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Electromagnetic fields act via activation of voltage-gated calcium channels to produce beneficial or adverse effects


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The direct targets of extremely low and microwave frequency range electromagnetic fields (EMFs) in producing non-thermal effects have not been clearly established. However, studies in the literature, reviewed here, provide substantial support for such direct targets. Twenty-three studies have shown that voltage-gated calcium channels (VGCCs) produce these and other EMF effects, such that the L-type or other VGCC blockers block or greatly lower diverse EMF effects. Furthermore, the voltage-gated properties of these channels may provide biophysically plausible mechanisms for EMF biological effects. Downstream responses of such EMF exposures may be mediated through Ca(2+) /calmodulin stimulation of nitric oxide synthesis. Potentially, physiological/therapeutic responses may be largely as a result of nitric oxide-cGMP-protein kinase G pathway stimulation. A well-studied example of such an apparent therapeutic response, EMF stimulation of bone growth, appears to work along this pathway. However, pathophysiological responses to EMFs may be as a result of nitric oxide-peroxynitrite-oxidative stress pathway of action. A single such well-documented example, EMF induction of DNA single-strand breaks in cells, as measured by alkaline comet assays, is reviewed here. Such single-strand breaks are known to be produced through the action of this pathway. Data on the mechanism of EMF induction of such breaks are limited; what data are available support this proposed mechanism. Other Ca(2+) -mediated regulatory changes, independent of nitric oxide, may also have roles. This article reviews, then, a substantially supported set of targets, VGCCs, whose stimulation produces non-thermal EMF responses by humans/higher animals with downstream effects involving Ca(2+) /calmodulin-dependent nitric oxide increases, which may explain therapeutic and pathophysiological effects.
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Electromagnetic fields act via activation of voltage-gated
calcium channels to produce beneficial or adverse effects
Martin L. Pall *
Professor Emeritus of Biochemistry and Basic Medical Sciences, Washington State University, Portland, OR, USA
Received: January 8, 2013; Accepted: May 20, 2013
Possible modes of action following
voltage-gated calcium channel stimulation
Therapeutic bone-growth stimulation
via Ca
/nitric oxide/cGMP/protein kinase G
/nitric oxide/peroxynitrite and
responses to EMF exposures: the example of
single-strand DNA breaks
Discussion and conclusions
The direct targets of extremely low and microwave frequency range electromagnetic fields (EMFs) in producing non-thermal effects have not
been clearly established. However, studies in the literature, reviewed here, provide substantial support for such direct targets. Twenty-three
studies have shown that voltage-gated calcium channels (VGCCs) produce these and other EMF effects, such that the L-type or other VGCC
blockers block or greatly lower diverse EMF effects. Furthermore, the voltage-gated properties of these channels may provide biophysically
plausible mechanisms for EMF biological effects. Downstream responses of such EMF exposures may be mediated through Ca
stimulation of nitric oxide synthesis. Potentially, physiological/therapeutic responses may be largely as a result of nitric oxide-cGMP-protein
kinase G pathway stimulation. A well-studied example of such an apparent therapeutic response, EMF stimulation of bone growth, appears to
work along this pathway. However, pathophysiological responses to EMFs may be as a result of nitric oxide-peroxynitrite-oxidative stress path-
way of action. A single such well-documented example, EMF induction of DNA single-strand breaks in cells, as measured by alkaline comet
assays, is reviewed here. Such single-strand breaks are known to be produced through the action of this pathway. Data on the mechanism of
EMF induction of such breaks are limited; what data are available support this proposed mechanism. Other Ca
-mediated regulatory changes,
independent of nitric oxide, may also have roles. This article reviews, then, a substantially supported set of targets, VGCCs, whose stimulation
produces non-thermal EMF responses by humans/higher animals with downstream effects involving Ca
/calmodulin-dependent nitric oxide
increases, which may explain therapeutic and pathophysiological effects.
Keywords: intracellular Ca
voltage-gated calcium channels
low frequency electromagnetic field exposure
oxidative stress
calcium channel blockers
An understanding of the complex biology of the effects of electromag-
netic fields (EMFs) on human/higher animal biology inevitably must
be derived from an understanding of the target or targets of such
fields in the impacted cells and tissues. Despite this, no understand-
ing has been forthcoming on what those targets are and how they
may lead to the complex biological responses to EMFs composed of
low-energy photons. The great puzzle, here, is that these EMFs are
comprised of low-energy photons, those with insufficient energy to
individually influence the chemistry of the cell, raising the question of
how non-thermal effects of such EMFs can possibly occur. The author
*Correspondence to: Martin L. PALL, Ph.D.,
Professor Emeritus of Biochemistry and Basic Medical
Sciences, Washington State University, 638 NE 41st Ave.,
Portland, OR 97232 USA
Tel: +01-503-232-3883
ª2013 The Author.
Journal of Cellular and Molecular Medicine Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd
This is an open access article under the terms of the Creative Commons Attribution License, which permits use,
distribution and reproduction in any medium, provided the original work is properly cited.
doi: 10.1111/jcmm.12088
J. Cell. Mol. Med. Vol 17, No 8, 2013 pp. 958-965
has found that there is a substantial literature possibly pointing to the
direct targets of such EMFs and it is the goal of this study to review
that evidence as well as review how those targets may lead to the
complex biology of EMF exposure.
The role of increased intracellular Ca
following EMF exposure
was already well documented more than 20 years ago, when Wallec-
zek [1] reviewed the role of changes in calcium signalling that were
produced in response EMF exposures. Other, more recent studies
have confirmed the role of increased intracellular Ca
following EMF
exposure, a few of which are discussed below. His review [1]
included two studies [2, 3] that showed that the L-type voltage-gated
channel blocker, verapamil could lower or block changes in response
to EMFs. The properties of voltage-gated calcium channels (VGCCs)
have been reviewed elsewhere [4]. Subsequently, extensive evidence
has been published clearly showing that the EMF exposure can act to
produce excessive activity of the VGCCs in many cell types [526]
suggesting that these may be direct targets of EMF exposure. Many
of these studies implicate specifically the L-type VGCCs such that var-
ious L-type calcium channel blockers can block responses to EMF
exposure (Table 1). However, other studies have shown lowered
responses produced by other types of calcium channel blockers
including N-type, P/Q-type, and T-type blockers (Table 1), showing
that other VGCCs may have important roles. Diverse responses to
EMFs are reported to be blocked by such calcium channel blockers
(Table 1), suggesting that most if not all EMF-mediated responses
may be produced through VGCC stimulation. Voltage-gated calcium
channels are essential to the responses produced by extremely low
frequency (including 50/60 Hz) EMFs and also to microwave fre-
quency range EMFs, nanosecond EMF pulses, and static electrical
and magnetic fields (Table 1).
In a recent study, Pilla [27] showed that an increase in intracellu-
lar Ca
must have occurred almost immediately after EMF exposure,
producing a Ca
/calmodulin-dependent increase in nitric oxide
occurring in less than 5 sec. Although Pilla [27] did not test whether
VGCC stimulation was involved in his study, there are few alternatives
that can produce such a rapid Ca
response, none of which has been
implicated in EMF responses. Other studies, each involving VGCCs,
summarized in Table 1, also showed rapid Ca
increases following
EMF exposure [8, 16, 17, 19, 21]. The rapidity of these responses rule
out many types of regulatory interactions as being involved in produc-
ing the increased VGCC activity following EMF exposure and sug-
gests, therefore, that VGCC stimulation in the plasma membrane is
directly produced by EMF exposure.
Possible modes of action following
VGCC stimulation
The increased intracellular Ca
produced by such VGCC activation
may lead to multiple regulatory responses, including the increased
nitric oxide levels produced through the action of the two Ca
modulin-dependent nitric oxide synthases, nNOS and eNOS.
Increased nitric oxide levels typically act in a physiological context
through increased synthesis of cGMP and subsequent activation of
protein kinase G [28, 29]. In contrast, in most pathophysiological
contexts, nitric oxide reacts with superoxide to form peroxynitrite, a
potent non-radical oxidant [30, 31], which can produce radical prod-
ucts, including hydroxyl radical and NO
radical [32].
Therapeutic bone-growth stimulation
via Ca
/nitric oxide/cGMP/protein
kinase G
An example of a therapeutic effect for bone repair of EMF exposure in
various medical situations includes increasing osteoblast differentia-
tion and maturation and has been reviewed repeatedly [3344]. The
effects of EMF exposure on bone cannot be challenged, although
there is still considerable question about the best ways to apply this
clinically [3344]. Our focus, here, is to consider possible mecha-
nisms of action. Multiple studies have implicated increased Ca
nitric oxide in the EMF stimulation of bone growth [4449]; three
have also implicated increased cGMP and protein kinase G activity
[46, 48, 49]. In addition, studies on other regulatory stimuli leading to
increased bone growth have also implicated increased cGMP levels
and protein kinase G in this response [5056]. In summary, then, it
can be seen from the above that there is a very well-documented
action of EMFs in stimulating osteoblasts and bone growth. The avail-
able data, although limited, support the action of the main pathway
involved in physiological responses to Ca
and nitric oxide, namely
/nitric oxide/cGMP/protein kinase G in producing such
/nitric oxide/peroxynitrite and
pathophysiological responses to EMF
exposures: the example of single-
strand DNA breaks
As was noted above, most of the pathophysiological effects of nitric
oxide are mediated through peroxynitrite elevation and consequent
oxidative stress. There are many reviews and other studies, implicat-
ing oxidative stress in generating pathophysiological effects of EMF
exposure [see for example 5764]. In some of these studies, the rise
in oxidative stress markers parallels the rise in nitric oxide, suggest-
ing a peroxynitrite-mediated mechanism [6467].
Peroxynitrite elevation is usually measured through a marker of
peroxynitrite-mediated protein nitration, 3-nitrotyrosine (3-NT). There
are four studies where 3-NT levels were measured before and after
EMF exposure [66, 6870]. Each of these studies provides some evi-
dence supporting the view that EMF exposure increases levels of per-
oxynitrite and therefore 3-NT levels [66, 6870]. Although these
cannot be taken as definitive, when considered along with the evi-
dence on oxidative stress and elevated nitric oxide production in
response to EMF exposure, they strongly suggest a peroxynitrite-
mediated mechanism of oxidative stress in response to EMFs.
ª2013 The Author.
Journal of Cellular and Molecular Medicine Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd
J. Cell. Mol. Med. Vol 17, No 8, 2013
Table 1 EMF responses blocked or lowered by calcium channel blockers
Ref. no. EMF type Calcium channel Cell type or organism Response measured
2 Pulsed magnetic
L-type Human lymphocytes Cell proliferation; cytokine
3 Static magnetic
field (0.1 T)
L-type Human polymorphonuclear
Cell migration; degranulation
5 ELF L-type Rat chromaffin cells Differentiation; catecholamine release
6 Electric field L-type Rat and mouse bone cells Increased Ca
, phospholipase A2, PGE2
7 50 Hz L-type Mytilus (mussel) immunocytes Reduced shape change, cytotoxicity
8 50 Hz L-type AtT20 D16V, mouse pituitary
increase; cell morphology,
premature differentiation
9 50 Hz L-type Neural stem/progenitor cells In vitro differentiation, neurogenesis
10 Static magnetic
L-type Rat Reduction in oedema formation
11 NMR L-type Tumour cells Synergistic effect of EMF on anti-tumour
drug toxicity
12 Static magnetic field L-type Myelomonocytic U937 cells Ca
influx into cells and anti-apoptotic
13 60 Hz L-type Mouse Hyperalgesic response to exposure
14 Single nanosecond
electric pulse
L-type Bovine chromaffin cells Very rapid increase in intracellular Ca
15 Biphasic electric current L-type Human mesenchymal stromal cells Osteoblast differentiation and cytokine
16 DC & AC magnetic
L-type b-cells of pancreas, patch clamped Ca
flux into cells
17 50 Hz L-type Rat pituitary cells Ca
flux into cells
18 50 Hz L-type, N-type Human neuroblastoma IMR32 and
rat pituitary GH3 cells
Anti-apoptotic activity
19 Nanosecond pulse L-type, N-type,
Bovine chromaffin cells Ca
dynamics of cells
20 50 Hz Not determined Rat dorsal root ganglion cells Firing frequency of cells
21 7001100 MHz N-type Stem cellderived neuronal cells Ca
dynamics of cells
22 Very weak electrical
T-type Sharks Detection of very weak magnetic fields
in the ocean
23 Short electric pulses L-type Human eye Effect on electro-oculogram
24 Weak static magnetic
L-type Rabbit Baroreflex sensitivity
25 Weak electric fields T-type Neutrophils Electrical and ion dynamics
26 Static electric fields,
L-type Bovine articular chondrocytes Agrican & type II collagen expression;
calcineurin and other Ca
EMF: electromagnetic field; ELF: extremely low frequency.
960 ª2013 The Author.
Journal of Cellular and Molecular Medicine Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd
Such a peroxynitrite-mediated mechanism may explain the many
studies showing the single-stranded breaks in DNA, as shown by
alkaline comet assays or the similar microgel electrophoresis assay,
following EMF exposures in most such studies [7189], but not in all
[9097]. Some of the factors that are reported to influence whether
such DNA single-strand breaks are detected after EMF exposure
include the type of cell studied [79, 86], dosage of EMF exposure
[78] and the type of EMF exposure studied [73, 77]. Oxidative
stress and free radicals have roles, both because there is a con-
comitant increase in oxidative stress and because antioxidants
have been shown to greatly lower the generation of DNA single-
strand breaks following EMF exposure [72, 75, 81, 82] as has
also been shown for peroxynitrite-mediated DNA breaks produced
under other conditions. It has also been shown that one can block
the generation of DNA single-strand breaks with a nitric oxide
synthase inhibitors [82].
Peroxynitrite has been shown to produce single-strand DNA
breaks [98100], a process that is inhibited by many but not all an-
tioxidants [99, 100]. It can be seen from this that the data on genera-
tion of single-strand DNA breaks, although quite limited, support a
mechanism involving nitric oxide/peroxynitrite/free radical (oxidative
stress). Although the data on the possible role of peroxynitrite in
EMF-induced DNA single-strand breaks are limited, what data are
available supports such a peroxynitrite role.
Discussion and conclusions
How do EMFs composed of low-energy photons produce non-thermal
biological changes, both pathophysiological and, in some cases,
potentially therapeutic, in humans and higher animals? It may be sur-
prising that the answer to this question has been hiding in plain sight
in the scientific literature. However, in this era of highly focused and
highly specialized science, few of us have the time to read the relevant
literature, let alone organize the information found within it in useful
and critical ways.
This study shows that:
1Twenty-three different studies have found that such EMF
exposures act via activation of VGCCs, such that VGCC channel
blockers can prevent responses to such exposures (Table 1).
Most of the studies implicate L-type VGCCs in these responses,
but there are also other studies implicating three other classes
of VGCCs.
2Both extremely low frequency fields, including 50/60 cycle
exposures, and microwave EMF range exposures act via activa-
tion of VGCCs. So do static electric fields, static magnetic fields
and nanosecond pulses.
3Voltage-gated calcium channel stimulation leads to
increased intracellular Ca
, which can act in turn to stimulate
the two calcium/calmodulin-dependent nitric oxide synthases
and increase nitric oxide. It is suggested here that nitric oxide
may act in therapeutic/potentially therapeutic EMF responses
via its main physiological pathway, stimulating cGMP and pro-
tein kinase G. It is also suggested that nitric oxide may act in
pathophysiological responses to EMF exposure, by acting as a
precursor of peroxynitrite, producing both oxidative stress and
free radical breakdown products.
4The interpretation in three above is supported by two spe-
cific well-documented examples of EMF effects. Electromagnetic
fields stimulation of bone growth, modulated through EMF
stimulation of osteoblasts, appears to involve an elevation/nitric
oxide/protein kinase G pathway. In contrast to that, it seems
likely that the EMF induction of single-stranded DNA breaks
involves a Ca
/elevation/nitric oxide/peroxynitrite/free radical
(oxidative stress) pathway.
It may be asked why we have evidence for involvement of VGCCs
in response to EMF exposure, but no similar evidence for involvement
of voltage-gated sodium channels? Perhaps, the reason is that there
are many important biological effects produced in increased intracel-
lular Ca
, including but not limited to nitric oxide elevation, but much
fewer are produced by elevated Na
The possible role of peroxynitrite as opposed to protein kinase G
in producing pathophysiological responses to EMF exposure raises
the question of whether there are practical approaches to avoiding
such responses? Typically peroxynitrite levels can be highly elevated
when both of its precursors, nitric oxide and superoxide, are high.
Consequently, agents that lower nitric oxide synthase activity and
agents that raise superoxide dismutases (SODs, the enzymes that
degrade superoxide) such as phenolics and other Nrf2 activators that
induce SOD activity [101], as well as calcium channel blockers may
be useful. Having said that, this is a complex area, where other
approaches should be considered, as well.
Although the various EMF exposures as well as static electrical
field exposures can act to change the electrical voltage-gradient
across the plasma membrane and may, therefore, be expected to
stimulate VGCCs through their voltage-gated properties, it may be
surprising that static magnetic fields also act to activate VGCCs
because static magnetic fields do not induce electrical changes on
static objects. However, cells are far from static. Such phenomena as
cell ruffling [102,103] may be relevant, where thin cytoplasmic sheets
bounded on both sides by plasma membrane move rapidly. Such
rapid movement of the electrically conducting cytoplasm, may be
expected to influence the electrical charge across the plasma mem-
brane, thus potentially stimulating the VGCCs.
Earlier modelling of electrical effects across plasma membranes
of EMF exposures suggested that such electrical effects were likely to
be too small to explain EMF effects at levels reported to produce bio-
logical changes (see, for example [22]). However, more recent and
presumably more biologically plausible modelling have suggested
that such electrical effects may be much more substantial [104109]
and may, therefore, act to directly stimulate VGCCs.
Direct stimulation of VGCCs by partial depolarization across the
plasma membrane is suggested by the following observations dis-
cussed in this review:
1The very rapid, almost instantaneous increase in intracellular
found in some studies following EMF exposure [8, 16, 17,
19, 21, 27]. The rapidity here means that most, if not all indi-
rect, regulatory effects can be ruled out.
2The fact that not just L-type, but three additional classes of
VGCCs are implicated in generating biological responses to EMF
ª2013 The Author.
Journal of Cellular and Molecular Medicine Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd
J. Cell. Mol. Med. Vol 17, No 8, 2013
exposure (Table 1), suggesting that their voltage-gated proper-
ties may be a key feature in their ability to respond to EMFs.
3Most, if not all, EMF effects are blocked by VGCC channel
blockers (Table 1).
4Modelling of EMF effects on living cells suggests that plasma
membrane voltage changes may have key roles in such effects
[104109]. Saunders and Jefferys stated [110] that ‘It is well
established that electric fields or exposure to low frequency
magnetic fields, will, if of sufficient magnitude, excite nerve tissue
through their interactions with voltage gated ion channels’.
They further state [110] that this is achieved by direct effects on
the electric dipole voltage sensor within the ion channel.
One question that is not answered by any of the available data is
whether what is known as ‘dirty electricity’ [111113], generated by
rapid, in many cases, square wave transients in EMF exposure, also
acts by stimulating VGCCs. Such dirty electricity is inherent in any
digital technology because digital technology is based on the use of
such square wave transients and it may, therefore, be of special con-
cern in this digital era, but there have been no tests of such dirty elec-
tricity that determine whether VGCCs have roles in response to such
fields, to my knowledge. The nanosecond pulses, which are essen-
tially very brief, but high-intensity dirty electricity do act, at least in
part, via VGCC stimulation (Table 1), suggesting that dirty electricity
may do likewise. Clearly, we need direct study of this question.
The only detailed alternative to the mechanism of non-thermal
EMF effects discussed here, to my knowledge, is the hypothesis of
Friedman et al. [114] and supported by Desai et al. [115] where the
apparent initial response to EMF exposure was proposed to be NADH
oxidase activation, leading to oxidative stress and downstream regu-
latory effects. Although they provide some correlative evidence for a
possible role of NADH oxidase [114], the only causal evidence is
based on a presumed specific inhibitor of NADH oxidase, diphenyle-
neiodonium (DPI). However, DPI has been shown to be a non-specific
cation channel blocker [116], clearly showing a lack of such specific-
ity and suggesting that it may act, in part, as a VGCC blocker. Conse-
quently, a causal role for NADH oxidase in responses to EMF
exposure must be considered to be undocumented.
In summary, the non-thermal actions of EMFs composed of low-
energy photons have been a great puzzle, because such photons are
insufficiently energetic to directly influence the chemistry of cells. The
current review provides support for a pathway of the biological action
of ultralow frequency and microwave EMFs, nanosecond pulses and
static electrical or magnetic fields: EMF activation of VGCCs leads to
rapid elevation of intracellular Ca
, nitric oxide and in some cases at
least, peroxynitrite. Potentially therapeutic effects may be mediated
through the Ca
/nitric oxide/cGMP/protein kinase G pathway. Patho-
physiological effects may be mediated through the Ca
/nitric oxide/
peroxynitrite pathway. Other Ca
-mediated effects may have roles as
well, as suggested by Xu et al. [26].
Conflicts of interest
The author confirms that there are no conflicts of interest.
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... Les premières attributions de symptômes aux ondes électromagnétiques de type radiofréquence provenant des téléphones datent de 1998, alors que ceux attribués aux antennes relais ont été décrits en 2002 par Santini et son équipe (Hocking, 1998;. Une première hypothèse est l'implication des radicaux libres (Pall, 2013(Pall, , 2014. Ces radicaux libres sont des molécules électroniquement instables en raison de la perte ou du gain d'un électron. ...
... Lorsque la concentration de ces radicaux devient trop importante, la cellule est en état de stress oxydatif. Dans un tel état, les radicaux libres agressent les composants cellulaires pouvant, dans les cas les plus avancés, conduire à des maladies telles que la maladie d'Alzheimer (Cubinkova et al., 2018) (Barbier et al.;Pall, 2013;Rao et al., 2008). Dans un deuxième temps, Pall émet comme sous-hypothèse que la production accrue de NO pourrait entraîner une synthèse de l'ion peroxynitrique (ONOO-) qui est à même de générer des radicaux libres (Pall, 2014). ...
... Une première hypothèse qui pourrait expliquer une variation de la réabsorption d'eau pourrait être une modification des concentrations en électrolytes circulants lors de la co-exposition. En effet, il a été montré que les CEM étaient impliqués dans l'ouverture de canaux ioniques (par stimulation de la membrane plasmique), ces ouvertures pourraient être la conséquence d'une dérégulation ionique (Pall, 2013). Cette dérégulation qui a été montrée de manière générale, pourrait être localisée au niveau de l'intestin. ...
Avec le développement des nouvelles technologies, l'exposition aux champs électromagnétiques est de plus en plus importante. En marge de ce développement, nos sociétés ont vu émerger des personnes présentant des symptômes qu'ils attribuent à une exposition aux champs électromagnétiques. Les résultats des études expérimentales antérieurs restant à controverse, l'objectif de ce travail est de voir si une exposition conjointe entre les champs électromagnétiques et le bruit conduit à une apparition ou une exacerbation des symptômes des champs électromagnétiques. Cette étude s'est portée sur différentes fonctions physiologiques chez une population juvénile : le sommeil, le système immunitaire, la prise alimentaire, la respiration et le comportement. Nos résultats montrent un comportement anxieux, une diminution de la locomotion ainsi qu'une augmentation du poids des animaux, associé à des variations dans le pattern alimentaire. Le sommeil et la respiration sont peu modifiés chez les animaux exposés aux champs électromagnétiques. Le système immunitaire des animaux exposés aux champs électromagnétiques présente des altérations au niveau du système immunitaire acquis avec une redistribution des sous-populations lymphocytaires en faveur d'une activation des cellules et de l'immunité humorale, mais sans variation du système immunitaire inné. L'altération de ce dernier système est observée lors de la co-exposition mais est différente de celle d'une exposition au bruit. Ce travail de thèse a permis de mettre en évidence différents effets des CEM, notamment un comportement anxieux et des variations immunitaire
... With this matching, natural EMF can influence biological communication phenomena in cell-tocell communication in the human body. 44 Pall (2013) also reported that exposure to EMF would promote Ca2+ influx via the voltage-gate Ca2+ channel, which can increase Ca2+ concentration in the cytosol and then cause biological effects. 45 Wang (2019) also indicated that extremely low-frequency magnetic stimulation can induce low-frequency activities and lead to resonance effects in the human brain. ...
... 44 Pall (2013) also reported that exposure to EMF would promote Ca2+ influx via the voltage-gate Ca2+ channel, which can increase Ca2+ concentration in the cytosol and then cause biological effects. 45 Wang (2019) also indicated that extremely low-frequency magnetic stimulation can induce low-frequency activities and lead to resonance effects in the human brain. 26 The "biophysical mechanism" for the human health effect mechanism may explain biological and human health effects of geomagnetic activity. ...
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Yu-Shu Huang,1,2 I Tang,1 Wei-Chih Chin,1,2 Ling-Sheng Jang,3 Chin-Pang Lee,1,2 Chen Lin,4 Chun-Pai Yang,5,6 Shu-Ling Cho7 1Division of Pediatric Psychiatry and Sleep Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 2College of Medicine, Chang Gung University, Taoyuan, Taiwan; 3Department of Electrical Engineering, National Cheng Kung University, Tainan, Taiwan; 4Department of Biomedical Sciences and Engineering, National Central University, Taoyuan, Taiwan; 5Department of Neurology, Kuang Tien General Hospital, Taichung, Taiwan; 6Department of Nutrition, Huang-Kuang University, Taichung, Taiwan; 7Department of Clinical Psychology, Fu Jen Catholic University, New Taipei City, TaiwanCorrespondence: Shu-Ling Cho, Department of Clinical Psychology, Fu Jen Catholic University, New Taipei City, Taiwan, Tel +886-2-29053443, Email lincho056384@gmail.comPurpose: Accumulated studies revealed that electromagnetic field can affect human brain and sleep, and the extremely low-frequency electromagnetic field, Schumann resonance, may have the potential to reduce insomnia symptoms. The purpose of this study was to investigate the responses of patients with insomnia to a non-invasive treatment, Schumann resonance (SR), and to evaluate its effectiveness by subjective and objective sleep assessments.Patients and Methods: We adopted a double-blinded and randomized design and 40 participants (70% female; 50.00 ± 13.38 year) with insomnia completed the entire study. These participants were divided into the SR-sleep-device group and the placebo-device group and were followed up for four weeks. The study used polysomnography (PSG) to measure objective sleep and used sleep diaries, Pittsburgh Sleep Quality Inventory (PSQI), Epworth Sleepiness Scale (ESS), and visual analogy of sleep satisfaction to measure subjective sleep. The 36-Item Short-Form Health Survey (SF-36) was used to evaluate quality of life. Chi-square test, Mann–Whitney U-test, and Wilcoxon test were used to analyze the data.Results: About 70% of the subjects were women, with an average age of 50± 13.38 years and an average history of insomnia of 9.68± 8.86 years. We found that in the SR-sleep-device group, objective sleep measurements (sleep-onset-latency, SOL, and total-sleep-time, TST) and subjective sleep questionnaires (SOL, TST, sleep-efficiency, sleep-quality, daytime-sleepiness, and sleep-satisfaction) were significantly improved after using the SR-sleep-device; in the placebo-device group, only such subjective sleep improvements as PSQI and sleep-satisfaction were observed.Conclusion: This study demonstrates that the SR-sleep-device can reduce the insomnia symptoms through both objective and subjective tests, with minimal adverse effects. Future studies can explore the possible mechanism of SR and health effects and, with a longer tracking time, verify the effectiveness and side effects.Keywords: insomnia, Schumann resonance, effectiveness, polysomnography, questionnaire
... Calcium ion channels, such as VGCC, can also mediate Ca 2+ influx into the cell in response to membrane depolarization and might activate ERK1/2 cascade acting downstream of Ras [142]. They have been considered as the main targets of PEMF action [143]. Petecchia et al. [50] detected an augmented expression of L-type VGCC when MSCs were stimulated with osteogenic media and PEMF for 27 days, while PEMF seemed to influence [Ca 2+ ] i after 9 days of exposure, leading to an increase of 30% compared to cells cultured in OM. ...
Mesenchymal stem cells (MSCs) play a major role in bone tissue engineering (BTE) thanks to their capacity for osteogenic differentiation and being easily available. In vivo, MSCs are exposed to an electroactive microenvironment in the bone niche, which has piezoelectric properties. The correlation between the electrically active milieu and bone's ability to adapt to mechanical stress and self-regenerate has led to using electrical stimulation (ES) as physical cue to direct MSCs differentiation towards the osteogenic lineage in BTE. This review summarizes the different techniques to electrically stimulate MSCs to induce their osteoblastogenesis in vitro, including general electrical stimulation and substrate mediated stimulation by means of conductive or piezoelectric cell culture supports. Several aspects are covered, including stimulation parameters, treatment times and cell culture media to summarize the best conditions for inducing MSCs osteogenic commitment by electrical stimulation, from a critical point of view. Electrical stimulation activates different signaling pathways, including bone morphogenetic protein (BMP) Smad-dependent or independent, regulated by mitogen activated protein kinases (MAPK), extracellular signal-regulated kinases (ERK) and p38. The roles of voltage gate calcium channels (VGCC) and integrins are also highlighted according to their application technique and parameters, mainly converging in the expression of RUNX2, the master regulator of the osteogenic differentiation pathway. Despite the evident lack of homogeneity in the approaches used, the ever-increasing scientific evidence confirms ES potential as an osteoinductive cue, mimicking aspects of the in vivo microenvironment and moving one step forward to the translation of this approach into clinic.
... The most noteworthy advantage of the alternating magnetic field in the therapeutic process is increasing blood flow in arterial vessels and capillaries, stimulating oxygen utilization and cellular respiration. Other significant aspects include its impact on wound healing and beneficial effects of tissue regeneration following mechanical or thermal damage and other states of interruption of tissue continuity [12,13]. In addition, it should be emphasized that the abovementioned analgesic, anti-inflammatory and regenerative effects are some of the main objectives pursued by the therapist in the treatment following dental and surgical procedures [14]. ...
Full-text available
Extremely Low-Frequency Electromagnetic Field (ELF MF) therapy is effective in the treatment of injury, inflammation and postoperative complications. Its clinical applications relate to bone unification, pain reduction, soft tissue oedema and the decrease of electric potentials in the oral cavity. It enhances regeneration of periapical bone lesions. It is obvious that cells (leukocytes, platelets, keratinocytes, osteoblasts) and proteins (fibrin, collagen, elastin and growth factors) exhibit alterations when exposed to an Extremely Low-Frequency Electromagnetic Field. The aim of the study was to evaluate the effect of an Extremely Low-Frequency Electromagnetic Field (ELF MF) on the parotid gland on the concentration of salivary immunoglobulin A. The study group consisted of 24 patients, aged 14–16, who underwent ELF MF on the parotid gland region. The control group comprised 25 matching persons. The IgA concentration in saliva samples was established using radial immunodiffusion. Following ELF MF, a statistically significant increase in the concentration of secretory immunoglobulin A was found in the study group, whereas in the control group, no statistically significant differences were noted. It can be concluded that an Extremely Low-Frequency Electromagnetic Field increases the activity of the immune system of the parotid gland.
We provide a multidimensional sequence of events that describe the electromagnetic field (EMF) stimulation and biological system interaction. We describe this process from the quantum to the molecular, cellular, and organismal levels. We hypothesized that the sequence of events of these interactions starts with the oscillatory effect of the repeated electromagnetic stimulation (REMFS). These oscillations affect the interfacial water of an RNA causing changes at the quantum and molecular levels that release protons by quantum tunneling. Then protonation of RNA produces conformational changes that allow it to bind and activate Heat Shock Transcription Factor 1 (HSF1). Activated HSF1 binds to the DNA expressing chaperones that help regulate autophagy and degradation of abnormal proteins. This action helps to prevent and treat diseases such as Alzheimer’s and Parkinson’s disease (PD) by increasing clearance of pathologic proteins. This framework is based on multiple mathematical models, computer simulations, biophysical experiments, and cellular and animal studies. Results of the literature review and our research point towards the capacity of REMFS to manipulate various networks altered in aging (Reale et al. PloS one 9, e104973, 2014), including delay of cellular senescence (Perez et al. 2008, Exp Gerontol 43, 307-316) and reduction in levels of amyloid-β peptides (Aβ) (Perez et al. 2021, Sci Rep 11, 621). Results of these experiments using REMFS at low frequencies can be applied to the treatment of patients with age-related diseases. The use of EMF as a non-invasive therapeutic modality for Alzheimer’s disease, specifically, holds promise. It is also necessary to consider the complicated and interconnected genetic and epigenetic effects of the REMFS-biological system’s interaction while avoiding any possible adverse effects.
Chondrogenesis is the process of differentiation of stem cells into mature chondrocytes. Such a process consists of chemical, functional, and structural changes which are initiated and mediated by the host environment of the cells. To date, the mechanobiology of chondrogenesis has not been fully elucidated. Hence, experimental activity is focused on recreating specific environmental conditions for stimulating chondrogenesis, and to look for a mechanistic interpretation of the mechanobiological response of cells in the cartilaginous tissues. There are a large number of studies on the topic that vary considerably in their experimental protocols used for providing environmental cues to cells for differentiation, making generalizable conclusions difficult to ascertain. The main objective of this contribution is to review the mechanobiological stimulation of stem cell chondrogenesis and methodological approaches utilized to date to promote chondrogenesis of stem cells in-vitro. In-vivo models will also be explored, but this area is currently limited. An overview of the experimental approaches used by different research groups may help the development of unified testing methods that could be used to overcome existing knowledge gaps, leading to an accelerated translation of experimental findings to clinical practice.
Background: Gastric cancer is one of the most prevalent and deadliest cancers in the world. Environmental factors including chemicals, sunlight, and electromagnetic fields can induce changes in gene expression. Though the resizing mechanism of its effect has not been fully recognized, free radicals are seen as the possible mechanism involved. Although low-frequency electromagnetic fields are not considered a carcinogenic factor, some studies have shown disruption in deoxyribonucleic acid (DNA) and gene expression in different cell categories. Objectives: This study was intendant to examine the effects of low-frequency electromagnetic flux densities of 0.2 and 2 mT on the expression of cathepsin L2 (CTSL2) and suppressor of cytokine signaling 3 (SOCS3) genes in adenocarcinoma gastric (AGS) cell lines. Methods: The AGS cell line was cultured in Hamas12 and was exposed to electromagnetic fields continuously and discontinuously for 18 hours. Moreover, Cell viability was assessed by the MTT (3-(4, 5-Dimethylthiazol-2-yl)) assay. The change in the expression of genes was measured by real-time polymerase chain reaction (PCR). Results: Low-frequency electromagnetic fields increased gene expression compared to the control group. The changes in the expression are directly associated with the electromagnetic field strength. Expression levels of CTSL2 were increased under the exposure of electromagnetic fields and this increase was significant when discontinuous exposure was applied (33.26 ± 7.4 fold change for 0.2mT and 64.4 ± 7.7 for 2mT, p- value
Much of the controversy over the cause of electrohypersensitivity (EHS) lies in the absence of recognized clinical and biological criteria for a widely accepted diagnosis. However, there are presently sufficient data for EHS to be acknowledged as a distinctly well-defined and objectively characterized neurologic pathological disorder. Because we have shown that 1) EHS is frequently associated with multiple chemical sensitivity (MCS) in EHS patients, and 2) that both individualized disorders share a common pathophysiological mechanism for symptom occurrence; it appears that EHS and MCS can be identified as a unique neurologic syndrome, regardless its causal origin. In this overview we distinguish the etiology of EHS itself from the environmental causes that trigger pathophysiological changes and clinical symptoms after EHS has occurred. Contrary to present scientifically unfounded claims, we indubitably refute the hypothesis of a nocebo effect to explain the genesis of EHS and its presentation. We as well refute the erroneous concept that EHS could be reduced to a vague and unproven “functional impairment”. To the contrary, we show here there are objective pathophysiological changes and health effects induced by electromagnetic field (EMF) exposure in EHS patients and most of all in healthy subjects, meaning that excessive non-thermal anthropogenic EMFs are strongly noxious for health. In this overview and medical assessment we focus on the effects of extremely low frequencies, wireless communications radiofrequencies and microwaves EMF. We discuss how to better define and characterize EHS. Taken into consideration the WHO proposed causality criteria, we show that EHS is in fact causally associated with increased exposure to man-made EMF, and in some cases to marketed environmental chemicals. We therefore appeal to all governments and international health institutions, particularly the WHO, to urgently consider the growing EHS-associated pandemic plague, and to acknowledge EHS as a new real EMF causally-related pathology.
This is a review of studies on the neurological effects of static/extremely-low frequency (ELF) electromagnetic fields (EMF). The review is mainly on research carried out in the last two decades. There are studies that showed effects on various neurotransmitters, including NMDA, serotonin, dopamine, endogenous opioids, etc. Each of these transmitters plays different critical roles on behavior and brain functions. Studies on behavioral effects of static/ELF EMF bear out these connections. Static/ELF EMF-induced behavorial and pathological effects, such as locomotor activity, memory and learning deficits, and neurological diseases (Alzheimer's, Parkinson's disease, Huntinton's diseases and atropical lateral scleroses, etc.) are discussed. Static/ELF EMF exposure has also been shown to have beneficial effects on functional deficits and progression of some neurological diseases. These fields provide a non-invasive treatment or treatment-adjuvant for these detrimental neurological conditions. Results suggest that free radicals, both reactive oxygen species and reactive nitric species could be involved. Depending on the conditions of exposure, either harmful or beneficial effects could result. It is important to carry out further investigation to identify these conditions. However, Caution should be taken to extrapolate the experimental data to human exposure, since higher field intensites than environmental levels were used in most laboratory research.
Parkinson’s disease (PD) is a neurological disorder in which oxidative stress and reactive oxygen species productions are proposed to be involved in its pathogenesis. Despite considerable advancement in Selenium’s (Se) molecular biology and metabolism, we do not know much about the cell type-specific pattern of Se distribution in the brain of PD humans and experimental animals. Although, there is plenty of evidence around the role of Se deficiency in PD’s pathogenesis impacting lipid peroxidation and reducing glutathione (GSH) and glutathione peroxidase (GPX). It has been suggested that Se has an inducible role in selenium-dependent GPX activity in PD animals and humans. However, calcium as a second messenger regulates the neuron cells’ essential activities, but its overloading leads to cellular oxidative stress and apoptosis. Therefore, Se’s antioxidant role can affect calcium signaling and alleviate its complications. There are signs of Se and Selenoproteins incorporation in protecting stress oxidative in various pathways. In conclusion, there is convincing proof for the crucial role of Se and Calcium in PD pathogenesis.
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During the past decade considerable evidence has accumulated demonstrating that nonthermal exposures of cells of the immune system to extremely low-frequency (ELF) electromagnetic fields (< 300 Hz) can elicit cellular changes that might be relevant to in vivo immune activity. A similar responsiveness to nonionizing electromagnetic energy in this frequency range has also been documented for tissues of the neuroendocrine and musculoskeletal system. However, knowledge about the underlying biological mechanisms by which such fields can induce cellular changes is still very limited. It is generally believed that the cell membrane and Ca(2+)-regulated activity is involved in bioactive ELF field coupling to living systems. This article begins with a short review of the current state of knowledge concerning the effects of nonthermal levels of ELF electromagnetic fields on the biochemistry and activity of immune cells and then closely examines new results that suggest a role for Ca2+ in the induction of these cellular field effects. Based on these findings it is proposed that membrane-mediated Ca2+ signaling processes are involved in the mediation of field effects on the immune system.
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Electromagnetic fields (EMFs) originating both from both natural and manmade sources permeate our environment. As people are continuously exposed to EMFs in everyday life, it is a matter of great debate whether they can be harmful to human health. On the basis of two decades of epidemiological studies, an increased risk for childhood leukemia associated with Extremely Low Frequency fields has been consistently assessed, inducing the International Agency for Research on Cancer to insert them in the 2B section of carcinogens in 2001. EMFs interaction with biological systems may cause oxidative stress under certain circumstances. Since free radicals are essential for brain physiological processes and pathological degeneration, research focusing on the possible influence of the EMFs-driven oxidative stress is still in progress, especially in the light of recent studies suggesting that EMFs may contribute to the etiology of neurodegenerative disorders. This review synthesizes the emerging evidences about this topic, highlighting the wide data uncertainty that still characterizes the EMFs effect on oxidative stress modulation, as both pro-oxidant and neuroprotective effects have been documented. Care should be taken to avoid methodological limitations and to determine the patho-physiological relevance of any alteration found in EMFs-exposed biological system.
Peroxynitrite decay in weakly alkaline media occurs by two concurrent sets of pathways which are distinguished by their reaction products. One set leads to net isomerization to NO3- and the other set to net decomposition to O-2 plus NO2-. At sufficiently high peroxynitrite concentrations, the decay half-time becomes concentration-independent and approaches a limiting value predicted by a mechanism in which reaction is initiated by unimolecular homolysis of the peroxo, O-O bond, i.e., the following reaction: ONOOH --> (OH)-O-. + (NO2)-N-.. This dynamical behavior excludes alternative postulated mechanisms that ascribe decomposition to bond rearrangement within bimolecular adducts. Nitrate and nitrite product distributions measured at very low peroxynitrite concentrations also correspond to predictions of the homolysis model, contrary to a recent report from another laboratory. Additionally, (1) the rate constant for the reaction ONOO- --> (NO)-N-. + O-.(2), which is critical to the kinetic model, has been confirmed, (2) the apparent volume of activation for ONOOH decay (DeltaV(double dagger) = 9.7 +/- 1.4 cm(3)/mol) has been shown to be independent of the concentration of added nitrite and identical to most other reported values, and (3) complex patterns of inhibition of O-2 formation by radical scavengers, which are impossible to rationalize by alternative proposed reaction schemes, are shown to be quantitatively in accord with the homolysis model. These observations resolve major disputes over experimental data existing in the literature; despite extensive investigation of these reactions, no verifiable experimental evidence has been advanced that contradicts the homolysis model.
Electric and electromagnetic fields are, collectively, one form of biophysical technique which regulate extracellular matrix (ECM) synthesis and may be useful in clinically stimulating repair of fractures and nonunions. Preclinical studies have shown that electric and electromagnetic fields regulate proteoglycan (PG) and collagen synthesis in models of endochondral ossification, and increase bone formation in vivo and in vitro. A substantial number of clinical studies have been done that suggest acceleration of bone formation and healing, particularly osteotomies and spine fusions, by electric and electromagnetic fields. Many of these studies have used randomized, placebo controlled designs. In osteotomy trials, greater bone density, trabecular maturation, and radiographic healing were observed in actively treated, compared with placebotreated patients. In spine fusions, average union rates of 80% to 90% were observed in actively treated patients across numerous studies compared with 65% to 75% in placebo-treated patients. Uncontrolled, longitudinal cohort studies of delayed and nonunions report mean union rates of approximately 75% to 85% in fractures previously refractory to healing. The few randomized controlled studies in delayed and nonunions suggest improved results with electric and electromagnetic fields compared with placebo treatment, and equivalent to bone grafts. Am J Orthop. 2004 Jan;33(1):27-30
The total current of Ca{sup 2+} ions through patch-clamped cell membranes was measured while exposing clonal insulin-producing β-cells (RINm5F) to a combination of DC and AC magnetic fields at so-called cyclotron resonance conditions. Previous experimental evidence supports the theory that a resonant interaction between magnetic fields and organisms can exist. This experiment was designed to test one possible site of interaction: channels in the cell membrane. The transport of Ca{sup 2+} ions through the protein channels of the plasma membrane did not show any resonant behavior in the frequency range studied.
Purpose: To investigate the effects of 12kV/m electric (E) field sourced by power lines on oxidative and nitrosative stress, and antioxidant status. Furthermore, the study aimed to examine the protective effects of N-Acetyl-L-cysteine (NAC) and epigallocatechin-gallate (EGCG) in the liver tissues of guinea pigs against the possible detriments of electromagnetic field exposure. Materials and methods: Guinea pigs were exposed to 50Hz 12kV/m E-field. NAC and EGCG were administerated intraperitoneally. Malonedialdehyde (MDA), a product of lipid peroxidation (LPO), and nitric oxide derivatives (nitrate (NO(3)), nitrite (NO(2)), total level of nitric oxide (NO(x)) were estimated as biomarkers of oxidative and nitrosative stress, respectively. Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and myeloperoxidase (MPO) were evaluated as endogenous antioxidant enzymes in liver tissues of the guinea pigs. Results: The results of our study indicated a significant increase in the levels of oxidant products (MDA, NO(3), NO(2), NO(x)), and a significant decrease in antioxidant enzyme (SOD, GSH-Px and MPO) activities. We also found that the individual or plus application of NAC and EGCG resulted in the reduction of oxidative stress prior to E field application. Conclusion: To conclude, extremely low frequency (ELF) electric field has potential harmful effects on the living organisms by enhancing the free radical production. NAC and EGCG might have hepatoprotective effects in ELF-E field induced oxidative and nitrosative stress.
This study shows that a non-thermal pulse-modulated RF signal (PRF), configured to modulate calmodulin (CaM) activation via acceleration of Ca(2+) binding kinetics, produced an immediate nearly 3-fold increase in nitric oxide (NO) from dopaminergic MN9D cultures (P<0.001). NO was measured electrochemically in real-time using a NO selective membrane electrode, which showed the PRF effect occurred within the first seconds after lipopolysaccharide (LPS) challenge. Further support that the site of action of PRF involves CaM is provided in human fibroblast cultures challenged with low serum and exposed for 15min to the identical PRF signal. In this case a CaM antagonist W-7 could be added to the culture 3h prior to PRF exposure. Those results showed the PRF signal produced nearly a two-fold increase in NO, which could be blocked by W-7 (P<0.001). To the authors' knowledge this is the first report of a real-time effect of non-thermal electromagnetic fields (EMF) on NO release from challenged cells. The results provide mechanistic support for the many reported bioeffects of EMF in which NO plays a role. Thus, in a typical clinical application for acute post operative pain, or chronic pain from, e.g., osteoarthritis, EMF therapy could be employed to modulate the dynamics of NO via Ca/CaM-dependent constitutive nitric oxide synthase (cNOS) in the target tissue. This, in turn, would modulate the dynamics of the signaling pathways the body uses in response to the various phases of healing after physical or chemical insult or injury.