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Vitamin D: A custodian of cell signalling stability in health and disease


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There is increasing evidence that a deficiency in vitamin D contributes to many human diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), hypertension and cardiovascular disease. The ability of vitamin D to maintain healthy cells seems to depend on its role as a guardian of phenotypic stability particularly with regard to the reactive oxygen species (ROS) and Ca2+ signalling systems. Vitamin D maintains the expression of those signalling components responsible for stabilizing the low-resting state of these two signalling pathways. This vitamin D signalling stability hypothesis proposes that vitamin D, working in conjunction with klotho and Nrf2 (nuclear factor-erythroid-2-related factor 2), acts as a custodian to maintain the normal function of the ROS and Ca2+ signalling pathways. A decline in vitamin D levels will lead to an erosion of this signalling stability and may account for why so many of the major diseases in man, which have been linked to vitamin D deficiency, are associated with a dysregulation in both ROS and Ca2+ signalling.
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Calcium Signalling: The Next Generation
Calcium Signalling: The Next
Held at Charles Darwin House, London, U.K., 9–10 October 2014.
Vitamin D: a custodian of cell signalling stability in
health and disease
Michael J. Berridge*
*The Babraham Institute, Babraham, Cambridge, CB22 3AT, U.K.
There is increasing evidence that a deficiency in vitamin D contributes to many human diseases such as
Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), hypertension and cardiovascular
disease. The ability of vitamin D to maintain healthy cells seems to depend on its role as a guardian of
phenotypic stability particularly with regard to the reactive oxygen species (ROS) and Ca
2 +
systems. Vitamin D maintains the expression of those signalling components responsible for stabilizing the
low-resting state of these two signalling pathways. This vitamin D signalling stability hypothesis proposes
that vitamin D, working in conjunction with klotho and Nrf2 (nuclear factor-erythroid-2-related factor 2),
acts as a custodian to maintain the normal function of the ROS and Ca
2 +
signalling pathways. A decline in
vitamin D levels will lead to an erosion of this signalling stability and may account for why so many of the
major diseases in man, which have been linked to vitamin D deficiency, are associated with a dysregulation
in both ROS and Ca
2 +
Cells communicate with each other through external signals
such as hormones, neurotransmitters and growth factors that
are detected by receptors, which mediate their effects through
intracellular messengers such as Ca
2 +
that plays a central
role in many different cellular processes. A feature of Ca
2 +
signalling is its versatility that enables cells to generate Ca
2 +
signals with very different spatial and temporal properties
[1]. Such versatility is achieved through cells having very
Key words: Alzheimer’s diseases, antioxidants, calcium, cardiac disease, Klotho, memory,
phenotypic stability, reactive oxygen species, redox, vitamin D.
Abbreviations: AD, Alzheimer’s disease; Bcl-2, B-cell lymphoma 2; BPD, bipolar disorder; CB,
calbindin D-28k; CHF, congestive heart failure; ER, endoplasmic reticulum; ET-1, endothelin-
1; G6PD, G-6-P dehydrogenase; IGF1, insulin growth factor 1; LTP, long-term potentiation;
MS, multiple sclerosis; NCX, Na
2 +
exchanger; NMDA, N-methyl-d-aspartate; NMDAR, N-
methyl-d-aspartate receptor; NO, nitric oxide; NOS, nitric oxide synthase; NOX, NADPH oxidase;
Nrf2, nuclear factor-erythroid-2-related factor 2; O
, superoxide; ONOO
, peroxynitrite; PD,
Parkinson’s disease; PIP
, phosphoinositide(3,4,5)P
; PMCA, plasma membrane Ca
2 +
-ATPase; Prx,
peroxiredoxin; ROS, reactive oxygen species; RXR, retinoid X receptor; RYR, ryanodine receptor;
sAHP, slow after hyperpolarization; SERCA, sarcoendoplasmic reticulum calcium transport ATPase;
SNc, substantia nigra pars compacta; SOD2, superoxide dismutase; SRC, steroid receptor
coactivator; STIM, stromal interaction molecule; TRX, thioredoxin; VDR, vitamin D receptor.
different signalling phenotypes, which are assembled from
a large Ca
2 +
signalling toolkit [2]. Very little is known
about the mechanisms responsible for maintaining the
phenotypic stability of these individual signalling systems.
Subtle remodelling of these signalling systems is one of the
main causes of many human diseases [2,3]. In this review, I will
explore emerging evidence that vitamin D may reduce the risk
of developing such diseases by maintaining the phenotypic
stability of the Ca
2 +
and redox signalling pathways.
Vitamin D and cell signalling stability
Vitamin D deficiency contributes to many different diseases
as illustrated in Figure 1 [4–6]. Just why vitamin D deficiency
should have such profound deleterious effects is not clear. I
shall develop a hypothesis that vitamin D acts as a custodian
of phenotypic stability of cell signalling pathways and
particularly the Ca
2 +
and redox signalling systems (Figure 1).
This Vitamin D-dependent phenotypic stability hypothesis is
further s upported by the fact that vitamin D, acting through
the vitamin D receptor (VDR), regulates the expression of
Biochem. Soc. Trans. (2015) 43, 349–358; doi:10.1042/BST20140279
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2015 Biochemical Society 349
Biochemical Society Transactions
350 Biochemical Society Transactions (2015) Volume 43, part 3
klotho and the nuclear factor-erythroid-2-related factor 2
(Nrf2), which also is key cellular regulator of phenotypic
stability. Klotho is included in the hypothesis as it is a similar
custodian of multiple cell signalling pathways.
Defects in klotho, which is an anti-aging gene, have
multiple effects such as growth retardation, osteoporosis,
cognitive defects, skin atrophy, osteopenia, hyperphos-
phatemia, endothelial dysfunction, Parkinsonian gait and
impaired hearing [7]. Klotho is a transmembrane protein that
contains a large extracellular domain. Following ectodomain
shedding, this external domain is released to function as a
humoral factor to control the insulin–IGF1 (insulin growth
factor 1), Wnt, p53/p21, cyclic AMP and protein kinase
C (PKC) signalling pathways [7] (Figure 2). Klotho can
suppress aging by increasing the expression of peroxiredoxins
(Prx-2 and Prx-3) and thioredoxin (TRX) reductase 1 (Trxrd-
1) to reduce oxidative stress [8]. By inhibiting the insulin–
IGF1 pathway, it increases the activation of forkhead box
O (FOXO) that up-regulates the expression of antioxidant
enzymes such as mitochondrial manganese–superoxide
dismutase (SOD2) and catalase [9]. Klotho regulates the
communication between neurons and oligodendrites during
myelin formation, which contributes to multiple sclerosis
(MS) [10].
Vitamin D regulates expression of the redox-sensitive
transcription factor Nrf2 that controls expression of many
antioxidant and detoxifying enzymes such as glutamate
cysteine ligase (GCL) that synthesizes the redox buf-
fer glutathione (GSH), glutathione S-transferase (GST),
haemoxygenase 1 (HO1), NAD(P)H quinone oxidase
1 (NQO1), peroxyredoxins, TRX and the sulfiredoxins
peroxyredoxins [11] (Figure 2). Alterations in Nrf-2 activity
may contribute to numerous diseases [12] many of which
are also linked to vitamin D deficiency thus emphasizing
the importance of vitamin D and Nrf2 as custodians of
phenotypic stability. There is compelling evidence to suggest
that vitamin D, klotho and Nrf-2 act in concert to maintain
the phenotypic stability of the Ca
2 +
and redox signalling
Vitamin D regulates Ca
2 +
and ROS
signalling stability
Redox signalling regulates a number of cellular processes
[13] and it also modulates the Ca
2 +
signalling system
[14] (Figure 3). For example, H
enhances endoplasmic
reticulum (ER) Ca
2 +
release by sensitizing the inositol 1,4,5-
trisphosphate receptors (InsP
Rs) [15,16] and ryanodine
receptors (RYRs) [17]. This Ca
2 +
release is also enhanced
by a reactive oxygen species (ROS)-dependant increase
in sarcoendoplasmic reticulum calcium transport ATPase
(SERCA) activity [18], which increases the ER Ca
2 +
concentration that then sensitizes both the RYRs and the
Rs. In a reciprocal way, entry of Ca
2 +
into the
mitochondria enhances energy metabolism resulting in an
increased formation of superoxide (O
nitric oxide synthase (NOS), which forms nitric oxide (NO)
that interacts with O
to form peroxynitrite (ONOO
is also activated by Ca
2 +
The plasma membrane and the mitochondria are the two
main sites of ROS formation (Figure 3). Many external signals
that bind to receptors coupled to phosphoinositide 3-kinase
(PI3K) produce phosphoinositide(3,4,5)P
stimulates NADPH oxidase (NOX) to form O
is then transformed to H
by SOD. Formation of
ROS by the mitochondria is a consequence of its energy
metabolism. Most of the electrons that enter the electron
transport chain are transferred to oxygen in an orderly
manner, but there is always a 1%–2 % leakage during which
an electron is transferred directly to oxygen to form O
by SOD.
As for other second messengers, there are enzyme systems
that can rapidly metabolize ROS to maintain low intracellular
levels [13]. Vitamin D regulates ROS metabolism by down-
regulating the NOX that generates ROS [19] and by up-
regulating the SOD that converts O
to H
[20]. It also
up-regulates G-6-P dehydrogenase (G6PD) to increase the
formation of NADPH that is used by GSH reductase (GR) to
generate the major redox buffer GSH [21] (Figure 3). Finally,
it up-regulates the expression of glutathione peroxidase (Gpx)
that converts H
to water [20].
Vitamin D maintains intracellular Ca
2 +
homoeostasis by
regulating the expression of Ca
2 +
signalling components
such as calbindin D-28k (CB), Na
2 +
exchanger (NCX)
and plasma membrane Ca
2 +
-ATPase 1b (PMCA1b) [22,23]
(Figure 3). The activity of N CX is also enhanced by klotho
that stimulates the Na
-ATPase that maintains the
gradient [24]. In addition, vitamin D can reduce Ca
2 +
levels by reducing the expression of the L-type voltage-gated
calcium 1.2 (Ca
1.2) channel [25].
Epigenetic regulation of vitamin D
Consistent with its proposed role as a custodian of pheno-
typic stability, vitamin D regulates epigenetic mechanisms
to maintain the transcription activity of those genes that
operate in its regulatory network [26] (Figure 2). Vitamin
D influences the epigenetic landscape by controlling both
the acetylation and the methylation states of gene promotor
regions. The VDR–RXR (retinoid X receptor) dimer recruits
histone acetyltransferases (HATs) such as p300–CBP and
steroid receptor coactivators 1 and 2 (SRC-1 and SRC-2)
that carry out the acetylation reactions that opens up the
chromatin structure to facilitate transcription.
Demethylation is also a critical event because many of the
genes regulated by vitamin D are silenced by methylation of
CpG islands located in their promotor regions. For example,
hypermethylation accounts for both the decline in SERCA2a
activity in cardiovascular disease [27] and the expression of
klotho during aging [28]. Such age-dependent hypermethyl-
ation is also evident in many diseases (cancer, cardiovascular
and neurodegenerative diseases) [29]. Hypermethylation of
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2015 Biochemical Society Biochem. Soc. Trans. (2015) 43, 350–358; doi:10.1042/BST20140279
Calcium Signalling: The Next Generation 351
Figure 1 Vitamin D-dependent phenotypic stability hypothesis
(A) Vitamin D acting together with klotho and Nrf2 activate the gene transcriptional events that are necessary to maintain
the phenotypic stability of the Ca
2 +
and redox signalling pathways. (B) A decline in this vitamin D–klotho–Nrf2 regulatory
network results in phenotypic instability of these signalling pathways. The abnormal cellular responses, resulting from
increases in both Ca
2 +
and redox signalling, play a major role in the development of many of the major diseases that have
been linked to vitamin D deficiency.
promotors in γ -Aminobutyric acid (GABA)ergic neurons
contributes to the phenotypic remodelling responsible for
schizophrenia and bipolar disorder (BPD) [30]. Since many
of these diseases have also been linked to vitamin D
deficiency, it is not surprising to find that vitamin D can
modulate the epigenetic landscape by controlling expression
of a number of key DNA demethylases such as Jumonji
C domain-containing demethylases 1A (JMJD1A), JMJD3,
lysine-specific demethylase 1 (LSD1) and LSD2 [31] that
contributes to its ability to maintain phenotypic stability.
Vitamin D deficiency in aging and disease
The incidence of many of the diseases that are associated with
vitamin D deficiency is lowest at the equator and become
more pronounced as the distance from the equator increases.
Diseases such as schizophrenia and Alzheimer’s disease (AD)
are also more common in dark-skinned individuals that
have migrated away from equatorial to more temperate
regions [5]. Evidence of this kind strongly indicates that
solar UV irradiation is a crucial factor in maintaining normal
healthy levels of vitamin D. This conclusion was strongly
supported by a report entitled Sunlight, Vitamin D and
Health published by the U.K. Government in 2006 that
concluded the following:
“Six out of 10 adults of working age in the UK, and
probably in other European countries too, are at risk of
chronic disease because they do not get enough vitamin D.”
Despite this strong association between vitamin D
deficiency and major diseases, there is little understanding of
how vitamin D functions normally to prevent these diseases. I
shall explore the hypothesis that a major contributory factor
for aging and the development of these diseases may be a
decline in the role of vitamin D, klotho and Nrf2 as custodians
of the Ca
2 +
and redox signalling pathways (Figure 1).
Vitamin D deficiency and aging
Vitamin D deficiency may contribute to the aging process
through its dysregulation of both the Ca
2 +
and the redox cell
signalling pathways. The role of Ca
2 +
dysregulation in aging,
which is particularly evident in neurons [32,33], is illustrated
by the gradual decline in cognition [34]. Memory formation
depends on the process of long-term potentiation (LTP)
driven by local elevations of Ca
2 +
within the dendritic spines
that arise f rom trains of action potentials. In aging, these
action potential trains are terminated prematurely by the
development of a slow after hyperpolarization (sAHP) that
depend on a build-up of Ca
2 +
that activates SK potassium
channels [34]. This inactivating Ca
2 +
signal, which depend
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352 Biochemical Society Transactions (2015) Volume 43, part 3
Figure 2 Vitamin D regulation of multiple genes as part of its role as a custodian of the phenotypic stability of cell signalling
Vitamin D binds to the VDR, which interacts with the RXR before binding to the vitamin D response element (VDRE) located
on a large number of vitamin D-sensitive target genes many of which are activated (green arrows) whereas some are
repressed (red arrows). The VDR complex alters the epigenetic landscape by recruiting histone acetylases such as p300–CBP
and the SRC-1 that acetylate chromatin and by increasing the expression of demethylases such as JMJD1A, JMJD3, LSD1and
LSD2 responsible for chromatin demethylation. Many of these genes regulate the Ca
2 +
and redox signalling pathways. In
addition, vitamin D controls the expression of klotho and Nrf2, which are also important regulators of multiple signalling
systems including the Ca
2 +
and redox signalling pathways.
on the opening of L-type voltage-dependent Ca
2 +
that provides trigger Ca
2 +
to activate RYRs, inhibits memory
in two ways: the sAHP curtails the spiking activity necessary
for LTP, whereas the increase in Ca
2 +
triggers long-term
depolarization (LTD) that erases memories formed during
LTP [34].
The development of this sAHP during aging depend on
alterations in both Ca
2 +
and ROS signalling that can be
directly attributed to vitamin D deficiency. An increase in
ROS signalling accounts for sensitization of the RYRs that
can be reversed by treating neurons with dithiothreitol (DTT)
[35]. The onset of the sAHP is also driven by an increase in
the expression of L-type channels and a decrease in the PMA
2 +
pump [36], all of which are associated with vitamin
D deficiency (Figure 2). The age-related development of the
sAHP can be reversed by treating neurons with Vitamin D
[37]. Subsequent studies on rats revealed that administration
of vitamin D could prevent the age-dependent cognitive
decline in spatial learning and memory as assessed by the
Morris water maze [38].
Cancer and metastasis
There is strong evidence linking vitamin D deficiency to
cancer [4,6,39–41]. Mortality rates from a variety of cancers
are higher in regions where there is less UV irradiation [40].
In addition, vitamin D can have anticancer effects when
administered to model systems of breast, ovary, lung and
prostate cancers [39]. Vitamin D seems to act by reducing cell
proliferation, angiogenesis and metastasis.
Vitamin D inhibits the G
/S transition of the cell cycle
by reducing the expression of cyclin D and by promoting
expression of the CDK (cyclin-dependent kinase) inhibitors
p21 and p27 [39,42] and growth-arrest and DNA-damage-
inducible protein 45 (GADD45) that normally act to suppress
cell proliferation [43] (Figure 2). Vitamin D deficiency may
also contribute to cancer development through increases
in both redox [44,45] and Ca
2 +
signalling [46]. Vitamin
D can reduce oxidative stress in human prostate epithelial
cells by increasing the antioxidant enzyme G6PD [21]. The
production of H
facilitates growth factor signalling by
inhibiting PTEN (phosphatase and tensin homologue) that
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Calcium Signalling: The Next Generation 353
Figure 3 The inter-relationship between the Ca
2 +
and redox signalling pathways
An increase in Ca
2 +
can promote formation of ROS through different mechanism: activation of NOX generates O
is converted into H
by SOD2. Generation of O
by the mitochondria is activated by Ca
2 +
, which can also stimulate
the NOS that forms NO that interacts with O
to form ONOO
. In a reciprocal way, an increase in cytosolic ROS can
markedly enhance Ca
2 +
signalling by either increasing the activity of various channels such as the InsP
Rs, RYRs and the
STIM–Orai1store operated Ca
2 +
entry pathway or inhibiting both the PMCA and the SERCA pumps. Vitamin D acts by either
enhancing (green arrows) or inhibiting (red arrow) the expression of components responsible for regulating these two
inter-connected signalling systems.
inhibits the hydrolysis of PIP
(Figure 3), which functions in
cell migration, proliferation and survival. Excess ROS levels
may also enhance the ERK (extracellular signal-regulated
kinase)–MAPK (mitogen-activated protein kinase) signalling
pathway because the tyrosine protein phosphatases that
reverse these signalling pathways are also inhibited by H
Vitamin D can also reduce Wnt–β-catenin signalling [47]. In
colon cancer cells, it induces the expression of Dickkopf-1
(DKK-1), which inhibits this pathway [48] and it reduces the
expression of the transcription factor β-catenin [49], which
is often activated in colon cancer. Vitamin D may also reduce
colorectal cancer by regulation the expression of the histone
demethylase JMJD1A that enables vitamin D to control cell
proliferation [50] (Figure 2).
The close link between oxidative stress and cancer [44,45] is
also evident in Nrf2 knockout mice, where there is an increase
in tumorigenesis that results from a decline in antioxidative
pathways. The ability of curcumin to inhibit the proliferation
of breast cancer cells may depend on Nrf2 activation [51].
Tumour growth is also very dependent on angiogenesis
to provide the blood supply to nourish proliferating cells.
Vitamin D reduces the proliferation of the endothelial cells
required to form new blood vessels [39]. In animal models,
the growth of solid tumours was suppressed by vitamin D
[52] that may act by reducing the expression of vascular
endothelial growth factor (VEGF), which is essential to
drive endothelial cell proliferation [53]. In human pancreatic
tumours, the surrounding stroma contains pancreatic stellate
cells (PCSs) that undergo a transdifferentiation to an
activated phenotype that not only sustains tumour cells
but also protects them from chemotherapy. Activation of
the VDR with calcipotriol restores the normal quiescent
phenotype, which makes the tumour much more susceptible
to chemotherapy [54].
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354 Biochemical Society Transactions (2015) Volume 43, part 3
Alzheimer’s disease
There are an increasing number of studies linking vitamin D
deficiency to AD [55]. VDR polymorphisms are associated
with the normal age-related decline in cognition and are also a
risk factor for AD [56–58]. In a study of older women, vitamin
D supplementation lowers the risk of developing AD [59]. A
decline in its custodial role in maintaining intracellular Ca
2 +
and redox homoeostasis may explain these deleterious effects
of vitamin D.
During normal aging, there are gradual changes in certain
2 +
signalling components such as the decline in the Ca
2 +
buffer CB that normally functions to restrict the amplitude of
2 +
signals [60]. A decline in this buffer, which is maintained
by vitamin D (Figure 2), may also increase the onset of AD
because mice expressing mutant amyloid precursor protein
(APP) also display a decline in the level of CB especially in
the dentate gyrus region of the hippocampus, which functions
in learning and memory [61].
AD is a progressive neurodegenerative disorder caused by
an increase in amyloid metabolism, which remodels neuronal
2 +
signalling pathways to reduce cognition and to promote
neuronal cell death [62–64]. One of the actions of amyloids is
to bind to the cellular prion protein (PrP
), which is coupled
to metabotropic glutamate receptor 5 (mGluR5) receptors to
increase the formation of InsP
to release internal Ca
2 +
The development of AD is also associated with an increased
formation of ROS [66–69] that would further increase Ca
2 +
signalling by sensitizing both the InsP
Rs and the RYRs
(Figure 3) [70]. In klotho mutant mice, there is a severe
decline in cognition that is associated with an increase in
oxidative stress [71,72] and there was a decline in Bcl-2 (B-
cell lymphoma 2) expression [71] that would enhance Ca
2 +
release, because Bcl-2 inhibits the ability of InsP
to activate
the InsP
receptor [73]. This amyloid-dependent increase in
2 +
signalling elevates the resting level of Ca
2 +
that may
then erase memories soon after they are formed [2,70,74].
Schizophrenia is a severe psychiatric condition brought about
by changes in brain rhythm synchronization, which are
caused by defects in fast-spiking inhibitory interneurons
[75,76]. Inflammation resulting from viral infections during
pregnancy has been implicated in schizophrenia [77]. Such
inflammation induces oxidative stress that reduces N-methyl-
D-aspartate (NMDA) receptor (NMDAR) activity and is
the basis of the NMDAR hypofunction hypothesis of
schizophrenia [78]. The ROS that oxidizes the NMDARs
depends on both O
and NO that interact with each other
to form ONOO
, which nitrosylates the N MDAR to reduce
the entry of Ca
2 +
responsible for the onset of schizophrenia
There are a number of epidemiological and animal model
studies that have linked low vitamin D levels to schizophrenia
[5,80]. The denitrosylation reaction, which functions to
reverse NMDAR nitrosylation depends on antioxidants such
as GSH and TRX. In schizophrenia, gene polymorphisms
have been described in the enzymes responsible for the
synthesis of GSH [81]. The vitamin D phenotypic stability
hypothesis is consistent with what is known about the
signalling defects responsible for schizophrenia [74,82].
Antioxidants such as GSH and NAC, which act to reduce
ROS activity, offer a novel pharmacological approach to
controlling schizophrenia and other psychiatric conditions
such as BPD [83].
Parkinson’s disease
Parkinson’s disease (PD), which is caused by the degeneration
and death of the dopaminergic (DA) neurons located in the
substantia nigra pars compacta (SNc), has been linked to
vitamin D deficiency [55]. Polymorphisms of the VDR, which
is strongly expressed in SNc neurons, is associated with PD
The pacemaker activity of these SNc neurons generates
regular pulses of Ca
2 +
every second, which depend on both
the entry of external Ca
2 +
and the release of internal Ca
2 +
As the concentration of Ca
2 +
buffers in these neurons is
very low relative to other neurons [85], much of this Ca
2 +
is handled by the mitochondria that enhances mitochondrial
energy metabolism and ROS formation (Figure 3). It is argued
that when vitamin D levels are low, the Ca
2 +
and ROS levels
will begin to rise and will activate the apoptosis that occurs
in the later stages of PD. There is a sense that mitochondrial
2 +
and ROS regulation in these SNc neurons is teetering
on the verge of oxidative and Ca
2 +
stress that makes them
particularly dependent on the ability of vitamin D to stabilize
the ROS and Ca
2 +
signalling pathways.
Hypertension, cardiovascular disease and atrial
There is strong evidence linking vitamin D deficiency
to hypertension and cardiovascular diseases [6]. In mice,
deletion of either 25(OH)D 1α-hydroxylase that synthesizes
vitamin D or VDR resulted in an increase in the renin–
angiotensin system, hypertension and the onset of cardiac
hypertrophy [86]. These abnormalities could be corrected by
treating the knockout mice with vitamin D [86] and vitamin D
supplementation markedly increased the survival of patients
suffering from cardiovascular diseases. The vitamin D-
dependent stability of the redox and Ca
2 +
signalling systems
plays a prominent role in protecting the cardiovascular
One of the primary actions of vitamin D is to curb the
renin–angiotensin system that prevents the hypertension that
is a major risk factor for heart disease. In patients with
type 2 diabetes, the associated hypertension was improved
following vitamin D supplementation [87]. Vitamin D acts by
preventing CREB (cAMP response element-binding protein)
from binding to the renin gene promotor to reduce renin
secretion [88], which reduces the hypertension that is a major
risk factor for heart disease.
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Calcium Signalling: The Next Generation 355
The excessive release of renin that occurs in vitamin D
deficiency results in an increased release of angiotensin II and
endothelin-1 (ET-1), which are potent vasoconstrictors that
contribute to hypertension. Angiotensin II activates NOX
to increases ROS formation, which enhances smooth muscle
cell C a
2 +
signalling and contraction that contributes to the
hypertension that is a f eature of vitamin D deficiency. Klotho
also protects the cardiovascular system by regulating the
NOS responsible for generating endothelium-derived NO
[89], which regulates vasomotor tone. Vitamin D can reduce
enhanced ROS levels in the renal arteries of hypertensive
patients by inhibiting the NOX enzyme that generates ROS
and by increasing the SOD-1 enzyme that metabolize ROS
Cardiac hypertrophy and congestive heart failure
The angiotensin II and ET-1 are also responsible for activating
cardiac hypertrophy resulting in congestive heart failure
(CHF) [2]. Under normal conditions, the heart receives
continuous pulses of Ca
2 +
to drive contraction without
initiating a change in transcription. However, in the presence
of these two hormones, which operate through the InsP
2 +
signalling pathway, there are subtle changes in the
spatial and temporal properties of the individual Ca
2 +
transients that are responsible for hypertrophy. Perinuclear
Rs function as coincident detectors to create the nuclear
2 +
signals responsible for driving the transcriptional
processes that initiate hypertrophy [90–96].
Vitamin D deficiency may also promote hypertrophy as
a result of the increased activity of the ROS–Ca
2 +
[97–98]. Angiotensin II and ET-1 stimulate NOX at the
plasma membrane to elevate ROS [99] that not only increases
the activity of the ion channels (Na
1.5 sodium channel,
1.2 channels and RYR2) and pumps (SERCA) that
contribute to the Ca
2 +
cycling events that occur during
each heartbeat, but it also acts indirectly to increase the
activity of the protein kinases A (PKA) and Ca
dependent protein kinase IIδ
) that act normally
to regulate cardiac activity [98]. These increased ROS and
2 +
signalling processes contribute to the alterations in
gene transcription that result in hypertrophy. Vitamin D
supplementation, which reduces these signalling pathways,
can markedly improve the outcome of patients suffering from
heart failure [100].
Cardiac arrhythmias
There is a relationship between vitamin D deficiency and
atrial fibrillation (AF) [101]. Activation of type 2 InsP
which modulate atrial cell contraction [102–104], may
account for the onset of AF. In the presence of ET-1, which is
increased during vitamin D deficiency, there is an increase in
that initiates atrial arrhythmias [102]. An increase in the
activity of these InsP
R2s in response to ROS, which occurs
as a result of vitamin D deficiency, would further enhance the
onset of AF. Increases in InsP
formation are also responsible
for the arrhythmogenic action of ET-1 in ventricular cardiac
myocytes [105].
Guardianship of the redox and Ca
2 +
signalling phenotypes
by the vitamin D–klotho–Nrf2 regulatory network depends
on the expression of those components that maintain the
low resting state of these two signalling pathways. It is
argued that during vitamin D deficiency there is a decline
in this custodial role resulting in abnormal cell activation.
However, this dysregulation is relatively modest in that cells
continue to carry out their basic functions. For example,
heart cells continue to contract and neurons continue to
communicate with each other, but there are subtle alterations
in the signalling events that gradually divert cells down a
pathological pathway. The medical community should pay
more attention to the importance of vitamin D, because
restoring normal levels of this vital hormone may prevent
the onset and progression of many of these major diseases. A
similar comment applies to researchers who should be more
aware that vitamin D deficiency could significantly alter the
responsiveness of both animals and isolated tissues.
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Received 21 October 2014
The Authors Journal compilation
2015 Biochemical Society
... Yet, recent reports suggest that the two isoforms of vitamin E might have differential effects on regulation of inflammation [6,7]. Vitamin D can reduce lipid peroxidation and act through the vitamin D receptor to reduce free radical production [5,8]. The primary source of vitamins A, C, and E precursors is diet; sun exposure is the primary source of vitamin D, but it can also be obtained through dietary intake [9,10]. ...
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Background Oxidative stress plays a key role in the pathogenesis of respiratory diseases; however, studies on antioxidant vitamins and respiratory outcomes have been conflicting. We evaluated whether lower serum levels of vitamins A, C, D, and E are associated with respiratory morbidity and mortality in the U.S. adult population. Methods We conducted a pooled analysis of data from the 1988–1994 and 1999–2006 National Health and Nutrition Examination Survey (participants aged ≥ 20 years). We estimated covariate-adjusted odds ratios (aOR) per interquartile decrease in each serum vitamin level to quantify associations with respiratory morbidity, and covariate-adjusted hazard ratios (aHR) to quantify associations with respiratory mortality assessed prospectively through 2015. Vitamin supplementation and smoking were evaluated as potential effect modifiers. Results Lower serum vitamin C increased the odds of wheeze among all participants (overall aOR: 1.08, 95% CI: 1.01–1.16). Among smokers, lower serum α-tocopherol vitamin E increased the odds of wheeze (aOR: 1.11, 95% CI: 1.04–1.19) and chronic bronchitis/emphysema (aOR: 1.13, 95% CI: 1.03–1.24). Conversely, lower serum γ-tocopherol vitamin E was associated with lower odds of wheeze and chronic bronchitis/emphysema (overall aORs: 0.85, 95% CI: 0.79–0.92 and 0.85, 95% CI: 0.76–0.95, respectively). Lower serum vitamin C was associated with increased chronic lower respiratory disease (CLRD) mortality in all participants (overall aHR: 1.27, 95% CI: 1.07–1.51), whereas lower serum 25-hydroxyvitamin D (25-OHD) tended to increase mortality from CLRD and influenza/pneumonia among smokers (aHR range: 1.33–1.75). Mortality from influenza/ pneumonia increased with decreasing serum vitamin A levels in all participants (overall aHR: 1.21, 95% CI: 0.99–1.48). In pooled analysis, vitamin C deficiency and 25-OHD insufficiency were associated with mortality from influenza/pneumonia, increasing mortality risk up to twofold. Conclusions Our analysis of nationally representative data on over 34,000 participants showed that lower serum levels of vitamins A, C, D, and α-tocopherol vitamin E are associated with increased respiratory morbidity and/or mortality in U.S. adults. The results underscore the importance of antioxidant vitamins in respiratory health.
... Vitamin D also has a non-traditional regulatory role in inflammation via its influence on oxidative stress pathways via nuclear factor-erythroid-2-related factor 2 (Nrf2), which regulates the expression of genes encoding antioxidant enzymes, apoptosis, inflammation, endothelial dysfunction, and cellular immunity [54,55]. Nrf2 activates the antioxidant response element (ARE), and activation of the ARE downregulates redox-sensitive and inflammatory genes, including nuclear factor-kB (NF-kB) [56]. ...
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Food insecurity in the United States has been exacerbated due to the socioeconomic strain of the coronavirus disease 2019 (COVID-19) pandemic. Populations experiencing poverty and, as a consequence, food insecurity in the United States are disproportionately affected by obesity, which was identified early in the pandemic as a major risk factor for increased susceptibility to COVID-19 infection and mortality. Given the focus on obesity and its role in immune dysregulation, it is also important to note the role of micronutrient deficiency, another sequalae of food insecurity. Micronutrients play an important role in the ability of the immune system to mount an appropriate response. Moreover, OBESE individuals are more likely to be micronutrient deficient. This review will explore the role of micronutrients, vitamin A, vitamin D, vitamin C, and zinc in respiratory immunity and COVID-19 and how micronutrient deficiency may be a possible confounder in obesity’s association with severe outcomes. By illuminating the role of micronutrients in COVID-19, this paper expands the discussion from food insecurity and obesity to include micronutrient deficiency and how all of these interact in respiratory illnesses such as COVID-19.
... Vitamin D appears to be involved in the control of serotonin formation, implying a link between vitamin D deficiency and depression (Patrick and Ames, 2015). Vitamin D has been theorized to act as a neuroactive hormone (Berridge, 2015a;Berridge, 2015b;Berridge, 2017). Furthermore, vitamin D has been postulated to modulate neuronal calcium ion levels and thereby to cause the onset of depressive symptoms, with vitamin D deficiency leading to elevated neuronal Ca 2+ and increasing depression (Berridge, 2017). ...
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Vitamin D has increasingly been associated with the pathophysiology of mental illness and has been suggested to have beneficial effects on depression in adults. Epidemiological studies concerning vitamin D and depression have found inconsistent results and many have significant methodological limitations. The available evidence suggests that depressed individuals show reduced vitamin D concentrations compared to controls without depression. Despite the available findings suggesting that hypovitaminosis D elevates the risk of depressive mood, the evidence of observational and interventional studies is insufficient to establish causality between low vitamin D levels and the occurrence of depression. The question of whether vitamin D sufficiency has protective efficacy against incident depression or recurrence requires future investigation. In order to examine the therapeutic efficacy of vitamin D, further well-designed, large-scale, long-term intervention trials of vitamin D supplementation in people of different age groups with depressive symptoms, diagnosed depression, postpartum depression or other depressive disorders are warranted. In short, current evidence cannot definitively establish whether vitamin D deficiency is a risk factor in the development of depression or whether vitamin D is effective in the treatment of depression.
... D vitamino veikimo mechanizmas depresijos kontekste. Viena iš pagrindinių D vitamino funkcijų yra palaikyti ląstelių, šiame kontekste, neuronų kalcio jonų ir laisvųjų radikalų homeostazę [15,16]. D vitaminas mažina L tipo CaV1.2 ir CaV1.3 kanalų hipokampe [17] ir žieviniuose neuronuose ekspresiją [18]. ...
Depresija yra vienas iš dažniausių psichiatrinių susir­gimų, pasitaikančių žmonių populiacijoje, stipriai pa­veikiantis gyvenimo kokybę ir darbingumą. Depresijos ligos etiologija yra sudėtinga, galutinai neišaiškinta, tu­rinti daugybę patogenezinių mechanizmų.. Pastaraisiais metais vis daugiau kalbama apie D vitamino trūkumo įtaką depresijos vystymuisi. Tyrimo tikslas − apžvelgti D vitamino reikšmę žmogaus organizmui ir išsiaiškinti, kaip jo trūkumas susijęs su depresijos ligos atsiradimu. Literatūros šaltinių paieška atlikta kompiuterinėse bibli­ografinėse mokslinių darbų bazėse PubMed ir Google Scholar, naudojant raktažodžius ir jų derinius. Anali­zei atrinkti ir išnalizuoti 23 moksliniai straipsniai an­glų kalba, atitinkantys tyrimo temą. Tyrimo rezultatai atskleidė, kad dvidešimtojo amžiaus devintajame de­šimtmetyje buvo padaryta reikšmingų neurobiologijos tyrimų, sakančių, jog D vitamino receptorių gausu CNS dalyse, glaudžiai susijusiose su depresijos patogeneze. D vitaminas riebaluose tirpus, jį žmogaus organizmas gali gauti trimis būdais: būnant apšviestam saulės, valgant specifinį maistą ir geriant D vitaminą, kaip maisto pa­pildą. Išvados: 1) vitamino D trūkumas gali būti vienas iš depresijos rizikos veiksnių; 2) patvirtinta koreliacija tarp mažos 25(OH)D koncentracijos ir padidėjusios de­presijos rizikos bei jos simptomų atsiradimo; 3) norma­laus D vitamino lygio kraujyje palaikymas gali padėti išvengti depresijos.
... Togha et al. (52) demonstrated that chronic migraineurs had lower total antioxidant non-enzymatic capacity and higher ROS levels than EM patients (52). Physiological vitD level decreases intracellular oxidative stress-related activities, upregulating the expression of several genes implicated in mitochondrial activity, defense against oxidative burst and aging, and particularly of the nuclear factor erythroid-2(Nf-E2)-related factor and of Klotho (45,(55)(56)(57)(58)(59). ...
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Several studies focused on the role of vitamin D (vitD) in pain chronification. This study focused on vitD level and pain chronification and extension in headache disorders. Eighty patients with primary headache underwent neurological examination, laboratory exams, including serum calcifediol 25(OH)D, and headache features assessment along with three questionnaires investigating depression, anxiety, and allodynia. The 86.8% of the population had migraine (48% episodic and 52% chronic). The 44.1% of patients had extracranial pain, and 47.6% suffered from allodynia. A vitD deficit, namely a serum 25(OH)D level <20 ng/ml, was detectable in 46.1% of the patients, and it occurred more frequently (p = 0.009) in patients suffering from chronic migraine (CM)–medication overuse migraine (MOH) (62.9%) than in episodic migraine (EM, 25.7%) or tension-type headache (TTH, 11.4%). The occurrence of extracranial pain and allodynia was higher in the CM-MOH than in the EM and in the TTH groups but was not related to the co-occurrence of vitD deficiency (Fisher's exact test p = 0.11 and p = 0.32, respectively). Our findings show that 25(OH)D deficit is also related to chronic headache, probably because of vitD anti-inflammatory and tolerogenic properties, reinforcing the idea of a neuroinflammatory mechanism underpinning migraine chronification.
... conditions such as systemic arterial hypertension, cancer, osteoarthritis, multiple sclerosis, and diabetes mellitus is described. 1,2,8 Although the main site of vitamin D metabolism (►Figure 1) is the skin, it also occurs in other properly functioning organs, such as the bowel, liver and kidney. 9,10 Cutaneous 7-dehydrocholesterol (pro-vitamin D3) is converted by ultraviolet B (UVB) radiation in cholecalciferol (vitamin D3), which can be also obtained from food sources. ...
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Vitamin D is a micronutrient essential to various systems from the human body, and it is not restricted to the classical function of bone mineralization. Its synthesis is mainly related to ultraviolet B (UVB) radiation exposure. Although Brazil is a tropical country with high levels of UVB radiation, counter-intuitively, a large number of Brazilians present vitamin D deficiency, which is also a worldwide issue. This review aims to approach clinical features and explore potential causes for this apparent contradiction through questions that could explain vitamin D deficiency in the Brazilian population. Resumo A vitamina D corresponde a um micronutriente essencial ao funcionamento de diversos sistemas do corpo humano, não se restringindo à clássica função de mineralização óssea. A sua síntese está relacionada principalmente à exposição à radiação ultravioleta B (UVB). O Brasil é um país tropical que apresenta altos índices de UVB, no entanto, ao contrário do que se pode imaginar, observa-se um grande número de brasileiros deficientes em vitamina D e essa deficiência se torna um problema de ordem mundial. Essa revisão tem por objetivo abordar características clínicas e explorar as possíveis causas para essa aparente contradição, por meio de questionamentos que poderiam explicar a deficiência de vitamina D na população brasileira.
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Vitamin D is a fat-soluble secosteroid, traditionally considered a key regulator of bone metabolism, calcium and phosphorous homeostasis. Its action is made possible through the binding to the vitamin D receptor (VDR), after which it directly and indirectly modulates the expression of thousands of genes. Vitamin D is important for brain development, mature brain activity and associated with many neurological diseases, including Parkinson’s disease (PD). High frequency of vitamin D deficiency in patients with Parkinson’s disease compared to control population was noted nearly twenty years ago. This finding is of interest given vitamin D’s neuroprotective effect, exerted by the action of neurotrophic factors, regulation of nerve growth or through protection against cytotoxicity. Vitamin D deficiency seems to be related to disease severity and disease progression, evaluated by Unified Parkinson’s Disease Rating Scale (UPDRS) and Hoehn and Yahr (H&Y) scale, but not with age of PD onset and duration of disease. Additionally, fall risk has been associated with lower vitamin D levels in PD. However, while the association between vitamin D and motor-symptoms seems to be possible, results of studies investigating the association with non-motor symptoms are conflicting. In addition, very little evidence exists regarding the possibility to use vitamin D supplementation to reduce clinical manifestations and disability in patients with PD. However, considering the positive balance between potential benefits against its limited risks, vitamin D supplementation for PD patients will probably be considered in the near future, if further confirmed in clinical studies.
Introduction: Vitamin D deficiency is widespread in the world and is prevalent in Muslim countries despite sufficient sunlight. Vitamin D deficiency disrupts mitochondrial function and enhances oxidative stress and leads to common diseases such as metabolic disorders. This study aimed to evaluate the efficacy of vitamin D supplementation on oxidative stress factors in students. Materials and Methods: This study was a randomized double-blind clinical trial. University students were randomly divided into two groups of control and treatment with a sample size of 26 and 25 in each group, respectively. Students received two pearls of 50,000 unit vitamin D or placebo at time zero and after 4 weeks. Before the beginning of the study and after 8 weeks, oxidative stress biomarkers including the total antioxidant capacity of plasma and lipid peroxidation were measured in the blood samples. Results: At the beginning of the study, there was no significant difference between the treatment group and placebo in the mean of vitamin D, but after the administration of vitamin D, this difference became significant. Vitamin D significantly increased the total antioxidant capacity (P=0.019) and decreased the lipid peroxidation (P=0.004) compared with the placebo group. Conclusion: The results of this study show the effect of monthly administration of 50,000 units of vitamin D on reducing oxidative stress in students.
Vitamins are wide a group of organic compounds that have to be obtained from the diet, necessary for the correct maintenance of the body normal functions. In the current era of natural foods for health, there is an increased interest in the vitamin supply through the diet by means of ready-to-eat foods and drinks and nutritionally rich foods either natural or minimally processed. Emerging technologies aim to improve the stability and bioaccesibility of vitamins in foods to maintain their functionality through their bioavailability, metabolism, and health-promoting activity, and these new technological approaches may affect the vitamin contents of foods during shelf-life, but at the same time, vitamins can be used as technological ingredient to improve the shelf-life of food products. The envisaged challenges and opportunities for vitamins for a healthier world are also introduced in this chapter. In summary, the physiological role of the vitamins, an extended overview of the current evidence on their health implications, as well as the relevance of emerging technologies affecting the food vitamins, and the available techniques of advanced analysis of vitamins will be considered in this chapter.
Respiratory system injury is the main cause of mortality for nitrogen mustard (NM)-induced damage. Previous studies indicate that reactive oxygen species (ROS) participates in NM-mediated respiratory injuries, but the detailed mechanism is not quite clear. Human bronchial epithelial cell lines 16HBE and BEAS-2B were treated with HN2, a type of NM. In detail, it was shown that HN2 treatment induced impaired cell viability, excessive mitochondrial ROS production and enhanced cellular apoptosis in bronchial epithelial cells. Moreover, impaired Sirt3/SOD2 axis was observed upon HN2 treatment, with decreased Sirt3 and increased acetylated SOD2 expression levels. Sirt3 overexpression partially ameliorated HN2-induced cell injury. Meanwhile, vitamin D3 treatment partially attenuated HN2-induced apoptosis and improved the mitochondrial functions upon HN2 intervention. In addition, HN2 exposure decreased VDR expression, thus inhibiting the Nrf2 phosphorylation and Sirt3 activation. Inhibition of Nrf2 or Sirt3 could decrease the protective effects of vitamin D3 and enhance mitochondrial ROS production via modulating mitochondrial redox balance. In conclusion, impaired VDR/Nrf2/Sirt3 axis contributed to NM-induced apoptosis, while vitamin D3 supplementation provides protective effects via the activation of VDR and the improvement of mitochondrial functions. This study provides novel mechanism and strategy for NM exposure-induced pulmonary injuries.
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Vitamin D is an important calcium-regulating hormone with diverse functions in numerous tissues, including the brain. Increasing evidence suggests that vitamin D may play a role in maintaining cognitive function and that vitamin D deficiency may accelerate age-related cognitive decline. Using aging rodents, we attempted to model the range of human serum vitamin D levels, from deficient to sufficient, to test whether vitamin D could preserve or improve cognitive function with aging. For 5-6 mo, middle-aged F344 rats were fed diets containing low, medium (typical amount), or high (100, 1,000, or 10,000 international units/kg diet, respectively) vitamin D3, and hippocampal-dependent learning and memory were then tested in the Morris water maze. Rats on high vitamin D achieved the highest blood levels (in the sufficient range) and significantly outperformed low and medium groups on maze reversal, a particularly challenging task that detects more subtle changes in memory. In addition to calcium-related processes, hippocampal gene expression microarrays identified pathways pertaining to synaptic transmission, cell communication, and G protein function as being up-regulated with high vitamin D. Basal synaptic transmission also was enhanced, corroborating observed effects on gene expression and learning and memory. Our studies demonstrate a causal relationship between vitamin D status and cognitive function, and they suggest that vitamin D-mediated changes in hippocampal gene expression may improve the likelihood of successful brain aging.
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The poor clinical outcome in pancreatic ductal adenocarcinoma (PDA) is attributed to intrinsic chemoresistance and a growth-permissive tumor microenvironment. Conversion of quiescent to activated pancreatic stellate cells (PSCs) drives the severe stromal reaction that characterizes PDA. Here, we reveal that the vitamin D receptor (VDR) is expressed in stroma from human pancreatic tumors and that treatment with the VDR ligand calcipotriol markedly reduced markers of inflammation and fibrosis in pancreatitis and human tumor stroma. We show that VDR acts as a master transcriptional regulator of PSCs to reprise the quiescent state, resulting in induced stromal remodeling, increased intratumoral gemcitabine, reduced tumor volume, and a 57% increase in survival compared to chemotherapy alone. This work describes a molecular strategy through which transcriptional reprogramming of tumor stroma enables chemotherapeutic response and suggests vitamin D priming as an adjunct in PDA therapy. PAPERFLICK:
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Generation of reactive oxygen species (ROS), leading to oxidative damage and neuronal cell death plays an important role in the pathogenesis of neurodegenerative disorders including Alzheimer's disease. The present study aimed to examine the mechanism by which the anti-aging protein Klotho exerts neuroprotective effects against neuronal damage associated with neurodegeneration and oxidative stress. Pretreatment of rat primary hippocampal neurons and mouse hippocampal neuronal cell line HT22 with recombinant Klotho protected these cells from glutamate and oligomeric amyloid β (oAβ)-induced cytotoxicity. In addition, primary hippocampal neurons obtained from Klotho overexpressing mouse embryos were more resistent to both cytotoxic insults, glutamate and oAβ, compared to neurons from wild type littermates. An anti-oxidative stress array analysis of neurons treated with Klotho revealed that Klotho significantly enhances the expression of the thioredoxin/peroxiredoxin (Trx/Prx) system with the greatest effect on the induction of Prx-2, an antioxidant enzyme, whose increase was confirmed at the mRNA and protein levels. Klotho-induced phosphorylation of PI3K/Akt pathway, a pathway important in apoptosis and longevity, was associated with sustained inhibitory phosphorylation of the transcription factor forkhead box O3a (FoxO3a), and was essential for the induction of Prx-2. Downregulation of Prx-2 expression using a lentivirus harboring shRNA abolished Klotho's ability to rescue neurons from glutamate-induced death and significantly, but not completely, inhibited cell death mediated by oAβ, suggesting that Prx-2 is a key modulator of neuroprotection. Thus, our results demonstrate, for the first time, the neuroprotective role of Klotho and reveal a novel mechanism underlying this effect.
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Aging is the primary risk factor for cognitive decline, an emerging health threat to aging societies worldwide. Whether anti-aging factors such as klotho can counteract cognitive decline is unknown. We show that a lifespan-extending variant of the human KLOTHO gene, KL-VS, is associated with enhanced cognition in heterozygous carriers. Because this allele increased klotho levels in serum, we analyzed transgenic mice with systemic overexpression of klotho. They performed better than controls in multiple tests of learning and memory. Elevating klotho in mice also enhanced long-term potentiation, a form of synaptic plasticity, and enriched synaptic GluN2B, an N-methyl-D-aspartate receptor (NMDAR) subunit with key functions in learning and memory. Blockade of GluN2B abolished klotho-mediated effects. Surprisingly, klotho effects were evident also in young mice and did not correlate with age in humans, suggesting independence from the aging process. Augmenting klotho or its effects may enhance cognition and counteract cognitive deficits at different life stages.
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Epigenetic mechanisms play a crucial role in regulating gene expression. The main mechanisms involve methylation of DNA and covalent modifications of histones by methylation, acetylation, phosphorylation, or ubiquitination. The complex interplay of different epigenetic mechanisms is mediated by enzymes acting in the nucleus. Modifications in DNA methylation are performed mainly by DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) proteins, while a plethora of enzymes, such as histone acetyltransferases (HATs), histone deacetylases (HDACs), histone methyltransferases (HMTs), and histone demethylases (HDMs) regulate covalent histone modifications. In many diseases, such as cancer, the epigenetic regulatory system is often disturbed. Vitamin D interacts with the epigenome on multiple levels. Firstly, critical genes in the vitamin D signaling system, such as those coding for vitamin D receptor (VDR) and the enzymes 25-hydroxylase (CYP2R1), 1α-hydroxylase (CYP27B1), and 24-hydroxylase (CYP24A1) have large CpG islands in their promoter regions and therefore can be silenced by DNA methylation. Secondly, VDR protein physically interacts with coactivator and corepressor proteins, which in turn are in contact with chromatin modifiers, such as HATs, HDACs, HMTs, and with chromatin remodelers. Thirdly, a number of genes encoding for chromatin modifiers and remodelers, such as HDMs of the Jumonji C (JmjC)-domain containing proteins and lysine-specific demethylase (LSD) families are primary targets of VDR and its ligands. Finally, there is evidence that certain VDR ligands have DNA demethylating effects. In this review we will discuss regulation of the vitamin D system by epigenetic modifications and how vitamin D contributes to the maintenance of the epigenome, and evaluate its impact in health and disease.
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Vitamin D is not really a vitamin but the precursor to the potent steroid hormone calcitriol, which has widespread actions throughout the body. Calcitriol regulates numerous cellular pathways that could have a role in determining cancer risk and prognosis. Although epidemiological and early clinical trials are inconsistent, and randomized control trials in humans do not yet exist to conclusively support a beneficial role for vitamin D, accumulating results from preclinical and some clinical studies strongly suggest that vitamin D deficiency increases the risk of developing cancer and that avoiding deficiency and adding vitamin D supplements might be an economical and safe way to reduce cancer incidence and improve cancer prognosis and outcome.
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Aging, a major risk factor in Alzheimer's disease (AD), is associated with an oxidative redox shift, decreased redox buffer protection, and increased free radical reactive oxygen species (ROS) generation, probably linked to mitochondrial dysfunction. While NADH is the ultimate electron donor for many redox reactions, including oxidative phosphorylation, glutathione (GSH) is the major ROS detoxifying redox buffer in the cell. Here, we explored the relative importance of NADH and GSH to neurodegeneration in aging and AD neurons from nontransgenic and 3xTg-AD mice by inhibiting their synthesis to determine whether NADH can compensate for the GSH loss to maintain redox balance. Neurons stressed by either depleting NAD(P)H or GSH indicated that NADH redox control is upstream of GSH levels. Further, although depletion of NAD(P)H or GSH correlated linearly with neuron death, compared with GSH depletion, higher neurodegeneration was observed when NAD(P)H was extrapolated to zero, especially in old age, and in the 3xTg-AD neurons. We also observed an age-dependent loss of gene expression of key redox-dependent biosynthetic enzymes, NAMPT (nicotinamide phosphoribosyltransferase), and NNT (nicotinamide nucleotide transhydrogenase). Moreover, age-related correlations between brain NNT or NAMPT gene expression and NADPH levels suggest that these genes contribute to the age-related declines in NAD(P)H. Our data indicate that in aging and more so in AD-like neurons, NAD(P)H redox control is upstream of GSH and an oxidative redox shift that promotes neurodegeneration. Thus, NAD(P)H generation may be a more efficacious therapeutic target upstream of GSH and ROS.
Conference Paper
Ca2+ is a universal second messenger used to regulate a wide range of cellular processes such as fertilization, proliferation, contraction, secretion, learning and memory. Cells derive signal Ca2+ from both internal and external sources. The Ca2+ flowing through these channels constitute the elementary events of Ca2+ signalling. Ca2+ can act within milliseconds in highly localized regions or it can act much more slowly as a global wave that spreads the signal throughout the cell, Various pumps and exchangers are responsible for returning the elevated levels of Ca2+ back to the resting state. The mitochondrion also plays a critical role in that it helps the recovery process by taking Ca2+ up from the cytoplasm. Alterations in the ebb and flow of Ca2+ through the mitochondria can lead to cell death. A good example of the complexity of Ca2+ signalling is its role in regulating cell proliferation, such as the activation of lymphocytes. The Ca2+ signal needs to be present for over two hours and this prolonged period of signalling depends upon the entry of external Ca2+ through a process of capacitative Ca2+ entry. The Ca2+ signal stimulates gene transcription and thus initiates the cell cycle processes that culminate in cell division.
The β-catenin signaling pathway is deregulated in nearly all colon cancers. Nonhypercalcemic vitamin D3 (1α,25-dehydroxyvitamin D3) analogues are candidate drugs to treat this neoplasia. We show that these compounds promote the differentiation of human colon carcinoma SW480 cells expressing vitamin D receptors (VDRs) (SW480-ADH) but not that of a malignant subline (SW480-R) or metastasic derivative (SW620) cells lacking VDR. 1α,25(OH)2D3 induced the expression of E-cadherin and other adhesion proteins (occludin, Zonula occludens [ZO]-1, ZO-2, vinculin) and promoted the translocation of β-catenin, plakoglobin, and ZO-1 from the nucleus to the plasma membrane. Ligand-activated VDR competed with T cell transcription factor (TCF)-4 for β-catenin binding. Accordingly, 1α,25(OH)2D3 repressed β-catenin–TCF-4 transcriptional activity. Moreover, VDR activity was enhanced by ectopic β-catenin and reduced by TCF-4. Also, 1α,25(OH)2D3 inhibited expression of β-catenin–TCF-4-responsive genes, c-myc, peroxisome proliferator-activated receptor δ, Tcf-1, and CD44, whereas it induced expression of ZO-1. Our results show that 1α,25(OH)2D3 induces E-cadherin and modulates β-catenin–TCF-4 target genes in a manner opposite to that of β-catenin, promoting the differentiation of colon carcinoma cells.
Background — Angiotensin II induces both cardiac and vascular smooth muscle (VSM) hypertrophy. Recent studies suggest a central role for a phagocyte-type NADPH oxidase in angiotensin II-induced VSM hypertrophy. The possible involvement of an NADPH oxidase in the development of cardiac hypertrophy has not been studied. Methods and Results — Mice with targeted disruption of the NADPH oxidase subunit gp91 phox (gp91 phox−/− ) and matched wild-type mice were subjected to subcutaneous angiotensin II infusion at a subpressor dose (0.3 mg/kg/day) for 2 weeks. Systolic blood pressure was unaltered by angiotensin II in either group. Angiotensin II significantly increased heart/body weight ratio, atrial natriuretic factor and β-myosin heavy chain mRNA expression, myocyte area, and cardiac collagen content in wild-type but not gp91 phox−/− mice. Angiotensin II treatment increased myocardial NADPH oxidase activity in wild-type but not gp91 phox−/− mice. Conclusions — A gp91 phox -containing NADPH oxidase plays an important role in the development of angiotensin II-induced cardiac hypertrophy, independent of changes in blood pressure.