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Special Issue "Hormesis and Transhormesis in Toxicology and Risk Assessment"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: closed (31 October 2016)

Special Issue Editors

Guest Editor
Prof. Dr. Aalt Bast

Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Health Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands
Website | E-Mail
Interests: pharmacology; nutrition; toxicology; pharmacy; medical and pharmaceutical chemistry; drug development; drug metabolism; drug safety; pharmacotherapy; reactive oxygen species; free radicals; antioxidants; oxidative stress; redox modulation; flavonoids; thiols; glutathione; reactive intermediates; lipid peroxidation; kinetics; structure activity relationship; biomarkers
Guest Editor
Prof. Dr. Guido R.M.M. Haenen

Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Health Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands
Website | E-Mail
Fax: +31 43 3884146
Interests: molecular biology; cell biology; biochemistry; analytical chemistry; pharmacy; medical chemistry; clinical pharmacology; toxicology; reactive oxygen species; free radicals; antioxidants; oxidative stress; redox modulation; nutrition; flavonoids; thiols; glutathione; reactive intermediates; lipid peroxidation; kinetics; structure activity relationship; biomarkers
Co-Guest Editor
Ms. Mireille M.J.P.E. Sthijns

Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Health Sciences, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands
Website | E-Mail
Interests: pharmacology; nutrition; toxicology; molecular biology; cell biology; reactive oxygen species; free radicals; antioxidants; oxidative stress; redox modulation; flavonoids; thiols; glutathione; reactive intermediates; kinetics; structure activity relationship

Special Issue Information

Dear Colleagues,

To prevent the toxicity of chemicals, ideally we should minimize our exposure. The best case scenario, of course, is to have no exposure at all, but, in the real world, this is not possible. Are we then just ‘sitting ducks’ for toxic chemicals in the environment to damage our bodies at will? No, we are much better prepared than we thought. Living organisms appear to be more flexible than we imagined and our cells have the ability to adapt to the presence of a poison. Perhaps, a little bit of bad might be good for you. This can be exemplified with the poison acrolein, a model compound used in the toxicological research of organ damage, especially that of the lung. Acrolein is present in the environment mainly through its use in the chemical industry and the incomplete combustion of fuel. Moreover, acrolein is a component of cigarette smoke.

Lung cells exposed to a low dose of acrolein are not damaged. On the contrary, the cells adapt and their protection against the poison is upgraded (Sthijns et al. 2014, Adaptation to acrolein through upregulating the protection by glutathione in human bronchial epithelial cells: The materialization of the hormesis concept). In toxicology, the notion that cells are flexible and can adapt has already existed for quite some time. This phenomenon is known as “hormesis”. It appeared that acrolein activates a sensor within the cell prompting the production of more natural antioxidant. In this way, the cells become resistant to doses that were clearly toxic before this adaptation process happened. The results obtained with acrolein demonstrate that this theoretical concept works in practice.

The pitfall is that hormesis should not be misinterpreted as carte blanche to take your daily dose of a poison to improve health; this would be unwise. The challenge is to somehow encourage hormetic adaptation to a toxic compound by another compound. The process that exposure to one compound results in hormetic adaptation to another compound we coin as transhormesis.

A wealth of data underpins the dynamics of cellular protection towards toxic compounds although this cellular flexibility has not yet been acknowledged in risk assessment procedures. Nevertheless, hormesis and transhormesis do influence how toxic a poison might be to us. Indeed, although the cells in our bodies must be ready to protect us at all times it makes no sense to wear a “suit of armour” 24 hours a day when there is no imminent threat. However, the research highlights how our body “senses” chemical threats so that we raise our defensive “shields” in time to protect us. Thus, in this way, our cells become stronger by exposure to a “little bit of bad”.

Prof. Dr. Aalt Bast
Dr. Guido R.M.M. Haenen
Guest Editors

Ms. Mireille M.J.P.E. Sthijns
Co-Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Hormesis
  • Transhormesis
  • Toxicology
  • Risk assessment
  • Adaptation
  • Exposure

Published Papers (6 papers)

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Research

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Open AccessArticle Follicle Loss and Apoptosis in Cyclophosphamide-Treated Mice: What’s the Matter?
Int. J. Mol. Sci. 2016, 17(6), 836; doi:10.3390/ijms17060836
Received: 13 April 2016 / Revised: 14 May 2016 / Accepted: 24 May 2016 / Published: 30 May 2016
Cited by 6 | PDF Full-text (4130 KB) | HTML Full-text | XML Full-text
Abstract
With increasing numbers of young female cancer survivors following chemotherapy, chemotherapy-induced fertility loss must be considered. Menstrual disorder and infertility are of particular concern in female cancer patients. We showed that treatment with the alkylating agent cyclophosphamide (CTX) could cause severe primordial follicle
[...] Read more.
With increasing numbers of young female cancer survivors following chemotherapy, chemotherapy-induced fertility loss must be considered. Menstrual disorder and infertility are of particular concern in female cancer patients. We showed that treatment with the alkylating agent cyclophosphamide (CTX) could cause severe primordial follicle loss and growing follicle apoptosis, resulting in loss of ovarian reserve. SPF C57BL/6 female mice were treated with a single dose of 120 mg/kg of CTX or saline as a control, and both sides of ovaries were collected three or seven days after injection. Following CTX treatment, the ovaries were mostly composed of collapsed oocytes and presented marked cortical fibrosis and a reduced number of follicles, especially primordial follicles. The loss of primordial follicles was confirmed by primordial follicle counting, immunohistochemistry and Western blot detection of DDx4/MVH. Follicle apoptosis was tested by a TUNEL assay and the number of TUNEL-positive follicle cells increased, as expected, in CTX-treated mice. Furthermore, expression of APAF-1 and cleaved caspase-3 was also increased after CTX treatment. Analysis of the PI3K/Akt/mTOR signaling pathway showed that CTX increased phosphorylation of Akt, mTOR and downstream proteins without affecting total levels. These results demonstrated that the CTX treatment led to the hyperactivation of the PI3K/Akt/mTOR signaling pathway in ovaries which may be related to primordial follicle loss and growing follicle apoptosis. Full article
(This article belongs to the Special Issue Hormesis and Transhormesis in Toxicology and Risk Assessment)
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Review

Jump to: Research

Open AccessReview Hormesis and Defense of Infectious Disease
Int. J. Mol. Sci. 2017, 18(6), 1273; doi:10.3390/ijms18061273
Received: 18 April 2017 / Revised: 16 May 2017 / Accepted: 20 May 2017 / Published: 15 June 2017
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Abstract
Infectious diseases are a global health burden and remain associated with high social and economic impact. Treatment of affected patients largely relies on antimicrobial agents that act by directly targeting microbial replication. Despite the utility of host specific therapies having been assessed in
[...] Read more.
Infectious diseases are a global health burden and remain associated with high social and economic impact. Treatment of affected patients largely relies on antimicrobial agents that act by directly targeting microbial replication. Despite the utility of host specific therapies having been assessed in previous clinical trials, such as targeting the immune response via modulating the cytokine release in sepsis, results have largely been frustrating and did not lead to the introduction of new therapeutic tools. In this article, we will discuss current evidence arguing that, by applying the concept of hormesis, already approved pharmacological agents could be used therapeutically to increase survival of patients with infectious disease via improving disease tolerance, a defense mechanism that decreases the extent of infection-associated tissue damage without directly targeting pathogenic microorganisms. Full article
(This article belongs to the Special Issue Hormesis and Transhormesis in Toxicology and Risk Assessment)
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Open AccessReview Hormetic Response to Low-Dose Radiation: Focus on the Immune System and Its Clinical Implications
Int. J. Mol. Sci. 2017, 18(2), 280; doi:10.3390/ijms18020280
Received: 19 December 2016 / Accepted: 17 January 2017 / Published: 27 January 2017
Cited by 3 | PDF Full-text (410 KB) | HTML Full-text | XML Full-text
Abstract
The interrelationship between ionizing radiation and the immune system is complex, multifactorial, and dependent on radiation dose/quality and immune cell type. High-dose radiation usually results in immune suppression. On the contrary, low-dose radiation (LDR) modulates a variety of immune responses that have exhibited
[...] Read more.
The interrelationship between ionizing radiation and the immune system is complex, multifactorial, and dependent on radiation dose/quality and immune cell type. High-dose radiation usually results in immune suppression. On the contrary, low-dose radiation (LDR) modulates a variety of immune responses that have exhibited the properties of immune hormesis. Although the underlying molecular mechanism is not fully understood yet, LDR has been used clinically for the treatment of autoimmune diseases and malignant tumors. These advancements in preclinical and clinical studies suggest that LDR-mediated immune modulation is a well-orchestrated phenomenon with clinical potential. We summarize recent developments in the understanding of LDR-mediated immune modulation, with an emphasis on its potential clinical applications. Full article
(This article belongs to the Special Issue Hormesis and Transhormesis in Toxicology and Risk Assessment)
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Open AccessReview PERM Hypothesis: The Fundamental Machinery Able to Elucidate the Role of Xenobiotics and Hormesis in Cell Survival and Homeostasis
Int. J. Mol. Sci. 2017, 18(1), 165; doi:10.3390/ijms18010165
Received: 29 October 2016 / Revised: 4 January 2017 / Accepted: 10 January 2017 / Published: 15 January 2017
Cited by 2 | PDF Full-text (2397 KB) | HTML Full-text | XML Full-text
Abstract
In this article the Proteasome, Endoplasmic Reticulum and Mitochondria (PERM) hypothesis is discussed. The complex machinery made by three homeostatic mechanisms involving the proteasome (P), endoplasmic reticulum (ER) and mitochondria (M) is addressed in order to elucidate the beneficial role of many xenobiotics,
[...] Read more.
In this article the Proteasome, Endoplasmic Reticulum and Mitochondria (PERM) hypothesis is discussed. The complex machinery made by three homeostatic mechanisms involving the proteasome (P), endoplasmic reticulum (ER) and mitochondria (M) is addressed in order to elucidate the beneficial role of many xenobiotics, either trace metals or phytochemicals, which are spread in the human environment and in dietary habits, exerting their actions on the mechanisms underlying cell survival (apoptosis, cell cycle regulation, DNA repair and turnover, autophagy) and stress response. The “PERM hypothesis” suggests that xenobiotics can modulate this central signaling and the regulatory engine made fundamentally by the ER, mitochondria and proteasome, together with other ancillary components such as peroxisomes, by acting on the energetic balance, redox system and macromolecule turnover. In this context, reactive species and stressors are fundamentally signalling molecules that could act as negative-modulating signals if PERM-mediated control is offline, impaired or dysregulated, as occurs in metabolic syndrome, degenerative disorders, chronic inflammation and cancer. Calcium is an important oscillatory input of this regulation and, in this hypothesis, it might play a role in maintaining the correct rhythm of this PERM modulation, probably chaotic in its nature, and guiding cells to a more drastic decision, such as apoptosis. The commonest effort sustained by cells is to maintain their survival balance and the proterome has the fundamental task of supporting this mechanism. Mild stress is probably the main stimulus in this sense. Hormesis is therefore re-interpreted in the light of this hypothetical model and that experimental evidence arising from flavonoid and hormesis reasearch. Full article
(This article belongs to the Special Issue Hormesis and Transhormesis in Toxicology and Risk Assessment)
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Figure 1

Open AccessReview The Emergence of the Dose–Response Concept in Biology and Medicine
Int. J. Mol. Sci. 2016, 17(12), 2034; doi:10.3390/ijms17122034
Received: 11 October 2016 / Revised: 21 November 2016 / Accepted: 22 November 2016 / Published: 5 December 2016
Cited by 6 | PDF Full-text (954 KB) | HTML Full-text | XML Full-text
Abstract
A historical assessment of the origin of the dose–response in modern toxicology and its integration as a central concept in biology and medicine is presented. This article provides an overview of how the threshold, linear and biphasic (i.e., hormetic) dose–response models emerged in
[...] Read more.
A historical assessment of the origin of the dose–response in modern toxicology and its integration as a central concept in biology and medicine is presented. This article provides an overview of how the threshold, linear and biphasic (i.e., hormetic) dose–response models emerged in the late 19th and early 20th centuries and competed for acceptance and dominance. Particular attention is directed to the hormetic model for which a general description and evaluation is provided, including its historical basis, and how it was marginalized by the medical and pharmacology communities in the early decades of the 20th century. Full article
(This article belongs to the Special Issue Hormesis and Transhormesis in Toxicology and Risk Assessment)
Figures

Figure 1

Open AccessReview Time in Redox Adaptation Processes: From Evolution to Hormesis
Int. J. Mol. Sci. 2016, 17(10), 1649; doi:10.3390/ijms17101649
Received: 14 July 2016 / Revised: 30 August 2016 / Accepted: 19 September 2016 / Published: 29 September 2016
Cited by 3 | PDF Full-text (1809 KB) | HTML Full-text | XML Full-text
Abstract
Life on Earth has to adapt to the ever changing environment. For example, due to introduction of oxygen in the atmosphere, an antioxidant network evolved to cope with the exposure to oxygen. The adaptive mechanisms of the antioxidant network, specifically the glutathione (GSH)
[...] Read more.
Life on Earth has to adapt to the ever changing environment. For example, due to introduction of oxygen in the atmosphere, an antioxidant network evolved to cope with the exposure to oxygen. The adaptive mechanisms of the antioxidant network, specifically the glutathione (GSH) system, are reviewed with a special focus on the time. The quickest adaptive response to oxidative stress is direct enzyme modification, increasing the GSH levels or activating the GSH-dependent protective enzymes. After several hours, a hormetic response is seen at the transcriptional level by up-regulating Nrf2-mediated expression of enzymes involved in GSH synthesis. In the long run, adaptations occur at the epigenetic and genomic level; for example, the ability to synthesize GSH by phototrophic bacteria. Apparently, in an adaptive hormetic response not only the dose or the compound, but also time, should be considered. This is essential for targeted interventions aimed to prevent diseases by successfully coping with changes in the environment e.g., oxidative stress. Full article
(This article belongs to the Special Issue Hormesis and Transhormesis in Toxicology and Risk Assessment)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: How hormesis can be a solution for low dose chemical mixtures-related diseases in human?
Author: Duk-Hee Lee
Affiliation: Department of Biomedical Science, Kyungpook National University, Daegu, Korea

Title: Patterns of hormetic reactions in clinical tumors by anticancer drugs
Authors: Thomas Efferth, et al.
Affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany

Type of Paper: Review
Title: PERM Hypothesis. The Fundamental Machinery Able to Elucidate the Role of Xenobiotics and Hormesis in Cell Survival and Homeostasis
Authors: Salvatore Chirumbolo 1,*, Geir Bjørklund 2
Affiliations: 1 Department of Medicine, Geriatric Unit, University of Verona, Verona, Italy; 2 Council for Nutritional and Environmental Medicine, Mo i Rana, Norway
Abstract: In this article the PERM hyothesis is discussed. The complex machinery made by three homeostatic mechanisms involving proteasome (P), endoplasmic reticulum (ER) and mitochondria (M) is addressed in order to elucidate the beneficial role of many xenobiotics, either trace metals or phytochemicals, which are spread in the human environment and in dietary habits, exert on the mechanisms underlying cell survival (apoptosis, cell cycle regulation, DNA repair and turnover, autophagy) and stress response. The “PERM hypothesis” suggests that xenobiotics are able to modulate this central signaling and regulatory engine made by ER, mithocondria and proteasome, together with other ancillary components, by acting on the energetic balance, redox system and macromolecule turnover. Reactive species and stressors are signaling molecules that could act as negative-modulating signals if PERM control is offline, impaired or dysregulated, such as in metabolic syndrome, degenerative disorders, chronic inflammation and cancer. Calcium is an important oscillatory input of this regulation and, in this hypothesis, might exert a role of maintaining the correct rhythm of this PERM modulation, probably chaotic in its nature. Hormesis is therefore re-interpreted at the light of this hypothetical model and experimental evidence, from flavonoid and hormesis research, then reported to support the hypothesis.

Title: Hormetic Response to Low-Dose Radiation: Focus on the Immune System and Its Clinical Implication
Authors: Lu Cai, et al.
Abstract: The interrelationship between ionizing radiation and the immune system is complex, multifactorial, and depends on the radiation dose/quality and immune cell types investigated. High-dose radiation usually results in immune suppress as common toxicity of radiation therapy. On the contrary, low-dose radiation (LDR) modulates a variety of immune response processes and clearly reveals the properties of immune hormesis. Although the underlying molecular mechanisms are not been fully explored, LDR has been clinically used for the treatment of chronic inflammatory, degenerative diseases and malignant tumors. These advancements in preclinical and clinical studies suggest that LDR-mediated immune-modulation is a well-orchestrated phenomenon and has great potential in clinical application. Thus, the purpose of the present review is to discuss recent developments in the understanding of low-dose irradiation immune modulating properties with special emphasis on its significance in clinical application.
Keywords: low-dose radiation; hormesis; stimulating effect; immune response

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