The Eicosanoids: Prostaglandins (PG) Thromboxanes Leukotrienes Related Compounds

Июль 27, 2022

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Биология
The Eicosanoids: Prostaglandins (PG) Thromboxanes Leukotrienes Related Compounds

Содержание

2. Eicosanoids Oxygenated products of polyunsaturated, long-chain, fatty acids From Greek eikosi ("twenty") Found in animals &
4. Linolenic acid an omega 3 fatty acid component of cell membranes essential for normal growth and
5. ARACHIDONIC ACID (AA) 5,8,11,14-eicosa tetra enoic acid An omega-6 fatty acid 20:4(ω-6) arachis – peanut AA,
9. Types of Phospholipases 1- Cytosolic (c) PLA 2: Chemical & physical stimuli, Ca dependent, high affinity
11. Prostanoids: PGs, TXA, prostacyclin Generated from PGH 2 by terminal enzymes isomerases & synthases Expressed in
13. Shift in product formation by changing precursor ThromboxaneA2 (TXA 2 ), powerful vasoconstrictor & platelet agonist,
14. Endoperoxide Synthases (Cyclooxygenases) PGH synthase-1 (COX-1) expressed constitutively in most cells produce prostanoid for housekeeping: gastric
16. PGH 2 metabolism products PGI 2 TXA 2 PGE2 PGF 2α By: prostacyclin, thromboxane, PGE &
18. Enzyme types 2 enzymes for PGF 2α synthesis: 9,11-endo peroxide reductase from PGH 2 9-keto reductase
19. Products of Lipoxygenase AA metabolism by 5-, 12-, 15-lipoxygenases (LOX) → hydro peroxy eicosa tetraenoic acid
21. Sites of leukotrienes synthesis 5-LOX present in: leukocyte (neutro-,baso-, eosin & monocyte-macrophages), dendritic mast cell
22. Transcellular biosynthesis Non-leukocyte cells (eg, endothel. cells) have enzymes downstream of 5-LOX/FLAP take up & convert
25. LTC 4 & LTD 4 Slow-reacting substance of anaphylaxis (SRS-A) secrete in asthma & anaphylaxis Potent
26. Isoprostanes COX independent production Not formed by COX so not inhibited by aspirin/NSAIDs Large amount x10
27. Isoprostanes Functions Biomrker of oxidative stress Potent vasoconstrictor in infu. to renal & other vessels may
28. Receptor Mechanisms Eicosanoids, not circulating hormone, Short t1/2 Ligands bind to G Pr -coupled receptors on
29. 1- Vascular Smooth Muscle Vasoconstrictors eicosanoids 1-TXA 2 potent Only SMC mitogen eicosanoid SMC exposure to
30. Vasodilatation 1- Vascular PGI 2 synthesis by COX-2 in SM & endothel. cells (major) inhibits SMC
31. 2. Gastrointestinal tract smooth muscle Contraction: Longitudinal muscle by & PGF 2α & PGE2 (via EP3)
32. 3. Airways Respiratory SM Relaxed by PGE 2 & PGI 2 Constrict by PGD 2, TXA
33. B. Platelets Low concent. PGE 2 ↑aggregation (via EP 3 ) higher concent. inhibit (via IP)
34. TXA 2 & Aspirin ↑ TXA 2 synthesis in platelet activation /aggregation ↑ urinary metabolites of
35. BP & renal function regulation Cortical COX2-derived PGE2& PGI2 1- maintain RBF & GFR via local
36. Hypertension (HT) HT associated ↑TXA 2, ↓PGE 2 & PGI 2 synthesis in some animal models
37. Central sensitization Peripheral pain stimulus → ↑spinal COX-1 &2 & PG release PG (mainly PG E2)→
38. Bone Metabolism PG abundant in skeletal tissue produced by osteoblasts & hematopoietic cells major effect (esp
39. COX inhibitors musculoskeletal effects Slow skeletal muscle healing interfere with PG effects on myocyte prolif., differentiation,
40. H. Eye PGE & PGF derivatives lower intraocular pressure mechanism? ↑ outflow of aqueous humor from
41. PGE2 & cancer Principal oncogen: initiation, progress, metastasis via ↑prolif. Angiogenesis, invasiveness, immunosuppress, inhibit apoptosis ↑express
42. Cancer & NSAIDS Pharmacol. inhibit or genetic delet. of COX-2→ inhibit tumor formation in models of
43. Syntheyic PG analogues Alprostadil (PGE 1 ) SM relaxant 1- infu. for maintain ductus arteriosus patent
44. Misoprostol (PGE1 analog) 1-approved for peptic ulcers prevention cytoprotective in high doses NSAIDs use for arthritis
45. epoprostenol in severe pulmonary /portopulmonary HT & prevent platelet aggregation in dialysis Machines Thromboxane (TXA 2)
46. Ophthalmology—Latanoprost PGF2α derivative extensive use topically in open-angle glaucoma Bimatoprost, travoprost, unoprostone newer, related drugs ↑outflow
47. COXs inhibition by Nonsteroidal anti-inflammatory drugs (NSAIDs) Traditional NSAIDs not selective for COX-1 or -2 Individual
48. Celecoxib Selectively inhibit. of COX-2 Advantage in patients seeking for pain relive while suffering from peptic
49. Aspirin Acetylates & irreversibly inhibits both COX1 & COX2 enzymes covalently Low doses ( (only isoform
50. Leukotrienes antagonists 1- 5-LOX inhibitor: zileuton 2- Selective CysLT 1 receptor antagonists: montelukast, zafirlukast,, pranlukast in
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Eicosanoids
Oxygenated products of
polyunsaturated, long-chain, fatty acids
From Greek

eikosi ("twenty")
Found in animals & plants
Highly potent
Wide spectrum of biologic activity

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Linolenic acid an omega 3 fatty acid
component of cell membranes
essential

for normal growth and development
converted to longer chain omega-3 fatty acids:
eicosa pentaenoic acid (EPA)
( major constituent of oils from fatty fish like salmon)
&
docosa hexaenoic acid (DHA)
These omega-3 fatty acids protect
CAD, sudden cardiac death, heart failure
through anti
- arrhythmic,-thrombotic,
-atherosclerotic, -inflammatory mechanism

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ARACHIDONIC ACID (AA) 5,8,11,14-eicosa tetra enoic acid
An omega-6 fatty acid 20:4(ω-6)
arachis

– peanut
AA, derived from:
1-dietary linoleic acid (a omega 6 Fatty acid)
2- as dietary constituent ingested
Released/ mobilized from membrane phospholipids by one or more lipases : phospholipase A 2 (PLA 2 )
AA transformed into metabolites called eicosanoids

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Types of Phospholipases
1- Cytosolic (c) PLA 2:
Chemical & physical

stimuli, Ca dependent,
high affinity for AA, acute release of AA
2- Inducible secretory (s) PLA 2:
in sustained or intense stimulation produce AA
3- Ca -independent (i) PLA 2
Under non-stimulated conditions, liberated AA reincorporated into cell membranes
negligible eicosanoid biosynthesis
4- Combination of PLC & di glyceride lipase

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Prostanoids: PGs, TXA, prostacyclin
Generated from PGH 2 by terminal enzymes

isomerases & synthases
Expressed in relatively cell-specific fashion
Chemical Differences of PGs :
(1) substituents of pentane ring ( E in PGE )
(2) number of side chains double bonds
(subscript :PGE 1, 2 )

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Shift in product formation by changing precursor
ThromboxaneA2 (TXA 2 ),

powerful vasoconstrictor & platelet agonist, synthesized from AA via COX
metabolism of EPA by COX→ TXA3 relatively inactive
Fatty acids of cold-water fish & plant substitute AA dietary EPA supplement →
↓cardiovascular disease & cancer
3-Series PG eg:PGE3 , partial agonists or antagonists of 2-series PG

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Endoperoxide Synthases (Cyclooxygenases)
PGH synthase-1 (COX-1) expressed constitutively in most cells
produce prostanoid

for housekeeping: gastric epithel. protection
PGH synthase-2 (COX-2) inducible by stimulus
immediate early-response gene product
up-regulate by:
shear stress, growth factors, tumor promoter, cytokines
major source of prostanoids in inflam. & cancer
Exceptions:
1- Endothel. COX-2: constitutive prostacyclin (PGI 2)
2- Renal COX2-derived prostanoids:
normal renal develop/function

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PGH 2 metabolism products
PGI 2
TXA 2
PGE2
PGF 2α
By:

prostacyclin, thromboxane, PGE & PGF synthases (PGIS, TXAS, PGES & PGFS)

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Enzyme types
2 enzymes for PGF 2α synthesis:
9,11-endo peroxide

reductase from PGH 2
9-keto reductase from PGE 2
3 enzymes for PGE 2 synthases:
microsomal (m) PGES-1
more inducible mPGES-2
cytosolic PGES
2 enzymes for PGDS isoforms:
lipocalin-type
hematopoietic PGDS

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Products of Lipoxygenase
AA metabolism by 5-, 12-, 15-lipoxygenases (LOX)
→ hydro peroxy

eicosa tetraenoic acid (HPETEs)→
hydroxy derivatives (HETEs) & leukotrienes
most investigated leukotrienes: products of 5-LOX

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Sites of leukotrienes synthesis
5-LOX present in:
leukocyte

(neutro-,baso-, eosin & monocyte-macrophages),
dendritic
mast cell

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Transcellular biosynthesis
Non-leukocyte cells (eg, endothel. cells)
have enzymes downstream of

5-LOX/FLAP
take up & convert leukocyte-derived LTA 4
or
endothelial cell use platelet PGH2 to synthesis PGI2

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LTC 4 & LTD 4
Slow-reacting substance of anaphylaxis (SRS-A)
secrete

in asthma & anaphylaxis
Potent bronchoconstrictor
Antileukotriene drug development:
1- 5-LOX enzyme inhibitors
2- leukotriene-receptor antagonists
3- inhibitors of: FLAP & phospholipase A 2

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Isoprostanes
COX independent production
Not formed by COX so not inhibited by

aspirin/NSAIDs
Large amount
x10 greater in blood/urine than COX derived PG
Storable

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Isoprostanes Functions
Biomrker of oxidative stress
Potent vasoconstrictor
in infu. to

renal & other vessels
may activate prostanoid receptors
Leukocyte & platelet adhesive interactions
angiogenesis, inflam.
Multiple isoprostanes formed coincidentally in oxidant stress→ difficult to assess their biologic functions

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Receptor Mechanisms
Eicosanoids, not circulating hormone, Short t1/2
Ligands bind to G Pr

-coupled receptors on cell surface in autocrine/ paracrine fashion
A single gene product identified for:
PGI 2 (IP), PGF 2α (FP), & TXA 2 (TP) receptors
4 distinct PGE 2 receptors (EPs 1–4) &
2 PGD 2 receptors

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1- Vascular Smooth Muscle Vasoconstrictors eicosanoids
1-TXA 2 potent
Only SMC

mitogen eicosanoid
SMC exposure to testosterone up-regulates SMC TP expression
2- PGF 2α
3- Isoprostane 8-iso-PGF 2α ( iPF 2 αIII)
via TP receptor

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Vasodilatation
1- Vascular PGI 2
synthesis by COX-2 in SM

& endothel. cells (major)
inhibits SMC prolif., use in pulmonary HT
2- PGE 2 produced by endothel.cells
vasodilator in microcirculation
↑ cAMP & ↓ Ca of SM, via IP & EP 4 receptors
3- PGD 2 vasodilator esp in niacin- induced flushing

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2. Gastrointestinal tract smooth muscle
Contraction:
Longitudinal muscle by & PGF 2α &

PGE2 (via EP3)
(via FP)
Circular muscle by PGF 2α & weakly by PGI 2
use of PGE 2 or PGF 2α → colicky cramps
Powerful contract. by Leukotrienes
Relaxtion by PGE 2 (via EP 4 )

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3. Airways Respiratory SM
Relaxed by PGE 2 & PGI 2

Constrict by PGD 2, TXA 2, PGF 2α, cysteinyl LT
> histamine
also stimulate mucus secretion→ mucosal edema
Bronchospasm in 10% of NSAID users, Shift AA from COX metabolism to leukotriene formation

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B. Platelets
Low concent. PGE 2 ↑aggregation (via EP 3 )
higher

concent. inhibit (via IP)
PGD 2 (via DP 1), PGI 2 (via IP) inhibit aggregat. ↑cAMP

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TXA 2 & Aspirin
↑ TXA 2 synthesis in platelet activation /aggregation

↑ urinary metabolites of TXA2 in MI & stroke
Irreversible inhibit of TXA 2 biosynthesis by
chronic low dose aspirin
10% TXA2 synthesis by macrophage COX-2 in smoker insensitive to low-dose aspirin
Inverse dose-response relation of Aspirin:
inhibit of PGI 2 synthesis at higher doses

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BP & renal function regulation
Cortical COX2-derived PGE2& PGI2
1- maintain

RBF & GFR via local vasodilating
esp in marginally functioning kidney &
volume-contract state
2- modulate systemic BP regulation water&Na excr
↑medullary COX -2 express & mPGES-1
in high salt intake
COX- 2-derived prostanoids ↑medullary blood flow & inhibit tubular Na reabsorption

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Hypertension (HT)
HT associated ↑TXA 2, ↓PGE 2 & PGI 2

synthesis in some animal models
↑TXA 2 formation in cyclosporine nephrotoxicity
PGF 2α may ↑ BP by renin release
FP antagonists potential antihypertensives

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Central sensitization
Peripheral pain stimulus →
↑spinal COX-1 &2 &

PG release
PG (mainly PG E2)→ ↑excitability spinal dorsal
horn neurons
1- ↑ pain intensity
2- extent area of pain perception
3- pain from normally innocuous stimuli

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Bone Metabolism
PG abundant in skeletal tissue
produced by osteoblasts &

hematopoietic cells
major effect (esp PGE 2, acting on EP 4 )
↑bone turnover, stimulate resorption/ formation
PG may mediate effects of mechanical forces on bones & bone changes in inflam.

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COX inhibitors musculoskeletal effects
Slow skeletal muscle healing
interfere with PG

effects on myocyte prolif., differentiation, fibrosis in response to injury
NSAIDs, esp COX-2 inhibitors
delay bone healing in experimental fractures
NSAID benefit? in Menopausal bone loss by PG

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H. Eye
PGE & PGF derivatives lower intraocular pressure
mechanism? ↑ outflow of

aqueous humor from anterior chamber via uveoscleral pathway

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PGE2 & cancer
Principal oncogen: initiation, progress, metastasis via ↑prolif. Angiogenesis, invasiveness,

immunosuppress, inhibit apoptosis
↑express mPGES-1 in tumor, potential use of inhibit.
↓carcinogenesis in mice lack EP 1, 2, 4 receptor Transactivation of epidermal growth factor receptor
linked with oncogenic activity of PGE 2
TXA 2 procarcinogen
macrophage COX-2 /platelet COX-1 derived

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Cancer & NSAIDS
Pharmacol. inhibit or genetic delet. of COX-2→ inhibit

tumor formation in models of colon, breast, lung,….
Incidental NSAIDs use ↓ risk of these cancers
Chronic low-dose aspirin not lower incidence but ↓cancer death
, COX ihibit. ↓ polyp formation in familial polyposis
NSAID →↓Breast cancer risk esp in hormone recpt +

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Syntheyic PG analogues
Alprostadil (PGE 1 ) SM relaxant

1- infu. for maintain ductus arteriosus patent in
neonates with vessels transposition awaiting
cardiac surgery
2- treatment of impotence by inj, into cavernosa

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Misoprostol (PGE1 analog)
1-approved for peptic ulcers prevention
cytoprotective in high

doses NSAIDs use for arthritis & history of associated ulcer
2- combination with progesterone antag.: mifepristone
(RU 486)
extremely effective/safe abortifacient in early pregnancy
Or Plus MTX
Side effect: diarrhea

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epoprostenol in severe pulmonary /portopulmonary HT &
prevent platelet aggregation

in dialysis Machines
Thromboxane (TXA 2) undesirable
(aggregation of platelets, vasoconstriction)
TXA 2 –receptor antagonists & synthesis inhibitors

Prostacyclin (PGI2) analogues

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Ophthalmology—Latanoprost
PGF2α derivative
extensive use topically in open-angle glaucoma
Bimatoprost,

travoprost, unoprostone
newer, related drugs
↑outflow of aqueous humor→↓intraocular press.
Iranian & Pfizer

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COXs inhibition by Nonsteroidal anti-inflammatory drugs (NSAIDs)
Traditional NSAIDs not selective for

COX-1 or -2
Individual variability in selectivity
Indomethacin & sulindac slightly selective for COX-1
Meclofenamate & ibuprofen: COX-1 = COX-2 inhib.

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Celecoxib
Selectively inhibit. of COX-2
Advantage in patients seeking for

pain relive while suffering from peptic ulcer disease
An expensive drug

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Aspirin
Acetylates & irreversibly inhibits both COX1 & COX2 enzymes covalently
Low

doses (< 100 mg/d) inhibit platelet COX-1
(only isoform in mature nonuclei Platelet)→
inhibit of TXA 2 biosynthesis

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Leukotrienes antagonists
1- 5-LOX inhibitor: zileuton
2- Selective CysLT 1 receptor antagonists:

montelukast, zafirlukast,, pranlukast
in mild to moderate asthma
(less effective than inhaled CS)

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The Eicosanoids: Prostaglandins (PG) Thromboxanes Leukotrienes Related Compounds

Содержание

Eicosanoids Oxygenated products of polyunsaturated, long-chain, fatty acids From Greek

Linolenic acid an omega 3 fatty acidcomponent of cell membranes essential

ARACHIDONIC ACID (AA) 5,8,11,14-eicosa tetra enoic acidAn omega-6 fatty acid 20:4(ω-6)arachis

Types of Phospholipases1- Cytosolic (c) PLA 2: Chemical & physical

Prostanoids: PGs, TXA, prostacyclinGenerated from PGH 2 by terminal enzymes

Shift in product formation by changing precursor ThromboxaneA2 (TXA 2 ),

Endoperoxide Synthases (Cyclooxygenases)PGH synthase-1 (COX-1) expressed constitutively in most cellsproduce prostanoid

PGH 2 metabolism products PGI 2 TXA 2 PGE2PGF 2α By:

Enzyme types 2 enzymes for PGF 2α synthesis: 9,11-endo peroxide

Products of LipoxygenaseAA metabolism by 5-, 12-, 15-lipoxygenases (LOX)→ hydro peroxy

Sites of leukotrienes synthesis 5-LOX present in: leukocyte

Transcellular biosynthesisNon-leukocyte cells (eg, endothel. cells) have enzymes downstream of

LTC 4 & LTD 4 Slow-reacting substance of anaphylaxis (SRS-A) secrete

IsoprostanesCOX independent production Not formed by COX so not inhibited by

Isoprostanes Functions Biomrker of oxidative stressPotent vasoconstrictor in infu. to

Receptor MechanismsEicosanoids, not circulating hormone, Short t1/2Ligands bind to G Pr

1- Vascular Smooth Muscle Vasoconstrictors eicosanoids1-TXA 2 potent Only SMC

Vasodilatation 1- Vascular PGI 2 synthesis by COX-2 in SM

2. Gastrointestinal tract smooth muscleContraction: Longitudinal muscle by & PGF 2α &

3. Airways Respiratory SM Relaxed by PGE 2 & PGI 2

B. PlateletsLow concent. PGE 2 ↑aggregation (via EP 3 ) higher

TXA 2 & Aspirin↑ TXA 2 synthesis in platelet activation /aggregation

BP & renal function regulationCortical COX2-derived PGE2& PGI2 1- maintain

Hypertension (HT) HT associated ↑TXA 2, ↓PGE 2 & PGI 2

Central sensitization Peripheral pain stimulus → ↑spinal COX-1 &2 &

Bone MetabolismPG abundant in skeletal tissue produced by osteoblasts &

COX inhibitors musculoskeletal effects Slow skeletal muscle healing interfere with PG

H. EyePGE & PGF derivatives lower intraocular pressuremechanism? ↑ outflow of

PGE2 & cancerPrincipal oncogen: initiation, progress, metastasis via ↑prolif. Angiogenesis, invasiveness,

Cancer & NSAIDSPharmacol. inhibit or genetic delet. of COX-2→ inhibit

Syntheyic PG analogues Alprostadil (PGE 1 ) SM relaxant

Misoprostol (PGE1 analog) 1-approved for peptic ulcers prevention cytoprotective in high

epoprostenol in severe pulmonary /portopulmonary HT & prevent platelet aggregation

Ophthalmology—Latanoprost PGF2α derivative extensive use topically in open-angle glaucoma Bimatoprost,

COXs inhibition by Nonsteroidal anti-inflammatory drugs (NSAIDs)Traditional NSAIDs not selective for

Celecoxib Selectively inhibit. of COX-2 Advantage in patients seeking for

AspirinAcetylates & irreversibly inhibits both COX1 & COX2 enzymes covalently Low

Leukotrienes antagonists 1- 5-LOX inhibitor: zileuton2- Selective CysLT 1 receptor antagonists:

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