2. ADAPALENE
• Vitamin A and its derivatives (retinoids) exert a
wide range of effects on embryonic development,
cell growth, differentiation, and apoptosis.
• Vitamin A cannot be synthesized by any animal
species and is only obtained through diet in the
form of retinol, retinyl ester, or β-carotene
• Ingested vitamin A is stored as retinyl esters in
hepatic stellate cells.
• Vitamin A and its derivatives (retinoids) exert a
wide range of effects on embryonic development,
cell growth, differentiation, and apoptosis.
• Vitamin A cannot be synthesized by any animal
species and is only obtained through diet in the
form of retinol, retinyl ester, or β-carotene
• Ingested vitamin A is stored as retinyl esters in
hepatic stellate cells.
4. Synopsis of the FGFR2b (Fibroblast growth factor) signaling pathway orchestrating all major downstream cascades
involved in the pathogenesis of acne. The three major downstream FGFR2b-signaling cascades: the MAPK (Mitogen-
activated protein kinase) pathway-inducing cell proliferation and MMP/Matrix metalloproteinase expression, the
PI3K/Akt- (Phospatidylinositol 3-kinase) and Shh/MC5R (Melanocortin-5 receptor) pathway-inducing lipogenesis and
terminal sebocyte differentiation, and the phospholipase Cg/protein kinace C pathway-inducing IL-1a, and
inflammatory reactions.
5. Hypothetical synopsis of anti-acne agents targeting the FGFR2 pathway. (1) Anti-androgens compete with an androgen
receptor and reduce FGF- ligand expression, (2) benzoyl peroxide induces lysosomal FGFR2 degradation by
ROS(Reactif oxygen spesies) formation, (3) azelaic acid depletes cellular ATP levels for phosphorylation events, (4)
atRA induces expression of Sprouty thereby inhibiting the MAPK cascade and induces MKP3 (MAP Kinase
phosphatase) for de-activation of ERK, 13cRA downregulates 5a-reductase 1 expression, and (5) tetracyclines inhibit the
expression and activity of MMPs.
6. • Retinol is reversibly oxidized by retinol
dehydrogenases to yield retinal. Subsequently,
retinal may be irreversibly oxidized to all-trans
retinoic acid (all-trans RA) by retinal
dehydrogenases and further oxidized by cytochrome
P450 enzymes (mainly CYP26) in hepatic tissue.
• All-trans RA isomerizes under experimental and
physiological conditions. Different isomers activate
different receptors and thus lead to different
biological effects. RAs designed to be receptor
specific can improve efficacy and avoid unwanted
side effects.
• Retinoids that specifically bind to RXR are called
rexinoids and have been effective in cancer
treatment.
• Retinol is reversibly oxidized by retinol
dehydrogenases to yield retinal. Subsequently,
retinal may be irreversibly oxidized to all-trans
retinoic acid (all-trans RA) by retinal
dehydrogenases and further oxidized by cytochrome
P450 enzymes (mainly CYP26) in hepatic tissue.
• All-trans RA isomerizes under experimental and
physiological conditions. Different isomers activate
different receptors and thus lead to different
biological effects. RAs designed to be receptor
specific can improve efficacy and avoid unwanted
side effects.
• Retinoids that specifically bind to RXR are called
rexinoids and have been effective in cancer
treatment.
7. Retinol
At-retinaldehyde
At-retinoic acid (RA)
Degradation
At-RA for T cells
Vitamin A (retinyl ester)
in food
Vitamin A (retinyl ester)
in food
REH: retinyl ester hydrolase ADH: alcohol
dehydrogenase AKR: aldo-keto reductase
RALDH: aldehyde dehydrogenase
CYP26: cytochrome P450
SDR: short-chain dehydrogenase/reductase
REH
AKR, SDR ADH1 & 4, SDR
RALDH1 & 2
CYP 26
Synthesis of retinoic acid in the dendritic cells of the in- testine. Vitamin A is consumed as
retinyl ester and hydrolyzed by retinyl ester hydrolase (REH). Retinol, entered into cells, is
oxi- dized to retinaldehyde by alcohol dehydrogenase (ADH) or short- chain
dehydrogenase/reductase (SDR). The reverse reaction is me- diated by aldo-keto reductase
(AKR) or SDR. Retinaldehyde can be converted to retinoic acid (all-trans retinoic acid or
At-RA) by retinaldehyde dehydrogenase (RALDH). Retinoic acid is degraded in cells by
cytochrome P450 (CYP26). It is known that dendritic cells in the gut-associated lymphoid
tissues (GALT) such as Peyer’s patches and MLN express high levels of ADH1, ADH4,
RALDH1, and/or RALDH2. The retinoic acid produced by dendritic cells can be exported
for other cells such as T cells during the cognate inter- action between dendritic cells and T
cells.
Degradation
8. Retinoid PathwayRetinoid Pathway
Retinoids absorbed from food are converted to retinol and bound to CRBP in the intestine. Then, retinol is converted to retinyl esters and enters into
blood circulation. The liver up takes retinyl esters, which are converted to retinol-RBP complex in the hepatocyte. In the serum, the retinol-RBP
complex is bound to transthyretin (TTR) in a 1:1 ratio to prevent elimination by the kidney and to ensure retinol is delivered to the target cell. The
uptake of retinol by the target cell is mediated by a trans-membrane protein named “stimulated by retinoic acid 6” (STRA6), which is a RBP receptor.
In the target cell, retinol either binds to CRBP or is oxidized to retinaldehyde by retinol dehydrogenase (RDH) in a reversible reaction. Then,
retinaldehyde can be oxidized by retinaldehyde dehydrogenase (RALDH) to RA. In the target cell, RA either binds to CRABP or enters the nucleus and
binds to nuclear receptors to regulate gene transcription. Alternatively, RA can mediate via nongenomic mechanism and regulate cellular function.
Hepatocytes not only process retinoids, but also are the target cells. In addition, hepatocytes located next to the storage site (stellate cell). Thus,
retinoid-mediated signaling must have a profound effect in regulating hepatocyte function and phenotype
9. Non-genomic Actions
• Retinoids also exert their effects via transcription
independent pathway, which can occur in the
presence or absence of nuclear receptor. Retinoids
mediated via RARs inhibit AP-1-regulated cell
proliferation
• RA also inhibits NFκB activity in mice
• Mediated through RARβ, RA changes the
intracellular Ca++ level and thus controls PI3K
activation in neural cell
• RARα can interact with mRNA in cytoplasm and
control translation
• Via nuclear receptor independent pathway, RA
rapidly activates cAMP response element (CREB)
binding protein in human bronchial epithelial cells
• Retinoids also exert their effects via transcription
independent pathway, which can occur in the
presence or absence of nuclear receptor. Retinoids
mediated via RARs inhibit AP-1-regulated cell
proliferation
• RA also inhibits NFκB activity in mice
• Mediated through RARβ, RA changes the
intracellular Ca++ level and thus controls PI3K
activation in neural cell
• RARα can interact with mRNA in cytoplasm and
control translation
• Via nuclear receptor independent pathway, RA
rapidly activates cAMP response element (CREB)
binding protein in human bronchial epithelial cells
10. The nongenomic RXRα actions. The cytoplasmic tRXRα through its interaction with p85α
subunit of PI3K or undefined factors associated with TNF-R1 regulates cell survival,
inflammation, and apoptosis. In addition, RXRα can target mitochondria through
heterodimerization with Nur77 to modulate mitochondria-dependent apoptosis.
11. ETANERCEPT
• RA is diagnosed through its distinc- tive effects
on the joints and in skin, and the diagnosis is
reinforced by the presence in serum of the
rheumatoid factor (RF), although its presence is
not mandatory for diagnosis of RA.
• RA is diagnosed through its distinc- tive effects
on the joints and in skin, and the diagnosis is
reinforced by the presence in serum of the
rheumatoid factor (RF), although its presence is
not mandatory for diagnosis of RA.
12. Important environmental and biological factors associated
with or possibly contributory to the pathogenesis of RA
• Cigarette smoking.
• Tumour necrosis factor (TNF)-a activity.
• Abnormal and inappropriate B-lymphocyte activity, i.e. abnormal
antibody production.
• Detection of circulating autoantibodies against Ig Fc; these
autoantibodies have been termed ‘rheumatoid factor’, and they may
be involved in the inappropriate presentation of antigens to T cells
by B cells.
• Abnormal activity of certain signalling pathways in synovial tissue,
e.g. the Wnt signalling pathway, which is involved in embryonic
development and cell renewal. In patients with RA, it has been
reported that the synovial cells have abnormally high activity of the
Wnt gene, as well as a number of other genes for several of the
cytokines, cell adhesion molecules and chemokines. At present, it
is not known whether these abnormalities are causative or a result
of the more fundamental abnormalities.
• Cigarette smoking.
• Tumour necrosis factor (TNF)-a activity.
• Abnormal and inappropriate B-lymphocyte activity, i.e. abnormal
antibody production.
• Detection of circulating autoantibodies against Ig Fc; these
autoantibodies have been termed ‘rheumatoid factor’, and they may
be involved in the inappropriate presentation of antigens to T cells
by B cells.
• Abnormal activity of certain signalling pathways in synovial tissue,
e.g. the Wnt signalling pathway, which is involved in embryonic
development and cell renewal. In patients with RA, it has been
reported that the synovial cells have abnormally high activity of the
Wnt gene, as well as a number of other genes for several of the
cytokines, cell adhesion molecules and chemokines. At present, it
is not known whether these abnormalities are causative or a result
of the more fundamental abnormalities.
13. TNF-α is a pleiotropic pro-inflammatory cytokine with many actions that are
central to the pathogenesis of rheumatoid arthritis . Along with
interleukin 1, another important pro-inflammatory cytokine, TNF-α has
therefore been a target for biological therapy in rheumatoid arthritis.
14. Mechanisms of TNF-α signaling in injured nerve. By occupying either of the two TNF-α receptors, the soluble TNF-α
protein can produce different effects ranging from apoptosis to up-regulation of itself, other proinflammatory cytokines,
or anti-inflammatory cytokines. While the full details of these effects are not known, it is clear that stimulation of the p38
mitogen-activated protein kinase (MAPK) pathway is a critical signaling mechanism. Activation of the JNK pathway can
produce radically different effects, depending in part on activity in the pathway. Studies with TNF-/- and TNFRI-/- and
RII-/- mice are helpful in defining the inter-relationships of cytokines and their receptors.
15. Biology of TNF production, receptor interaction and signaling. Stimulation of a TNF-producing cell (top)
results in cell surface expression of tmTNF trimers and enzymatic cleavage by TACE to release sTNF. Both
tmTNF and sTNF can bind to cell surface TNFR1 or TNFR2 on a TNF-responsive cell (bottom), initiating
signaling pathways that lead to apoptosis or NF-κB activation and inflammatory gene activation. The
induction of apoptosis by sTNF via TNFR1 involves internalization of the ligand–receptor complex and
association of death domains (DD) in the cytoplasmic tail of TNFR1 with adapter proteins and is normally
blocked by FADD-like IL-1β–converting enzyme (FLICE). Reverse signaling can be initiated by TNFR2 or
TNF antagonist binding to cell surface tmTNF, resulting in cytokine suppression or apoptosis. Soluble TNF
receptors (sTNFR1 and sTNFR2) can be released from a TNF-responsive cell following enzymatic cleavage
16. In the pathophysiology of RA, Crohn's disease and psoriasis, TNF is produced at high concentrations by a variety of cell types,
presumably induced by endogenous or microbial stimuli. A cascade and network of cellular responses mediated by TNF that are
common to these 3 diseases are shown in the enclosed area in the center of the diagram. Mechanisms and cellular features restricted
to a particular disease are shown outside of the enclosed area.
17. Four categories of putative mechanisms of action of TNF antagonists are illustrated. The large panel illustrates the primary mechanisms of
action, resulting from direct blocking of TNFR-mediated biologic activities. In these instances, the TNF antagonists bind to the cognate
ligands (sTNF or tmTNF for all 5 TNF antagonists and additionally LTα3 and LTα2β1 for etanercept), thereby blocking their capacities to
bind TNFR1 or TNFR2. The right panel illustrates several mechanisms induced by the binding of TNF antagonists to tmTNF, which can
include reverse signaling via tmTNF or cytotoxicity of the tmTNF-bearing cell by CDC or ADCC. The small panel on the lower left illustrates
2 LTαβ-mediated mechanisms thought to be blocked by etanercept, the only TNF antagonist that binds LT family members. The lower
center panel shows pharmacokinetic-related mechanisms that involve TNF antagonist binding to FcRn or forming complexes with sTNF or
antidrug (TNF antagonist) antibodies.
Denotes a TNF antagonist (infliximab, etanercept, adalimumab, certolizumab, golimumab). Denote TNFR1 and TNFR2. ETN =
etanercept.
18. • The pharmacological class of TNF alpha
inhibitors includes etanercept (Enbrel)
infliximab (Remicade) and adalimumab
(HUMIRA)
• etanercept molecule consists of 2 extracellular
domains of human soluble TNF receptor p75
that binds to TNF and a Fc fragment of human
IgG that serves as a stabilizer.
• The pharmacological class of TNF alpha
inhibitors includes etanercept (Enbrel)
infliximab (Remicade) and adalimumab
(HUMIRA)
• etanercept molecule consists of 2 extracellular
domains of human soluble TNF receptor p75
that binds to TNF and a Fc fragment of human
IgG that serves as a stabilizer.
19. • Etanercept is also a recombinant protein
composed of an immunoglobulin backbone and
two p75TNF-α soluble receptors. It is given as a
twice-weekly subcutaneous injection.
• Etanercept is also a recombinant protein
composed of an immunoglobulin backbone and
two p75TNF-α soluble receptors. It is given as a
twice-weekly subcutaneous injection.
20. Etanercept
in psioriasis
Dendritic cells,
lymphocytes,
macrophages,
neutrophils,
Chemokines for T, DCs,
& polys
IFN , TNF, IL-23 regulated
products
DC activation & DC
Apoptosis T activation
Blood vessels
iNOS
Adhesion proteins
? VEGF
Epidermis
IL-19, 20
? Anti-apoptotic
proteins
iNOS
NF B activation
• TNF blockade ‘‘tunes’’ pro-inflammatory gene expression and reverses psoriatic phenotype. Etanercept
differentially affects immune cells, blood vessels, and the epidermis, resulting in decreased inflammation and
epidermal normalization. Leukocyte infiltration is interrupted by a reduction in chemotactic cytokines regulated
by IFN-g, TNF-a, and IL-23. This effect may be enhanced by the prevention of cellular adhesion and migration
by reductions in iNOS, adhesion proteins, and possibly VEGF. These results, in conjunction with decreases in
cytokine production, iNOS, NF-kB expression, and possibly anti-apoptotic proteins, promote normalization of the
epidermis. There is decreased activation of NF-kB in epidermal and dermal cells, which may result in the
apoptosis of DCs and possibly other cell types. Decreased DC counts and activation result in decreased T-cell
activation. These effects may collectively interrupt the self-sustaining cycle of inflammation and account for
plaque clearance.
Apoptosis T activation
NF B activation
Inflammation Inflammation Normalization
22. migraine is benign recurring headache and/or
neurological dysfunction usually attended by pain-
free interludes and often provoked by stereotyped
stimuli.
They were influenced by (1) the association between
migraine relieving properties of ergotamine tartrate
infusion and arterial vasoconstriction and (2) the
finding that compression of the common carotid
artery or superficial temporal artery reduces pain in
many migraine attacks.
migraine is benign recurring headache and/or
neurological dysfunction usually attended by pain-
free interludes and often provoked by stereotyped
stimuli.
They were influenced by (1) the association between
migraine relieving properties of ergotamine tartrate
infusion and arterial vasoconstriction and (2) the
finding that compression of the common carotid
artery or superficial temporal artery reduces pain in
many migraine attacks.
23. • The vasoconstrictive properties of triptans are
mediated by an action on 5-HT1B in arterial
smooth muscle
• The triptans are also thought to inhibit the
abnormal activation of peripheral nociceptors.
In an experimental model of migraine, called
sterile neurogenic inflammation, an abnormal
activation of nociceptors in the dura mater
triggers vascular changes, including plasma
protein extravasation (PPE)
• The vasoconstrictive properties of triptans are
mediated by an action on 5-HT1B in arterial
smooth muscle
• The triptans are also thought to inhibit the
abnormal activation of peripheral nociceptors.
In an experimental model of migraine, called
sterile neurogenic inflammation, an abnormal
activation of nociceptors in the dura mater
triggers vascular changes, including plasma
protein extravasation (PPE)