Hormesis Theory
Hormesis Theory
Hormesis Theory
Review
Less Can Be More: The Hormesis Theory of Stress Adaptation
in the Global Biosphere and Its Implications
Volker Schirrmacher
Academic Editor: Letizia Polito Keywords: oxidative stress; low-dose radiation; metabolic switch; homeostasis; epigenetic memory;
warburg effect; memory T cells; bone marrow; Nrf2; oncolysis; immunogenic cell death
Received: 4 January 2021
Accepted: 10 March 2021
Published: 13 March 2021
1. Introduction
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in Hormesis describes a dose-response relationship to stressors with a low-dose stimula-
published maps and institutional affil- tion and high-dose inhibition. The effect of the carcinogen dioxin on the development of
iations. breast cancer in rats serves as an example. In a low dose region, the frequency of tumors is
greatly reduced when compared to no dioxin or to a high dose [1]. When testing the dose-
response curve of chemotherapeutics, antibiotics, non-steroidal inhibitors of inflammation
(NSAIDs), or toxins, a U-curve is seen with a reduction of toxic side effects at the nadir [2].
Copyright: © 2021 by the author.
Hormesis is an evolutionary ancient biphasic dose-response of cells and it is a highly
Licensee MDPI, Basel, Switzerland.
generalizable phenomenon [2]. A hormesis database from 2005 contains 5600 dose-response
This article is an open access article
relationships over about 900 broadly diversified chemicals and physical agents [3]. Even hy-
distributed under the terms and drocarbons induce hormesis in biota at doses up to 100 times smaller than the toxicological
conditions of the Creative Commons threshold [4].
Attribution (CC BY) license (https:// The linear non-threshold model (LNTM) extrapolates the late effects of high-dose
creativecommons.org/licenses/by/ exposure to ionizing radiation to the low-dose range and it is actually the cornerstone of
4.0/).
current radiation protection policies. Advances in molecular and evolutionary biology, can-
cer immunology, epidemiological, and animal studies have cast serious doubts regarding
the validity and reliability of LNTM [5]. Hormesis has emerged as a central concept of risk
assessment for carcinogens and non-carcinogens. It has significant implications for clinical
medicine [6].
This review, similar to a previous review on mitochondria [7], starts with evolution of
this phenomenon on earth. Hormesis effects are described and explained in biochemical
and molecular terms with special attention to the immune system. Clinical implications
are exemplified in the fields of psychiatry, neurodegenerative diseases, cardiovascular
diseases, metabolic syndrome, autoimmune diseases, and cancer. Hormesis effects are also
described in plant cells with implications for agriculture. This review sheds light on the
archaic origin of the adaptive stress response and elucidates its global validity.
2. Evolutionary Origin
2.1. The Beginnings
During billions of years, life on earth had to adapt to the changing environmental
conditions. The anaerobic atmosphere gradually became enriched with oxygen (O2 ) due to
the invention of photosynthesis by cyanobacteria. Thus, an antioxidant network evolved in
bacteria to cope with the toxic effects of this new element in the atmosphere. The glutathion
(GSH) system can exemplify this. After several hours of oxygen exposition of bacteria, a
hormetic response can be seen at the transcriptional level by up-regulating nuclear factor
erythroid 2-related factor (Nrf2)-mediated expression of the enzymes involved in GSH
synthesis. In phototrophic bacteria, adaptations also eventually occurred at the epigenetic
and genetic level [8].
A chemo defense system. A chemo defense system has been proposed to have evolved
very early protecting organisms against toxic substances. Mechanisms that are involved, for
example, lipophilic compounds, hydrophilic compounds, oxidants, acidosics, genotoxics,
and metals. By analogy with the later evolving immune defense system, the chemo defense
system can be characterized, as follows: partial immaturity of the young, inducibility,
non-specificity, and specificity [9].
Hormesis via quorum sensing (QS) receptors. The hydrogen ion concentration (H+ or
+
H3 O ) of an aqueous solution (logarithmic measure via pH)) was demonstrated to affect
the hormesis response of bacteria. The pH profiles of certain compounds affected the
luminescence response of the Vibrio qinghaiensis sp.-Q67 [10]. The compounds display-
ing hormesis bound more easily to the α subunit of luciferase than to the ß subunit [10].
Luminescence in Allivibrio fischeri bacteria was studied to investigate hormetic mecha-
nism of sulfonamides (SAs) on bacterial QS cell-cell communication. It was suggested
that SAs acted on quorum sensing LitR proteins to change their active forms. This then
induced hormetic effects on luxR (QS signal receptor, [11]), and thereby affected the lumi-
nescence [12]. SAs triggered time-dependent hormetic effects on growth of Escherichia
(E. coli) bacteria over a time span of 24 h. It was reported that SAs bind with adenylate
cyclase at a low dose and with dihydropteroate synthase at a high dose. New insights
revealed a role of energy source in this hormesis system [13].
Protection against UV light. The protective effects of the monoterpenes camphor,
eucalyptol, and thujone were studied in E. coli K12 bacteria. The results were consistent
with a hormesis response. At a low dose, the agents protected the bacteria against UV-
induced mutagenesis and carcinogen 4-nitroquinoline-1-oxide (4NQO)-induced DNA
strand breaks. Similar effects were seen with DNA repair proficient mammalian Vero
cells [14].
Ionizing radiation hormesis. Radiation hormesis and toxicity were investigated with
luminous marine bacteria. Bioluminescence intensity was used as physiologic parameter
to study the effects of exposure to alpha- and beta-emitting radionuclides (americium-241,
uranium-235 + 238, and tritium). Three successive stages of response were detected: (1) the
Biomedicines 2021, 9, 293 3 of 30
absence of effects (stress recognition); (2) activation (adaptive response); and, (3) Inhibition
(suppression of physiological function, i.e., radiation toxicity) [15].
Glycohormesis. Experiments with cells from yeast strains revealed that hormesis en-
ables the cells to handle accumulating toxic metabolites during increased energy flux [16].
Reactive carbonyl (RCS) and reactive oxygen (ROS) species caused cellular damage through
the production of advanced glycation endproducts (AGEs) and oxidative stress. Precondi-
tioning with methylglyoxal (MG) led to changes in metabolism and activated the protein
quality control system (PQS). It was concluded that, next to mitohormesis, there also exists
glycohormesis. A direct link between metabolic and proteotoxic stress was suggested.
Specific therapeutic interventions, e.g., the manipulation of chaperone systems, might open
new fields for drug development and the treatment of diseases involving increased RCS
and ROS levels, such as diabetes mellitus (DM) and neurodegenerative diseases [16].
Fasting stress and differentiation induction. Dietary restriction stress can induce the
reproduction cycle in slime molds. Slime molds (Dictyostelium) belong to a branch that
separated from archaea before the fungus kingdom Mycota. A proteome-based eukaryotic
phylogenetic tree from 2005 is based on six archaebacterial proteomes: Malaria parasite
(Plasmodium faciparum), green alga (Clamydomonas reinhardtii), rice (Oryza sativa), maize
(Zea mays), fish (Fugus rubripes), and mosquito (Anopheles gambiae). It revealed that slime
molds belong to a branch that is designated as Amoebozoan [16]. Dictyostelim discoideum
is an important source of structural and functional information. In the case of dietary
restriction stress, single cells aggregate and induce stalk-cell differentiation via polyketide
differentiation-inducing factor-1. On top of the stalk, in the fruit body, further differentia-
tion steps occur [17]. Thus, fasting induced signals for the reproduction cycle, including a
change from a unicellular to a multicellular organism.
Fasting-induced autophagy. The aim of another investigation was to test an anti-
oxidative cellular protection effect of fasting-induced autophagy as a mechanism for
hormesis. Marine snails (Common periwinkle, Littoria littoria) were used as an animal
model. These snails were deprived of algal food for seven days to induce an augmented
autophagic response in their hepatopancreatic digestive cells (analogues of hepatocytes).
Fasting significantly increased cellular health in terms of lysosomal membrane stability,
reduced lipid peroxidation, and lysosomal/cellular triglyceride. It reduced potentially
harmful lipofuscin, an age-pigment of proteinaceous aggregates [18].
Fasting, endoplasmatic reticulum (ER) stress, and proteostasis. Studies in worms, such as
Caenorhabditis (C. elegans), demonstrated that dietary restriction improved proteostasis
and increased the life span. The mechanism worked through ER hormesis. The unfolded
protein response (UPR) of the ER helped to maintain proteostasis in the cell [19].
Responses to environmental stress. In C. elegans, environmental stresses were shown to
induce inheritable survival advantages via germline-to-soma communication. Animals
that were subjected to various stressors during developmental stages exhibited increased
resistance to oxidative stress and proteotoxicity. The increased resistance was transmitted
to the subsequent generations that were grown under unstressed conditions through
epigenetic alterations. In the parental somatic cells the insulin/insulin-like growth factor
(IGF) signaling effector DAF-16/FOXO and the heat-shock factor HSF-1 mediated the
formation of epigenetic memory. This was maintained through the histone H3 lysine
4 trimethylase complex in the germline across generations. The elicitation of memory
required the transcription factor (TF) SKN-1 (homology of mammalian Nrf2) in somatic
tissues [20].
The positive effects of mild stress on ageing and lifespan have been mainly studied and
documented in cells from worms (C. elegans) and insects (Drosophila melanogaster) [21]. Mild
stress, including hypergravity [22] and mild cold stress [23], protects and improves animal
performance. Hormesis is known by multiple names: preconditioning, conditioning, pre-
treatment, cross tolerance, and adaptive homeostasis [24]. Dietary restriction (DR), fasting
(FA), and cold exposure (CE) are hormetic stress models [25]. Rapid stress hardening (RCH)
is the fastest acclimatory response to low temperature known and it is a key adaptation for
Biomedicines 2021, 9, 293 4 of 30
coping with thermal variability, especially for ectotherms such as crustaceans, terrestrial
arthropods, amphibians, and reptiles. It was originally reported in 1987 in a Science paper.
When the flesh fly Sarcophaga crassipalpis was exposed to cold shock at −10 ◦ C for 2 h,
this caused >80% mortality. However, when only 30 min. of exposure to 0 ◦ C preceded
the same cold shock, mortality decreased to <50% [26]. Molecular mechanisms that were
associated with RCH across species revealed biological processes, such as allelic variation,
transcription (e.g., heat shock proteins, cryoprotectant synthesis), translation (e.g., calcium
signaling, redox balance), post-translational modifications (e.g., p38/MAP kinase, mRNA
surveillance), and biochemical changes (e.g., cryoprotectant accumulation and membrane
fluidity) [26].
Over time, hormesis has become recognized as a fundamental concept in biology. It
affects, for example, toxicology, microbiology, medicine, public health, and agriculture [27].
Table 1 provides an overview of the main features, mechanisms, and effects of part II.
Inducer/Modulator/Target
Stress Feature Mol Mechanism Effect
I/M/T
Oxidative stress Glutathion system (M) TF Nrf2 Homeostasis
Chemodefence Metals, genotoxics (I) inducibility Protection
Sulfonamides (I)
pH Adenyl cyclase Energy
QS luxR (M)
UV light Monoterpens (M) 4NQO UV protection
Luminous marine
Radiation 3 response levels Adaptive response
bacteria (T)
Mithormesis,
RCS and ROS PQS of yeast (M) Protection
glycohormesis
Unicellular to multicellular Polyketide
Reproduction
Fasting transformation by differentiation
cycle
Dictyostelium (M) Inducing factor 1
Reduction of
Marine snails (T) Autophagy
Fasting lipofuscin
Caenorhabditis (worm) (T) SNK-1/Nrf
Epigenetic memory
Hormesis is an evolutionary ancient biphasic dose-response of cells and a highly generalizable phenomenon.
I = Inducer; M = Modulator; T = Target; RCS = Reactive carbon species; ROS = Reactive oxygen species;
QS luxR = Quorum sensing signal receptor; PQS = Protein quality control system; TF = Transcription factor;
Nrf2 = Nuclear factor erythroid 2-related factor; 4NQO = Carcinogen 4-nitroquinoline-1-oxide; SNK-1 = Homology
to mammalian Nrf2.
2.2. Nrf2 and Its Role in Anti-Oxidative and Anti-Inflammatory Cellular Responses
A protein that is homologous to the transcription factor Nrf2 already existed in the
worm C. elegans. The Nrf2 signaling pathway in mammals plays a pivotal role in controlling
the expression of antioxidant genes and exerts anti-inflammatory functions. Molecular
details have recently been elucidated [28]. Under normal homeostatic conditions, in the
cytosol of mammalian cells, Kelch-like ECH-associated protein 1 (Keap1) homodimerizes
with an E3 ligase. This complex (Keap1-Cul3-RBX1) interacts with the Keap1 binding
domain of Nrf2 and it leads to Nrf2 ubiquitination and degradation [28].
Certain cystein residues of Keap1 are highly reactive and susceptible to covalent
modifications by ROS, RNS, H2 S, and other electrophiles and by ER stress. S-sulfenylation,
S-nitrosylation and S-sulfhydration of these critical cysteins causes conformational changes
of Keap1. This, together with phosphorylation of Nrf2 by protein kinases, promotes the
dissociation of Nrf2 and its stabilization. This is followed by Nrf2 nuclear translocation,
heterodimerization with small Maf proteins (sMaf), and binding to the anti-oxidant re-
Biomedicines 2021, 9, 293 5 of 30
sponse elements (AREs), leading to the transcription of ARE-driven genes, such as heme
oxygenase-1 (HO-1) [28].
In addition to this Nrf2 signaling pathway, Nrf2 interferes with the nuclear factor
kappa-light-chain-enhancer of activated B (NFκB) pathway that initiates inflammation.
Inflammation is a response to a variety of biological threats, such as infection by pathogens
and tissue injury. The first step is the detection of an infection signal and/or damaged tissue
signal. Such signals are mediated by pathogen-associated molecular patterns (PAMPs)
and damage-associated molecular patterns (DAMPs). These exogenous and endogenous
molecular patterns are recognized via pattern recognition receptors (PRRs), which are
expressed by immune cells. Toll-like receptors (TLRs) or inflammosomes activate specific
immune signaling pathways result in the activation of NFκB.
The response to TLR activation starts with the phosphorylation of the NFκB/IkB
complex and the dissociation of NFκB from IκB. This is followed by the translocation
of NFκB to the nucleus and the induction and transcription of genes coding for pro-
inflammatory cytokines (e.g., interleukin-1-beta (Il-1ß), IL-6, tumor necrosis factor-alpha
(TNF-α), and others. These cytokines then recruit immune cells, such as monocytes
and neutrophils, at the site of infection or tissue damage. Their activation leads to the
generation of reactive oxygen and nitrogen species (ROS, RNS), which cause damage
of macromolecules, such as proteins and DNA. Under normal physiological conditions,
such as wound healing, restoration blocks any further neutrophil recruitment and then
re-establishes tissue homeostasis.
However, in chronic “inflammation”, the risk of cellular damage is multifold. Sustained
inflammatory response causes tissue injury. The release of chemokines and prostaglandins
recruits further inflammatory cells, resulting in a respiratory burst and elevated oxidative
stress. The activation of transcription factors, such as NFκB and Nrf2, are key components
of inflammation signaling cascades and oxidative stress responses. The above described
Nrf2/HO-1 axis, activated by ROS, can interfere with NFκB in inflammation. This includes
the inhibition of NFκB activation, blocking the degradation of IκB-α, degradation of NFκB,
and inhibition of NFκB nuclear translocation. The latest insights into these complex
regulatory interactions have recently been excellently reviewed [28]. Table 2 provides an
overview of Nfr2 and its role in anti-oxidative and anti-inflammatory cellular responses.
Table 2. Nrf2 and its role in anti-oxidative and anti-inflammatory cellular responses.
Figure 1. Example of a hormesis effect. The effect of dioxin on the development of breast cancer in
rats. In a low dose (0.001 mm/kg/day) the incidence of tumors is strongly reduced. According to
Kaiser, J. [46].
4.2. Increase of Longevity and Tissue Protection by Macrophages as Hormesis Effects against
Biological Threats
A study with fruit flies (Drosophila melanogaster) reported that pathogenic fungus
spore challenge increases the longevity and fecundity, but results in reduced anti-fungal
immune function [48]. Thus, the beneficial effects of low level exposure to toxins and other
stressors may not necessarily, and under all conditions, help the immune system [48].
Another study demonstrated a hormesis mediated dose-sensitive shift in macrophage
activation patterns. The activation or polarization of macrophages to pro- or anti-
inflammatory states evolved as an adaptation to protect against biological threats. The
study demonstrated: (1) many pharmacological, chemical, and physical agents can mediate
a shift between pro- and anti-inflammatory activation states; and, (2) these shifts display
biphasic dose-response relationships that are characteristic of hormesis. The study also
revealed that preconditioning similarly mediates tissue protection by the polarization of
macrophages. However, in this case, the direction was towards an anti-inflammatory
phenotype [49].
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The microbiome also influences hormesis. A review of the literature revealed influ-
ences on oncogenesis and therapy. Microorganisms were documented to have the ability to
perturb risks of cancer and enhance hormesis after irradiation [50].
Sensor/Modulator/Target
Stressor Mol Mechanism Effect
S/M/T
LDR NK cells (S) p38/MAPK cytotoxicity
iNOS, Orchestration of T cell
LDR Macrophages, M1 (S)
oxidative burst immunotherapy
p38/MAPK,
Cytokine secretion,
CD4 and CD8 T cells (S) NFκB,
LDR CTL activity
T regulatory cells (S) JNK
downregulation
IL-10 down
OXPHOS shift to
LDR B cells (S) NFκB, CD23
aerobic glycosylation
Increased longevity
and fecundity;
Fungus spore toxin Drosophila (T)
decreased immune
function
Biological threats,
Macrophages (S) M1/M2 shift Tissue protection
infection by microbes
Memory T cells (M),
Transient dietary CXCR4/CXCL12 Enhanced protective
conservation in bone
restriction (DR) adipogenesis function
marrow
The immune system is continuously influenced by hormetic effects of environmental compounds, physical
influences and drug and food interactions. S = Sensor, M = Modulator, T = Target; LDR = Low dose radiation;
MAPK = Mitogen-activated protein kinase; iNOS = Inducible nitric oxide synthase; NFκB = Nuclear factor kappa
B; JNK = c-Jun N-terminal kinase; CXCR4 = Chemokine receptor; CXCL12 = chemokine; OXPHOS = Oxidative
phosphorylation.
5. Clinical Implications
5.1. Low Stimulatory Effects of Toxic Compounds
Formaldehyde (FA) is the first example. This is an indoor environmental pollutant,
classified as a carcinogen. Human K562 leukemia cells and human 16HBE brochial ep-
ithelial cells were exposed to different concentrations of FA. At low concentrations, FA
promoted proliferation of both cell types by inducing key molecules of cell division like
CyclinD-cdk4 (cyclin-dependent kinase 4) and E2F1 (E2F transcription factor 1). In addi-
tion, key molecules of the Warburg effect were increased: pyruvate kinase isozyme M2
(PKM2), glucose, glucose transporter 1 (GLUT1), lactic acid, and lactate dehydrogenase A
(LDHA) [52].
The second example is hydrogen peroxide. LDR (<100 mGy) mediates nanomolar
release of hydrogen peroxide (H2 O2 ) as a stable product of water radiolysis. H2 O2 has
recently been recognized as a central redox signaling molecule. LDR utilizes known
molecular master switches, such as Nrf2/Keap1 or NFκB, to promote adaptive resistance.
It has been proposed that LDR mediates its hormetic effects via H2 O2 signaling [53].
Biomedicines 2021, 9, 293 9 of 30
5.2. Psychiatry
Lithium (Li) is one compound with a hormetic effect in psychiatry. Salts of Li are
-carbonate, -acetate, -sulfate, -citrate, -orotate, and -gluconate. They are used as medicines
in psychiatry to treat manic episodes and depressions, therapy resistant schizophrenia, and
other indications. New studies in the fruit fly Drosophila suggest that Li promotes longevity.
The life-extending mechanism that is involved the inhibition of glycogen synthase kinase-3
(GSK-3) and activation of the transcription factor Nrf-2. High levels of Nrf-2 activation
conferred stress resistance, while low levels additionally promoted longevity [54].
Syndrome/Modulator/
Stressor Mol Mechanism Effect
Target S/M/T
Stress resistance
Toxic compound Li Psychiatry (S) GSK-3, Nrf-2
Longevity
Ag-Nanoparticles (Ag-NPs) Astroglioma cells (T) MuD and p38/ERK Beneficial
Formaldehyde Bronchial epithelial cells (T) CyclinD-cdk4, E2F1 Warburg effect
LDR H2 O2 signaling (M) Nrf2/Keap1, NFkB Redox signaling
Neurodegenerative disorders (S),
Mitochondria, autophagy,
ROS Curcumin (M) Protection
apoptosis
Inflammasomes (T)
Upregulation of Treg
LDR Autoimmune diseases (S) Regulation of negative effects
Inhibition of cytokines
Neuroprotection,
H2 O2 NLRP3 inflammasome (T) PAC1-R neurotrophic and
neurogenesis effects
Cardiovascular diseases (S), Ca2+ homeostasis,
ROS Cardioprotection
MitoPQ (M) mitochondrial homeostasis
Vascular cells (T), Mitochondrial redox
ROS Vasodilation
EPICAT (M) regulation
Exampels of hormetic inducers in a variety of clinical syndroms. Syndrome = Field of clinical implication; M = Modulator; T = Tar-
get; LDR = Low dose radiation; NLRP3 = Nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing
inflammasome; ROS = Reactive oxygen species; GSK-3 = Glycogen synthase kinase-3; Nrf-2 = Nuclear factor erythroid 2-related factor;
MuD = Mushroom body defect, a microtubule-associated protein that contributes to mitotic spindle function; ERK = Extracellular-regulated
protein kinase; CyclinD-cdk4 = CyclinD-cyclin-dependent kinase 4; E2F1 = E2F transcription factor 1; Keap1 = Kelch-like ECH-associated
protein 1; PAC1-R = Pituitary adenylate cyclase-activating polypeptide receptor 1; EPICAT = (-)-Epicatechin.
therapy. In radiation therapy, lower doses and accurate stereotactic targeting might enable
antigen-releasing (immunogenic) doses of radiation to be delivered to the tumor with
a sparing of surrounding normal tissue. Coupled with emerging immunotherapies, the
future of cancer treatment may consist in more localized debulking surgery, repositioned
CT, and radiotherapy in combination with immunotherapy and targeted therapies [85].
6.2. Hormetic Aspects of Targeted Therapies, Oncolytic Viruses and Cancer Vaccines
6.2.1. Hormetic Aspects of Small Molecule Inhibitors (SMIs)
The mammalian target of rapamycin (mTOR) regulates, among others, aerobic gly-
colysis in carcinomas. It regulates the metabolism of glucose, amino acids, fatty acids,
lipids, and nucleotides. Small molecule inhibitors (SMIs) might be suited to target cancer-
associated molecules that are associated with mTOR and glycolysis [86]. SMIs must
optimally fit into an enzyme’s active site to inhibit its functional (e.g., tyrosine kinase)
activity. This means that the dose-response relationship is non-linear and it has an optimum
at a molecular enzyme to inhibitor ratio of 1:1.
particles per tumor cell [94]. (3). In the years between 1990 and 2008 (the time-point of
the authors retirement at the German Cancer Research Center in Heidelberg, Germany),
translational research allowed for creating a human virus-modified vaccine homologous
to ESb-NDV. It was designated as Autologous Tumor cell Vaccine that was modified by
NDV infection (ATV-NDV) [95]. Delayed-type hypersensitivity (DTH) skin reactivity was
used as first immunogenicity assay in Phase I studies in cancer patients. These studies
revealed that an optimal virus to tumor cell ratio was seen at about 10 virus particles per
tumor cell [96]. Findings (1)–(3). can be well interpreted as a hormesis effect. Similar dose
responses existed for mice and human.
The results that were obtained with the vaccine ATV-NDV were true for the lentogenic
NDV strain Ulster, which has only monocyclic replication capacity in tumor cells. In the
DC-based vaccine IO-VACR [97,98] that is being used since 2015 at the Immune-Oncological
Center Cologne (IOZK) Germany, the patient-derived NDV oncolysate is obtained with a
mesogenic NDV strain that shows multicyclic replication capacity. In this case, the virus to
tumor cell ratio can be titrated down to 1 or 0.1 virus particles per tumor cell. More than
one million tumor cells are normally used in a tumor cell-based (ATV-NDV) or DC-based
(IO-VACR ) vaccine.
The concept of individualized, multimodal immunotherapy (IMI), which was devel-
oped at IOZK, combines immunogenic cell death (ICD) treatment via NDV with modulated
electrohyperthermia (mEHT) and IO-VACR DC vaccination. A recent data analysis of 70
treated adult patients that were from Glioblastoma multiforme (GBM) revealed that IMI,
in combination with maintenance chemotherapy, provides a strategy towards improving
the overall survival rate [99]. In the same review, the concept of randomized controlled
immunotherapy clinical trials for GBM has been questioned and challenged [99].
The Rho GTPase Rac1 plays an important role in GBM cell migration and invasion.
Interestingly, Rac1 is also a target of NDV infection. It is involved in viral entry, during
syncytium induction, and upon actin reorganization [100,101]. NDV-induced syncytium
formation triggers autophagy, which is mediated through the activation of the AMPK
(energy-sensing AMP-activated protein kinase)-mTORC1-ULK1 (autophagy-initiating pro-
tein kinase) pathway [102]. This network plays a role in autophagy and in maintaining
cellular energy and nutrient homeostasis.
Solid tumor microenvironments contain regions of hypoxia, in which a distinct tran-
scription factor (i.e., hypoxia inducible factor (HIF)) is active. A velogenic NDV strain
was applied in order to compare the oncolytic effect against a clear cell carcinoma line
under normoxic and hypoxic conditions. It was found that NDV could break resistance to
hypoxia. Hypoxia even augmented oncolytic activity, regardless of the HIF levels in the
cells [103].
Resistance to therapy is a major obstacle to cancer treatment. NDV was reported
to have the potential to break resistance not only to hypoxia, but also to chemo- and
radiotherapy, to apoptosis, to tumor-necrosis-factor-related apoptosis-inducing ligand
(TRAIL), and to immune checkpoint blockade [104].
NDV pre-treatment of cancer patients before vaccination has an immune conditioning
effect. Immune cells are primed towards a type I interferon response via signaling through
cytoplasmic RIG-I receptor and through plasma membrane expressed type I interferon
receptor [105]. Upon NDV infection in vitro, human DCs become programmed within
18 hrs. into DC1 polarization. A sophisticated study revealed that the antiviral response
of human DCs to NDV infection is highly reproducible and dictated by a choreographed
cascade of 24 transcription factors leading to the upregulation of 779 genes [106].
The dose-response to vaccines is not linear, as mentioned above. A determination of
maximally tolerable dose, as required from toxicology, is meaningless in immunology. With
regard to the vaccine ATV-NDV, the first study of post-operative vaccination of breast cancer
patients defined a dose above one million cells and below five million cells and cell viability
of the irradiated cells above 50% as high quality parameters, based on patient survival [94].
Competence and polarization of the patient’s immune system are other parameters of
Biomedicines 2021, 9, 293 15 of 30
protamine-protected RNA and naked RNA can be used in vivo in mice to elicit specific
CTLs and antibodies [113]. The other study [114] introduced an additional two innovative
procedures for further optimization of RNA vaccination. (1) Use of the mouse ear pinna as
vaccination site and (2) the use of self-replicating infectious RNA. The mouse ear pinna
had been shown before to be a vaccination site superior to other commonly used sites [115].
The self-replicating RNA vaccine made use of the Semliki Forest virus replicase to drive
RNA expression of the lacZ gene coding for ß-gal. A 100-fold lower dose of polynucleotide
was sufficient in comparison to a lacZ DNA vector for achieving a protective response
against lacZ-transfected tumor cells with self-replicating RNA [114].
Thus, mRNA-based vaccines are not new. One of the two studies from 20 years ago
was performed in Tübingen (Germany) in the laboratories of Hans-Georg Rammensee,
the other study was performed in Heidelberg (Germany) at the German Cancer Research
Center in the laboratories of the author of this review.
numbers of macrophages were associated with a better outcome than very low or very
high numbers [123].
A high expression of Nrf2 was found to be associated with increased tumor-infiltrating
lymphocytes and cancer immunity in ER-positive/HER2-negative breast cancer. This
was based on in silico analyses in 5443 breast cancer patients from several large patient
cohorts. High Nrf2 tumors were highly infiltrated by immune cells (CD8+, CD4+, and
DCs) and stromal cells (adipocytes, fibroblasts, and keratinocytes [124]. In contrast, the
negative effects of Nrf2 expression have been reported for glioblastoma [125] and lung
adenocarcinoma [126]. Tumor entities presenting oncogenic activation of Nrf2 were found
to be associated with drug resistance and immune evasion [125,126].
The chapter will be finished with two case reports from Shuji Kojima and colleagues
from the Department of Radiation Biosciences, Tokyo University of Science, Chiba, Japan.
The first deals with treatment of cancer and inflammation (ulcerative colitis) by low-dose
ionizing radiation. The three case reports support the clinical efficacy of low dose radiation
hormesis in patients with these diseases [127]. The second publication reports four cases of
radon therapy as a primary or an adjuvant treatment for different types of cancer [128]. It
is recommended to perform clinical trials to determine the best radon concentration for the
treatment of different types of cancers and in different stages of progression [128]. Table 5
provides an overview of the main features, mechanisms, and effects of part VI.
Inducer/Modulator/Target
Feature Mol Mechanism Effect
I/M/T
mTOR (T): Metabolism of Targeted inhibition
Small molecule Aerobic glycolysis, glucose, amino acids, by SMIs
inhibitor (SMI) Truncated TCA cycle, fatty acids, lipids, of carcinoma growth,
MG production (M) nucleotides MG as hormetin
NDV (I): HSP27 Oncolysis,
low-dose optimum for phosphorylation, Immunogenic cell
Oncolytic virus
oncolysis, CTL induction proteasomal protein death (ICD),
and DTH reactivity degradation immune stimulation
Increase of ROS Hormetic low-dose
SR59230A ß3-adrenoreceptor (M)
and cancer cell death anti-cancer effect
Intermediate
Tumor infiltrating
Hodgkin lymphoma (T) CD68+, CD163 numbers associated
macrophage
with better prognosis
Cancer and Three case reports of
LDR Radiation hormesis
ulceratice colitis (T) positve effects
Cancer (T),
Four case reports of
Radon primary or adjuvant Radiation hormesis
positive effects
treatment
Examples of hormetic inducers in cancer therapy. mTOR = Mammalian target of rapamycin; I = Inducer;
M = Modulator; T = Target; NDV = Newcastle disease virus; LDR = Low-dose radiation; OXPHOS = Oxida-
tive phosphorylation; TCA = Tricarbonic acid cycle; MG = methylglyoxal; CTL = Cytotoxic T lymphocyte;
DTH = Delayed-type hypersensitivity; HSP27 = Heat-shock protein 27.
heavy metals were an increase in the auxin and flavonol content and the maintenance of
H2 O2 at the same level as the control plants [129].
Nanoparticle silver (AgNP) treatment of maize has a beneficial, possibly hormetic,
effect on the plants roots. However, a recent analysis of the maize rhizospere revealed
significant multiple unintended effects of nanosilver use on corn. Specifically, the microbial
rhizome community structure and expressed genes of both prokaryotic and eukaryotic
microorganisms was studied. Diversity analysis indicated a significant decrease in richness.
Among the phylum bacteria, some groups (e.g., Chloroflexi and Planctomycetes) decreased
significantly, while other groups (e.g., Acidobacteria, Bacteroidetes, and Proteobacteria
(Alpha and Gamma)) were increased in response to nanosilver exposure. Among the phy-
lum fungi, an increase in abundance was observed, including potentially phytopathogenic
groups. Certain species from the genus Diplodia are causal agents of stalk and ear rot
in maize, and this genus showed a 5.5 fold increase under nanosilver exposure. It was
concluded that the disruption of natural biocontrol could cause phytopathogen increase.
Compromised nitrogen cycling, possible phytopathogen selection, and plant hormesis
effects were detected via metatranscriptome analysis. In the long term, this could turn out
to be negative to crop productivity and ecosystem health [130].
Additionally, some herbicides, like glyphosate, 2,4-D and paraquat, at low dose,
exert a hormetic response. When ROS are produced, H2 O2 acts as a signaling molecule
that promotes cell walls malleability, allowing for inward water transport causing cell
expansion [131,132].
Silicon (Si) is a beneficial element that has been proven to influence plant responses,
including growth, development, and metabolism in a hormetic manner. After oxygen,
Si is the second most abundant element in the Earth’s crust. It covers up to 32% of the
litosphere. It is found as silicates and Si minerals, combined with oxygen or elements, like
aluminum (Al), manganese (Mg), calcium (Ca), sodium (Na), iron (Fe), and potassium (K).
In plants, Si can only be absorbed as monosialic acid (Si(OH)4 ). It is then transported and
mainly deposited in the cell apoplast. Si concentrations in plants fluctuate between 0.1%
and 10% of the total dry mass. Seven of the 10 most produced crops in the world are Si
accumulators, and these respond positively to Si applications. These crops include rice,
wheat, barley, sugarcane, soybean, and sugar beet [133].
A recent study [133], performed with pepper plants (Capsicum annuum L.) revealed
hormetic dose-response effects of Si on growth and concentrations of chlorophyll, amino
acids, and sugars during the early developmental stage. Si was supplied as calcium silicate
(CaSiO3 ) in the nutrient solution. It was applied at four levels: 0, 60, 125, and 250 mg L−1 .
Si differentially affected plant growth and metabolism, depending on the concentration
applied. Si might act as a signal to promote amino acid remobilization to support the
increased demand of nitrogen during grain development. Si interacts with key components
of plant signaling systems. This includes binding to the hydroxyl groups of proteins
involved in cell signaling. It can also act as a signaling modulator by interacting with
cationic co-factors of enzymes influencing stress responses.
As sessile organisms, plants have evolved unique mechanisms that enable them to
face the complexity of environmental changes. Future recommendations to agronomists
will include Si applications to fields that are deficient in the element. The rapid pace of
global climate change leads to new challenges for agriculture and food production [133].
Table 6 provides an overview of the main features, mechanisms, and effects of part VII.
Biomedicines 2021, 9, 293 19 of 30
Modulator/Target
Herbicid Mol Mechanism Effect
M/T
Increase in auxin Hormetic stimulation
Metal: Cd or Pb ROS (M)
andflavonol of shoot growth
Positive effect on plants Negative effect on
Metal: Ag-NP Maize (T)
roots rhizome
Increased water
Glyphosate, 2,4-D, H2 O2 as signaling
ROS (M) transport causing cell
Paraquat molecule
expansion
Si accumulators: rize,
Si binding to hydroxyl Hormetic effect on
wheat, barley,
Silicon (Si) groups of proteins growth, chlorophyll,
sugarcane, soybean,
involved in signaling amino acids and sugars
sugarbeet (T)
Examples of herbicides with hormetic effects. M = Modulator; T = Target; Cd = cadmium; Pb = lead;
Ag-NP = silver-nanoparticles; ROS = Reactive oxygen species; H2 O2 = Hydrogenperoxide.
assembly, peptide biosynthesis, metabolic processes, ATP metabolic process, and regulation
of translation. The repression of genes that are involved in ribosome biosynthesis and
translation was shared between the two cell types.
3. The duration and magnitude of the transcriptional response dependent on the
intensity of stress. In yeast cells, extreme heat shock (25 ◦ C to 37 ◦ C) elicited a greater
transcriptional response than lower heat shock. In Hbt. salinarum cells the duration and
magnitude of response was tested with regard to oxidative stress. This was exerted by the
redox cycling agent paraquat. Low concentrations were 0.25 mM, high concentrations 4 mM.
HhHigh-dose treatment mounted a higher magnitude change when compared to low-dose.
Gene expression returned to nearly pre-treatment levels after 150 min of exposure.
4. The induction of the transcriptional response specific to stress exposure. In yeast
cells, a reciprocal environmental shift (37 ◦ C to 25 ◦ C) caused a rapid transition to basal
expression levels without the peak seen under the condition of 3. Similarly, Hbt. salinarum
cultures recovering from oxidative stress returned rapidly to basal expression levels without
exhibiting ESR-like transcriptional characteristics. Similar, non-reciprocal dynamics were
observed upon treatment with hydrogen peroxide.
In conclusion, upon sensing changes in the surrounding environment, Hbt. salinarum
exhibits transient transcriptional dynamics that are characterized by the induction and
repression of large portions of the genome (criteria 1 and 2). This response is specific to
stressful conditions and sensitive to the magnitude of stress (criteria 3 and 4). It was further
suggested that TrmB family proteins are candidate regulators of the ESR in archaea [134].
Stressors that were tested across archaeal species were specific to the respective niche
of the extremophile of interest, including hypo-osmotic shock for halophiles, temperature
extremes for hyperthermophiles, and others. A common trend was that genes encoding
core cellular processes required for rapid growth are repressed during stress. In particular,
the repression of translation has been reported across species and stress conditions. Thus,
it is appropriate to talk about global genome-wide transcriptional programs as conserved
features of the ESR. Table 7 provides an overview of the main features, mechanisms, and
effects of part VIII.
9. Global Aspects
Oxygen, approximately two billion years ago, a waste product of photosynthetic
cyanobacteria, induced oxidative stress. Gradually, the production of ROS became a
driver of physiological and pathological processes. Low-level ROS play an important
role as redox-signaling molecules in a wide spectrum of pathways that are involved in
Biomedicines 2021, 9, 293 21 of 30
the maintenance of cellular homeostasis and regulating key transcription factors (e.g.,
Nrf2/Keap1, NFκB/IκB, AP-1, p53, and HIF-1) [132].
Melatonin, in coordination with the circadian rhythms, is involved in stress adap-
tive responses [136]. This hormone is produced in animals by the pineal gland and in
plants under stress. Substantial evidence was provided of a melatonin-induced biphasic
dose-response relationship. This showed similarities to those of broad toxicological and
pharmacological hormesis literature. This example from chronobiology means, for instance,
for medicine, that finding the right dose is not all, the right time point for drug application
is also important.
Melatonin may act as a conditioning agent protecting organisms against subsequent
health threats within a hormetic framework. The incorporation of melatonin-induced
hormesis in research protocols has the potential to enhance the treatment of neuropsychi-
atric diseases and cancers. It may also help in the protection against environmental stress
in plants and to increase plant productivity [136].
Hormesis has been suggested to promote evolutionary change and the rescue of
phenotypic plasticity [137]. Genetic recombination, nonlethal mutations, activity of trans-
posable elements, or gene expression are some of the molecular mechanisms through which
hormesis might enable organisms to maintain, or even increase, evolutionary fitness in
stressful environments. These mechanisms span the tree of life from plants to vertebrates.
The inheritance of epigenetic memory provides the offspring with survival advantages [20].
Three complex biochemical systems operate for cellular homeostasis and they are in-
volved in hormesis: the proteasome (P), the endoplasmic reticulum (ER), and mitochondria
(M). These components have been united in the PERM hypothesis [138]. The PERM hypoth-
esis can explain via hormesis the beneficial role of many xenobiotics, either trace metals or
phytochemicals, which are spread in the human environment and dietary habits. These
exert their actions on the mechanisms that underlie cell survival (apoptosis, autophagy, cell
cycle regulation, DNA repair, and turnover) and stress response. They act on the energy
balance, redox system, and macromolecular turnover. If PERM-mediated control is offline,
impaired, or dysregulated, reactive species (RCS, ROS, RNS) and stressors could have a
negative effect. That seems to be the case in metabolic syndrome, degenerative disorders,
chronic inflammation, and cancer [7]. Ionized calcium might play a role in maintaining the
correct rhythm of PERM modulation [138].
Another recent review emphasizes that environmental, physical, and nutritional
hormetins lead to the stimulation and strengthening of the maintenance and repair systems
in cells and tissues. Exercise, extreme temperature (heat or frost), and irradiation are
examples of physical hormetins. The molecular mechanisms of the hormetic response
include modulation of: (1) transcription factor Nrf2 activating the synthesis of glutathione
and the subsequent protection of the cell; (2) DNA methylation and epigenetics; and, (3)
microRNA [139].
Rewriting the history of toxicology and pharmacology is an appeal to change of
paradigm. This is due to the fundamental biological basis of environmental hormesis.
Low doses of environmental agents have recently been reported to induce autophagy, a
critical adaptive response that essentially protects all cell types. Hormesis can also be
transgenerational via epigenetics. The reviewer appeals to stakeholders in toxicology and
pharmacology to re-examine the process of risk assessment, with the goal of optimizing
public health, rather than simply avoiding harm [140]. Table 8 provides an overview of the
main features, mechanisms, and effects of part IX.
Biomedicines 2021, 9, 293 22 of 30
10. Discussion
Hormesis is a theory of non-linear dose-response relationship. It can explain many,
but not all, phenomena about how cells respond to low-dose exposure of stressors. Not all
responses are beneficial to host survival. One example should elucidate this. Tumor dor-
mancy is an important, but not yet well understood, phenomenon in cancer research. Using
dormancy models of lung and ovarian cancer, it was recently described that modified lipids
that are derived from stress-activated neutrophils lead to reactivation of dormant tumor
cells. Stress hormones cause rapid release of proinflammatory S100A8/A9 proteins by
neutrophils. These induce the activation of myeloperoxidase, resulting in the accumulation
of oxidized lipids. Upon release from neutrophiles, these lipids upregulate the fibroblast
growth factor pathway. This causes tumor cell exit from dormancy and the formation of
new tumor lesions [141]. Thus, stress factors can also exert detrimental effects.
The developing immune system serves as a novel target for disruption by environ-
mental chemicals and drugs. The effects can significantly influence later-life health risks.
Optimal mitochondrial function is critical during embryonic development. Mitochondria
play a key role in early signaling cascades and epigenetic programming [142]. The right nu-
trition is very important in the perinatal period because of epigenetic imprinting. Neonatal
brain injury has been linked to an iron-dependent form of cell death (ferroptosis) that is
characterized by enhanced lipid peroxidation [143].
Mitochondria are sensitive targets of environmental toxins, potentially even at levels
that are considered to be safe under current regulatory limits. Twenty-four anthropogenic
chemicals were recently tested for their effects on embryonic oxygen consumption rate
(eOCR). Each chemical, depending upon the concentration, resulted in a unique eORC
response profile. Non-monotonic dose response effects and mitochondrial hormesis were
detected with some chemicals. The authors conclude that mitochondrial responses to
chemicals are highly dynamic and warrant careful consideration when determining the
mitochondrial toxicity of a given chemical [144].
The range of postnatal health risks linked to developmental immunotoxicity (DIT)
is influenced by the natural progression of prenatal to neonatal development. Pregnancy
imposes a Th2-bias in utero. This produces a delay in the acquisition of Th1 functional
capacity in the newborn. Because hormesis has been shown to be an important factor
in the modulation of the adult immune system, more research is required to understand
potentially opposing the dose-response effects of xenobiotics for the immune system of the
fetus, neonate, and juvenile. A direct linkage between immune dysfunction and chronic
disease has become abundantly apparent in recent years [145].
Biomedicines 2021, 9, 293 23 of 30
This review has reported the positive hormetic effects of transient dietary restriction
(DR) and intermittent metabolic switching (IMS). This is in contrast to the permanent stress
of starvation and malnutrition worldwide. In 1989, 23 leading hunger experts in their
Bellagio Declaration defined four achievable goals to overcome hunger: eliminate famine
death; end hunger in half of the world’s poorest households; reduce by half malnutrition of
mothers and small children; and, eradicate iodine and vitamin A deficiencies [146]. In 2009,
the WHO and UNICEF recommended a transition to WHO growth standards to identify
wasting for children aged from six to under 60 months. This has led to the evolution of
a worldwide logistic system to provide emergency food aid. Malnutrition worldwide
includes a spectrum of nutrient-related disorders that are major public health problems:
intrauterine growth retardation, protein–energy malnutrition, iodine deficiency disorders,
vitamin A deficiency, iron deficiency anemia, and overweight and obesity [147]. Infants
aged under six months are often excluded from nutrition surveys. However, the fact is that,
in developing countries, large numbers of infants under six months are wasted. A data
analysis from 2011, using WHO standards, revealed that about three million infants under
six months were severely wasted and 2.5 million moderately wasted worldwide [148].
The principles of hormesis have entered the field of physical exercise and athletic
performance training. The effects of exercise on the innate immune system are influenced,
among others, by stress proteins, such as HSP72. Regular exercise can induce immuno-
neuroendocrine stabilization in persons with deregulated inflammatory and stress feedback
by reducing the presence of stress hormones and inflammatory cytokines. Nevertheless,
biomedical side effects of exercise need to be considered [149]. According to evolutionary
biology, organisms may exhibit growth under stress, a phenomenon that is designated
as antifragility. For coaches and their athletes, a key question is how to design training
conditions to help athletes develop the kinds of physical, physiological, and behavioral
adaptations underlying antifragility. A recent review discusses how to determine opti-
mal stress loads for antifragility in climbing. It includes individualized load-response
profiles [149].
Recent developments in low-dose effects research provide a novel means in environ-
mental toxicology and ecotoxicology to improve the quality of hazard and risk assess-
ment [150]. Herbicide hormesis is commonly observed at subtoxic doses of herbicides and
other phytotoxins. However, it can cause undesired effects in which weeds are uninten-
tionally exposed to hormetic doses in adjacent fields [151]. There may also be stimulatory
effects of low concentrations of herbicides as environmental contaminants spread over
estuaries and lakes. One example are the phytoplankton blooms. A recent hormetic re-
search on Microcystis aeruginosa and Selenastrum capricornutum suggests that the blooms
were triggered by herbicides and involved cytochrome b559 , ROS, and NO [152]. It was
recommended that, in environmental toxicology and ecotoxicology, rethinking is necessary
to provide more reliable estimates of risk assessment and optimize health [150].
Homeostasis describes a system of balance of a cell with respect to energy and envi-
ronment. Mitochondria play an important role in maintaining homeostasis [7]. Hormesis,
which should not be mixed-up with homeopathy, describes the biochemical mechanisms
of a cell’s adaptation to low-dose stress.
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