Preconditioning is hormesis part II: How the conditioning dose mediates protection: Dose optimization within temporal and mechanistic frameworks
TL;DR: The present analysis reveals that hormetic biphasic dose responses were associated with both the conditioning process and the protective effects elicited following the challenging dose, indicating that the biological/biomedical effects induced by conditioning represent a specific type of hormetic dose response and thereby contribute significantly to a generalization of the hormetic concept.
About: This article is published in Pharmacological Research.The article was published on 2016-08-01. It has received 157 citations till now.
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15 Sep 2017
TL;DR: A working compartmentalization of hormesis is established into ten categories that provide an integrated understanding of the biological meaning and applications of horm Genesis to aid in designing and interpreting future studies.
Abstract: Hormesis refers to adaptive responses of biological systems to moderate environmental or self-imposed challenges through which the system improves its functionality and/or tolerance to more severe challenges. The past two decades have witnessed an expanding recognition of the concept of hormesis, elucidation of its evolutionary foundations, and underlying cellular and molecular mechanisms, and practical applications to improve quality of life. To better inform future basic and applied research, we organized and re-evaluated recent hormesis-related findings with the intent of incorporating new knowledge of biological mechanisms, and providing fundamental insights into the biological, biomedical and risk assessment implications of hormesis. As the literature on hormesis is expanding rapidly into new areas of basic and applied research, it is important to provide refined conceptualization of hormesis to aid in designing and interpreting future studies. Here, we establish a working compartmentalization of hormesis into ten categories that provide an integrated understanding of the biological meaning and applications of hormesis.
283 citations
TL;DR: It is shown that pre- and postconditioning are specific types of hormesis, and the first documentation that hormetic effects account for preconditioning induced early and delayed windows of protection are provided.
161 citations
TL;DR: The most promising areas of research, immediate and future goals for the field, and the potential for hormesis theory to inform tDCS research were discussed at a recent meeting of researchers in the fields of neuroscience, psychology, engineering, and medicine as mentioned in this paper.
Abstract: The US Air Force Office of Scientific Research convened a meeting of researchers in the fields of neuroscience, psychology, engineering, and medicine to discuss most pressing issues facing ongoing research in the field of transcranial direct current stimulation (tDCS) and related techniques. In this study, we present opinions prepared by participants of the meeting, focusing on the most promising areas of research, immediate and future goals for the field, and the potential for hormesis theory to inform tDCS research. Scientific, medical, and ethical considerations support the ongoing testing of tDCS in healthy and clinical populations, provided best protocols are used to maximize safety. Notwithstanding the need for ongoing research, promising applications include enhancing vigilance/attention in healthy volunteers, which can accelerate training and support learning. Commonly, tDCS is used as an adjunct to training/rehabilitation tasks with the goal of leftward shift in the learning/treatment effect curves. Although trials are encouraging, elucidating the basic mechanisms of tDCS will accelerate validation and adoption. To this end, biomarkers (eg, clinical neuroimaging and findings from animal models) can support hypotheses linking neurobiological mechanisms and behavioral effects. Dosage can be optimized using computational models of current flow and understanding dose-response. Both biomarkers and dosimetry should guide individualized interventions with the goal of reducing variability. Insights from other applied energy domains, including ionizing radiation, transcranial magnetic stimulation, and low-level laser (light) therapy, can be prudently leveraged.
146 citations
TL;DR: It is proposed that hormesis can provide a compelling platform for sophisticated, next-generation plant science and help clarify the ecological consequences of low-level stress.
129 citations
TL;DR: How hormesis enhances resilience to normal aging and protects against a broad spectrum of neurodegenerative, cardiovascular, and other diseases, as well as trauma and other threats to health and well-being is assessed.
Abstract: This paper tells the story of how hormesis became recognized as a fundamental concept in biology, affecting toxicology, microbiology, medicine, public health, agriculture, and all areas related to enhancing biological performance. This paper assesses how hormesis enhances resilience to normal aging and protects against a broad spectrum of neurodegenerative, cardiovascular, and other diseases, as well as trauma and other threats to health and well-being. This paper also explains the application of hormesis to several neurodegenerative diseases such as Parkinson’s and Huntington’s disease, macrophage polarization and its systematic adaptive protections, and the role of hormesis in enhancing stem cell functioning and medical applications.
127 citations
Cites background from "Preconditioning is hormesis part II..."
...Since hormesis defines the magnitude and limits of biological plasticity it has widespread and significant implications for drug development, disease resistance and other activities designed to enhance biological performance and to acquire resilience via procedures such as pre-and post-conditioning [9,10]....
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...These adaptive response/preconditioning protective findings were significant not only because they affected mutation production, which was considered the underlying mechanism of cancer, but because they paved the way for extending the preconditioning concept to a vast range of other diseases and injuries that could be prevented/minimized by hormetic strategies [9,10]....
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...This belief in linearity at low doses would be challenged by another contemporary prominent radiation geneticist, William Russell, Oak Ridge National Laboratories, using the mouse specific locus test with over two million mice in his iterative radiation-induced mutational studies (see [9,10] for a detailed review)....
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References
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TL;DR: The multiple anginal episodes that often precede myocardial infarction in man may delay cell death after coronary occlusion, and thereby allow for greater salvage of myocardium through reperfusion therapy, which is proposed to protect the heart from a subsequent sustained ischemic insult.
Abstract: We have previously shown that a brief episode of ischemia slows the rate of ATP depletion during subsequent ischemic episodes. Additionally, intermittent reperfusion may be beneficial to the myocardium by washing out catabolites that have accumulated during ischemia. Thus, we proposed that multiple brief ischemic episodes might actually protect the heart from a subsequent sustained ischemic insult. To test this hypothesis, two sets of experiments were performed. In the first set, one group of dogs (n = 7) was preconditioned with four 5 min circumflex occlusions, each separated by 5 min of reperfusion, followed by a sustained 40 min occlusion. The control group (n = 5) received a single 40 min occlusion. In the second study, an identical preconditioning protocol was followed, and animals (n = 9) then received a sustained 3 hr occlusion. Control animals (n = 7) received a single 3 hr occlusion. Animals were allowed 4 days of reperfusion thereafter. Histologic infarct size then was measured and was related to the major baseline predictors of infarct size, including the anatomic area at risk and collateral blood flow. In the 40 min study, preconditioning with ischemia paradoxically limited infarct size to 25% of that seen in the control group (p less than .001). Collateral blood flows were not significantly different in the two groups. In the 3 hr study, there was no difference between infarct size in the preconditioned and control groups. The protective effect of preconditioning in the 40 min study may have been due to reduced ATP depletion and/or to reduced catabolite accumulation during the sustained occlusion. These results suggest that the multiple anginal episodes that often precede myocardial infarction in man may delay cell death after coronary occlusion, and thereby allow for greater salvage of myocardium through reperfusion therapy.
7,750 citations
TL;DR: It is suggested that Post-con is as effective as Pre-con in reducing infarct size and preserving endothelial function, and may be clinically applicable in coronary interventions, coronary artery bypass surgery, organ transplantation, and peripheral revascularization where reperfusion injury is expressed.
Abstract: Ischemic preconditioning (Pre-con) is an adaptive response triggered by a brief ischemia applied before a prolonged coronary occlusion. We tested the hypothesis that repetitive ischemia applied during early reperfusion, i.e., postconditioning (Post-con), is cardio-protective by attenuating reperfusion injury. In anesthetized open-chest dogs, the left anterior descending artery (LAD) was occluded for 60 min and reperfused for 3 h. In controls (n = 10), there was no intervention. In Pre-con (n = 9), the LAD was occluded for 5 min and reperfused for 10 min before the prolonged occlusion. In Post-con (n = 10), at the start of reperfusion, three cycles of 30-s reperfusion and 30-s LAD reocclusion preceded the 3 h of reperfusion. Infarct size was significantly less in the Pre-con (15 +/- 2%, P < 0.05) and Post-con (14 +/- 2%, P < 0.05) groups compared with controls (25 +/- 3%). Tissue edema (% water content) in the area at risk was comparably reduced in Pre-con (78.3 +/- 1.2, P < 0.05) and Post-con (79.7 +/- 0.6, P < 0.05) versus controls (81.5 +/- 0.4). Polymorphonuclear neutrophil (PMN) accumulation (myeloperoxidase activity, Deltaabsorbance.min-1.g tissue-1) in the area at risk myocardium was comparably reduced in Post-con (10.8 +/- 5.5, P < 0.05) and Pre-con (13.4 +/- 3.4, P < 0.05) versus controls (47.4 +/- 15.3). Basal endothelial function measured by PMN adherence to postischemic LAD endothelium (PMNs/mm2) was comparably attenuated by Post-con and Pre-con (15 +/- 0.6 and 12 +/- 0.6, P < 0.05) versus controls (37 +/- 1.5), consistent with reduced expression of P-selectin on coronary vascular endothelium in Post-con and Pre-con. Endothelial function assessed by the maximal vasodilator response of postischemic LAD to acetylcholine was significantly greater in Post-con (104 +/- 6%, P < 0.05) and Pre-con (109 +/- 5%, P < 0.05) versus controls (71 +/- 8%). Plasma malondialdehyde (microM/ml), a product of lipid peroxidation, was significantly less at 1 h of reperfusion in Post-con (2.2 +/- 0.2, P < 0.05) versus controls (3.2 +/- 0.3) associated with a decrease in superoxide levels revealed by dihydroethidium staining in the myocardial area at risk. These data suggest that Post-con is as effective as Pre-con in reducing infarct size and preserving endothelial function. Post-con may be clinically applicable in coronary interventions, coronary artery bypass surgery, organ transplantation, and peripheral revascularization where reperfusion injury is expressed.
2,121 citations
TL;DR: When human lymphocytes were cultured with [3H]thymidine, which acts as a source of low-level chronic radiation, and then exposed to 150 rad of x-rays at 5, 7, 9, or 11 hours before fixation, the yield of chromatid aberrations was less than the sum of the yields of aberration induced by [3 H]thcyidine and x-ray separately.
Abstract: When human lymphocytes were cultured with [3H]thymidine, which acts as a source of low-level chronic radiation, and then exposed to 150 rad of x-rays at 5, 7, 9, or 11 hours before fixation, the yield of chromatid aberrations was less than the sum of the yields of aberrations induced by [3H]thymidine and x-rays separately. Often fewer aberrations were found after exposure to radiation from both sources than were found after exposure to x-rays alone. At the same fixation times, nonradioactive thymidine did not affect the yield of x-ray-induced aberrations. The same phenomenon occurred at earlier fixation times, after exposure to 30 or 40 rad of x-rays and [3H]thymidine. This response is analogous to the adaptive response to alkylating agents whereby prior treatment with small doses for a long period reduces the damage occurring from large doses of similar agents given for a short time.
804 citations
TL;DR: The relationship between ambient concentration of various mutagens and resulting mutation rate was determined and the first mutagen studied was MNNG and the results were totally unexpected.
Abstract: MOST studies on mutagenesis involve exposing a growing population of cells to a large dose of mutagen for a short period. In a natural environment, however, cells are probably exposed more often to a low concentration of mutagens for long periods. We therefore measured the accumulation of mutants in Escherichia coli cells growing continuously in the presence of very low concentrations of mutagens. Because many mutagens are highly unstable, it was necessary to devise a system in which cells could be continuously exposed to fresh mutagen. To do this we took advantage of the fact that certain bacteria can grow and divide while attached to the underside of a Millipore filter. This system was originally developed by Helmstetter and Cummings1 as a means of producing synchronous cells, because as growth medium is passed through the filter it carries away with it the unattached daughter from each pair of newly divided cells. The mutagen to be studied can therefore be stored in stable conditions and only mixed with the growth medium immediately before being passed through the filter; for example the mutagen N-methyl-N′-nitro-nitro-soguanidine (MNNG) can be stored in citrate buffer at pH 5.0 in which it has a half life of 40 h compared with 2.3 h in synthetic minimal media2,3. We had intended to determine the relationship between ambient concentration of various mutagens and resulting mutation rate. The first mutagen studied was MNNG and the results were totally unexpected.
666 citations
University of Massachusetts Amherst1, University of Toledo2, Miami University3, Food and Drug Administration4, Yale University5, University of Louisville6, University of Western Ontario7, Taipei Medical University8, University of Rochester9, University of South Florida10, Eli Lilly and Company11, United States Department of Agriculture12, University of Düsseldorf13, Harvard University14, College of the Holy Cross15, University of Colorado Boulder16, Michigan State University17, Indiana University18, Jilin University19, University of Texas Health Science Center at San Antonio20, University of Louisiana at Monroe21, McMaster University22, RTI International23, University of Florida24, Kansas State University25, University of California, Irvine26, University of Michigan27, Aarhus University28, North Carolina State University29, Stanford University30, Lovelace Respiratory Research Institute31, University of Wyoming32, University of Tasmania33, Binghamton University34, New York Medical College35, National Institutes of Health36
TL;DR: This article offers a set of recommendations that scientists believe can achieve greater conceptual harmony in dose-response terminology, as well as better understanding and communication across the broad spectrum of biological disciplines.
635 citations