ArticlePDF AvailableLiterature Review

Effects of magnesium deficiency - More than skin deep


Abstract and Figures

Dead Sea and magnesium salt therapy are two of the oldest forms of treatment for skin disease and several other disorders, supported by a body of largely anecdotal evidence. In this paper we review possible pathways for penetration of magnesium ions through the epidermis to reach the circulation, in turn replenishing cellular magnesium levels. We also discuss mechanisms for intercellular movement of magnesium ions and possible mechanisms for the interaction between magnesium ions and inflammatory mediators. Upon addition of magnesium ions in vitro, the expression of inflammatory mediators such as tumour necrosis factor α (TNFα) and nuclear factor κβ (NFκβ) is down regulated. Dysregulation of these and other inflammatory mediators has been linked to several inflammatory disorders, including asthma, arthritis, atherosclerosis and neuroinflammation.
Content may be subject to copyright.
Effects of magnesium deficiency More than skin deep
Navin Chandrakanth Chandrasekaran
, Christopher Weir
, Sumaya Alfraji
, Jeff Grice
Michael S Roberts
and Ross T Barnard
School of Chemistry and Molecular Biosciences, Australian Infectious Diseases Research Centre, The University of Queensland,
Queensland 4072, Australia;
School of Medicine, Translational Research Institute, The University of Queensland, Wooloongabba,
Queensland 4102, Australia;
Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of
Melbourne, Parkville, Victoria 3052, Australia
Corresponding author: Ross T Barnard. Email:
Dead Sea and magnesium salt therapy are two of the oldest forms of treatment for skin disease and several other disorders,
supported by a body of largely anecdotal evidence. In this paper we review possible pathways for penetration of magnesium ions
through the epidermis to reach the circulation, in turn replenishing cellular magnesium levels. We also discuss mechanisms for
intercellular movement of magnesium ions and possible mechanisms for the interaction between magnesium ions and inflam-
matory mediators. Upon addition of magnesium ions in vitro, the expression of inflammatory mediators such as tumour necrosis
factor a (TNFa) and nuclear factor jb (NFjb) is down regulated. Dysregulation of these and other inflammatory mediators has been
linked to several inflammatory disorders, including asthma, arthritis, atherosclerosis and neuroinflammation.
Keywords: Magnesium, inflammation, skin
Experimental Biology and Medicine 2014; 239: 1280–1291. DOI: 10.1177/1535370214537745
Dead Sea therapy is one of the oldest forms of treatment for
skin disease and some chronic inflammatory diseases like
arthritis and psoriasis.
Much of the research to date has
attributed the clinical effects of Dead Sea therapy to its min-
eral composition; mostly to magnesium salts.
salts, such as magnesium sulphate (Epsom salts), have long
been used as a spa product and as a therapeutic to manage
clinical conditions.
The central question addressed by this review is, ‘What
are the underlying mechanisms by which magnesium ions
could play a role in the regulation of inflammatory
responses in the skin and systemically?’’ Several systematic
studies have been conducted in humans, over the last two
decades, in an effort to understand the effect of magnesium
ions (Mg
) in healing skin disorders. These will be
reviewed. There has been renewed interest over the past
decade in understanding the role of magnesium salts in
clinical medicine, nutrition and physiology. This review
will discuss the known clinical effects of magnesium defi-
ciency, and both summarise and suggest molecular mech-
anisms that could mediate the inflammation induced by
magnesium deficiency. We first discuss transdermal absorp-
tion as a possible route of administration for prevention and
treatment of magnesium deficiency and for controlling
Transdermal absorption of magnesium
Transport of Mg
across skin is a critical precondition for
the function of topical, therapeutic compounds in treating
skin and inflammatory diseases. Transdermal absorption is
a potentially important route of transport for components
that are involved in biological processes.
Even though
much research has been carried out in the area of cutaneous
permeation and transdermal absorption,
that lead to permeation of Mg
ions through the skin are
not clearly understood and need further research.
Past studies on magnesium and other metal ion perme-
ation through human skin demonstrated that it is not read-
ily absorbed under normal physiological conditions, when
the skin is intact and healthy.
However, there is a con-
siderable body of anecdotal and research data that attributes
to magnesium a role in skin barrier and epidermal recovery
after damage.
In the case of compromised stratum cor-
neum (SC), the viable epidermis and nerve endings (in
atopic dermatitis [AD]) are exposed to incoming particles
and chemicals.
There is no effective barrier to restrict the
movement of magnesium ions to epidermal cells or nerve
ISSN: 1535-3702 Experimental Biology and Medicine 2014; 239: 1280–1291
Copyright ß 2014 by the Society for Experimental Biology and Medicine
at UQ Library on February 20, 2015ebm.sagepub.comDownloaded from
endings, thus permitting a role for Mg
in skin recovery
and modulation of the immune or nervous systems.
The permeability of the skin is modified in pathological
conditions, with both macroscopic and microscopic
that would allow penetration of magnesium
below the SC, and subsequent transport or diffusion by
mechanisms to be discussed below. Thus it is necessary to
consider both the normal skin as well as barrier compro-
mised or diseased skin.
In normal skin, the SC forms the outermost layer,
formed by continuous replacement from the newly differ-
entiated daughter cells of keratinocyte stem cells, displa-
cing outwards.
It functions as a physical barrier
hindering, but not completely preventing, transdermal
penetration through its cellular structure.
The radius of
the hydrated magnesium ion relative to the radius of the
dehydrated ion is greater compared to other ions such as
calcium, potassium and sodium.
Irrespective of oral or
transdermal administration, this greater radius could ster-
ically and energetically hinder transport across cellular
membranes. A review article by Lansdown
reports that
magnesium in the form of hydrous polysilicate (talc) is
not readily absorbed by normal skin, however, commonly
used therapeutic formulations of magnesium utilize other
salts such as chloride, or sulphates. The absorption kin-
etics such as solubility and permeation coefficients of
chlorides and sulphates are different to those of polysili-
Moreover, Table 7 in the same review article
presents a positive score for percutaneous absorption of
magnesium ions (although the temperature conditions are
not specified). The same article cites the ability of Mg
bind to hair.
This provides the possibility of magnesium
permeation by shunt diffusion. Shunt diffusion is the
mechanism by which diffusion occurs through hair fol-
licles, pilosebaceous units and sweat glands,
these constitute a small proportion of skin surface area,
with the density dependent on the location of the skin. In
the case of bulk diffusion, water soluble molecules are
able to enter through 10 A
pores created by protein sub-
units in the lipid of SC.
These could provide an
entrance for hydrated magnesium, the radius of which
is 4.76 A
Subsequently, the transport of Mg
cells could be facilitated by transmembrane proteins
such as SLC41A1 and transient receptor potential mela-
statin 7 (TRPM7).
SLC41A2, a cell surface transmem-
brane protein with its N-terminus outside and C-terminus
inside the cell membrane, is responsible for magnesium
transport across the plasma membrane.
Immunohistochemistry on epidermal cells has demon-
strated a plasma membrane localization of murine
The N-terminus of this protein, accessible to
extracellular components, is involved in transcellular
movement of Mg
, which is in turn required for homeo-
stasis, cell growth and neuronal function.
Similarly, the
human SLC41A1 functions as a Mg
involved in magnesium homeostasis in epithelial cells.
Another important mechanism by which Mg
lular homeostasis in humans is facilitated, is via the protein
Knockout of TRPM7 in DT40 B cells (derived
from an avian leucosis virus induced bursal lymphoma in
a white leghorn chicken) resulted in lowered intracellular
and inhibition of cellular proliferation.
Under stress
(apoptotic stimuli), the TRPM7-knockdown fibroblast cell
line (3T3-M7shRNA6) was more resistant to apoptosis and
had a lower intracellular concentration of reactive oxygen
species (ROS) compared to control cells. This suggests a
role for Mg
, mediated by the magnesium transporter
TRPM7, in cell survival and regulation of cellular ROS
Another factor influencing percutaneous absorption of
magnesium ions through skin, is the negative charge car-
ried on the surface of tissues.
Accordingly, it is likely that
the positively charged magnesium ions can be absorbed on
the negatively charged SC, enhancing the retention time
and bioavailability on the skin surface.
This coupled
with bulk diffusion and the factors mentioned above
could enhance magnesium ion penetration through
normal human skin.
In normal human skin, factors such as temperature and
humidity, osmolarity, dehydration and penetration enhan-
cers, could lead to enhanced percutaneous absorption of
magnesium. In certain therapies, increased temperature
conditions can also provide improved skin permeability
enabling penetration of mineral salts.
A study con-
ducted to measure the effect of heat on skin permeabil-
ity showed a strong dependence of permeability on
temperature. Short pulses of high temperature resulted
in increases in calcein permeability in human cadaver
In relation to Dead Sea therapy on normal
human skin, the high salt concentration coupled with
the hydrated state of the skin could together cause an
osmotic effect,
leading to increased flux of ions through
the skin due to a concentration gradient across the skin.
However, in commercially available topical magnesium
formulations it is likely that penetration enhancers
would be necessary in order to enhance passage through
the SC layer in normal skin. The role of these enhancers is
to penetrate into the skin, reversibly decrease the barrier
resistance of the SC and to create a water equilibrium
between SC and viable epidermis.
Control of inflammation by magnesium:
Possible mechanisms
It is well established that Mg
deficiency has a direct influ-
ence on inflammation.
However, the molecular mechan-
isms by which Mg
suppresses inflammation are unclear.
A possible link could be activation by Mg
of the thiamine
pyrophosphate (TPP)-dependent riboswitch, resulting in
increased synthesis of thiazole from thiazole pyrophos-
(see Figure. 1). The TPP-dependant riboswitch is
the only known functional riboswitch mechanism in
eukaryotes and it is known that TPP binding to thiA ribos-
witch is increased by Mg
The adenine rich sites on
the riboswitch bind Mg
leading to structural changes
favouring TPP binding.
The TPP-dependant thiA ribos-
witch up-regulates thiazole synthase, an enzyme required
for catalysing the conversion of thiazole pyrophosphate to
Chandrasekaran et al. Mg
deficiency More than skin deep 1281
at UQ Library on February 20, 2015ebm.sagepub.comDownloaded from
Thiazole derivatives have a spectrum of anti-
inflammatory and neuroprotective activities.
Molecular mechanisms and inflammatory
Illnesses related to inflammation following a state of
chronic or acute hypomagnesaemia are well documented,
both in humans and experimental rat models.
However, there is a paucity of information in the literature
regarding the cascade of molecular events culminating in
inflammation during hypomagnesaemia.
Here we review known molecular mechanisms and
propose additional ones that could be responsible for
inflammation resulting from Mg
deficiency, additionally
suggesting how this might relate to inflammation loca-
lized in the skin. Firstly an examination of how the hypo-
magnesaemic state results in tumour necrosis factor a
(TNFa) and nuclear factor jb (NFjb) activation will be
considered, in view of the importance as inducers of tran-
scription of pro-inflammatory genes. These changes pave
the way for pro-inflammatory cytokine responses, fol-
lowed by alteration of macrophage and neutrophil activ-
ity, including their participation in a pro-inflammatory
positive feedback loop (see Figure 2).
Magnesium in TNFa and NFjb signalling
It has been demonstrated that hypomagnesaemia in
and in people with metabolic syndrome
in elevated serum concentrations of TNFa compared to
healthy counterparts (in the human studies), or controls
(in rodent studies). An elevation in TNFa and magnesium
deficiency was also observed in obese human subjects when
compared to healthy and moderately overweight individ-
A recent study revealed that TNFa levels declined
following in-vivo administration of MgSO
to human sub-
Additional work showed that the magnesium ion
component, not the sulphate, was responsible for the
immunomodulatory effect.
Other research has shown
that magnesium deficiency in mice with a knockout of the
gene encoding the TNFa receptor (TNFaR) caused less
adverse effects on bone loss than in the wild-type controls
fed the same diet.
These results suggest an inverse rela-
tionship between magnesium intake, TNFa concentration
and TNF actions mediated by the TNFaR. The physiological
significance of these observations becomes evident in the
context of the known pro-inflammatory actions of TNFa.
TNFa is a regulatory cytokine produced by various cell
types including macrophages, T-helper cells (CD4þ T
cells) and natural killer (NK) cells.
The predominant role
Figure 1 Possible influence of Mg
in thiazole synthesis in turn resulting in anti-inflammatory properties. Thiamine pyrophosphate (TPP), an activated form of
thiamine binds to thiA riboswitch in the presence of magnesium ions (Mg
). An adenine rich site in the riboswitch binds Mg
increasing the affinity of TPP binding.
The riboswitch undergoes structural change then expresses thiazole synthase,
resulting in the formation of TPP intermediate and in turn forming thiazole derivatives.
Thiazole derivatives are known to inhibit cyclooxygenase, hindering the formation of prostanoids, in turn producing anti-inflammatory effects.
The thiA riboswitch is
the only known eukaryotic riboswitch.
1282 Experimental Biology and Medicine Volume 239 October 2014
at UQ Library on February 20, 2015ebm.sagepub.comDownloaded from
of this cytokine is the systemic regulation of immune cells
with beneficial outcomes such as augmented recruitment of
defence mechanisms during infection, including fever
However, in common with all endogenous
immune mediators, balance is essential and a prolonged
high serum concentration of TNFa results in prolonged
inflammation and effective damage locally and systemic-
Systemic diseases such as systemic lupus erythema-
tosis and local organ diseases including psoriasis and
osteoarthritis are all associated with dysregulation
(increased concentrations) of this cytokine.
The biosynthesis of TNFa is increased by an array of
stimuli including hypoxia, trauma, complement compo-
and various cytokines including interleukin 1 (IL-1),
IL-17 interferon-c (IFN-c) and granulocyte macrophage
colony-stimulating factor (GM-CSF).
It has been shown
in vitro, using various cell culture models (including
human and rat cell lines) that under hypomagnesaemic con-
ditions in the culture medium, the concentrations of the
aforementioned cytokines show an increase compared to
concentrations in cell lines maintained under normomagne-
saemic conditions.
The increased concentration of IL-1
and IL-17
can result in establishment of positive feedback
loops (which can occur locally or systemically depending
on the disease in question; see reviews referenced
more details beyond the scope of this review), with TNFa
facilitating the generation of IL-1 and IFN-c, in turn driving
further TNFa effects.
Transcription of TNFa is gov-
erned by NFjb, the inflammation-related transcriptional
discussed in more detail below.
Figure 2 General summarized pathway of inflammation following hypomagnesaemia. Evidence suggests that hypomagnesaemic conditions can exacerbate trauma
and hypoxia (leading to increased oxidative damage to cells and tissues from free radicals,
and stimulates the production of interleukin 1 (IL-1), IL-17, interferon c
(IFN-c) and granulocyte macrophage colony-stimulating factor (GM-CSF). The presence of these soluble proteins allows for the stimulation of various immune cells to
produce tumour necrosis factor a (TNFa) and its reciprocal receptor (for cell surface presentation) following the nuclear translocation of nuclear factor jb (NFjb) acting
as a transcription factor. The secretion of TNFa from cells (after TNFa converting enzyme (TACE) converts tm TNFa to its soluble form) allows for autocrine and paracrine
effects that upon TNFa binding facilitates amplification of inflammatory responses such as transcription, translation and secretion of more TNFa, IL-1, IL6 and IFN-c.A
positive feedback loop is established and the latter two cytokines cause inflammation. Normally prostaglandins, IL-10 and corticosteroids have an inhibitory effect on
TNFa transcription; however this is promoted by Mg
and may therefore be disrupted in hypomagnesaemic conditions.
Chandrasekaran et al. Mg
deficiency More than skin deep 1283
at UQ Library on February 20, 2015ebm.sagepub.comDownloaded from
Negative feedback loops also operate, these are known
to regulate TNFa levels by inhibition of transcription of
This negative feedback arises when TNFa
stimulates the production of molecules that inhibits TNFa
transcription including prostaglandins, IL-10 and cortico-
steroids. Mg
is also known to promote prostaglandin
synthesis, and so it can be speculated that in the hypomag-
nesaemic individual, the negative feedback loop is dis-
rupted, with less feedback control over elevated TNF-a
It remains to be determined what levels of
magnesium deficiency tip the balance towards uncontrolled
positive feedback in humans, resulting in clinically observ-
able effects. Nor is it known how prolonged such effects
would be. There is a paucity of data regarding the effects
of Mg
on IL-10 or corticosteroid levels, hence the inter-
action between Mg
and the endocrine system is ripe for
After translation, TNFa exists in a cell-surface bound
precursor form, termed transmembrane TNFa (tmTNFa).
This intermediate is converted to a soluble cytokine via
TNFa-converting enzyme.
Both tmTNFa and sTNFa
are biologically active and capable of binding to their recep-
tors, TNFR1 and TNFR2, triggering different downstream
signalling events, which result in outcomes such as apop-
tosis, necroptosis, transcriptional factor AP-1 activation, or
NFjb activation and translocation to the nucleus.
binding has occurred between TNFa and its receptor
(either TNFR1 or 2), a conformational change occurs in
the latter, followed by the interaction between the intracel-
lular domains of TNFR and other proteins including
TRAF2, cIAP1 and cIAP2, forming a complex. This complex
formation leads to the activation of the IJB kinase (IKK)
complex. The IKB complex consists of two kinase subunits,
which phosphorylate the NFjb inhibitor protein IJBa, tag-
ging it for the ubiquitin-proteosome pathway of degrad-
ation. This allows NFjb to freely translocate to the
nucleus where it coordinates the transcription of genes
such as cIAP1/2 and TRAF2, which are important in the
regulation of NFjb and apoptotic pathways.
Interplay and importance of Ca
and Mg
NFjb activity is regulated by various secondary messengers
including intracellular calcium ions ðCa
. In rats fed a
deficient diet, where plasma Mg
fell to 60% of con-
trol levels, a rise in Ca
levels was observed.
This rise in
secondary to a decrease in Mg
is seen in a variety of
systems including human patient studies, rodent models
and cell culture (including immune cells), all of which are
mentioned in the 2010 review by Rayssiguier et al.
increased Ca
can induce formation of reactive oxygen
intermediates following an oxidative burst from cells such
as neutrophils,
which in turn cause phosphorylation of
IJB (through an as yet unknown mechanism), which will
release the active form of NFjb for nuclear translocation.
The critical role of Ca
in the NFjb pathway is sup-
ported by the observation that Ca
chelators prevent the
induction of NFjb activity in vivo in murine models.
Other research has shown that when Mg
deficient rats
were fed a Ca
deficient diet, the inflammatory effect
was greatly reduced (as measured by reduced inflamma-
tion scores, prevention of leucocytosis and reduced spleno-
megaly) when compared to other hypomagnesaemic rats.
Once the active NFjb crosses the nucleus it up-regulates the
transcription of TNFa.
It should be mentioned, how-
ever, that the evidence for NFjb-mediated TNFa expression
is mostly limited to murine models, and studies relating to
humans are limited.
However, in 2010 one study uti-
lized mouse bone marrow-derived dendritic cells to dem-
onstrate NFjb-mediated positive expression of the TNFa
Additionally it would be of interest to study
whether a high Ca
, low Mg
state up-regulates NFjb
activity and TNFa expression permitting TNFa synergism
with STAT6 to switch B cells to IgE production.
This is
important to establish the role of IgE in atopic and inflam-
matory conditions such as AD.
The antagonism between Mg
and Ca
, and competi-
tion for binding sites on receptors, enables Mg
to over-
come the toxic effects produced by excessive Ca
concentrations in cells of the immune system that are
located in the brain (human microglial cells in tissue cul-
In the case of neuroinflammation, in vitro experi-
mentation has shown that an influx of Ca
into microglia
(brain resident macrophages) and THP-1 cells activates
their associated purinergic receptors and subsequently
is effective in ameliorating the neuro-
toxic effect produced by over-activation of human micro-
glial cells that occurs as a result of elevated levels of
inflammatory cytokines in the cells such as TNF-a, IL-6
and nitrite ions.
These agents are released as a result
of intracellular inflammatory pathway activation, via P38
MAPK and NFjb.
Pro-inflammatory cytokine responses and
resident microflora
In addition to stimulating TNFa transcription, NFjb acti-
vates the transcription of IL-6 and IFN-c after binding to
the cognate promoter regions.
These potent pro-
inflammatory cytokines have been shown to be present in
high levels during periods of Mg
Additionally, in one study of septic shock using ex vivo
human whole-blood, it was shown that following addition
of Mg
, the baseline level of TNFa and IL-6 production
This observation provides further evidence of the
inverse relationship between these inflammatory mediators
and magnesium concentration.
However, the concentra-
tion of Mg
was well above physiologically relevant
More research in other conditions, using a similar
experimental set up is needed to further elucidate links
between Mg
levels in human blood and pro-inflamma-
tory cytokine production. Further, a more recent study,
using THP-1 cells isolated from human neonatal cord
blood, found that treatment with Mg
(at levels known
to be clinically effective in vivo) reduced the production of
IL-1b, TNF-a and IL-8 cytokines and IL-6 in cord blood
IL-6 exerts effects on a variety of cells including T and B
lymphocytes, hepatocytes, hematopoietic progenitor cells
1284 Experimental Biology and Medicine Volume 239 October 2014
at UQ Library on February 20, 2015ebm.sagepub.comDownloaded from
and fibroblasts, with consequent systemic effects such as
acute phase reactant protein production, immunoglobulin
synthesis and naive CD4þ T cell differentiation into Th17
cells. IL-17 secreted from Th17 cells is responsible for auto-
immune tissue injury.
In relation to skin pathology, it has
been shown that the epidermis from psoriatic skin produces
high levels of IL-6 in addition to over-expression of TNFR,
due in turn to the higher levels of IFN-c.
Many of the
characteristic phenotypic features of keratinocytes from
psoriatic skin, including growth activation and ICAM-1
up-regulation, are a result of the actions of IL-6, TNFa
and IFN-c.
The histological features of psoriasis such
as the presence and accumulation of inflammatory cells
(including polymorphonuclear leukocytes) and epidermal
hyperplasia have been attributed to elevated TNFa activ-
Given the aforementioned studies
indicating a
role for magnesium in modulating the production of pro-
inflammatory cytokines such as IL-6 and TNFa, there may
be a role for magnesium-containing compounds in the treat-
ment of psoriasis. However, whether such treatment would
be effective in either acute or chronic cases, differing levels
of severity, or what the most effective dose and route of
administration would be (i.e. topical or oral) remain to
be shown.
Another interesting finding is that mice fed on a Mg
deficient diet for four days showed higher levels of IL-6 and
TNFa mRNA in the liver and intestine, a drop in the
levels of the mRNA of zonula occludens-1, occludin and
proglucagon in the ileum (three factors controlling gut bar-
rier integrity and function) and possessed reduced gut
bifidobacteria levels when compared to controls.
Bifidobacterium strains have been shown to repress inflam-
mation in a variety of situations including studies of ulcera-
tive colitis and skin inflammation (i.e. acne).
respect to skin inflammation, Bifidobacterium strains
appear to facilitate reduction in substance P, a molecule
that increases TNFa expression. One study in human
female volunteers demonstrated a reduction in sensitive
skin and heightened resistance to physical and chemical
insults to the skin (in contrast to a negative control cream)
following topical application of B. longum spp. products.
Additionally, in the same paper, the authors report a statis-
tically significant reduction in markers of inflammation
(including oedema, mast cell degranulation and TNFa
release) following the application of a B. longum preparation
on ex-vivo human skin explants.
However, in the above mentioned
mouse study, the
animals on a Mg
-deficient diet for 21 days demonstrated
a potentially compensatory increase in caecal Bifidobacteria
levels, restoration of intestinal barrier function and a
waning of inflammation when compared to control mice.
This is in contrast to mice on the same diet for four days
only; in the latter case decreased levels of Bifidobacteria, and
an increase in IL-6, TNFa and other markers of pathology
were present. Drawing generalizable conclusions from this
study is difficult given that it was a mouse-model study
(not human) and measurements of bacteria and relevant
mRNA levels were not continued after 21 days. If there
was adaptation, were there any other long-term adverse
effects on physiology? In the future it will also be important
to work out the complex relationship between the gut bac-
teria and cytokine responses; is it bidirectional or unidirec-
tional? What feedback loops exist? Moreover, the regulation
is unlikely to be the same for all cytokines. These are all
questions that need to be investigated.
Changes in macrophages and neutrophils
In rodent studies, a state of hypomagnesaemia has been
associated with the activation of macrophages and neutro-
It has been suggested that this is due to the
increase in circulating pro-inflammatory mediators, includ-
ing substance P, IL-6, TNFa and IFN-c; however, given that
macrophages and neutrophils are amongst the cells that
produce these cytokines, it remains difficult to say whether
the aforementioned cells are activated by these substances
or if they are activated directly by the low levels of Mg
re and colleagues suggest that it is due to
the latter, a drop in circulating Mg
concentration, which
would lead to a significant increase in Ca
turn stimulating cellular proliferation. Whilst macrophages
are also able to be activated independently of Ca
example, via the lipopolysaccharide pathway), the Ca
dependent activation pathway results in a more rapid
expression of IL-6.
Aside from enhanced protein expression of IL-6 and
TNFa, activated macrophages also demonstrate increased
expression of IL-1 proteins in Mg
-deficient rats when
compared to a control group. In the same study it was
postulated that this contributed to cardiac lesions (IL-1 pro-
motes expression of endothelin from heart endothelial cells
which causes vasospasm).
Additionally, IL-1 is antagon-
istic to endothelial proliferation, suggesting another mech-
anism behind the lesions seen.
Furthermore, in the skin,
IL-1 is implicated in wound repair and skin pathology, with
IL-1 receptor (IL-1R) knockout mice demonstrating reduced
cutaneous and deep tissue fibrosis and scarring and restor-
ation of skin architecture.
Neutrophils are capable of releasing superoxide anions
via their NADPH oxidase system and can contribute to
tissue damage during Mg
deficiency, as demonstrated
in a study which also demonstrated phagocytic activity of
neutrophils in rats on a magnesium deficient diet.
study also showed that the free radical production from
neutrophils is inhibited when high Mg
levels are present
in the extracellular space.
was also found to inhibit
superoxide in cultured human neutrophils.
The latter
experiment also revealed synergistic inhibition of super-
oxides with the addition of zinc ions to the magnesium
Neutrophil migration to the skin, a process
that promotes keratinocyte apoptosis is TNFa dependant.
These phenomena are key features of hyper-proliferative
skin diseases such as psoriasis.
Clinical implications of magnesium deficiency
Magnesium is a micronutrient required for normal growth
and development. Numerous clinical disorders have been
associated with magnesium deficiency. Inflammation is a
primary reaction brought about by magnesium deficiency,
Chandrasekaran et al. Mg
deficiency More than skin deep 1285
at UQ Library on February 20, 2015ebm.sagepub.comDownloaded from
creating oxidative stress and subsequent immune stress.
The clinical disorders could be a consequence of this
stress response.
Magnesium ions bind to macromol-
ecules and cell membranes. Mg
is known to affect cellular
functions, including the transport of potassium and Ca
modulation of signal transduction, cell proliferation and
energy metabolism.
Early stages of Mg
deficiency can
be characterized by a wide range of symptoms such as
anorexia, vomiting, weakness, paraesthesia, muscular
cramps, irritability and impaired cognitive functioning
reflected by a decreased attention span. Mg
is related to poor dietary Mg
intake, often as a result of
lifestyle changes, leading to the aforementioned health dis-
deficiency triggers inflammatory
responses, including abnormal calcium homeostasis, acti-
vation of N-methyl-
D-aspartate (NMDA) receptors, release
of neurotransmitters, membrane oxidation and activation of
NFjb (see previous section, ‘Magnesium in TNFa and
NFjb signalling’).
Some of the important inflamma-
tion-related clinical disorders, known to be caused by or
exacerbated by, magnesium deficiency, are outlined below.
The pathogenesis of asthma, a chronic inflammatory dis-
order involves activation of NFjb and, expression of pro-
inflammatory cytokines, chemokines and inflammatory
mediators (IFN-c and ROS).
In this pathological condi-
tion, NFjb activation leads to dysregulation of cytokines
and infiltration of inflammatory cells such as mononuclear
cells and fibroblasts in the lung.
Indeed, increased
NFjb activity has been observed in the airways of asthmatic
In acute asthma, the therapeutic effect of mag-
nesium is well established.
Studies in acute asthma have
shown that intravenous and inhaled magnesium sulphate
) improved lung function and reduced hospitaliza-
tion frequency, particularly in patients with the lowest
levels of forced expired volume.
In chronic asthma
patients with persistent airflow limitation short-term treat-
ment with magnesium inhalations had no statistically sig-
nificant, direct bronchodilating effect, however, clinical
observations suggested heterogeneity in the response, prob-
ably related to treatment intensity, and supported further
exploration of magnesium administration in those
A characteristic property of Mg
is its antagonism of
(see prior section ‘Interplay and importance of Ca
and Mg
signalling’). It competes with Ca
for entry
into cells through voltage-gated channels and receptors
and inhibits Ca
release from the sarcoplasmic
The synovial fluid from patients with rheumatoid arth-
ritis contains elevated levels of TNFa (an activator of NFjb),
which is important in the pathogenesis.
ciency can lead to lipid peroxidation and membrane oxida-
tion, which in turn activates the NFjb pathway.
Activation of inflammatory responses due to Mg
ciency causes chronic inflammation leading to different
types of arthritis, depending on the site of NFjb activation.
Studies in humans indicate that low Mg
intake and
blood plasma concentration are linked with enhanced risk
of atherosclerotic disease.
Atherosclerosis is currently
classified as an inflammatory disease, having interactions
between modified lipoproteins, macrophages, T lympho-
cytes and the components of arterial walls,
leading to
the development of atherosclerotic lesions. Experimental
results suggest regression of such lesions and suppression
of atherogenesis in low-density lipid receptor deficient mice
fed with Mg
Infusion of Mg
at supra-
physiological concentrations causes vasodilation of coron-
ary arteries and systemic vasculature, antiarrhythmic
effects and platelet inhibition.
Studies also show dietary
administration of Mg
attenuates atherosclerotic lesions
by lowering serum cholesterols and triglycerides in choles-
terol fed animals.
On the basis of these studies, it appears
that Mg
concentration regulates lipid metabolism and
reduces atherosclerosis in animal models.
Even though the immune system and, in particular, the
inflammatory response operates systemically, the inter-rela-
tionship between inflammation occurring in the nervous
system and systemic inflammation needs to be better
understood. It is widely accepted that several neurological
disorders are characterised by an inflammatory compo-
There are several drugs undergoing test that
are posited to act by reducing neurodegeneration, at least
in part through inhibition of the inflammatory response of
glial cells.
However, these drugs exert their effect
throughout the body, resulting in global immunosuppres-
It would be ideal for such drugs to specifically
target the glial cells and control inflammation in the brain
without producing systemic immunosuppression.
Studies conducted in mice using the compound 4,6-diphe-
nyl-3-(4-(pyrimidin-2-yl)piperazin-1-yl) pyridazine
(MW01-5-188WH), aimed at selective suppression of neu-
roinflammation, has yielded some positive outcomes with-
out producing extra-neural inflammation.
administration could potentially be an effective
treatment of neurodegenerative diseases via its antagonism
of Ca
channels. This selectively suppresses neuroinflam-
If treatment for neurodegenerative diseases
involved administration of Mg
locally to the brain, it
could conceivably avoid the generalised stress on the
immune system that is caused by non-targeted anti-inflam-
matory drugs. Experiments conducted on rat ischaemic and
excitotoxic brain injury models shows the activity of Mg
as a neuroprotective agent.
This is achieved by
blockade of NMDA receptors and enhancement of
regional cerebral blood flow to ischaemic areas of the
brain. Mg
also inhibits entry of Ca
into cells through
voltage-operated and receptor-operated channels.
The nervous and immune systems interact bi-direction-
ally. Mg
deficiency is known to induce a systemic stress
response by activating neuroendocrine pathways, modify-
ing production and activity of neuromediators such as
acetylcholine, catecholamines and substance P. These have
well established roles in the progression of both local and
systemic inflammatory responses.
Administration of
has been shown to block Ca
traffic through cell
surface channels, acting as a broad inhibitor of neuroinflam-
Elevated systemic levels of Mg
have been
shown to reduce damaging consequences of Ca
neuroinflammation in Parkinson’s disease and Alzheimer’s
1286 Experimental Biology and Medicine Volume 239 October 2014
at UQ Library on February 20, 2015ebm.sagepub.comDownloaded from
AD is a skin disease that is a result of interactions
between skin, nervous system and immune cells. Nerve
growth factor (NGF) is a neurotrophin, mainly produced
in the basal keratinocytes and are present in elevated
levels in plasma of AD patients.
In normal skin, less
expression of NGF was found.
These NGFs are
known to be involved in the extension of C-fibres and pro-
mote increased density of nerve endings. In AD this results
in exposure of a high density of unprotected nerves to exter-
nal conditions, leading to the itch and scratch cycle that
characterizes the disease.
Semaphorin3A (Sema3A) is
another factor involved in the development of AD. It is an
axon guidance molecule that inhibits outgrowth of sensory
neurons. It does so by binding to plexin–A1-4 and its co-
receptor neuropilin-1 (NRP-1), subduing the effects caused
by NGFs.
Sema3A acts by suppressing nerve exten-
sion, and inhibition of histamine release from mast cells
(existing treatments for AD rely on blocking the histamine
receptors (H1-R) with anti-histamines or topical steroids).
Further, Sem3A also binds to NRP-1.
NRP-1 is known to
activate the NFjb pathway and to initiate keratinocyte
One study has shown that increased calcium ion concen-
tration (0.45–0.75 mmol/L) in normal human epidermal
keratinocytes augments the expression of Sema3A.
While calcium and magnesium have antagonist effects at
the cellular level, it is possible that the skin barrier recovery
after treatment with Dead Sea minerals (comprising cal-
cium and magnesium salts) is due to the combined role of
calcium in upregulating Sema3A, and the prevention by m
magnesium of mast cell degranulation through other mech-
anisms (potentially via effects on TNFa or STAT-6
However, a direct role for magnesium ions in regulation
of Sema3A and NGFs remains to be established, and is an
important area for further investigation, given the role of
these factors in AD.
In relation to skin disease, a clinical study was conducted
on 30 AD candidates, in which subjects were tested over six
weeks for transepidermal water loss (TEWL), skin hydra-
tion, skin redness and skin roughness.
Upon treating one
of their arms with a 5% Dead Sea salt solution at 38–42
and the other arm with tap water (38–42
C) as control, an
improvement in TEWL, with reduction in AD symptoms in
the Dead Sea salt treated group was shown.
Further work
is needed, to confirm these studies and to measure the intra-
cellular and molecular correlates of the structural changes
in the skin.
Absorption of Mg
ions across the normal SC could occur
under conditions of elevated temperature or changed
hydration conditions (for example high salt concentrations).
Absorption of magnesium will take place in cases of skin
pathology or injury, where there is physical disruption of
the SC. Subsequently, transmembrane proteins, such as
SLC41A2 could assist intercellular transport of magnesium
ions, leading to further penetration through the organ sys-
The action of magnesium ion as an anti-inflamma-
tory agent could be via several pathways, such as activation
of the TPP-dependant riboswitch.
Magnesium deficiency
results in activation of TNFa and NFjb, which can further
facilitate pro-inflammatory cytokines.
It would also be
of interest to study the effect of Mg
on the synergism
between TNF-a and STAT6, a mediator of IgE receptor
mediated mast cell responses in late phase allergic
responses and AD.
Experimental data from humans
and mice suggest an inverse relationship between magne-
sium intake and TNFa concentration, in addition to several
other markers of inflammation.
The hypomagnes-
aemic condition increases the influx of calcium into cells,
resulting in elevated NFjb activity.
Evidence for acti-
vation of neutrophils and macrophages by calcium ions in
mice has also been found.
Collectively, the inflammatory
responses triggered by magnesium deficiency can result in
clinical disorders. The interaction between Mg
inflammatory mediators is ripe for investigation. For exam-
ple, there is a paucity of data relating to the effects of Mg
on IL-10 or corticosteroid concentrations. More research is
needed to further elucidate links between Mg
levels in
human blood and pro-inflammatory cytokines. The effect
of treatment with magnesium containing compounds in
acute or chronic diseases with differing levels of severity,
and the most effective doses and routes of administration in
these cases, remain to be systematically determined.
Although a role of magnesium deficiency in neurodegen-
erative disease is established, and may be mediated by
interaction of magnesium ions with glial cells,
the inter-
relationship between inflammation in the nervous system
and systemic inflammation needs to be better understood.
Thus, there exist plausible mechanisms by which several
metabolic and inflammatory conditions might potentially
be alleviated through magnesium administration, either
systemically or locally. These mechanisms are ripe for fur-
ther investigation.
Author contributions: All authors participated in the writ-
ing, review and editing of this manuscript. NCC and CW
contributed equally to the writing of this manuscript.
This work was funded by grants from the University of
Queensland, The National Health and Medical Research coun-
cil of Australia, and Cancer Council Queensland.
1. Sukenik S, Abu-Shakra M, Kudish S, Flusser D. Dead Sea and Tiberias as
health resort areas for patients suffering from different types of arthritis.
Harefuah 2006;145:117–22
2. Shani J, Eevn-paz Z, Avrach WW, Rubinstein N, Livshin R, Justesen NPB,
Harkmark W. Topical replacement therapy of psoriasis by Dead Sea salts.
Dermatosen 1991;39:49–53
3. Proksch E, Nissen HP, Bremgartner M UC. Bathing in magnesium rich
Dead Sea salt improves skin barrier function, enhances skin hydration,
and reduces inflammation in atopic dry skin. Int J Dermatol 2005;44:151–7
4. Durlach J, Guiet-Bara a, Page
s N, Bac P, Bara M. Magnesium chloride or
magnesium sulfate: a genuine question. Magnes Res 2005;18:187–92
5. Brisson P. Percutaneous absorption. Can Med Assoc J 1974;110:1182–5
6. Kligman AM. A biological brief on percutaneous absorption. Drug Dev
Ind Pharm 1983;9:521–60
Chandrasekaran et al. Mg
deficiency More than skin deep 1287
at UQ Library on February 20, 2015ebm.sagepub.comDownloaded from
7. Winkelmann RK. The relationship of the structure of the epidermis to
percutaneous absorption. Br J Dermatol 1969;81:11–22
8. Lansdown AB. Physiological and toxicological changes in the skin
resulting from the action and interaction of metal ions. Crit Rev Toxicol
9. Hosty
nek JJ, Hinz RS, Lorence CR, Price M, Guy RH. Metals and the
skin. Crit Rev Toxicol 1993;23:171–235
10. Jahnen-Dechent W, Ketteler M. Magnesium basics. Clin Kidney J
11. Abels DJ, Even-Paz Z, Efron D. Bioclimatology at the Dead Sea in Israel.
Clin Dermatol 2014;14:653–8
12. Boaz M, Shtendik L, Oron M, Portugal-Cohen M, Kohen R, Biro A,
Cernes R, Barnea Z, Maor Z, Katzir Z. A randomized controlled clinical
trial comparing the efficacy of Dead Sea mineral-enriched body lotion
versus two types of placebo in the treatment of cutaneous dryness,
itching, peeling and tightness in hemodialysis patients. Nephron Clin
Pract 2009;113:169–76
13. Halevy S, Giryes H, Friger M, Sukenik S. Dead sea bath salt for the
treatment of psoriasis vulgaris: a double-blind controlled study. JEur
Acad Dermatol Venereol 1997;9:237–42
14. Takano N, Sakurai T, Kurachi M. Effects of anti-nerve growth factor
antibody on symptoms in the NC/Nga mouse, an atopic dermatitis
model. J Pharmacol Sci 2005;99:277–86
15. Washington N, Washington C, Wilson CG. Structure of the skin; passage
of drug through the skin. Physiological pharmaceutics: barriers to drug
absorption. London: Taylor and Francis Group, 2001, pp. 182–7
16. Denda M, Katagiri C, Hirao T, Maruyama N, Takahashi M. Some
magnesium salts and a mixture of magnesium and calcium salts
accelerate skin barrier recovery. Arch Dermatol Res 1999;291:560–3
17. Ainsworth C. Skin: into the breach. Nature 2011;479:S12–13
18. Brown P. Atopy: marching with allergies. Nature 2011;479:S14–15
19. Denda M. Skin barrier function as a self-organizing system. Cell
20. Maguire ME, Cowan JA. Magnesium chemistry and biochemistry.
Biometals 2002;15:203–10
21. McCallum DI, Hall GF. Umbilical granulomata–with particular refer-
ence to talc granuloma. Br J Dermatol 1970;83:151–6
22. Tye MJ, Hashimoto K, Fox F. Talc granulomas of the skin. JAMA
23. Kopito L, Elian E, Shwachman H. Sodium, potassium, calcium, and
magnesium in hair from neonates with cystic fibrosis and in amniotic
fluid from mothers of such children. Pediatrics 1972;49:620–4
24. Elias PM, Tsai J, Menon GK, Holleran WM, Feingold KR. The potential
of metabolic interventions to enhance transdermal drug delivery.
Investig Dermatol Symp Proc 2002;7:79–85
25. Diebler H, Eigen M, Ilgenfritz G, Maass G, Winkler R. Kinetics and
mechanism of reactions of main group metal ions with biological car-
riers. Pure Appl Chem Int Union Pure Appl Chem 1969;20:93–116
26. Eigen M. Fast elementary steps in chemical reaction mechanisms. Pure
Appl Chem Int Union Pure Appl Chem 1963;6:97–116
27. Sahni J, Nelson B, Scharenberg AM. SLC41A2 encodes a plasma-
membrane Mg
transporter. Biochem J 2007;401:505–13
28. Chen H-C, Su L-T, Gonza
n O, Overton JD, Runnels LW. A key
role for Mg(2þ) in TRPM7’s control of ROS levels during cell stress.
Biochem J 2012;445:441–8
29. Sahni J, Scharenberg AM. TRPM7 ion channels are required for sus-
tained phosphoinositide 3-kinase signaling in lymphocytes. Cell Metab
30. Rojanasakul Y, Wang LY, Bhat M, Glover DD, Malanga CJ, Ma JK. The
transport barrier of epithelia: a comparative study on membrane per-
meability and charge selectivity in the rabbit. Pharm Res 1992;9:1029–34
31. Piemi MP, Korner D, Benita S, Marty JP. Positively and negatively
charged submicron emulsions for enhanced topical delivery of anti-
fungal drugs. J Control Release 1999;58:177–87
32. Singh I, Morris AP. Performance of transdermal therapeutic systems:
effects of biological factors. Int J Pharm Investig 2011;1:4–9
33. Roberts MS, Cross SE, Pellet MA. Skin transport. Dermatological and
transdermal formulations. New York: Markel Dekker, 2002, pp. 1–30
34. Park J-H, Lee J-W, Kim Y-C, Prausnitz MR. The effect of heat on skin
permeability. Int J Pharm 2008;359:94–103
35. Hirvonen J, Murtoma
ki L, Kontturi K. Effect of diffusion potential,
osmosis and ion-exchange on transdermal drug delivery: theory and
experiments. J Control Release 1998;56:33–9
36. Williams AC, Barry BW. Penetration enhancers. Adv Drug Deliv Rev
37. Nowacki W, Daveau M, Malpuech-Bruge C. Inflammatory response
following acute magnesium deficiency in the rat. Biochim Biophys Acta
38. Yamauchi T, Miyoshi D, Kubodera T, Nishimura A, Nakai S,
Sugimoto N. Roles of Mg
in TPP-dependent riboswitch. FEBS Lett
39. Kubodera T, Watanabe M, Yoshiuchi K, Yamashita N, Nishimura A,
Nakai S, Gomi K, Hanamoto H. Thiamine-regulated gene expression of
Aspergillus oryzae thiA requires splicing of the intron containing a
riboswitch-like domain in the 5
-UTR. FEBS Lett 2003;555:516–20
40. Lai EC. RNA sensors and riboswitches: self-regulating messages. Curr
Biol 2003;13:R285–91
41. Winkler W, Nahvi A, Breaker RR. Thiamine derivatives bind messenger
RNAs directly to regulate bacterial gene expression. Nature
42. Kumar A, Rajput CS, Bhati SK. Synthesis of 3-[4
-yl]-2-[(substituted azetidinone/thiazolidinone)-amino-
methyl]-6-bromoquinazolin-4-ones as anti-inflammatory agent. Bioorg
Med Chem 2007;15:3089–96
43. Holla BS, Malini KV, Rao BS, Sarojini BK, Kumari NS. Synthesis of some
new 2,4-disubstituted thiazoles as possible antibacterial and anti-
inflammatory agents. Eur J Med Chem 2003;38:313–8
44. Kalkhambkar RG, Kulkarni GM, Shivkumar H, Rao RN. Synthesis of
novel triheterocyclic thiazoles as anti-inflammatory and analgesic
agents. Eur J Med Chem 2007;42:1272–6
45. Rostom SAF, el-Ashmawy IM, Abd el Razik HA, Badr MH,
Ashour HMA. Design and synthesis of some thiazolyl and thiadiazolyl
derivatives of antipyrine as potential non-acidic anti-inflammatory,
analgesic and antimicrobial agents. Bioorg Med Chem 2009;17:882–95
46. Koufaki M, Kiziridi C, Nikoloudaki F, Alexis MN. Design and synthesis
of 1,2-dithiolane derivatives and evaluation of their neuroprotective
activity. Bioorg Med Chem Lett 2007;17:4223–7
47. Guerrero-Romero F, Rodrı
n M. Hypomagnesemia, oxidative
stress, inflammation, and metabolic syndrome. Diabetes Metab Res Rev
48. Rude RK, Wei L, Norton HJ, Lu SS, Dempster DW, Gruber HE.
TNFalpha receptor knockout in mice reduces adverse effects of mag-
nesium deficiency on bone. Growth Factors 2009;27:370–6
49. Aringer M, Feierl E, Steiner G, Stummvoll G, Ho
fler E, Steiner C,
Radda I, Smolen J, Graninger W. Increased bioactive TNF in human
systemic lupus erythematosus: associations with cell death. Lupus
50. Rodriguez-Mora
n M, Guerrero-Romero F. Elevated concentrations of
TNF-alpha are related to low serum magnesium levels in obese subjects.
Magnes Res 2004;17:189–96
51. Sugimoto J, Romani AM, Valentin-Torres AM, Luciano AA, Ramirez
Kitchen CM, Funderburg N, Mesiano S, Bernstein HB. Magnesium
decreases inflammatory cytokine production: a novel innate immuno-
modulatory mechanism. J Immunol 2012;188:6338–46
52. Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis
factor antagonist mechanisms of action: a comprehensive review.
Pharmacol Ther 2008;117:244–79
53. Silswal N, Singh AK, Aruna B, Mukhopadhyay S, Ghosh S,
Ehtesham NZ. Human resistin stimulates the pro-inflammatory cyto-
kines TNF-alpha and IL-12 in macrophages by NF-kappaB-dependent
pathway. Biochem Biophys Res Commun 2005;334:1092–101
54. Bowcock AM, Krueger JG. Getting under the skin: the immunogenetics
of psoriasis. Nat Rev Immunol 2005;5:699–711
55. Stannus O, Jones G, Cicuttini F, Parameswaran V, Quinn S, Burgess J,
Ding C. Circulating levels of IL-6 and TNF-a are associated with knee
radiographic osteoarthritis and knee cartilage loss in older adults.
Osteoarthritis Cartilage 2010;
1288 Experimental Biology and Medicine Volume 239 October 2014
at UQ Library on February 20, 2015ebm.sagepub.comDownloaded from
56. Bussie
re FI, Tridon A, Zimowska W, Mazur A, Rayssiguier Y. Increase in
complement component C3 is an early response to experimental mag-
nesium deficiency in rats. Life Sci 2003;73:499–507
57. Weglicki WB. Hypomagnesemia and inflammation: clinical and basic
aspects. Annu Rev Nutr 2012;32:55–71
58. Barbagallo M, Dominguez LJ. Magnesium and aging. Curr Pharm Des
59. Ferre
S, Baldoli E, Leidi M, Maier JAM. Magnesium deficiency pro-
motes a pro-atherogenic phenotype in cultured human endothelial cells
via activation of NFkB. Biochim Biophys Acta 2010;1802:952–8
60. Maier JAM, Malpuech-bruge C, Rayssiguier Y, Mazur A. Low magne-
sium promotes endothelial cell dysfunction: implications for athero-
sclerosis, inflammation and thrombosis. Biochim Biophys Acta
61. Ogura H, Murakami M, Okuyama Y, Tsuruoka M, Kitabayashi C,
Kanamoto M, Nishihara M, Iwakura Y, Hirano T. Interleukin-17 pro-
motes autoimmunity by triggering a positive-feedback loop via inter-
leukin-6 induction. Immunity 2008;29:628–36
62. Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 cells. Annu
Rev Immunol 2009;27:485–517
63. Weber A, Wasiliew P, Kracht M. Interleukin-1 (IL-1) pathway. Sci Signal
64. Bachwich PR, Chensue SW, Larrick JW, Kunkel SL. Tumor necrosis
factor stimulates interleukin-1 and prostaglandin E2 production in
resting macrophages. Biochem Biophys Res Commun 1986;136:94–101
65. Dinarello CA, Cannon JG, Wolff SM, Bernheim HA, Beutler B,
Cerami A, Figari IS, Palladino MA, O’Connor JV. Tumor necrosis factor
(cachectin) is an endogenous pyrogen and induces production of
interleukin 1. J Exp Med 1986;163:1433–50
66. Beutler B, Cerami A. Cachectin and tumour necrosis factor as two sides
of the same biological coin. Nature 1986;320:584–8
67. Collart MA, Baeuerle P, Vassalli P. Regulation of tumor necrosis factor
alpha transcription in macrophages: involvement of four kappa B-like
motifs and of constitutive and inducible forms of NF-kappa B. Mol Cell
Biol 1990;10:1498–506
68. Foey AD, Parry SL, Williams LM, Feldmann M, Foxwell BM,
Brennan FM. Regulation of monocyte IL-10 synthesis by endogenous
IL-1 and TNF-alpha: role of the p38 and p42/44 mitogen-activated
protein kinases. J Immunol 1998;160:920–8
69. De Jong EC, Vieira PL, Kalinski P, Kapsenberg ML. Corticosteroids
inhibit the production of inflammatory mediators in immature mono-
cyte-derived DC and induce the development of tolerogenic DC3.
J Leukoc Biol 1999;66:201–4
70. Abbott L, Nadler J, Rude RK. Magnesium deficiency in alcoholism:
possible contribution to osteoporosis and cardiovascular disease in
alcoholics. Alcohol Clin Exp Res 1994;
Black RA. Tumor necrosis factor-a converting enzyme. Int J Biochem Cell
Biol 2002;34:1–5
72. Kriegler M, Perez C, DeFay K, Albert I, Lu SD. A novel form of TNF/
cachectin is a cell surface cytotoxic transmembrane protein: ramifica-
tions for the complex physiology of TNF. Cell 1988;53:45–53
73. Cabal-Hierro L, Lazo PS. Signal transduction by tumor necrosis factor
receptors. Cell Signal 2012;24:1297–305
74. Vince JE, Pantaki D, Feltham R, Mace PD, Cordier SM, Schmukle AC,
Davidson AJ, Callus BA, Wong WW-L, Gentle IE, Carter H, Lee EF,
Walczak H, Day CL, Vaux DL, Silke J. TRAF2 must bind to cellular
inhibitors of apoptosis for tumor necrosis factor (tnf) to efficiently
activate nf-{kappa}b and to prevent tnf-induced apoptosis. J Biol Chem
75. Wang Y, Zhang P, Liu Y, Cheng G. TRAF-mediated regulation of
immune and inflammatory responses. Sci China Life Sci 2010;53:159–68
76. Malpuech-Bruge
re C, Rock E, Astier C, Nowacki W, Mazur A,
Rayssiguier Y. Exacerbated immune stress response during experi-
mental magnesium deficiency results from abnormal cell calcium
homeostasis. Life Sci 1998;63:1815–22
77. Rayssiguier Y, Libako P, Nowacki W, Rock E. Magnesium deficiency
and metabolic syndrome: stress and inflammation may reflect calcium
activation. Magnes Res 2010;23:73–80
78. Waddell TK, Fialkow L, Chan CK, Kishimoto TK, Downey GP.
Potentiation of the oxidative burst of human neutrophils. A signaling
role for L-selectin. J Biol Chem 1994;269:18485–91
79. Pahl HL, Baeuerle PA. Activation of NF-kappa B by ER stress requires
both Ca
and reactive oxygen intermediates as messengers. FEBS Lett
80. Bussie
re FI, Gueux E, Rock E, Mazur A, Rayssiguier Y. Protective effect
of calcium deficiency on the inflammatory response in magnesium-
deficient rats. Eur J Nutr 2002;41:197–202
81. Yamauchi S, Ito H, Miyajima A. IjBZ, a nuclear IjB protein, positively
regulates the NF-jB-mediated expression of proinflammatory cyto-
kines. Proc Natl Acad Sci 2010;107:11924–9
82. Drouet C. Enhancers and transcription factors controlling the induci-
bility of the tumor necrosis factor-cx promoter. J Immunol
83. Baeuerle PA, Henkel T. Function and activation of NF-kappa B in the
immune system. Annu Rev Immunol 1994;12:141–79
84. Shea LM, Beehler C, Schwartz M, Shenkar R, Tuder R. Hyperoxia
activates NF-KB and increases TNF-a. J Immunol 1996;157:3902–8
85. Geha RS, Jabara HH, Brodeur SR. The regulation of immunoglobulin E
class-switch recombination. Nat Rev Immunol 2003;3:721–32
86. Lee M, Jantaratnotai N, McGeer E, McLarnon JG, McGeer PL. Mg
ions reduce microglial and THP-1 cell neurotoxicity by inhibiting Ca
entry through purinergic channels. Brain Res 2011;1369:21–35
87. Acun
a-Castillo C, Coddou C, Bull P, Brito J, Huidobro-Toro JP.
Differential role of extracellular histidines in copper, zinc, magnesium
and proton modulation of the P2X7 purinergic receptor. J Neurochem
88. Zhao ML, Liu JS, He D, Dickson DW, Lee SC. Inducible nitric oxide
synthase expression is selectively induced in astrocytes isolated from
adult human brain. Brain Res 1998;813:402–5
89. Libermann TA, Baltimore D. Activation of interleukin-6 gene expres-
sion through the NF-KB transcription factor. Mol Cell Biol
90. Young HA, Hardy KJ. Role of interferon-gamma in immune cell
regulation. J Leukoc Biol 1995;58:373–81
91. Mazur A, Maier JAM, Rock E, Gueux E, Nowacki W, Rayssiguier Y.
Magnesium and the inflammatory response: potential physiopatho-
logical implications. Arch Biochem Biophys 2007;458:48–56
92. Weglicki WB, Chmielinska JJ, Kramer JH, Mak IT. Cardiovascular and
intestinal responses to oxidative and nitrosative stress during pro-
longed magnesium deficiency. Am J Med Sci 2011;342:125–8
93. Weglicki WB, Dickens BF, Wagner TL, Chmielinska JJ, Phillips TM.
Immunoregulation by neuropeptides in magnesium deficiency: ex
vivo effect of enhanced substance P production on circulating T
lymphocytes from magnesium-deficient mice. Magnes Res 1996;9:3–11
94. Nowacki W, Malpuech-Bruge
re C, Rock E, Rayssiguier Y. High-mag-
nesium concentration and cytokine production in human whole blood
model. Magnes Res 2009;22:93–6
95. Suzuki-Kakisaka H, Sugimoto J, Tetarbe M, Romani AM, Ramirez
Kitchen CM, Bernstein HB. Magnesium sulfate increases intracellular
magnesium reducing inflammatory cytokine release in neonates. Am J
Reprod Immunol 2013;70:213–20
96. Tanaka T, Narazaki M, Kishimoto T. Therapeutic targeting of the
interleukin-6 receptor. Annu Rev Pharmacol Toxicol 2012;52:199–219
97. Krueger JG, Krane JF, Carter DM, Gottlieb AB. Role of growth factors,
cytokines, and their receptors in the pathogenesis of psoriasis.
J Investig Dermatol 1990;94:135S–40S
98. Groves RW, Allen MH, Ross EL, Barker JN, MacDonald DM. Tumour
necrosis factor alpha is pro-inflammatory in normal human skin and
modulates cutaneous adhesion molecule expression. Br J Dermatol
99. Biedermann T, Kneilling M, Mailhammer R, Maier K, Sander CA,
Kollias G, Kunkel SL, Hu
ltner L, Ro
cken M. Mast cells control neu-
trophil recruitment during T cell-mediated delayed-type hypersensi-
tivity reactions through tumor necrosis factor and macrophage
inflammatory protein. J Exp Med 2000;192:1441–52
100. Chan JR, Blumenschein W, Murphy E, Diveu C, Wiekowski M,
Abbondanzo S, Lucian L, Geissler R, Brodie S, Kimball AB,
Chandrasekaran et al. Mg
deficiency More than skin deep 1289
at UQ Library on February 20, 2015ebm.sagepub.comDownloaded from
Gorman DM, Smith K, de Waal Malefyt R, Kastelein R a,
McClanahan TK, Bowman EP. IL-23 stimulates epidermal hyperplasia
via TNF and IL-20R2-dependent mechanisms with implications for
psoriasis pathogenesis. J Exp Med 2006;203:2577–87
101. Pachikian BD, Neyrinck AM, Deldicque L, Backer FC De, Catry E,
Dewulf EM, Sohet FM, Bindels LB, Everard A, Francaux M, Guiot Y,
Cani PD, Delzenne NM. Changes in intestinal bifidobacteria levels are
associated with the inflammatory response in magnesium-deficient
mice. J Nutr 2010;140:509–14
102. Setoyama H, Imaoka A, Ishikawa H, Umesaki Y. Prevention of gut
inflammation by Bifidobacterium in dextran sulfate-treated gnoto-
biotic mice associated with bacteroides strains isolated from ulcerative
colitis patients. Microbes Infect 2003;5:115–22
103. Bowe WP, Logan AC. Acne vulgaris, probiotics and the gut-brain-skin
axis - back to the future? Gut Pathog 2011;3:1
104. Gue
niche A, Bastien P, Ovigne JM, Kermici M, Courchay G,
Chevalier V, Breton L, Castiel-Higounenc I. Bifidobacterium longum
lysate, a new ingredient for reactive skin. Exp Dermatol 2010;19:1–8
105. Bussie
re FI, Gueux E, Rock E, Girardeau JP, Tridon A, Mazur A,
Rayssiguier Y, Girardeau J. Increased phagocytosis and production of
reactive oxygen species by neutrophils during magnesium deficiency
in rats and inhibition by high magnesium concentration. Br J Nutr
106. Weglicki WB, Phillips TM, Freedman a M, Cassidy MM, Dickens BF.
Magnesium-deficiency elevates circulating levels of inflammatory
cytokines and endothelin. Mol Cell Biochem 1992;110:169–73
107. Mak IT, Dickens BF, Komarov AM, Wagner TL, Phillips TM,
Weglicki WB. Activation of the neutrophil and loss of plasma gluta-
thione during Mg-deficiency–modulation by nitric oxide synthase
inhibition. Mol Cell Biochem 1997;176:35–9
108. Marriott I, Mason MJ, Elhofy A, Bost KL. Substance P activates NF-kB
independent of elevations in intracellular calcium in murine macro-
phages and dendritic cells. J Neuroimmunol 2000;102:163–71
109. Ferre
S, Mazur A, Maier JAM. Low-magnesium induces senescent
features in cultured human endothelial cells. Magnes Res 2007;20:66–71
110. Uchida T, Itoh H, Nakamura Y, Kobayashi Y, Hirai K, Suzuki K,
Sugihara K, Kanayama N, Hiramatsu M. Zinc and magnesium ions
synergistically inhibit superoxide generation by cultured human
neutrophils–a promising candidate formulation for amnioinfusion
fluid. J Reprod Immunol 2010;85:209–13
111. Uchi H, Terao H, Koga T, Furue M. Cytokines and chemokines in the
epidermis. J Dermatol Sci 2000;24:S29–38
112. Petrault I, Zimowska W, Mathieu J, Bayle D, Rock E, Favier A,
Rayssiguier Y, Mazur A. Changes in gene expression in rat thymocytes
identified by cDNA array support the occurrence of oxidative stress in
early magnesium deficiency. Biochim Biophys Acta 2002;1586
13. Libby P. Inflammatory mechanisms: the molecular basis of inflamma-
tion and disease. Nutr Rev 2007;65:140–6
114. Saris NE, Mervaala E, Karppanen H, Khawaja JA, Lewenstam A,
Magnesium. An update on physiological, clinical and analytical
aspects. Clin Chim Acta 2000;294:1–26
115. Altura BM, Altura BT. Cardiovascular risk factors and magnesium:
relationships to atherosclerosis, ischemic heart disease and hyperten-
sion. Magnes Trace Elem 2011;10:182–92
116. Zandsteeg AMG, Hirmann P, Pasma HR, Yska J-P, ten Brinke A. Effect
of MgSO
on FEV
in stable severe asthma patients with chronic air-
flow limitation. Magnes Res 2009;22:256–61
117. Bochner BS. Immunological aspects of allergic asthma. Annu Rev
Immunol 1994;12:295–335
118. Yamamoto Y, Gaynor RB. Therapeutic potential of inhibition of the NF-
kappaB pathway in the treatment of inflammation and cancer. J Clin
Invest 2001;107:135–42
119. Dunnett J, Nayler WG. Calcium efflux from cardiac sarcoplasmic
reticulum: effects of calcium and magnesium. J Mol Cell Cardiol
120. D’Angelo EK, Singer HA, Rembold CM. Magnesium relaxes arterial
smooth muscle by decreasing intracellular Ca
without changing
intracellular Mg
. J Clin Invest 1992;89:1988–94
121. Feldmann M, Maini SRN. Role of cytokines in rheumatoid arthritis: an
education in pathophysiology and therapeutics. Immunol Rev
122. Altura BM, Gebrewold A, Zhang A, Altura BT. Low extracellular
magnesium ions induce lipid peroxidation and activation of nuclear
factor-kappa B in canine cerebral vascular smooth muscle: possible
relation to traumatic brain injury and strokes. Neurosci Lett
123. Ma J, Folsom AR, Melnick SL, Eckfeldt JH, Sharrett AR, Nabulsi AA,
Hutchinson RG, Metcalf PA. Associations of serum and dietary mag-
nesium with cardiovascular disease, hypertension, diabetes, insulin,
and carotid arterial wall thickness: the ARIC study. Atherosclerosis
Risk in Communities Study. J Clin Epidemiol 1995;48:927–40
124. Hellerstein EE, Vitale JJ, White PL, Hegsted DM, Zamcheck N,
Nakamura M. Influence of dietary magnesium on cardiac and renal
lesions of young rats fed an atherogenic diet. J Exp Med
125. Whelton PK, Klag MJ. Magnesium and blood pressure: review of the
epidemiologic and clinical trial experience. Am J Cardiol
126. Woods KL. Possible pharmacological actions of magnesium in acute
myocardial infarction. Br J Clin Pharmacol 1991;32:3–10
127. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM,
Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE,
Frautschy S, Griffin WS, Hampel H, Hull M, Landreth G, Lue L,
Mrak R, Mackenzie IR, McGeer PL, O’Banion MK, Pachter J,
Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Shen Y, Streit W,
Strohmeyer R, Tooyoma I, Van Muiswinkel FL, Veerhuis R, Walker D,
Webster S, Wegrzyniak B, Wenk G, Wyss-Coray T. Inflammation and
Alzheimer’s disease. Neurobiol Aging 2000;21:383–421
128. McGeer PL, McGeer EG. Inflammation and the degenerative diseases
of aging. Ann N Y Acad Sci 2004;1035:104–16
129. Ralay Ranaivo H, Craft JM, Hu W, Guo L, Wing LK, Van Eldik LJ,
Watterson DM. Glia as a therapeutic target: selective suppression of
human amyloid-beta-induced upregulation of brain proinflammatory
cytokine production attenuates neurodegeneration. J Neurosci
130. Giulian D. Microglia and the immune pathology of Alzheimer disease.
Am J Hum Genet 1999;65:13–8
131. Craft JM, Watterson DM, Van Eldik LJ. Neuroinflammation: a potential
therapeutic target. Expert Opin Ther Targets 2005;9:887–900
132. Marinov MB, Harbaugh KS, Hoopes PJ, Pikus HJ, Harbaugh RE.
Neuroprotective effects of preischemia intraarterial magnesium sul-
fate in reversible focal cerebral ischemia. J Neurosurg 1996;85:117–24
133. McDonald JW, Silverstein FS, Johnston MV. Magnesium reduces
(NMDA)-mediated brain injury in perinatal rats. Neurosci Lett
134. Weglicki WB, Phillips TM, Mak IT, Cassidy MM, Dickens BF,
Stafford R, Kramer JH. Cytokines, neuropeptides, and reperfusion
injury during magnesium deficiency. Ann N Y Acad Sci
135. Klegeris A, Bissonnette CJ, McGeer PL. Modulation of human micro-
glia and THP-1 cell toxicity by cytokines endogenous to the nervous
system. Neurobiol
Aging 2005;26:673–82
136. Pincelli C, Sevignani C, Manfredini R, Grande A, Fantini F, Bracci-
Laudiero L, Aloe L, Ferrari S, Cossarizza A, Giannetti A. Expression
and function of nerve growth factor and nerve growth factor receptor
on cultured keratinocytes. J Invest Dermatol 1994;103:13–8
137. Dou Y-C, Hagstro
mer L, Emtestam L, Johansson O. Increased nerve
growth factor and its receptors in atopic dermatitis: an immunohis-
tochemical study. Arch Dermatol Res 2006;298:31–7
138. Wolfgang A Nockher, Sanchaita Sonar, Harald Renz. Neurotrophins.
Allergy and allergic diseases. New York, NY: Wiley-Blackwell, 2008:507
139. Tominaga M, Takamori K. An update on peripheral mechanisms and
treatments of itch. Biol Pharm Bull 2013;36:1241–7
140. Kruger RP, Aurandt J, Guan K-L. Semaphorins command cells to
move. Nat Rev Mol Cell Biol 2005;6:789–800
141. Neufeld G, Kessler O. The semaphorins: versatile regulators of tumour
progression and tumour angiogenesis. Nat Rev Cancer 2008;8:632–45
1290 Experimental Biology and Medicine Volume 239 October 2014
at UQ Library on February 20, 2015ebm.sagepub.comDownloaded from
142. Ikezawa Z, Komori J, Ikezawa Y, Inoue Y, Kirino M, Katsuyama M,
Aihara M. A role of staphyococcus aureus, interleukin-18, nerve growth
factor and semaphorin 3A, an axon guidance molecule, in pathogen-
esis and treatment of atopic dermatitis. Allergy Asthma Immunol Res
143. Nikoletta N, Katalin F, Sarolta B, Istvan B, Zsuzsanna BC, Lajos K,
Marta S. NRP1 activates NF-jB signaling pathway and initiates
proliferation in keratinocytes. Int J Genomic Med 2013;1:102
144. Fukamachi S, Bito T, Shiraishi N, Kobayashi M, Kabashima K,
Nakamura M, Tokura Y. Modulation of semaphorin 3A expression by
calcium concentration and histamine in human keratinocytes and
fibroblasts. J Dermatol Sci 2011;61:118–23
145. Malaviya R, Uckun FM. Role of STAT6 in IgE receptor/FcepsilonRI-
mediated late phase allergic responses of mast cells. J Immunol
146. Ichiro Katayama, Hiroyuki Murota, Ken Igawa, Takahiro Satoh,
Kiyoshi Nishioka, Hiroo Yokozeki A. Targeting STAT6 in
atopic eczema/dermatitis. In: Ruby Pawankar, Stephen T. Holgate,
Lanny J. Rosenwasser (ed.) Allergy Frontiers: Future Perspectives. Tokyo:
Springer, 2010, pp.167–78
147. Song Y, Li TY, van Dam RM, Manson JE, Hu FB. Magnesium intake and
plasma concentrations of markers of systemic inflammation and
endothelial dysfunction in women. Am J Clin Nutr 2007;85:1068–74
148. Sara AC, Yiqing S, Lauren N, Lesley T, Ian H dB, Fran T, Robert W,
Simin L. Relations of dietary magnesium intake to biomarkers of
inflammation and endothelial dysfunction in an ethnically diverse
cohort of postmenopausal women. Diab Care 2010;33:304–10
149. Rayssiguier Y, Gueux E, Nowacki W, Rock E, Mazur A. High fructose
consumption combined with low dietary magnesium intake may
increase the incidence of the metabolic syndrome by inducing
inflammation. Magnes Res 2006;19:237–43
150. Brown DM, Donaldson K, Borm PJ, Schins RP, Dehnhardt M,
Gilmour P, Jimenez LA, Stone V. Calcium and ROS-mediated activa-
tion of transcription factors and TNF-alpha cytokine gene expression
in macrophages exposed to ultrafine particles. Am J Physiol Lung Cell
Mol Physiol 2004;286:L344–53
151. Kelepouris E, Agus ZS. Hypomagnesemia: renal magnesium hand-
ling. Semin Nephrol 1998;18:58–73
(Received February 9, 2014, Accepted April 14, 2014)
Chandrasekaran et al. Mg
deficiency More than skin deep 1291
at UQ Library on February 20, 2015ebm.sagepub.comDownloaded from
... Permeability of the skin to magnesium ions doi:10.1684/mrh.2016.0402 could be dependent on pathways associated with appendages, glands, hair follicles, hydration state or integrity of the SC [5]. The barrier property of SC has been widely discussed, with the general view promulgated in the literature that the layer acts as a selective barrier to transport of ions [6,7]. ...
... Å 3 [ 4 3 (4.76) 3 ] in the hydrated state, but based on the ionic radii of dehydrated and hydrated magnesium ions, i.e., 0.87 Å and 4.76 Å respectively [10][11][12][13], we calculated that the hydrated radius of the ion is only 5.47 fold ( 4.76 Å 0.87 Å ) greater than its dehydrated radius. Based on our recalculation, and on published data showing systemic effects of topical magnesium [1,5], we postulated that the hydrated magnesium ion could potentially penetrate by bulk diffusion through the 10 Å pores formed by protein subunits in the lipid membrane [5,14], or by other means, such as hair follicles. To test this postulate, we conducted experiments to test and visualize magnesium penetration, localization and concentration in human epidermis. ...
... Å 3 [ 4 3 (4.76) 3 ] in the hydrated state, but based on the ionic radii of dehydrated and hydrated magnesium ions, i.e., 0.87 Å and 4.76 Å respectively [10][11][12][13], we calculated that the hydrated radius of the ion is only 5.47 fold ( 4.76 Å 0.87 Å ) greater than its dehydrated radius. Based on our recalculation, and on published data showing systemic effects of topical magnesium [1,5], we postulated that the hydrated magnesium ion could potentially penetrate by bulk diffusion through the 10 Å pores formed by protein subunits in the lipid membrane [5,14], or by other means, such as hair follicles. To test this postulate, we conducted experiments to test and visualize magnesium penetration, localization and concentration in human epidermis. ...
Magnesium is an important micronutrient essential for various biological processes and its deficiency has been linked to several inflammatory disorders in humans. Topical magnesium delivery is one of the oldest forms of therapy for skin diseases, for example Dead Sea therapy and Epsom salt baths. Some anecdotal evidence and a few published reports have attributed amelioration of inflammatory skin conditions to the topical application of magnesium. On the other hand, transport of magnesium ions across the protective barrier of skin, the stratum corneum, is contentious. Our primary aim in this study was to estimate the extent of magnesium ion permeation through human skin and the role of hair follicles in facilitating the permeation. Upon topical application of magnesium solution, we found that magnesium penetrates through human stratum corneum and it depends on concentration and time of exposure. We also found that hair follicles make a significant contribution to magnesium penetration.
... 50-60%) are mineralised in the bones, about 40-45% of this element is present in muscles and other soft tissues and about 1% is located in the extracellular fluid (saris et al. 2000, vormann 2003). Magnesium absorption takes place over the entire length of the colon (in the ileum and jejunum), thus the inflammation of the GI tract and other disorders of the GI may disturb magnesium absorption (ChandraseKaran et al. 2014). Increased kidney elimination may also influence magnesium status. ...
... In the second group of 'a potentially significant' category (amikacin, gentamicin, tobramycin, laxatives, pentamidine, tacrolimus and carboplatin), magnesium monitoring is of importance especially when one of the following occurs: clinical manifestations are apparent; persistent hypokalaemia, hypocalcaemia or alkalosis are present; other precipitating factors for hypomagnesaemia coexist; or treatment is with more than one potentially hypomagnesaemic drug. In the third group with diuretics, treatment should be started only if hypomagnesaemia is accompanied by symptoms or clinically significant relevant laboratory findings (ChandraseKaran et al. 2014). As there is a high percentage of patients treated with chemotherapy and radiotherapy, this may produce significant toxicity to patients in conjunction with electrolyte imbalance and hypomagnesaemia, which may further lead to interruption of cancer treatment and increased mortality. ...
Full-text available
Magnesium deficiency among oncological patients is a complex condition. Hypomagnesaemia is observed during anti-cancer chemotherapy and during treatment of certain co-existing disorders. Assessing magnesium status is difficult, as serum levels have little correlation with total body magnesium status. Thus, the aim of this study was to provide more recent data about possible ways of magnesium insufficiency among oncological patients with focus on health status, pharmacological treatment and magnesium-rich food products' intake. 380 oncological patients (304 reliable surveys) with concurrent chemotherapy, radiotherapy and surgery from the Clinical The mean magnesium dietary intake was 224 mg daily among women and 295 mg per day among men, which was found insufficient. Consumption of some food products rich in magnesium such as cacao, legumes, nuts and seeds was found to be scarce. Dietary supplementation of magnesium was also inadequate (3%). In addition, high daily consumption of coffee (67.1%) and strong tea (81.85%) was reported. Moreover, obesity (47.8%), together with gastrointestinal disorders as diarrhoea and vomiting (52%) persist which may further contribute to magnesium deficiency. Patient medication record has also revealed previous intake of some drugs that have a highly susceptibility in the development of hypomagnesemia. Regular monitoring for enteritis and hypomagnesemia with timely intervention as well as magnesium-rich food products included in daily diet could help improve compliance, and decrease treatment interruptions and thereby achieve the optimum treatment outcome.
... Therefore, it is posited that magnesium intake can improve hair loss in women [13]. Magnesium may also have beneficial effect on skin lesions and acne; for instance, previous studies have shown that magnesium improves collagen production in the skin, whilst low magnesium intake may cause inflammation [14]. Also, serum magnesium levels have been shown to be low in patients with acne [15], and co-supplementation of magnesium and myoinositol was reported to improve acne [16] Magnesium may have favorable effect on components of quality of life including depression [17,18], where previous studies showed that magnesium supplementation improved depression in diabetic and non-diabetic patients [19,20]. ...
... Using topical magnesium has been reported to result in increased skin hydration and skin permeability, repairing barriers, and facilitating skin proliferation by penetrating beneath the stratum corneum. A local inflammatory process was observed in the skin among subjects with magnesium deficiency [14], and aa cross-sectional study showed that there was a direct association between severity of vulgaris acne and magnesium level [48]; however, the evidence is equivocal. Two clinical trials reported the impact of magnesium containing drugs/supplements on acne. ...
Full-text available
Background Abnormal uterine bleeding (AUB), alopecia, low quality of life, and acne are considered as complications of polycystic ovary syndrome (PCOS). We hypothesized that magnesium supplementation would yield beneficial effects on PCOS related complications. Objective To examine the effects of magnesium supplementation on AUB, alopecia, quality of life, and acne. Methods In this parallel randomized clinical trial, we randomly assigned 64 women with PCOS to the magnesium group (n = 32) or placebo group (n = 32) for 10 weeks. AUB, alopecia, quality of life, and acne were assessed by the International Federation of Gynecology and Obstetrics criterion, the Sinclair Scale, the Health Survey Quality of Life Questionnaire, and the Global Acne Grading System, respectively. This randomized clinical trial was registered at (IRCT20130903014551N9). Results Magnesium supplementation significantly improved the components of quality of life including physical functioning (p = 0.011), role limitations due to physical health (p = 0.012), role limitations due to emotional problems (p < 0.001), energy/fatigue (p = 0.005), emotional wellbeing (p < 0.001), social functioning (p = 0.002), general health (p = 0.013), and total quality of life (p < 0.001), compared with placebo. No significant effect was observed on acne, alopecia, and AUB. Conclusion Magnesium supplementation in women with PCOS had a significant positive effect on improving total quality of life. Trial registration This randomized clinical trial was registered at on 2020–10-18 (Registration Code: IRCT20130903014551N9).
... Psoriasis is immunerelated disease characterised by hyperproliferation with incomplete differentiation of keratinocytes (Rajitha et al. 2019). Mg 2? deficiency is reported in psoriatic patients, and topical magnesium therapy is one of the oldest treatment options for the disease (Shahidi-Dadras et al.2012;Chandrasekaran et al. 2014). Topically applied Mg 2? can cross the stratum corneum barrier depending upon the time and concentration of exposure. ...
Full-text available
Magnesium (Mg²⁺) is the 2nd most abundant intracellular cation, which participates in various enzymatic reactions; there by regulating vital biological functions. Magnesium (Mg²⁺) can regulate several cations, including sodium, potassium, and calcium; it consequently maintains physiological functions like impulse conduction, blood pressure, heart rhythm, and muscle contraction. But, it doesn’t get much attention in account with its functions, making it a “Forgotten cation”. Like other cations, maintenance of the normal physiological level of Mg²⁺ is important. Its deficiency is associated with various diseases, which point out to the importance of Mg²⁺ as a drug. The roles of Mg²⁺ such as natural calcium antagonist, glutamate NMDA receptor blocker, vasodilator, antioxidant and anti-inflammatory agent are responsible for its therapeutic benefits. Various salts of Mg²⁺ are currently in clinical use, but their application is limited. This review collates all the possible mechanisms behind the behavior of magnesium as a drug at different disease conditions with clinical shreds of evidence.
... In most cases, magnesium deficiency is asymptomatic, although it may lead to severe complications such as seizures and cardiac arrhythmia. Also restlessness, agitation, nervousness, irritability, attention-deficit hyperactivity disorder in children, depression, migraine, headache, muscle cramps, stroke, inflammation and oxidative stress have been reported with magnesium deficiency (petrault et al. 2002, rayssiGuier et al. 2006, yary et al. 2013, chanDrasekaran et al. 2014, Bain et al. 2015, Black at al. 2015. As magnesium is involved in many essential biological processes, it is extremely important to treat hypomagnesaemia according to its severity and proper magnesium serum concentration (shahBah et al. 2017). ...
Full-text available
Oncological diseases are a major global public health concern. Magnesium deficiency is a complex condition and assessing magnesium status is difficult, as serum levels have little correlation with total body magnesium status. The aetiology of certain forms of cancer is partly related with intake of magnesium especially in colorectal cancer patients and in males. Thus, the aim of present study was to provide more recent data about magnesium dietary intake among oncological patients. We analysed 24-hour dietary reliable surveys from 304 participants aged ≥ 19 years old from the Clinical Department of Oncological Surgery, MSW Hospital, Olsztyn, Poland from the three wards: chemotherapy, radiotherapy and surgery. Data were collected between January 2013 and April 2016. The mean magnesium dietary intake was 224±13 mg/d among women and 295±15 mg/d among men. When compared with estimated average requirement over 30 years of age (265 mg/d for women, 350 mg/d for men) this was found insufficient. In addition, magnesium intake was decreased with increasing age (p < 0.01), and men had higher intakes of magnesium than women (p < 0.01). Slight variations were observed in certain groups of education. Place of residence had the least effect on magnesium status in analysed diets. Additionally, dietary magnesium supplementation was scarce and insufficient among the oncological patients (1%). Substantial numbers of oncological patients fail to consume adequate magnesium in their diets. Patient education is needed to adopt an adequate and balanced diet which will provide a support for oncological treatment to be more effective.
... Recently, Chandrasekaran and colleagues proposed a novel potential mechanism by which Mg inhibits inflammation. Mg could be involved in the activation of the thiamine pyrophosphatedependent riboswitch, resulting in the increased synthesis from thiazole pyrophosphate of thiazole, which inhibits cyclooxygenase and hinders the formation of prostanoids [58]. This review underscores that there are many questions still open and highlights the need for more research to delineate a clear picture of how Mg, its transporters and sensors contribute to the modulation of acute inflammation. ...
Magnesium contributes to the regulation of inflammatory responses. Here, we focus on the role of magnesium in acute inflammation. Although present knowledge is incomplete to delineate an accurate scenario and a schedule of the events occurring under magnesium deficiency, it emerges that low magnesium status favors the induction of acute inflammation by sensitizing sentinel cells to the noxious agent, and then by participating to the orchestration of the vascular and cellular events that characterize the process.
... The combination of TNFα and TNFα receptors can result in outcomes such as apoptosis, transcriptional factor activator protein 1 (AP-1) activation, or nuclear factor-kB (NF-kB) activation and translocation to the nucleus [22]. NF-kB can promote the synthesis of IL-6 and IFN-γ and also can up-regulate the transcription of TNFα, thereby promoting inflammation [23]. Notably, Mg ++ significantly attenuated the levels of inflammatory mediators and the NF-kB pathway by enhancing phosphoinositide 3-kinase (PI3K)/Akt activity [24,25]. ...
... Hypomagnesaemia in rodents (153) and in humans with metabolic syndrome (154) provoke an elevation in TNF-a serum concentration compared to healthy counterparts. It also exacerbates the stimulation of immune cells such as macrophages, T-helper cells and natural killer cells, which activate NF-kB transcription factor and increase cytokine expression leading to inflammation (155). ...
Cardiovascular disease (CVD) is a universal problem in modern society. Atherosclerosis is the leading cause of CVD resulting in high rate of mortality in the population. Nutrition science has focused on the role of essential nutrients in preventing deficiencies, at the present time, the nutritional strategies are crucial to promote health and intervene with these global noncommunicable diseases. In many cases, diet is a major driving force, which is much easier to change and follow than other factors. It is important to establish that the first strategy to treat atherosclerosis is to modify lifestyle habits, focusing on the beneficial properties of specific nutrients. In the last decades, epidemiological, clinical and experimental studies have demonstrated that diet plays a central role in the prevention of atherosclerosis. In this review we will focus on the effect of specific foods, nutrients and bioactive compounds, including epidemiological facts, potential mechanisms of action and dietary recommendations to reduce the risk of atherosclerosis. In particular, we include information about fiber, plant sterols and stanols, niacin, taurine, olive oil, omega 3 fatty acids, antioxidants, minerals, methyl nutrients and soy. In addition, we also show that dysbiosis of the intestinal microbiota associated with a consumption of certain animal food sources can generate some metabolites that are involved in the development of atherosclerosis and its consequences on CVD. According to the epidemiological, clinical and experimental studies we suggest a recommendation for some dietary foods, nutrients and bioactive compounds to support the complementary clinical management of patients with atherosclerosis. Copyright © 2015 IMSS. Published by Elsevier Inc. All rights reserved.
We prepared and characterized Magnesium based particles using remains of Inca fruit seeds after oil press and then checked its antioxidant activity. Seeds were obtained from the company after 2 different processing methods: dried and baked powder of the oil cake (Inca DP) & seed material that was frozen directly after oil pressing process (Inca FC). These two are remaining by product of the oil pressing process and we extracted them separately with 75% ethanol in water (v/v). Then the extracts were used for Mg based particle preparation and characterized using UV–Visible spectrophotometry, FT-IR spectroscopy and SEM. Finally, DPPH antioxidant property of the extracts and the particles was studied. Extraction process yielded approximately 10% of total weight fruit material and almost 10–15% of the particles yielded from 100 mg of the extract. The UV–Visible spectroscopic analyses showed presence of a maximum absorption peak was observed around 200 – 210 nm and FT-IR analyses confirmed the presence of MgO microparticles. Structural analyses with SEM showed a highly aggregated, irregularly shaped particles. Further while studying the antioxidant potential of extract and microparticles, the Inca FC showed appreciable activity than Inca DP. The antioxidant potential of Mg-Inca FC & DP were better than their respective extracts. In conclusion, the Mg-Inca was successfully prepared and it showed significantly better antioxidant activity than the Inca extracts. Further studies on conversion and stabilization of the Mg-Inca particles into nano form with more stability will help us to identify and improve the biological properties of Inca.
Magnesium is the fourth most abundant mineral in the body and the second most abundant intracellular divalent cation in the body, and is a cofactor for more than 300 metabolic reactions in the body. Magnesium deficiency could be related to oxidative stress and chronic inflammatory conditions, such as obesity, cancer, atherosclerosis, hypertension, osteoporosis, and type 2 diabetes mellitus. Research on the effects of hypomagnesemia on the gastrointestinal tract, however, has studied less than other conditions. The focus of this chapter will be on the effects of hypomagnesemia on oxidative stress and inflammation in several chronic diseases.
Stratum corneum of human epidermis maintains keratinocytes covered with elongated microvilli, whose size and regularity are distinct in psoriasis. As the Dead-Sea is known for balneotherapy of psoriasis, we focus on one factor involved in its medical effect: the minerals. We treated psoriatic patients either by daily bathing for four weeks in the Dead-Sea or with topical applications of three different Dead-Sea minerals for 48 h. Skin surface biopsies were taken before and after the treatments, and X-ray fuorescence (XRT) and scanning electron microscopy (SEM) were performed. SEM demonstrated regression of the microvilli after bathing and partial regression after locally-applied Dead-Sea brine and mud. XRT revealed that replenishment of Magnesium ions in the psoriatic keratinocytes correlated well with diminution of the psoriatic microvilli in the same patients.
Charged submicron emulsions are a priori interesting candidates for the delivery of drugs in and/or through the skin. In the present study, it was possible by using stearylamine or deoxycholic acid (DCA) to incorporate either econazole or miconazole nitrate, respectively, in positively and negatively charged submicron emulsions. The investigation of the relationship between the physicochemical properties of the vehicles, especially the charge of the emulsion and skin permeation, was conducted ex vivo during percutaneous absorption experiments using hairless female rat skin. In addition, drug quantification was carried out using two different analytical techniques (HPLC and radioactivity measurements) in order to examine if the drug analysis approach might affect the results. The results clearly indicate that the surface-modified droplets have a significant influence on the diffusion through the skin. Furthermore, the method of preparation of the formulation and subsequently the analytical method of drug concentration measurement are able to influence the results of percutaneous experiments.
Recombinant human tumor necrosis factor (rTNF alpha) injected intravenously into rabbits produces a rapid-onset, monophasic fever indistinguishable from the fever produced by rIL-1. On a weight basis (1 microgram/kg) rTNF alpha and rIL-1 produce the same amount of fever and induce comparable levels of PGE2 in rabbit hypothalamic cells in vitro; like IL-1, TNF fever is blocked by drugs that inhibit cyclooxygenase. At higher doses (10 micrograms/kg) rTNF alpha produces biphasic fevers. The first fever reaches peak elevation 45-55 min after bolus injection and likely represents a direct action on the thermoregulatory center. During the second fever peak (3 h later), a circulating endogenous pyrogen can be shown present using passive transfer of plasma into fresh rabbits. This likely represents the in vivo induction of IL-1. In vitro, rTNF alpha induces the release of IL-1 activity from human mononuclear cells with maximal production observed at 50-100 ng/ml of rTNF alpha. In addition, rTNF alpha and rIFN-gamma have a synergistic effect on IL-1 production. The biological activity of rTNF alpha could be distinguished from IL-1 in three ways: the monophasic pyrogenic activity of rIL-1 was destroyed at 70 degrees C, whereas rTNF alpha remained active; anti-IL-1 neutralized IL-1 but did recognize rTNF alpha or natural cachectin nor neutralize its cytotoxic effect; and unlike IL-1, rTNF alpha was not active in the mitogen-stimulated T cell proliferation assay. The possibility that endotoxin was responsible for rTNF alpha fever and/or the induction of IL-1 was ruled-out in several studies: rTNF alpha produced fever in the endotoxin-resistant C3H/HeJ mice; the IL-1-inducing property of rTNF alpha was destroyed either by heat (70 degrees C) or trypsinization, and was unaffected by polymyxin B; pyrogenic tolerance to daily injections of rTNF alpha did not occur; levels of endotoxin, as determined in the Limulus amebocyte lysate, were below the minimum rabbit pyrogen dose; and these levels of endotoxin were confirmed by gas chromatography/mass spectrometry analysis for the presence of beta-hydroxymyristic acid. Although rTNF alpha is not active in T cell proliferation assays, it may mimic IL-1 in a T cell assay, since high concentrations of rTNF alpha induced IL-1 from epithelial or macrophagic cells in the thymocyte preparations. These studies show that TNF (cachectin) is another endogenous pyrogen which, like IL-1 and IFN-alpha, directly stimulate hypothalamic PGE2 synthesis. In addition, rTNF alpha is an endogenous inducer of IL-1.(ABSTRACT TRUNCATED AT 400 WORDS)
A focus on skin barrier disorders has opened up new thinking about how allergies kick in.
SURGICAL GLOVE TALC can cause granulomas in various intestinal and pelvic organs.1 In the skin, localized silica granulomas due to the glove talc have been observed in surgical scars2,3 and as the result of the impregnation of the skin by silicious particles, such as glass or sand, following an injury.' 5 Extensive talc granulomas of the skin have not been reported, to our knowledge.Report of a Case A 45-year-old woman was admitted to the hospital because of the development of increasing numbers of lumps on her shoulders, buttocks, and thighs. These nodules had been developing for the past two years and were at sites where she has had as many as 500 boils over the past eight to ten years. Many of these boils were treated by incision and drainage. The nodules have not appeared on areas of the body where she has not had furuncles. She also
Containing 350 illustrations, tables, and equations and covering AAPS/FDA guidelines for the experimentation and analysis of in vivo and in vitro percutaneous absorption, this reference provides comprehensive coverage of the development, preparation, and application of topical and transdermal therapeutic systems. Recognized international experts discuss the bioequivalence of dermatological and transdermal dosage forms. They explore the biochemistry and treatment of skin diseases, the structure and function of the skin, adverse dermal responses to drug formulations, mechanisms of drug transport through barrier membranes, and methods for measuring and modulating percutaneous permeation.
Because (i) endothelial cells are important players in cardiovascular diseases and (ii) Mg deficiency promotes atherosclerosis, thrombosis and hypertension, we evaluated whether low concentrations of Mg could directly affect endothelial behavior. We found that low Mg concentrations reversibly inhibit endothelial proliferation, and this event correlates with a marked down-regulation of the levels of CDC25B. The inhibition of endothelial proliferation is due to an up-regulation of interleukin-1 (IL-1), since an antisense oligonucleotide against IL-1 could prevent the growth inhibition observed in cells exposed to low concentrations of the cation. We also report the up-regulation of Vascular Cell Adhesion Molecule-1 (VCAM) and Plasminogen Activator Inhibitor (PAI)-1 after Mg deficiency. VCAM is responsible, at least in part, of the increased adhesion of monocytoid U937 cells to the endothelial cells grown in low magnesium. In addition, endothelial migratory response is severely impaired. By cDNA array, we identified several transcripts modulated by exposure to low Mg, some of which—c-src, ezrin, CD9, cytohesin and zyxin—contribute to endothelial adhesion to substrates and migration.In conclusion, our results demonstrate a direct role of low magnesium in promoting endothelial dysfunction by generating a pro-inflammatory, pro-thrombotic and pro-atherogenic environment that could play a role in the pathogenesis cardiovascular disease.
Skin Barrier function which protects internal organs from the environment resides in the uppermost thin heterogeneous layer, called stratum corneum. The stratum corneum is composed of dead protein-rich cells and intercellular lipid domains. This two-compartment structure is renewed continuously and when the barrier function is damaged, it is repaired immediately. Under low humidity, the stratum corneum becomes thick, the lipid content in the stratum corneum increases and water impermeability is enhanced. The heterogeneous field in the epidermis induced by ions, such as calcium and potassium regulates the self-referential, self-organizing system to protect the living organism.