Journal Issue:
Dose-Response: An International Journal: Volume 7, Issue 2

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2009-30-06
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RADIATION-STIMULATED EPIGENETIC REPROGRAMMING OF ADAPTIVE-RESPONSE GENES IN THE LUNG: AN EVOLUTIONARY GIFT FOR MOUNTING ADAPTIVE PROTECTION AGAINST LUNG CANCER
(2009-06-01) Scott, Bobby R; Belinsky, Steven A.; Leng, Shuguang; Lin, Yong; Wilder, Julie A; Damiani, Leah A
Humans are continuously exposed to low-level ionizing radiation from natural sources. However, harsher radiation environments persisted during our planet’s early years and mammals survived via an evolutionary gift - a system of radiation-induced natural protective measures (adaptive protection). This system includes antioxidants, DNA repair, apoptosis of severely damaged cells, epigenetically regulated apoptosis (epiapoptosis) pathways that selectively remove precancerous and other aberrant cells, and immunity against cancer. We propose a novel model in which the protective system is regulated at least in part via radiation-stress-stimulated epigenetic reprogramming (epireprogramming) of adaptive-response genes. High-dose radiation can promote epigenetically silencing of adaptive-response genes (episilencing), for example via promoter-associated DNA and/or histone methylation and/or histone deacetylation. Evidence is provided for low linear-energy-transfer (LET) radiation-activated natural protection (ANP) against high-LET alpha-radiation-induced lung cancer in plutonium-239 exposed rats and radon-progeny-exposed humans. Using a revised hormetic relative risk model for cancer induction that accounts for both epigenetic activation (epiactivation) and episilencing of genes, we demonstrate that, on average, >80% of alpha-radiation-induced rat lung cancers were prevented by chronic, low-rate gamma-ray ANP. Interestingly, lifetime exposure to residential radon at the Environmental Protection Agency’s action level of 4 pCi L–1 appears to be associated with on average a > 60% reduction in lung cancer cases, rather than an increase. We have used underlined italics to indicate newly introduced terminology.
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LINEAR AND NON-LINEAR DOSE-RESPONSE FUNCTIONS REVEAL A HORMETIC RELATIONSHIP BETWEEN STRESS AND LEARNING
(2009-06-01) Zoladz, Phillip R; Diamond, David M
Over a century of behavioral research has shown that stress can enhance or impair learning and memory. In the present review, we have explored the complex effects of stress on cognition and propose that they are characterized by linear and non-linear doseresponse functions, which together reveal a hormetic relationship between stress and learning. We suggest that stress initially enhances hippocampal function, resulting from amygdala-induced excitation of hippocampal synaptic plasticity, as well as the excitatory effects of several neuromodulators, including corticosteroids, norepinephrine, corticotropin- releasing hormone, acetylcholine and dopamine. We propose that this rapid activation of the amygdala-hippocampus brain memory system results in a linear doseresponse relation between emotional strength and memory formation. More prolonged stress, however, leads to an inhibition of hippocampal function, which can be attributed to compensatory cellular responses that protect hippocampal neurons from excitotoxicity. This inhibition of hippocampal functioning in response to prolonged stress is potentially relevant to the well-described curvilinear dose-response relationship between arousal and memory. Our emphasis on the temporal features of stress-brain interactions addresses how stress can activate, as well as impair, hippocampal functioning to produce a hormetic relationship between stress and learning.
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THE STIMULATORY EFFECTS OF TOPICAL APPLICATION OF RADIOACTIVE LANTERN MANTLE POWDER ON WOUND HEALING
(2009-06-01) Mortazavi, SMJ; Rahmani, MR; Rahnama, A; Saeed-Pour, A; Nouri, E; Hosseini, N; Aghaiee, MM
Some people in different parts of Iran use burned mantles as a wound healing medicine. To perform surface area measurement, twenty rats were divided randomly into two groups of 10 animals each. The 1st group received topical burned radioactive lantern mantle powder at 1st-3rd day after making excision wounds. The 2nd group received nonradioactive lantern mantle powder. For histological study, 36 male rats randomly divided into two groups of 18 animals each. Full thickness excision wound (314±31.4 mm2) was made on the dorsal neck in all animals after inducing general anesthesia. For the first 3 days, cases received topical application of the radioactive lantern mantle powder. Finally, to measure the tensile strength, an incision was made on the dorsal neck of the rats. Surface area measurement of the wounds showed a progressive surface reduction in both groups. Histological study showed a significant statistically difference between cases and controls with respect to fibrinoid necrosis and neutrophilic exudate at the days 3 and 14. Considering the existence of granulation tissue, a significant difference was observed between case and control groups at days 3 and 7. Tensile strength study showed no significant difference between the cases and controls until 30 days after excision.
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QUANTIFICATION OF HORMESIS IN ANTICANCER-AGENT DOSE-RESPONSES
(2009-06-01) Nascarella, Marc A; Stanek, III, Edward J.; Hoffmann, George R; Calabrese, Edward J
Quantitative features of dose responses were analyzed for 2,189 candidate anticancer agents in 13 strains of yeast (Saccharomyces cerevisiae). The agents represent a diverse class of chemical compounds including mustards, other alkylating agents, and antimetabolites, inter alia. Previous analyses have shown that the responses below the toxic threshold were stimulatory and poorly predicted by a threshold dose-response model, while better explained by a hormetic dose-response model. We determined the quantitative features of the hormetic concentration-responses (n = 4,548) using previously published entry and evaluative criteria. The quantitative features that are described are: (1) the width of the concentration range showing stimulation above 10% of the control (mean of 5-fold), (2) the maximum stimulation of the concentration-responses (mean of 27% above the control), and (3) the width from the maximum stimulation to the toxicological threshold (mean of 3.7-fold). These results show that 52.5% of the 2,189 chemicals evaluated display hormetic concentration-responses in at least one of the 13 yeast strains. Many chemicals showed hormesis in multiple strains, and 24 agents showed hormesis in all 13 strains. The data are compared to previously reported quantitative features of hormesis based on published literature.
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