VITAMINS
VLA 23.4.2019
VITAMIN A
 Since the identification of fat soluble A a century ago,
retinoids (vitamin A and its natural and synthetic
analogs) have been the most extensively studied of
the fat soluble vitamins.
 This research has identified essential roles for
retinoids in many different aspects of mammalian
physiology including embryonic development, adult
growth and development, maintenance of immunity,
maintenance of epithelial barriers and vision.
VITAMIN A AND BETA-CAROTENE
 Roles in the Body
 Vitamin A in Vision
Helps to maintain the cornea
Conversion of light energy into nerve impulses at
the retina
Rhodopsin is a light-sensitive pigment of the
retina that contains a protein called opsin.
Rhodopsin
retinal visual
cycle
Hyperpolarization
receptor potential
formation due to
decomposition of
rhodopsin
VITAMIN A AND BETA-CAROTENE
 Roles in the Body
 Vitamin A in Protein Synthesis and Cell
Differentiation
 Through cell differentiation, vitamin A allows cells to
perform specific functions.
 Epithelial cells
 Epithelial tissues on the outside of the body form the
skin.
 Epithelial tissues on the inside of the body form the
mucous membranes.
VITAMIN A AND BETA-CAROTENE
 Roles in the Body
 Vitamin A in Reproduction and Growth
 Sperm development in men
 Normal fetal development in women
 Growth in children
 Remodeling of the bone involves osteclasts, osteoblasts,
and lysosomes.
 Osteoclasts are cells that destroy bone growth.
 Osteoblasts are cells that build bones.
 Lysosomes are sacs of degradative enzymes that destroy bones.
VITAMIN A AND BETA-CAROTENE
 Roles in the Body
 Beta-Carotene as an Antioxidant
Beta-carotene helps protect the body from
diseases, including cancer.
VITAMIN AND ITS METABOLITS
All-trans-retinoic acid (atRA) is a highly potent derivative of vitamin A that is required for
virtually all essential physiological processes and functions because of its involvement in
transcriptional regulation of over 530 different genes .
atRA is necessary for differentiation and development of fetal and adult tissues, stem cell
differentiation, and apoptosis; for support of reproductive functions , immune response, and
regulation of energy homeostasis
atRA exerts its actions by serving as an activating ligand of nuclear atRA receptors (RAR α, β, and
γ) and peroxisome proliferator-activated receptors (PPAR β/δ), which form heterodimers with
retinoid X receptors.
The concentration of atRA during embryonic development is tightly controlled in a
spatial and temporal manner, and in adult tissues, it is maintained within a very narrow range
that is specific for each given tissue. If the control mechanisms fail and the concentration of
atRA exceeds or falls below the optimal range, tissues and cells undergo pathophysiological
changes that in most severe cases can lead to disease. Thus, the maintenance of optimal atRA
levels is essential for life.
CRBP = cellular retinol binding protein
LIGANDS FOR RA
 RA IS FUNCTIONING BY:
 RAR (izoforms ,  and )
 RXR (izoforms ,  and )
 RAR:RXR heterodimers
RXR and its partners
in nuclear receptor
function
VITAMIN A AND BETA-CAROTENE
 Vitamin A Deficiency
 Blindness
Xerophthalmia
 Xerosis is the first stage where the cornea becomes dry and hard.
 Keratomalacia is the softening of the cornea.
 Keratinization
 Epithelial cells secrete a protein called keratin—the hard, inflexible
protein of hair and nails.
 Changes in epithelial cells results in keratinization, rough, dry and
scaly skin.
 Deficiency disease is called hypovitaminosis A
XEROPHTHALMIA
VITAMIN A AND BETA-CAROTENE
 Vitamin A Deficiency
 Because vitamin A is stored in the body, it would
take a year or more to develop a deficiency in the
presence of inadequate intake.
 Infectious Diseases
 Impaired immunity correlates with vitamin A deficiency in children.
 The goals of worldwide health organizations include vitamin A
supplementation.
 Night Blindness
 First detectable sign of vitamin A deficiency
 Inability to see in dim light or inability to recover sight after a flash of bright
light
VITAMIN A AND BETA-CAROTENE
 Vitamin A deficiency is a major health problem in the
world.
 Toxicity is often associated with abuse of supplements.
 Plant foods provide carotenoids, such as beta-carotene,
some of which have vitamin A activity.
 Animal foods provide compounds that are easily
converted to retinol.
 Retinol binding protein (RBP) allows vitamin A to be
transported throughout the body.
VITAMIN A AND BETA-CAROTENE
 Vitamin A Toxicity
 Can occur with concentrated amounts of the
preformed vitamin A from animal foods, fortified
foods, or supplements.
 Consuming excessive amounts of beta-carotene from supplements can
be harmful.
 Bone Defects
 Increased activity of osteoclasts causes weakened bones and contributes to
osteoporosis and fractures.
VITAMIN A AND BETA-CAROTENE
 Vitamin A Toxicity
 Birth Defects
 Teratogenic risk is possible, resulting in abnormal
fetal development and birth defects.
 Vitamin A supplements are not recommended the
first trimester of pregnancy.
 Not for Acne
 Massive doses for teens are not effective on acne.
 Accutane is made from vitamin A, but is chemically
different. It is toxic during growth and can cause birth
defects.
 Retin-A fights acne, the wrinkles of aging, and other
skin disorders.
VITAMIN A AND BETA-CAROTENE
 Vitamin A Toxicity
 Toxicity is called hypervitaminosis A
 Chronic toxicity symptoms include liver
abnormalities.
 Acute toxicity symptoms include blurred vision,
nausea, vomiting, vertigo, headaches, and pressure
in the skull.
 Upper level for adults: 3000 μg/day
VITAMIN A AND BETA-CAROTENE
 Vitamin A in Foods
 Retinol is found in fortified milk, cheese, cream,
butter, fortified margarine, and eggs.
 Beta-carotene
 Spinach and other dark green leafy vegetables
(chlorophyll pigment masks the color)
 Deep orange fruits like apricots and cantaloupe
 Deep orange vegetables like squash, carrots, sweet
potatoes, and pumpkin
 White foods are typically low in beta-carotene.
 Liver is rich in vitamin A.
VITAMIN D
 Vitamin D is a nonessential nutrient that
acts like a hormone in the body.
 The body can make vitamin D with help
from sunlight.
Copyright ©2006 American Society for Clinical Investigation
Holick, M. F. J. Clin. Invest. 2006;116:2062-2072
VITAMIN D
 Roles in the Body
 Vitamin D in Bone Growth
Helps to maintain blood levels of calcium and
phosphorus
Works in combination with other nutrients and
hormones
Vitamin A, vitamin C, vitamin K
Parathormone and calcitonin
Collagen
Calcium, phosphorus, magnesium, and
fluoride
VITAMIN D DEFICIENCY
 Rickets
 Affects mainly children worldwide
 Deficiency symptoms
 Inadequate calcification of bones
 Growth retardation
 Misshapen bones- bowing of the legs
 Enlargement of the ends of long bones
 Deformities of ribs,
 Lax muscles (resulting in a protruding abdomen) and
muscle spasms
CALCIUM, VITAMIN D, AND PARATHYROID
HORMONE
 The active 1,25 dihydroxy vitamin D (calcitriol), is not
only necessary for optimal intestinal absorption of
calcium and phosphorus, but also exerts a tonic
inhibitory effect on parathyroid hormone (PTH)
synthesis, so that there are dual pathways that can
lead to secondary hyperparathyroidism.
 Vitamin D deficiency and secondary
hyperparathyroidism can contribute not only to
accelerated bone loss and increasing fragility, but also
to neuromuscular impairment that can increase the risk
of falls.
Regulation of gene expresssion by VDR
TARGET GENES FOR VITAMIN D
Gene Transcription
Receptor for vitamin D (VDR) increased
Proteins bindingí Ca (calbindins) increased
Calcium pump increased
Osteokalcin increased
Alkalic phosphatase increased
24-hydroxylase increased
PTH decreased
1-hydroxylase decreased
Collagen decreased
Interleukin-2 decreased
Interferon  decreased
VITAMIN D DEFICIENCY
Osteomalacia
Affects adults
Soft, flexible, brittle, deformed bones
Progressive weakness
Pain in pelvis, lower back, and legs
OSTEOMALACIA AND RICKETS
 Classically, the deficiency of vitamin D,
essential for the absorption of calcium,
has been the major cause of rickets in
the child and osteomalacia in the adult
resulting in absence or delay in the
mineralization of growth cartilage or
newly formed bone collagen.
OSTEOMALACIA AND RICKETS
 As a consequence of a low serum phosphate and
normal serum calcium.
 Two such conditions are x-linked
hypophosphatemic rickets/osteomalacia and
oncogenic osteomalacia.
 When present, the signs of rickets and
osteomalacia in the low serum phosphate states
are indistinguishable from the classic
hypocalcemic states.
X-LINKED HYPOPHOSPHATEMIC OSTEOMALACIA
 The condition is characterized by low
tubular reabsorption of phosphate in the
absence of secondary
hyperparathyroidism.
 X-linked hypophosphatemia occurs in
about 1 in 25,000 and is considered the
most common form of genetically
induced rickets.
ONCOGENIC OSTEOMALACIA
 Oncogenic osteomalacia is a
paraneoplastic syndrome in which a
bone or soft tissue tumor or tumor-like
lesion induces hypophosphatemia and
low vitamin D levels that reverse when
the inciting lesion is resected.
ONCOGENIC OSTEOMALACIA
 In the past 15 or so years, a humoral factor,
phosphotonin, has been identified in clinical and
experimental studies as being responsible for the serum
biochemical changes.
 Phosphotonin causes hyperphosphaturia by inhibiting
the reabsorption of phosphate by the proximal renal
tubules.
 Fibroblast growth factor 23, phosphate-regulating gene
with homologies to endopeptides located on the ‘x’
chromosome (PHEX) and matrix extracellular
phosphoglycoprotein (MEPE) are candidates proposed
for the production of phosphatonin and the altered
pathophysiology in oncogenic osteomalacia.
VITAMIN D TOXICITY
 More likely compared to other vitamins
 Vitamin D from sunlight and food is not likely to
cause toxicity.
 High-dose supplements may cause toxicity.
 Toxicity symptoms
 Elevated blood calcium
 Calcification of soft tissues (blood vessels, kidneys,
heart, lungs, and tissues around joints)
 Frequent urination
VITAMIN E
 The principal role of vitamin E is to protect tissue against unwanted, destructive
oxidation Vitamin E is the most effective lipid-soluble antioxidant present in our cells.
 Because vitamin E is an antioxidant, and because it has long been known that
oxidation plays an important role in, it was presumed that vitamin E would be
protective against cancer. However, perhaps because of the long induction times
before overt tumors are observed and the long period over which supplementation
must occur to provide protection, evidence for an anticancer effect for vitamin E in
humans has developed more slowly than has evidence for the role of vitamin E in
preventing heart disease.
 The hypothesis that links vitamin E and cardiovascular diseases (CVD) posits that
the oxidation of unsaturated lipids in the LDL particle, as well as the complex
sequelae that flow from this oxidation, play a crucial role in the pathogenesis of
atherosclerosis. This theory is now generally accepted, and this theory provides a
strong biological plausibility for the role of vitamin E in preventing CVD.
VITAMIN E
 There are four different tocopherol compounds,
but only the alpha-tocopherol has vitamin E
activity in human beings.
 Vitamin E as an Antioxidant
 Stops the chain reaction of free radicals
 Protection of polyunsaturated fatty acids and
vitamin A
 Protects the oxidation of LDLs
VITAMIN E
 Vitamin E Deficiency - Symptoms
 Loss of muscle coordination and reflexes
 Impaired vision and speech
 Nerve damage
 Erythrocyte hemolysis (breaking open of red blood cells)
 Supplements do not prevent or cure muscular dystrophy.
 Fibrocystic breast disease responds to vitamin E treatment.
 Intermittent claudication responds to vitamin E treatment.
VITAMIN E
 Vitamin E Toxicity
 Rare and the least toxic of the fat-soluble vitamins
 Upper level for adults: 1000 mg/day
 May augment the effects of anticlotting medication
 Vitamin E Recommendations (2000 RDA)
 RDA adults: 15 mg/day
VITAMIN E DEFICIENCY AND IMMUNE
RESPONSE QUALITY IN MEN
Immune response Results
Mitogenesis of T-cells Decreased
Production of IL-2 Decreased
Fagocytosis of PMNs Decreased
Chemotaxis of PMNs Decreased
VITAMIN E AND HEALTH
 α-Tocopherol is a required nutrient that functions as a peroxyl radical
scavenger. If the diet contains inadequate amounts of vitamin E, then
insufficient amounts are absorbed and the erythrocyte is a key target tissue
susceptible to oxidative damage, which leads to anemia. In contrast, if α-TTP
is lacking or non-functional, then the dietary α-tocopherol is absorbed,
erythrocytes can acquire α-tocopherol and are protected, but the body does
not retain α-tocopherol, leading to its depletion in tissues. In this latter case,
the most susceptible tissues are the large-caliber sensory neurons in the
peripheral nerves.
 Ultimately, all tissues become depleted and signs of deficiency are severe
due to free-radical damage. Although vitamin E-specific pathways and
molecular targets have been sought in a variety of studies, the most likely
explanation as to why humans require α-tocopherol is that it is a fat-soluble
antioxidant.
„ORPHAN” NUCLEAR RECEPTORS
 “Orphan” nuclear receptors include receptors
for fatty acids (peroxisome-proliferator activated
receptors (PPARs)), bile acids (farnesoid X
receptor), oxysterols (liver X receptors), as well
as lipophilic xenobiotics (PXR) and constitutive
androstane receptor (CAR).
VITAMIN E AND ATHEROSCLEROSIS PREVENTION
Target Function
LDL Antioxidant
Endothelial and other cells
Potentiates arachidonate release and affects
prostane production and activity
Endothelium Inhibits cell adhesion
Endothelium
Protects nitric oxide and endothelial cell
dependent vasoactivity
Smooth muscle cell Inhibits proliferation
Platelet Inhibits adhesion and aggregation
Neutrophils Reduces leukotriene synthesis
Blood cells Reduces leukotriene urinary excretion
Monocytes
Reduced adhesion, decreased production of
oxidants, and altered cytokine expression
VITAMIN K
 Also known as phylloquinone, menaquinone, menadione, and
naphthoquinone
 Vitamin K is unique in that half of human needs are met
through the action of intestinal bacteria.
 Vitamin K is essential in blood clotting.
 deficiency can cause uncontrolled bleeding.
 Deficiencies can occur in newborn infants and people taking
antibiotics.
VITAMIN K
 Vitamin K is a fat-soluble vitamin, which is involved in blood coagulation
mediated by maintaining the activity of coagulation factors in the liver.
 Vitamin K also has extrahepatic actions and has been shown to prevent
bone fractures in clinical studies.
 Lack of vitamin K is associated with several geriatric diseases, including
osteoporosis, osteoarthritis, dementia and arteriosclerosis.
 Vitamin K contributes to the prevention and treatment of some kinds of
malignancies.
 In addition to its established roles as a cofactor of γ-glutamyl carboxylase
(GGCX) in mediating post-transcriptional modifications, vitamin K has a
different mode of action mediated by transcriptional regulation of SXR/PXR
target genes.
VITAMIN K
 Two forms: fylochinone and menachinone.
Fylochinone (vitamin K1) is contained in green
vegetables and in some plant oils. Menachinone
(vitamin K2) is of animal and bacterial origin
 Vitamin K2 is a transcriptional regulator of genes
specific for bone. Its effect is realized by SXR (steroid
and xenobiotic receptor) which supports osteoblastic
markers expressions.
SXR AND NECHANISM OF ITS EFFECT
Inoue KH a Inoue S: J Bone Miner Meat (2008) 26: 9-12
SXR AND VITAMIN K
Inoue KH a Inoue S: J Bone Miner Meat (2008) 26: 9-12
Dietary components that can alter epigenetics. The enzymes involved in the DNA methylation cycle are
dependent on the availability of essential cofactors: folate, and vitamins B12 and B6. In their abundance,
DNA methyl transferases (DNMTs) readily transfer methyl groups to cytosine residues; however, in the
absence of appropriate cofactors, methionine is converted back to its precursors, homocysteine and Sadenosyl
homocysteine. Excess S-adenosyl homocysteine levels inhibit DNMT activity, thus they can
reduce/prevent DNA methylation and compromise gene silencing. The cycle can be potentially rescued by
supplementation with these essential vitamins, to clear elevated homocysteine levels and restore DNA
methylation processes
Br J Pharmacol. 2010 Jan; 159(2): 285–303.
REDUCTIVE AND OXIDATIVE STRESS
 Reductive stress (RS) is the counterpart
oxidative stress (OS), and can occur in
response to conditions that shift the redox
balance of important biological redox
couples, such as the NAD+/NADH,
NADP+/NADPH, and GSH/GSSG, to a more
reducing state.
 Overexpression of antioxidant enzymatic
systems leads to excess reducing equivalents
that can deplete reactive oxidative species,
driving the cells to RS. Int J Mol Sci. 2017 Oct; 18(10): 2098.
REDUKČNÍ A OXIDAČNÍ STRES
 A feedback regulation is established in which chronic RS induces
OS, which in turn, stimulates again RS. Excess reducing equivalents
may regulate cellular signaling pathways, modify transcriptional
activity, induce alterations in the formation of disulfide bonds in
proteins, reduce mitochondrial function, decrease cellular
metabolism, and thus, contribute to the development of some
diseases in which NF-κB, a redox-sensitive transcription factor,
participates.
 Diseases: cardiomyopathy, hypertrophic cardiomyopathy,
muscular dystrophy, pulmonary hypertension, rheumatoid arthritis,
Alzheimer’s disease, and metabolic syndrome, among others.
 Chronic consumption of antioxidant supplements, such as
vitamins and/or flavonoids, may have pro-oxidant effects that
may alter the redox cellular equilibrium and contribute to RS, even
diminishing life expectancy.
Int J Mol Sci. 2017 Oct; 18(10): 2098.
REDUCTIVE STRESS
 RS is characterized by an excess of reducing equivalents. It leads
to a decrease of ROS production through antioxidant enzyme
overexpression that may cause an alteration in the redox state of
intracellular higher NAD+/NADPH, and GSH/GSSG ratio.
 A balance in Se and iron levels is needed for several biological
functions in the human body, and its excess and/or insufficient
intake can result in adverse health effects and contribute to RS.
 RS alters the mitochondrial function, causes misfolding of proteins,
and may participate in several inflammation-associated diseases.
 Hyperglycemic conditions induce RS through inhibition of the
insulin receptor by selenium-GPx-1 overexpression.
 .
Participation of several agents such as the reducing equivalents, antioxidant enzymes and
pathologies in reductive stress. Abbreviations: G6PD = glucose 6 phosphate dehydrogenase,
NAD = nicotinamide adenine dinucleotide, NAD+ = nicotinamide adenine dinucleotide oxidized,
NADH = nicotinamide adenine dinucleotide reduced, NADPH = nicotinamide adenine dinucleotide
phosphate reduced, GSH = glutathione, GSSG = glutathione disulfide, PPP = pentose phosphate
pathway, γ-glutamyl-cysteine synthase, GSHS = glutathione synthetase, GPx = Glutathione
peroxidase, Trx = thioredoxin, Grd = glutaredoxin, TNFα = tumor necrosis factor alpha, NrF2 =
erythroid related factor 2, IL6 = interleukin 6, ROS = reactive oxidative species, OS = oxidative
stress, ER = endoplasmic reticulum, Se = selenium, Hsp = heat shock protein, GR = glutathione
reductase.
Int J Mol Sci. 2017 Oct; 18(10): 2098
Oxidační stres
 je spjat se zmenšením počtu antioxidačních molekul, jako
alfa-tokoferol.
 Alfa-tokoferol specificky snižuje proliferaci buněk hladké
svaloviny cév v závislosti na koncentraci. Snižuje přitom
aktivitu protein kinázy C zvýšením aktivity protein fosfatázy
2A1, který defosforyluje PKC-alfa, což vede ke změnám
složení a vazby transkripčního faktoru pro AP-1 na DNA.
 několik genů v buňkách hladké svaloviny cév mění svou
transkripci pod vlivem alfa-tokoferolu. Zvyšuje se transkripce i
translace alfa-tropomyosinu, ale jen pod vlivem alfatokoferolu,
nikoliv beta-tokoferolu
 PKC-alfa se v průběhu života zvyšuje 8x, podobně jako MMP-
1, která degraduje kolagen. Alfa-tokoferol snižuje expresi
MMP, aniž ovlivňuje aktivitu TIMP-1.
 Antioxidační vitamíny, poylfenoly a estrogeny konzumované
ve vysokých koncentracích mohou navodit prooxidační stnt
stav.
Signalizace oxidačního stresu. Cytokiny a ROS indukují aktivaci NF-B.
Tato aktivace zabraňuje apoptóze buněk navozované TNF upregulací
antiapoptotických genů
Oxidační stres
 nezávisle na doprovodných proměnných,
jako je tkáňová reakce, moduluje expresi
genů pro kolagen in vivo.
 Rovnováha v oxidačním-antioxidačním
stavu je důležitou determinantou pro funkci
imunocytů.
 Zajišťuje:
 udržování integrity a funkčního stavu
membránových lipidů, celulárních proteinů
a NK
 kontrolu signální transdukce buněk
imunitního systému
 kontrolu genové exprese buněk imunitního
systému
Antioxidační obranný systém
Možná místa působení antioxidant.
Absorbce, modifikace, distribuce a účinky molekul s antioxidačními
účinky in vitro
Vitamin C – antioxidant
Vitamin C – antioxidant
OXIDATIVE STRESS
 Is defined as disequilibrium between oxidants and
antioxidants which potentially can lead to damage of
cells and/ or of cellular structures.
CHAIN TRANSPORTING ELECTRONS
DEFENDING AGAINST FREE RADICALS
 Limiting free radical formation
 Destroying free radicals or their precursors
 Stimulating antioxidant enzyme activity
 Repairing oxidative damage
 Stimulating repair enzyme activity
Signaling of oxidative stress
Antioxidative defence system
Možná místa působení antioxidant.
Absorption, modification, distribution and effects of molecules with
antioxidation effects in vitro
VITAMIN C AND EPIGENETIC REGULATION
 Vitamin C is an essential nutrient for those
mammals that cannot biosynthesize it,
including primates, guinea pigs and certain
species of bats.
 Deficiency in the vitamin leads to scurvy,
through disruption of the extracellular matrix
secondary to loss of proline hydroxylase activity
and consequent interruption of collagen
biosynthesis.
 Vitamin C can cause genome-wide changes in
epigenetic marks on DNA and can accelerate
cell state transitions along the pathway of
reprogramming of somatic cells to pluripotency.
These actions of vitamin C relate not to its
antioxidant activity but to its role as a cofactor
and electron donor for iron-dependent
oxidoreductases.
VITAMIN C AND EPIGENETIC REGULATION
 In 2010, two independent studies showed that
the addition of vitamin C to the medium used to
culture human pluripotent stem cells resulted
in genome-wide demethylation in these cells
and that this addition of vitamin C could
enhance reprogramming of mouse and human
cells to pluripotency.
TET
 Members of this important class of enzymes
include ten-eleven translocation (TET) enzymes,
which can convert 5-methylcytosine to 5hydroxymethylcytosine
(5hmC) in DNA, a
process hypothesized to be critical to active
DNA demethylation.
 DNA demethylation is an integral part of the
epigenetic remodeling that occurs during
reprogramming; thus, TET activity might be
critical for the reprogramming process.
Gene regulation by TET proteins. (A) Enzymatic activity of TET. TET proteins, with the co-factors Fe2+ and αketoglutarate
(αKG), use oxygen to oxidize 5mC into 5hmC, generating CO2 and succinate as by-products. The
enzymatic activity of TET can be modulated by additional factors. For instance, vitamin C (ascorbate) can
enhance TET activity, potentially via reduction of the iron ion. On the other hand, the “oncometabolite” 2hydroxyglutarate
(2-HG), generated in acute myeloid leukemia and glioblastoma by recurrent dominant-active
mutants of isocitrate dehydrogenase 1 or 2 (IDH1/2), inhibits TET activity. Furthermore, lack of oxygen in
hypoxia also inhibits TET function. (B) Model of TET-mediated enhancer regulation. Prior to the commissioning of
an enhancer, pioneer transcription factor (indicated as TF1) binds to nucleosomal DNA and recruits TET which
oxidizes the surrounding 5mC into 5hmC (and/or other oxi-mCs), facilitating DNA demethylation. TET proteins
and, TF1 promote enhancer accessibility by recruiting nucleosome remodeling complexes, thus allowing binding of
secondary transcription factors (indicated here as TF2) that are otherwise inhibited by DNA methylation or the
presence of nucleosomes.
Front Immunol. 2019; 10: 210
TET
 In the presence of vitamin C, cells lacking TET1
undergo reprogramming more efficiently and
this effect is related to the levels of 5hmC at
loci involved in a key early step of
reprogramming, the mesenchymal-to-epithelial
transition (MET).
The role of TET2 in myeloid differentiation and function
(A)TET2 regulates myeloid cell differentiation. TET2, together with the thymine DNA glycosylase (TDG), facilitate
active DNA demethylation and promotes lineage-specific gene expression during the differentiation of
osteoclasts, macrophages, and dendritic cells from human monocytes.
(B)TET2 regulates the function of myeloid cells. In mouse and human macrophages, TET2 repressed expression of
the pro-inflammatory cytokines IL-1β and IL-6. In plasmacytoid dendritic cells, CXXC5 recruited TET2 to an
intragenic CpG island in Irf7 (interferon regulatory factor 7), facilitating the demethylation and maintaining basal
expression. As a result, loss of Cxxc5, and to a lesser extent Tet2, resulted in decreased levels of IRF7,
decreased type I interferon (IFN-I) production, and decreased anti-viral responses.
Front Immunol. 2019; 10: 210
The role of cancer stem cells and EMT in homeostasis and carcinogenesis. Normal stem cells
in epithelial tissues play an essential role in homeostasis. However, since they are long-term
residents, they are able to accumulate sufficient genetic or epigenetic alterations to give rise
to cancer stem cells that contribute to the etiology and progression of tumors. Because
tumor progression is associated with the loss of epithelial characteristics, a motile
phenotype, degradation of the basal lamina and ability to survive outside the epithelium,
the normal cellular processes involved in EMT play a key role in the multi-stage evolution
from a benign to an invasive, malignant tumor. In addition, the establishment of a distant
metastasis can be seen as MET. EMT = epithelial–mesenchymal transition;
EMT =
mesenchymal
–epithelial
transition
Tumor progression and the key events in the epithelial-mesenchymal (EMT) and the
mesenchymal-epithelial (MET) transitions. (1,2) Epithelial carcinomas undergo the EMT to escape
the tumor mass, resulting in (3) minimal residual disease. (4) Re-epithelialization is necessary to
develop a new malignant process. (5,6) Cells that undergo the EMT are de-differentiated and
well adapted to perform intravasation and maintain circulation. (7) This fact assists in the
extravasation process. (8) In this de-differentiated stage, cells can remain as micro-metastases
in the bone marrow. (9) Reversal of the epithelial phenotype through the MET may occur,
promoting the formation of macro-metastases and the death of osteoblasts.
Nitric Oxide. 2019 Apr 19. pii: S1089-8603(18)30305-7. doi: 10.1016/j.niox.2019.04.009
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