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      Umbelliprenin Mediates Its Apoptotic Effect by Hormesis: A Commentary

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      1 ,
      Dose-Response
      SAGE Publications
      hormesis, umbelliprenin, apoptosis induction, apoptosis inhibition, direct stimulation

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          Abstract

          Introduction Despite common dose–response curves, a compound may have the opposite effect in small doses as in large doses. This phenomenon is named hormesis. Calabrese et al have reported that many toxic substances, environmental hormones, inorganic compounds, and even irradiation induce hormesis. They modulate the growth of cultured cells in a biphasic fashion, either stimulating or inhibiting the growth of cultured cells at low and high concentrations, respectively. 1,2 There are 2 hormetic models: overcompensation stimulation and direct stimulation. Overcompensation stimulation is based on observations that the hormetic stimulatory response in the low-dose zone (ie, below the traditional toxic threshold) can result from an overcompensation following an initial disruption in homeostasis. 3 With respect to the time component of this model, the dose response is a series of time-based snapshots. 3 Contrary to overcompensation stimulation, direct stimulation model employs multiple doses with only 1 time point. It can happen by 2 mechanisms: receptor-mediated or cell-signaling-mediated. In several studies, researchers identified an essential cell-signaling pathway as well as the receptor. 4 Umbelliprenin (umb) is a naturally sesquiterpene coumarin, which is synthesized by ferula species. Apoptosis induction is one of the umb effects. Ziai et al investigated the properties of this effect. 5 -7 Based on our previous findings, 7 part of our previous data will be reanalyzed with respect to hormetic dose–response relationship. Materials and Methods In our previous study, 7 we incubated Jurkat T-CLL cells with different concentrations (10, 25, 50, and 100 µM) for different times (16, 20, 24, and 48 hours). The cytotoxicity and apoptosis induction (total apoptosis, total necrosis, early apoptosis, and late apoptosis) were measured by annexin V-FITC/PI double staining flow cytometry. Part of the study was published 7 ; here, part of the previous data is presented by Microsoft Excel 2010 and interpreted based on hormesis phenomenon. Results Based on our previous findings, 7 we found the hormetic phenomenon for some of the times of incubation (but not for all of them). The best hormetic effect is found for total and late apoptosis after 48 hours of incubation (Figure 1). Figure 1. Total (A) and late (B) apoptosis induction by umbelliprenin after 48 hours incubation in Jurkat cells. Umbelliprenin induces and inhibits apoptosis by hormetic effect. In low doses, umbelliprenin increases the percentage of apoptosis, and in high doses, it decreases the percentage of apoptosis. Data are shown as mean ± standard deviation. Error bars represent 95% confidence interval. Discussion The hormetic dose–response relationship has become the object of considerable investigation across the broad range of biological/biomedical disciplines concerned with dose/concentration–response relationships over the past 2 decades. 4 Hormetic models are overcompensation stimulation and direct stimulation. While overcompensation is tested based on multiple doses with multiple time points, direct stimulation employs multiple doses with only 1 time point. Because of umb-induced/inhibited apoptosis in multiple doses with only 1 time point, we can conclude that total and late apoptosis induction by different concentrations of umb followed direct stimulation hormetic model (Figure 1). In our previous findings, we showed that umb activates intrinsic and extrinsic pathways of apoptosis by the activation of caspase-8 and -9, respectively. 5,6 The extrinsic pathway of apoptosis is mediated by tumor necrosis factor receptor. Therefore, based on professor Calabrese’s findings, umb has a hormetic mechanism for both receptor and signaling pathway. 4 Szabaldi documented numerous examples of biphasic dose responses in the pharmacological literature. He showed that it was mediated by a single agonist acting upon 2 receptor subtypes, one affecting a stimulatory pathway and the other an inhibitory pathway. Although the subtype affecting the stimulatory pathway had far fewer receptors with considerably greater affinity for the agonist, the subtype affecting inhibition typically had far less affinity for the agonist but much greater capacity (ie, more receptors). 8 We can conclude that umb mediates its hormetic effect by 2 subtype receptors. This hypothesis requires further analysis in the future. In conclusion, hormetic phenomenon was observed in the apoptosis induction/inhibition by umb at different times of incubation. However, the present data may not suffice for the complete interpretation of its hormetic effect and requires further elucidation.

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          Most cited references8

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          Hormetic mechanisms.

          This article provides the first extensive documentation of mechanisms of hormetic dose/concentration responses. The mechanisms selected were principally those mediated via receptor and/or cell signaling pathways. Mechanisms are reported for greater than 100 agents affecting nearly 400 dose/concentration responses from a wide range of chemical classes, affecting a broad range of cell types and endpoints. Regardless of the model (i.e. in vitro or in vivo), inducing agent, endpoint, or receptor/cell signaling pathway mediated mechanism, the quantitative features of the hormetic dose/concentration responses are similar, suggesting that the magnitude of the response is a measure of biological plasticity, within a broad range of biological contexts. These findings represent an important advance in the understanding of the hormetic dose/concentration response, its generalizability and potential biomedical applications, including drug discovery/efficacy assessment and the risk assessment process.
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            Paradigm lost, paradigm found: the re-emergence of hormesis as a fundamental dose response model in the toxicological sciences.

            This paper provides an assessment of the toxicological basis of the hormetic dose-response relationship including issues relating to its reproducibility, frequency, and generalizability across biological models, endpoints measured and chemical class/physical stressors and implications for risk assessment. The quantitative features of the hormetic dose response are described and placed within toxicological context that considers study design, temporal assessment, mechanism, and experimental model/population heterogeneity. Particular emphasis is placed on an historical evaluation of why the field of toxicology rejected hormesis in favor of dose response models such as the threshold model for assessing non-carcinogens and linear no threshold (LNT) models for assessing carcinogens. The paper argues that such decisions were principally based on complex historical factors that emerged from the intense and protracted conflict between what is now called traditional medicine and homeopathy and the overly dominating influence of regulatory agencies on the toxicological intellectual agenda. Such regulatory agency influence emphasized hazard/risk assessment goals such as the derivation of no observed adverse effect levels (NOAELs) and the lowest observed adverse effect levels (LOAELs) which were derived principally from high dose studies using few doses, a feature which restricted perceptions and distorted judgments of several generations of toxicologists concerning the nature of the dose-response continuum. Such historical and technical blind spots lead the field of toxicology to not only reject an established dose-response model (hormesis), but also the model that was more common and fundamental than those that the field accepted.
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              Hormesis: principles and applications.

              Hormesis has emerged as a central concept in biological and biomedical sciences with significant implications for clinical medicine and environmental risk assessment. This paper assesses the historical foundations of the dose-response including the threshold, linear and hormetic models, the occurrence and frequency of the hormetic dose response in the pharmacological and toxicological literature, its quantitative and temporal features, and underlying mechanistic bases. Based upon this integrative foundation the application of hormesis to the process of risk assessment for non-carcinogens and carcinogens is explored.
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                Author and article information

                Journal
                Dose Response
                Dose Response
                DOS
                spdos
                Dose-Response
                SAGE Publications (Sage CA: Los Angeles, CA )
                1559-3258
                24 May 2017
                Apr-Jun 2017
                : 15
                : 2
                : 1559325817710035
                Affiliations
                [1 ]Faculty of Medicine, Physiology and Pharmacology Department, Sabzevar University of Medical Sciences, Sabzevar, Iran
                Author notes
                [*]Omid Gholami, Faculty of Medicine, Physiology and Pharmacology Department, Sabzevar University of Medical Sciences, Sabzevar, Iran. Email: omidghphd@ 123456gmail.com
                Article
                10.1177_1559325817710035
                10.1177/1559325817710035
                5446103
                336e9b1e-7cf4-41e3-bad5-c227feb366e1
                © The Author(s) 2017

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

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                April-June 2017

                hormesis,umbelliprenin,apoptosis induction,apoptosis inhibition,direct stimulation

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