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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.
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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
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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
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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.
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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.
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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
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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,
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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.
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(Received February 9, 2014, Accepted April 14, 2014)
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... 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. ...
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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).
... Tis study was not able to identify the mechanism by which magnesium acetate signifcantly increased AQP3 expression levels relative to the increases in AQP3 expression levels caused by other magnesium compounds, and this is a subject for future investigation. Magnesium-rich Dead Sea therapy support that magnesium is useful in treating skin conditions [11,27]. Te results of this study showed that one of the mechanisms by which magnesium improves skin function is the upregulated expression of AQP3, a skin function molecule. ...
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Several studies have shown that magnesium can be a useful tool in preventing various skin disorders. However, the mechanism remains unclear. In this study, we analyzed the mechanism by which magnesium improves skin function, focusing on the water channel aquaporin-3 (AQP3), which is a cutaneous functional molecule. Magnesium compounds (magnesium acetate, magnesium chloride, magnesium sulfate, and magnesium lactate) were added to human epidermal keratinocyte HaCaT cells, and the mRNA and protein expression levels of AQP3 were analyzed. We also investigated the mechanism by which magnesium acetate regulates AQP3 expression. Several magnesium compounds were individually added to HaCaT cells, and 6 hours later, the AQP3 mRNA expression level in the treated cells was significantly increased compared to that in the control cells. Among the magnesium compounds, magnesium acetate had a strong effect and markedly increased the AQP3 mRNA expression level by approximately 3.5 times and the protein expression level by approximately 3 times. Magnesium acetate also enhanced the phosphorylation of cAMP response element-binding protein (CREB), which is involved in AQP3 transcription. Furthermore, the increase in AQP3 expression levels induced by magnesium acetate was suppressed by treatment with the protein kinase A (PKA) inhibitor H-89. Magnesium compounds increased the expression level of AQP3 in epidermal keratinocytes and may have a skin-moisturizing effect. The magnesium-induced phosphorylation of CREB may be associated with the activation of the cAMP/PKA pathway. Overall, magnesium compounds may be useful for the prevention and treatment of age-associated xeroderma.
... 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. ...
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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.
... Products of thiazole metabolism have been shown to have antiinflammatory and neuroprotective effects and low concentrations of thiazole can, therefore, promote a proinflammatory state. Hypomagnesemia has also be shown to result in elevated levels of tumor necrosis factor alpha (TNFα) which leads to the transcription of interleukin-6 and interferon-c, two cytokines with pro-inflammatory actions [16]. Furthermore, magnesium plays a role in the suppression of N-methyl-d-aspartate (NMDA) receptors and its deficiency leads to NMDA receptor hyperexcitability. ...
... 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). ...
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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.
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The utilization of materials in medical implants, serving as substitutes for non-functional biological structures, supporting damaged tissues, or reinforcing active organs, holds significant importance in modern healthcare, positively impacting the quality of life for millions of individuals worldwide. However, certain implants may only be required temporarily to aid in the healing process of diseased or injured tissues and tissue expansion. Biodegradable metals, including zinc (Zn), magnesium (Mg), iron, and others, present a new paradigm in the realm of implant materials. Ongoing research focuses on developing optimized materials that meet medical standards, encompassing controllable corrosion rates, sustained mechanical stability, and favorable biocompatibility. Achieving these objectives involves refining alloy compositions and tailoring processing techniques to carefully control microstructures and mechanical properties. Among the materials under investigation, Mg- and Zn-based biodegradable materials and their alloys demonstrate the ability to provide necessary support during tissue regeneration while gradually degrading over time. Furthermore, as essential elements in the human body, Mg and Zn offer additional benefits, including promoting wound healing, facilitating cell growth, and participating in gene generation while interacting with various vital biological functions. This review provides an overview of the physiological function and significance for human health of Mg and Zn and their usage as implants in tissue regeneration using tissue scaffolds. The scaffold qualities, such as biodegradation, mechanical characteristics, and biocompatibility, are also discussed.
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.
Magnez pełni bardzo wiele funkcji w ludzkim organizmie, jest kofaktorem enzymów, chroni przed chorobami sercowo-naczyniowymi, usprawnia pracę układu odpornościowego, jest też budulcem kości i zębów. Skutki jego niedoboru, takie jak częste skurcze mięśni, są dobrze znane. Doustna suplementacja magnezem jest szeroko rozpowszechniona w społeczeństwie. Naukowcy dogłębnie przebadali tę formę suplementacji i udowodnili jej skuteczność, jednak doniesienia z ostatnich lat wskazują, że efektywniejsza wydaje się terapia transdermalna (np. oleje magnezowe – wodne roztwory chlorku magnezu). Za taką terapią przemawiają dobra wchłanialność przez skórę, dostarczanie pierwiastka bezpośrednio do komórek oraz pominięcie drogi pokarmowej w procesie absorpcji. Zarówno w piśmiennictwie naukowym, jak i na portalach medycznych pojawiają się artykuły dowodzące skuteczności stosowanej przezskórnie terapii, a część autorów decyduje się na stwierdzenie, iż jest ona skuteczniejsza niż tradycyjna terapia doustna. Praca stanowi przegląd piśmiennictwa oraz prowadzonych w ostatnich latach badań dotyczących transdermalnej terapii magnezem oraz jej skuteczności.
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.
Hyperoxia-associated production of reactive oxygen species leads to neutrophil infiltration into the lungs and increased pulmonary proinflammatory cytokine expression. However, the initial events induced by hyperoxia, and leading to acute inflammatory lung injury, remain incompletely characterized. To explore this issue, we examined nuclear transcriptional regulatory factor (NF-kappaB and NF-IL-6) activation and cytokine expression in the lungs following 12 to 48 h of hyperoxia exposure. No increases in cytokine (IL-1beta, IL-6, IL-10, TGF-beta, TNF-alpha, IFN-gamma) expression nor in NF-kappaB activation were found after 12 h of hyperoxia. Following 24 h of hyperoxia, NF-kappaB activation and increased levels of TNF-alpha mRNA were present in pulmonary lymphocytes. By 48 h of hyperoxia, amounts of IFN-gamma and TNF-alpha protein as well as mRNA were increased in the lungs, and NF-kappaB continued to show activation, even though no histologic abnormalities were present. These results show that hyperoxia activates NF-kappaB in the lungs before any increase in proinflammatory cytokine protein occurs, and suggest that NF-kappaB activation may represent an initial event in the proinflammatory sequence induced by hyperoxia.
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.