was investigated. To this aim a reference strain of Escherichia coli, MG1655, was exposed to six decreasing doses of Tetracycline (between 0.12 and 0.00375 μg/ml), much lower than the Minimal Inhibitory Concentration (4 μg/ml). An hormetic increase was observed at the intermediate concentrations (0.015-0.03 μg/ml) of the tested range. The Colony Forming Unit number, indeed, rose up to 141% and 121% as compared to the control. At the highest (0.12 μg/ml) and lowest (0.00375 μg/ml) concentrations a slight decrease in CFU number was found. Results demonstrated that, in Escherichia coli, low concentrations of Tetracycline bias the bacterial numerical increase through a hormetic response; the dose-response curve describing this numerical increase is an U-inverted curve. Furthermore, these data confirm that hormesis is common to many - if not all - living systems, including bacteria; they underline the relevance of a deepened knowledge of both the effects and the possible consequences of exposure to low doses of contaminants.
Hormesis; Antibiotic; Escherichia coli MG1655; Tetracycline; Biphasic dose-response; Bacterial growth
Approximately 160,000 people evacuated the area around the Fukushima Dai-ichi NPP shortly after it was damage by the earthquake and tsunami. The evacuation order applied to 70,000 of them, while the other 90,000 left voluntarily and returned soon afterward. After more than two years, most of the 70,000 are still not allowed to return to their homes. The 1100 disaster-related deaths caused by the evacuation order show that this pre-cautionary action, taken to minimize cancer risks, was not “conservative.” In this paper, recent studies are reviewed on the consequences of the radioactive releases and on the benefits of many medical treatments with low doses of radiation that were carried out until the 1950s, before the radiation scare was created. Recent research has shed light on the high rate of spontaneous double-strand breaks in DNA and the adaptive protections in cells, tissues and humans that are up-regulated by low radiation. These defences prevent, repair, remove and replace damage, from all causes including external agents. Cancer mortality is reduced. The ICRP’s concept of radiation risk is wrong. It should revert to its 1934 concept, which was a tolerance dose of 0.2 roentgen (r) per day based on more than 35 years of medical experience.
The atomic bomb survivor cancer mortality data have been used in the past to justify the use of the linear no-threshold (LNT) model for estimating the carcinogenic effects of low dose radiation. An analysis of the recently updated atomic bomb survivor cancer mortality dose-response data shows that the data no longer support the LNT model but are consistent with a radiation hormesis model when a correction is applied for a likely bias in the baseline cancer mortality rate. If the validity of the phenomenon of radiation hormesis is confirmed in prospective human pilot studies, and is applied to the wider population, it could result in a considerable reduction in cancers. The idea of using radiation hormesis to prevent cancers was proposed more than three decades ago, but was never investigated in humans to determine its validity because of the dominance of the LNT model and the consequent carcinogenic concerns regarding low dose radiation. Since cancer continues to be a major health problem and the age-adjusted cancer mortality rates have declined by only ∼10% in the past 45 years, it may be prudent to investigate radiation hormesis as an alternative approach to reduce cancers. Prompt action is urged.
LNT Model; Radiation Hormesis; Adaptive Response; Atomic Bomb Survivors
As concentration (dose) of health care providers increases, health outcomes (responses) are expected to be favorable (e.g., decrease in mortality rates). Accordingly, this data-driven, ecological study compares hypertension mortality rates in the U.S. by state to concentrations of doctors of chiropractic (DC) and medical doctors (MD). DC and MD concentrations (per 10,000 population) were separately compared to 2008 hypertension death rates using Spearman correlation analysis and linear regression (where appropriate). DC concentrations revealed a stronger beneficial association with hypertension death rates (r = −0.430, p = 0.0020) compared to MD concentrations (r = −0.029 with an observed outlier, and r = −0.085 without the outlier; both coefficients not statistically significant). Linear regression revealed that an average national decrease of approximately one hypertension death per 100,000 population (95% CI = −1.4 to −0.4) would be expected with an increase of one DC per 10,000 population within the range in this study (1.0 to 5.2 DCs per 10,000 population). Since this is an observational study, causal inference is not claimed. The study is intended as a first step to research having other designs such as case-control.
Physician; chiropractic; hypertension; mortality
Implementation of EPA’s Stage 2 Disinfection Byproducts Rules (DBPR) in Northern Kentucky will cause a water rate increase of over 25%. Hence a review was undertaken, considering both economics and science in the context of President Obama’s 2009 scientific integrity directive. The rules purport to avoid up to 0.49% of new bladder cancers by reducing the levels of DBPs in drinking water – a benefit so small that failure to implement will not cause unreasonable risk to health (URTH). It suggests at most one Northern Kentucky death avoided over 17 years for a cost of $136,000,000 ($1700 per household). Even this small benefit is probably overstated. EPA finds no “causal link” between DBPs and bladder cancer, and EPA acknowledges problems with the epidemiological data used in their calculation: the data appear contradictory and inconsistent, may be skewed toward “positive” results, and suggest different cancer sites than animal studies. Two similar international agencies disagree with EPA’s conclusions. The science is based on the Linear No Threshold (LNT) dose response model for DBPs, but this may not be the correct model. 83% of EPA’s epidemiological data show a statistical possibility that low levels of DBPs might be beneficial or have no effect.
Disinfection byproducts (DBP); Trihalomethane (THM); EPA Water Regulations; Chlorinated Drinking water; LNT model; Hormesis
The aim of this paper is to assess the historical role of radiotherapy in the treatment of sinus infections. This assessment involved a literature-based review of how radiotherapy was used to treat sinus infections in the first half of the 20th century. Low doses of x-rays were used with considerable success to treat nearly 3,000 patients of sinus infection in a span of 12 years with these cases being reported in leading medical journals as case studies. The mechanism of x-ray induced reduction of inflammation and increased tissue repair is uncertain but appears to be related to the development of a multifactorial and integrative anti-inflammatory phenotype.
sinusitis; radiotherapy; dose response; x-rays; history of medicine; inflammation
In this study, we aimed to establish the emission of UV photons when HPV-G cells and associated materials (such as the cell substrate and cell growth media) are exposed to low LET radiation. The potential role of UV photons in the secondary triggering of biological processes led us to hypothesize that the emission and absorption of photons at this wavelength explain some radiation induced “bystander effects” that have previously been thought to be chemically mediated. Cells were plated in Petri-dishes of two different sizes, having different thicknesses of polystyrene (PS) substrate, and were exposed to β-radiation from 90Y produced by the McMaster Nuclear Reactor. UV measurements were performed using a single photon counting system employing an interference-type filter for selection of a narrow wavelength range, 340±5 nm, of photons. Exposure of the cell substrates (which were made of polystyrene) determined that UV photons were being emitted as a consequence of β particle irradiation of the Petri-dishes. For a tightly collimated β-particle beam exposure, we observed 167 photons in the detector per unit μCi in the shielded source for a 1.76 mm thick substrate and 158 photons/μCi for a 0.878 mm thick substrate. A unit μCi source activity was equivalent to an exposure to the substrate of 18 β-particles/cm2 in this case. The presence of cells and medium in a Petri-dish was found to significantly increase (up to a maximum of 250%) the measured number of photons in a narrow band of wavelengths of 340±5 nm (i.e. UVA) as compared to the signal from an empty control Petri-dish. When coloured growth medium was added to the cells, it reduced the measured count rate, while the addition of transparent medium in equal volume increased the count rate, compared to cells alone. We attribute this to the fact that emission, scattering and absorption of light by cells and media are all variables in the experiment. Under collimated irradiation conditions, it was observed that increasing cell density in medium of fixed volume resulted in a decrease in the observed light output. This followed a roughly exponential decline. We suggest that this may be due to increased scattering at the cell boundary and absorption of the UV in the cells. We conclude that we have measured UVA emitted by cells, cell medium and cell substrates as a consequence of their irradiation by low LET β-particle radiation. We suggest that these secondary UV photons could lead to effects in non-targetted cells. Some effects that had previously been attributed to a chemically mediated “bystander effect” may in fact be due to secondary UV emission. Some radiation bystander effect studies may require re-interpretation as this phenomenon of UV emission is further investigated.
IBIL; HPV-G cells; Ultraviolet; Luminescence; β-particles
Research reported here relates to comparing the relative effectiveness of 320-kV X rays compared to Cs-137 gamma rays for two in vivo endpoints in C.B-17 mice after whole-body exposure: (1) cytotoxicity to bone marrow cells and splenocytes evaluated at 24-hours post exposure and (2) bone marrow and spleen reconstitution deficits (repopulation shortfalls) evaluated at 6 weeks post exposure. We show that cytotoxicity dose-response relationships for bone marrow cells and splenocytes are complex, involving negative curvature (decreasing slope as dose increases), presumably implicating a mixed cell population comprised of large numbers of hypersensitive, modestly radiosensitive, and resistant cells. The radiosensitive cells appear to respond with 50% being killed by a dose < 0.5 Gy. The X-ray relative biological effectiveness (RBE), relative to gamma rays, for destroying bone marrow cells in vivo is > 1, while for destroying splenocytes it is < 1. In contrast, dose-response relationships for reconstitution deficits in the bone marrow and spleen of C.B-17 mice at 6 weeks after radiation exposure were of the threshold type with gamma rays being more effective in causing reconstitution deficit.
X rays; gamma rays; RBE; cytotoxicity; bone marrow; splenocytes
To analyze the long-term effects of exposure to low-dose γ-irradiation on survival and life span in directly irradiated Daphnia magna and their offspring. Materials and methods: One-day-old Daphnia magna were exposed to 10, 100 and 1000 mGy of acute γ-rays. The life-span of irradiated and control animals, as well as their non-exposed progeny was analyzed. Results: Irradiation at dose of 100 and 1000 mGy resulted in a significant decrease in the life span of irradiated Daphnia. The data presented here also show that the survival of non-exposed first-generation offspring of irradiated parents is significantly compromised, thus implying the presence of transgenerational effects. Conclusion: The results of our study show that low-dose irradiation significantly reduces the life-span of directly exposed Daphnia and their first-generation offspring. The observed compromised viability is most likely attributed to non-targeted effects of ionizing radiation.
low-dose irradiation; Daphnia; life-span; transgenerational
The animal model Caenorhabditis elegans was employed to study polyphenol- and humic substances-induced hormetic changes in lifespan. A detailed insight into the underlying mechanism of hormesis was uncovered by applying whole genome DNA microarray experimentation over a range of quercetin (Q), tannic acid (TA), and humic substances (HuminFeed®, HF) concentrations. The transcriptional response to all exposures followed a non-linear mode which highlighted differential signaling and metabolic pathways. While low Q concentrations regulated processes improving the health of the nematodes, higher concentrations extended lifespan and modulated substantially the global transcriptional response. Over-represented transcripts were notably part of the biotransformation process: enhanced catabolism of toxic intermediates possibly contributes to the lifespan extension. The regulation of transcription, Dauer entry, and nucleosome suggests the presence of distinct exposure dependent differences in transcription and signaling pathways. TA- and HF-mediated transcript expression patterns were overall similar to each other, but changed across the concentration range indicating that their transcriptional dynamics are complex and cannot be attributed to a simple adaptive response. In contrast, Q-mediated hormesis was well aligned to fit the definition of an adaptive response. Simple molecules are more likely to induce an adaptive response than more complex molecules.
Caenorhabditis elegans; Transcript Expression; Humic Substances; Lifespan Extension; Quercetin; Tannic Acid
Exposures to fine particulate matter (PM2.5) in air (C) have been suspected of contributing causally to increased acute (e.g., same-day or next-day) human mortality rates (R). We tested this causal hypothesis in 100 United States cities using the publicly available NMMAPS database. Although a significant, approximately linear, statistical C-R association exists in simple statistical models, closer analysis suggests that it is not causal. Surprisingly, conditioning on other variables that have been extensively considered in previous analyses (usually using splines or other smoothers to approximate their effects), such as month of the year and mean daily temperature, suggests that they create strong, nonlinear confounding that explains the statistical association between PM2.5 and mortality rates in this data set. As this finding disagrees with conventional wisdom, we apply several different techniques to examine it. Conditional independence tests for potential causation, non-parametric classification tree analysis, Bayesian Model Averaging (BMA), and Granger-Sims causality testing, show no evidence that PM2.5 concentrations have any causal impact on increasing mortality rates. This apparent absence of a causal C-R relation, despite their statistical association, has potentially important implications for managing and communicating the uncertain health risks associated with, but not necessarily caused by, PM2.5 exposures.
Air pollution health effects; PM2.5; time series; mortality rates; cardiovascular disease; causality; Granger-Sims; conditional independence tests; J-shaped dose-response curve
Low-dose ionizing radiation (LDR) may lead to suppression of smoking-related lung cancer. We examined the effects of a known cigarette smoke carcinogen Benzo[a]pyrene (B[a]P) alone or in combination with fractionated low-dose gamma radiation (60 – 600 mGy total dose) on the induction of lung neoplasms in the A/J mouse. Our results show that 600 mGy of gamma radiation delivered in six biweekly fractions of 100 mGy starting 1 month after B[a]P injection significantly inhibits the development of lung adenomas per animal induced by B[a]P. Our data also indicated that the six biweekly doses suppressed the occurrence of spontaneous hyperplastic foci in the lung, although this suppression failed to reach statistical significance when analyzed as average foci per lung possibly related to the small sample sizes used for the control and test groups.
Low-dose gamma-radiation; Benzo[a]pyrene; lung cancer