15-Deoxy-Δ12,14-prostaglandin J2
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Cyclopentenone prostaglandins are a subset of
prostaglandin The prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are derive ...
s (PGs) or prostanoids (see eicosanoid#Classic eicosanoids and eicosanoid#Nonclassic eicosanoids) that has 15-deoxy-Δ12,14-prostaglandin J2 (15-d-Δ12,14-PGJ2), Δ12-PGJ2, and PGJ2 as its most prominent members but also including PGA2, PGA1, and, while not classified as such, other PGs. 15-d-Δ12,14-PGJ2, Δ12-PGJ2, and PGJ2 share a common mono-unsaturated
cyclopentenone 2-Cyclopentenone is a ketone with chemical formula and CAS number 930-30-3. It is structurally similar to cyclopentanone, with the additional feature of α-β unsaturation in the ring system. 2-Cyclopentenone contains two functional groups, a k ...
structure as well as a set of similar biological activities including the ability to suppress inflammation responses and the growth as well as survival of cells, particularly those of cancerous or neurological origin. Consequently, these three cyclopentenone-PGs and the two epoxyisoprostanes are suggested to be models for the development of novel anti-inflammatory and anti-cancer drugs. The cyclopenentone prostaglandins are structurally and functionally related to a subset of
isoprostane The isoprostanes are prostaglandin-like compounds formed ''in vivo'' from the free radical-catalyzed peroxidation of essential fatty acids (primarily arachidonic acid) without the direct action of cyclooxygenase (COX) enzymes. The compounds were d ...
s viz., two cyclopentenone isoprostanes, 5,6-epoxyisoprostane E2 and 5,6-epoxisoprostane A2.


Biochemistry

In cells, COX-1 and COX-2 metabolize
arachidonic acid Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''arachi ...
to PGH2 which is then converted to
PGE2 Prostaglandin E2 (PGE2), also known as dinoprostone, is a naturally occurring prostaglandin with oxytocic properties that is used as a medication. Dinoprostone is used in labor induction, bleeding after delivery, termination of pregnancy, and ...
by any one of three isozymes,
PTGES Microsomal prostaglandin E synthase-1 (mPGES-1) or Prostaglandin E synthase is an enzyme that in humans is encoded by the ''PTGES'' gene. The protein encoded by this gene is a glutathione-dependent prostaglandin E synthase. The expression of this ...
,
PTGES2 Microsomal prostaglandin E synthase-2 (mPGES-2) or Prostaglandin E synthase 2 is an enzyme that in humans encoded by the ''PTGES2'' gene located on chromosome 9. The protein encoded by this gene is a membrane-associated prostaglandin E synthase, ...
, and
PTGES3 Prostaglandin E synthase 3 (cytosolic) is an enzyme that in humans is encoded by the PTGES3 gene. The protein encoded by this gene is also known as p23 which functions as a chaperone which is required for proper functioning of the glucocorticoid ...
or, alternatively, to PGD2 by either of two enzymes, a glutathione-independent synthase termed lipocalin-type
Prostaglandin D2 synthase Prostaglandin-H2 D-isomerase (PTGDS) is an enzyme that in humans is encoded by the ''PTGDS'' gene. Function The protein encoded by this gene is a glutathione-independent prostaglandin D synthase that catalyzes the conversion of prostaglandin ...
(PTGDS or L-PGDS) and a glutathione-dependent hematopoietic-type H-
PGDS PGDS protein is a protein that in humans is encoded by the ''HPGDS'' gene. Prostaglandin-D synthase is a sigma class glutathione-S-transferase family member. The enzyme catalyzes the conversion of PGH2 to PGD2 and plays a role in the production o ...
or PTGDS2; the COX's also metabolizes dihomo-gamma-linolenic acid to PGH1 which is metabolized by one of the three PTGES isomzymes to
PGE1 Prostaglandin E1 (PGE1), also known as alprostadil, is a naturally occurring prostaglandin which is used as a medication. In infants with congenital heart defects, it is delivered by slow injection into a vein to open the ductus arteriosus unti ...
(see eicosanoid#Prostanoid pathways). PGE2, PGE1, and PGD2 undergo a dehydration reaction PGA2, PGA1, and PGJ2, respectively. PGD2 conversions form the most studied cyclopentenone PGs. These conversions are as follows: *PGD2 is a 20 carbon
arachidonic acid Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''arachi ...
metabolite with double bonds between carbons 5,6 and 13,14, a carbon-carbon bond between carbons 8 and 12 (which establishes its cyclopentanone ring), hydroxyl residues attached to carbons 9 and 15, and a ketol residue (i.e. oxygen double bonded to carbon) attached to carbon 11. PGD2 undergoes a spontaneous (i.e. non-enzymatic) dehydration reaction (i.e. removal of two hydrogen atoms and one oxygen atom .e. H2O across its 9-hydroxyl-carbon 10 region to form a new 9,10 double bond to become PGJ2 possessing a cyclopentenone ring (i.e. the ring contains one double bond) replacing the cyclopentanone ring (i.e. the ring has no double bonds) of PGD2. Carbon 9 thereby becomes chemically reactive as an
electrophilic In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carri ...
center. *PGJ2 undergoes a spontaneous isomerization reaction in which the carbon 13,14 double bound shifts to the carbon 12,13 position to become Δ12-PGJ2 with a second electrophilic center site established at carbon 13. *Δ12-PGJ2 undergoes a spontaneous dehydration reaction across its 15-hydroxyl-carbon 14 region to form a new double bound between carbons 14 and 15 thereby becoming 15-deoxy-Δ12,14-PGJ2 with retained electrophilic sites at carbons 9 and 13. Carbon 9 is more electrophilic than carbon 13 and therefore is more active than carbon 9 in forming covalent bonds with other molecules. PGE2 and PGE1 are 20 carbon metabolites of arachidonic acid and
dihomo-γ-linolenic acid Dihomo-γ-linolenic acid (DGLA) is a 20-carbon ω−6 fatty acid. (also called, cis,cis,cis-8,11,14-Eicosatrienoic acid) In physiological literature, it is given the name 20:3 (ω−6). DGLA is a carboxylic acid with a 20-carbon chain and thre ...
, respectively, with a double bond between carbons 13 and 14, a carbon-carbon bond between carbons 8 and 12 (which establishes their cyclopentanone structure), hydroxyl residues at carbons 11 and 15, and a ketol residue at carbon 9. They differ in that PGE2 has, while PGE1 lacks, a double bound between carbons 5 and 6. Both PGs undergo a dehydration reaction across their 11-hydroxyl-carbon 10 regions to form a new double bond between carbons 10 and 11 to become PGA2 and PGA1, respectively, with a cyclopenenone ring replacing the cyclopentaonon rings or their precursors and a newly established electrophilic site at carbon 11. This electrophilic site is probably less electrophilic that the carbon 9 sites of Δ12-PGJ2 and 15-deoxy-Δ12-PGJ2 The
cyclopentenone 2-Cyclopentenone is a ketone with chemical formula and CAS number 930-30-3. It is structurally similar to cyclopentanone, with the additional feature of α-β unsaturation in the ring system. 2-Cyclopentenone contains two functional groups, a k ...
structures of PGA2, PGA1, PGJ2, Δ12-PGJ2, and 15-d-Δ12,14-PGJ2 possess α,β-unsaturated carbonyl groups (see Carbonyl group#α,β-Unsaturated carbonyl compounds) which serve to establish high levels of chemical reactivity at nearby carbons 9, 11, and/or 13. These carbons are electrophiles that readily form covalent bonds by acting as acceptors in
Michael reaction In organic chemistry, the Michael reaction or Michael addition is a reaction between a Michael donor (an enolate or other nucleophile) and a Michael acceptor (usually an α,β-unsaturated carbonyl) to produce a Michael adduct by creating a carbon ...
s to form covalent bonds with exposed
nucleophile In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...
sites, particularly thiol residues, in diverse
proteins Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
. The reaction inactivates or reduces the activity of various functionally important target proteins and is one mechanism by which cylopentenone PGs influence cell function. All of the reactions undergone by the above cited PGs occur spontaneously (i.e. are enzyme-independent) in aqueous media. This biochemistry sets very important limitations on the study of the cyclopentenone PGs and to a lesser extent on PGE2, PGE1, and PGD2: a) detection of the cyclopentenone PGs in tissues may and has often reflected their formation during tissue preparation; b) detection of PGE2, PGE1, and PGD2 in tissues may be underestimated because of losses due to their conversion to cyclopentenone PGs; c) the activities, as studied in vitro or in vivo, of PGJ2 may reflect its conversion to Δ12-PGJ2 or 15-deoxy-Δ12,14-PGJ2, those of Δ12-PGJ2 may reflect its conversion to 15-deoxy-Δ12,14-PGJ2, and those of PGE2, PGE1, or PGD2 may reflect their conversion to any of the cyclopentenone PGs; and d) the attachment of these compounds, similar to that in other Michael reactions, is reversible and therefore may be underestimated or go undetected in studies.


Mechanisms of action


G protein coupled receptors

The PGJ2 series of cyclopentenone PGs bind to and activate the G protein-coupled receptor,
Prostaglandin DP2 receptor Prostaglandin D2 receptor 2 (DP2 or CRTH2) is a human protein encoded by the PTGDR2 gene and GPR44. DP2 has also been designated as CD294 (cluster of differentiation 294). It is a member of the class of prostaglandin receptors which bind with and ...
, with 15-deoxy-Δ12,14-PGJ2 and PDJ2 exhibiting potencies comparable to PGD2 (i.e. Ki
equilibrium constants The equilibrium constant of a chemical reaction is the value of its reaction quotient at chemical equilibrium, a state approached by a dynamic chemical system after sufficient time has elapsed at which its composition has no measurable tendency ...
~20-45 nanomolar) and Δ12-PGJ2 having 10-fold lesser potency, at least on mouse DP2 receptor. These PGJ2's also bind and activate a second G protein-coupled receptor, Prostaglandin DP1 receptor, but require high concentrations to do so; this activation is not considered physiological. DP2 and DP1 are G protein-coupled receptors, with the DP2 receptor coupled to
Gi alpha subunit Gi protein alpha subunit is a family of heterotrimeric G protein alpha subunits. This family is also commonly called the Gi/o (Gi /Go ) family or Gi/o/z/t family to include closely related family members. G alpha subunits may be referred ...
-dependent depression of cellular
cAMP Camp may refer to: Outdoor accommodation and recreation * Campsite or campground, a recreational outdoor sleeping and eating site * a temporary settlement for nomads * Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...
levels and causing the potentiation cell injury in neural tissue cultures and with the DP1 receptor coupled to Gs alpha subunit-dependent increases in cellular cAMP levels and the suppression of cell injury in neural tissue cultures.


Peroxisome proliferator-activated receptor gamma

PGD2, PGJ2, Δ12-PGJ2, and 15-deoxy-Δ12,14-PGJ2 activate the transcription factor, PPARγ, with 15-deoxy-Δ12,14-PGJ2 being the most potent of the four PGs. Accordingly, further studies have focused on 15-deoxy-Δ12,14-PGJ2. This PG directly binds with and activates PPARγ thereby inducing the
transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, the fir ...
of genes containing the PPARγ response element. In consequence of this action, 15-deoxy-Δ12,14-PGJ2 causes cells to engage the pathway of Programmed cell death termed
Paraptosis Paraptosis (from the Greek παρά ''para'', "related to" and apoptosis) is a type of programmed cell death, morphologically distinct from apoptosis and necrosis. The defining features of paraptosis are cytoplasmic vacuolation, independent o ...
, a form of cell suicide that differs from
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
by involving cytoplasmic vacuolization and mitochondrial swelling rather than plasma membrane blebbing, nuclear condensation and fragmentation, and apoptotic bodies. 15-Deoxy-Δ12,14-PGG2's activation of PPARγ and the induction of paraptosis is responsible for inhibiting the growth of cultured human breast, colon, prostate, and perhaps other cancer cell lines. Studies indicated the anti-inflammatory actions of the cylopenentone prostaglandins show no or little dependency on their PPARγ-activating capacity.


Covalent modification of proteins

The
electrophilic In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carri ...
centers in the cyclopentenone ring of cylopentenone PGs form
covalent bond A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atoms ...
s with exposed nucleophilic centers, primarily the sulfur atom in the thiol residues of
cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, sometime ...
residues.
Proteomics Proteomics is the large-scale study of proteins. Proteins are vital parts of living organisms, with many functions such as the formation of structural fibers of muscle tissue, enzymatic digestion of food, or synthesis and replication of DNA. In ...
analyses have detected 368 proteins that are covalently modified by 15-deoxy-Δ12,14-PGJ2; these include numerous
plasma membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...
, cell signaling, glycolytic enzyme, cytoskeletal, and
Chaperone (protein) In molecular biology, molecular chaperones are proteins that assist the conformational folding or unfolding of large proteins or macromolecular protein complexes. There are a number of classes of molecular chaperones, all of which function to assi ...
s. This results in the addition of the PG to the protein by a Michael addition reaction and important modifications in the activity of target proteins that have key functions in cells. 15-Deoxy-Δ12,14-PGJ2 shows the greatest reactivity and has been the focus of these studies. Proteomic studies indicate that PGJs form adducts with over 358 proteins. This adduct formation has been studied with several functionally and/or clinically important proteins such as: *IKK-β subunit of IκB kinase: IκB serves to retain NFκB in the cell cytoplasm thereby inhibiting it from entering the nucleus and acting as a transcription factor (see
IkB kinase IKB is an initialism that can refer to * International Klein Blue, a deep blue hue * IκB -kappa-B a protein complex * IKB Deutsche Industriebank, a German bank * Ikebukuro Station, JR East station code * Isambard Kingdom Brunel Isambard K ...
) to induce the transcription of genes, many of which contribute to regulating inflammatory responses. 15-deoxy-Δ12,14-PGJ2 forms an adduct with the IKK-β subunit of IκB kinase thereby inhibiting the kinases activity thereby promoting the entry of NFκB into the nucleus and stimulating the transcription of more than 15O proteins many of which regulate inflammatory responses. The net effect of this inhibition is to inhibit and/or refers inflammation. * KEAP1: cytosolic KEAP1 serves to promote the degradation of Nrf2 by proteasomes thereby inhibiting this transcription factor from entering the nucleus and stimulating the transcription of numerous genes that for diverse antioxidant proteins such as HMOX1 which encodes the carbon monoxide-forming and anti-inflammatory protein, HO-1 (see Carbon monoxide#Chemistry and Carbon monoxide#Physiology). 15-Deoxy-Δ12,14-PGJ2 forms adducts with KEAP1 cysteines 273 and 288 thereby blocking its ability to suppress activation of Nrf2's induction of antioxidant proteins. The ability of cyclopentenone prostaglandins to promote the transcription of Nrf2-dependent genes appears critical to their anti-inflammatory actions. *
eIF4A The eukaryotic initiation factor-4A (eIF4A) family consists of 3 closely related proteins EIF4A1, EIF4A2, and EIF4A3. These factors are required for the binding of mRNA to 40S ribosomal subunits. In addition these proteins are helicases that f ...
: eIF4A is an RNA helicase is essential for
protein translation In molecular biology and genetics, translation is the process in which ribosomes in the cytoplasm or endoplasmic reticulum synthesize proteins after the process of transcription of DNA to RNA in the cell's nucleus. The entire process is ...
. 15-Deoxy-Δ12,14-PGJ2 forms an adduct with cysteine 264 in eIF4A to inhibit protein translation and cause TRAF2, an intracellular signaling protein required for the cell stimulating actions of the pro-inflammatory cytokine,
TNFα Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
, to sequester in cellular
stress granule Stress granules are dense aggregations in the cytosol composed of proteins and RNAs that appear when the cell is under stress. The RNA molecules stored are stalled translation pre-initiation complexes: failed attempts to make protein from mRNA. St ...
s. The inhibition of protein translation can trigger programmed cell death responses while the sequestration of TRAF2 may suppress inflammatory responses. PGA1 has similar although less potent effects on protein translation and TRAF2 sequestration and therefore may also form an adduct with, and thereby inactivate, eIF4a. *
UCHL1 Ubiquitin carboxy-terminal hydrolase L1 (, ''ubiquitin C-terminal hydrolase'', ''UCH-L1'') is a deubiquitinating enzyme. Function UCH-L1 is a member of a gene family whose products hydrolyze small C-terminal adducts of ubiquitin to generate ...
: PGA1, Δ12-PGJ2, and 15-deoxy-Δ12,14-PGJ2 form adducts with the UCHL1 (Ubiquitin carboxy-terminal hydrolase L1), a protein that is found to be deposited as aggregate in the pathologically involved tissues of Parkinson's disease and well as other neurodegenerative diseases. In further studies, 15-deoxy-Δ12,14-PGJ2 was found to trigger Uch-L1 aggregate formation and suggested that this reaction may contribute to the development and/or progression of these diseases. *
H-Ras GTPase HRas, from "Harvey Rat sarcoma virus", also known as transforming protein p21 is an enzyme that in humans is encoded by the gene. The ''HRAS'' gene is located on the short (p) arm of chromosome 11 at position 15.5, from base pair 522,241 t ...
: 15-Deoxy-Δ12,14-PGJ2 forms a covalent bond with cysteine 184 on H-ras thereby activating this signaling protein and promoting the proliferation of cells. * Epoxide hydrolase: 15-Deoxy-Δ12,14-PGJ2 inhibits soluble
epoxide hydrolase 2 Soluble epoxide hydrolase (sEH) is a bifunctional enzyme that in humans is encoded by the EPHX2 gene. sEH is a member of the epoxide hydrolase family. This enzyme, found in both the cytosol and peroxisomes, binds to specific epoxides and converts ...
by forming
adducts An adduct (from the Latin ''adductus'', "drawn toward" alternatively, a contraction of "addition product") is a product of a direct addition of two or more distinct molecules, resulting in a single reaction product containing all atoms of all co ...
with its catalytic cysteine (Cys521) residue. This effect blocks the ability of the hydrolase to inactivate epoxyeicosatrienoic acids (EETs), particularly 14,15-EET. The EETs cause the vasodilation of arteries, including those of the heart. By blocking the production of 14,15-ETE and at least theoretically of other vasodilating ETEs,
Epoxydocosapentaenoic acid Epoxide docosapentaenoic acids (epoxydocosapentaenoic acids, EDPs, or EpDPEs) are metabolites of the 22-carbon straight-chain omega-3 fatty acid, docosahexaenoic acid (DHA). Cell types that express certain cytochrome P450 (CYP) epoxygenases metab ...
s, and/or
Epoxydocosapentaenoic acid Epoxide docosapentaenoic acids (epoxydocosapentaenoic acids, EDPs, or EpDPEs) are metabolites of the 22-carbon straight-chain omega-3 fatty acid, docosahexaenoic acid (DHA). Cell types that express certain cytochrome P450 (CYP) epoxygenases metab ...
s, 15-deoxy-Δ12,14-PGJ2 appears to cause the dilation of coronary arteries and thereby protect against cardiac
ischemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems wi ...
and heart attack in a rat model. One or more of the cyclopentenone prostaglandins also regulate other cell signaling pathways although the exact mechanism(s) behind this is not always clear. It (they) regulates signaling by: a) inhibiting the STAT3- Janus kinase pathway to block cellular pro-inflammatory responses; b) stimulating
Suppressor of cytokine signaling 1 Suppressor of cytokine signaling 1 is a protein that in humans is encoded by the ''SOCS1'' gene. ''SOCS1'' orthologs have been identified in several mammals for which complete genome data are available. Function This gene encodes a member of t ...
, Suppressor of cytokine signaling 3, and Src homology 2 domain-containing protein phosphatase 2 pathways to inhibit the actions of pro-inflammatory cytokines; c) inhibiting the activation of
ERK1 Mitogen-activated protein kinase 3, also known as p44MAPK and ERK1, is an enzyme that in humans is encoded by the ''MAPK3'' gene. Function The protein encoded by this gene is a member of the mitogen-activated protein kinase (MAP kinase) famil ...
,
ERK2 Mitogen-activated protein kinase 1, (MAPK 1), also known as ERK2, is an enzyme that in humans is encoded by the ''MAPK1'' gene. Function The protein encoded by this gene is a member of the MAP kinase family. MAP kinases, also known as extrace ...
, Akt and a p38 mitogen-activated protein kinases pathways to inhibit the actions of pro-inflammatory cytokines and/or the differentiation of progenitor cells to pro-inflammatory Dendritic cells; d) regulating the cell cycle and cell proliferation by stimulating
p21 p21Cip1 (alternatively p21Waf1), also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1, is a cyclin-dependent kinase inhibitor (CKI) that is capable of inhibiting all cyclin/CDK complexes, though is primarily associated ...
, cFos, Erg-1, and
cMyc ''Myc'' is a family of regulator genes and proto-oncogenes that Genetic code, code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' (MYC), ''l-myc'' (MYCL), and ''n-myc'' (N-Myc, MYCN). ''c-myc'' (a ...
or inhibiting N-Myc,
Cyclin D1 Cyclin D1 is a protein that in humans is encoded by the ''CCND1'' gene. Gene expression The CCND1 gene encodes the cyclin D1 protein. The human CCND1 gene is located on the long arm of chromosome 11 (band 11q13). It is 13,388 base pairs lon ...
,
Cdk4 Cyclin-dependent kinase 4 also known as cell division protein kinase 4 is an enzyme that in humans is encoded by the ''CDK4'' gene. CDK4 is a member of the cyclin-dependent kinase family. Function The protein encoded by this gene is a member o ...
, and Insulin-like growth factor 1; and e) regulating agents such as HSP70,
GPR78 Probable G-protein coupled receptor 78 is a protein that in humans is encoded by the ''GPR78'' gene. G protein-coupled receptors (GPCRs, or GPRs) contain 7 transmembrane domains and transduce extracellular signals through heterotrimeric G protei ...
, Gadd153,
Ubiquitin B Ubiquitin is a protein that in humans is encoded by the ''UBB'' gene. Function Ubiquitin is one of the most conserved proteins known in eukaryotic organisms. Ubiquitin is required for ATP-dependent, non-lysosomal intracellular protein degradat ...
, and Ubiquitin C which contribute to the degradation of abnormal proteins.


Preclinical Studies


Cellular Studies

Acting by inhibiting or stimulating the signaling pathways cited in the previous section, the cyclopentenone prostaglandins, principally 15-deoxy-Δ12,14-PGJ2, Δ12-PGJ2, PGJ2 and, in fewer studies, PGA2 and PGA1 have been shown to inhibit the function and/or survival of various pro-inflammatory, neurological, and other cell types. The three PGJ2 cyclopentenone prostaglandins induce apoptosis in rodent cultured neuron cells by a mechanism that involves inhibiting the
Phosphoinositide 3-kinase Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
signaling pathway; this inhibition is independent of their ability to activate PPARγ or their prostaglandin DP2 receptor.


Animal Studies

15-deoxy-Δ12,14-PGJ2, Δ12-PGJ2, PGJ2 and, in fewer studies, PGA2 and PGA1 inhibit the inflammatory response and tissue damage that follow experimentally-induced pancreatitis; glomerulonephritis;
arthritis Arthritis is a term often used to mean any disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, swelling, and decreased range of motion of the affected joints. In som ...
; spinal cord, brain, and lung injury; injury due to
ischemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems wi ...
in the heart, brain, kidney, and gut; and stress-induced central nervous system trauma. Rat Cerebral cortex neurons and human neuroblastoma
SH-SY5Y SH-SY5Y is a human derived cell line used in scientific research. The original cell line, called SK-N-SH, from which it was subcloned was isolated from a bone marrow biopsy taken from a four-year-old female with neuroblastoma. SH-SY5Y cells are o ...
cells become apoptotic when treated with
micromolar Molar concentration (also called molarity, amount concentration or substance concentration) is a measure of the concentration of a chemical species, in particular of a solute in a solution, in terms of amount of substance per unit volume of sol ...
levels of 15-d-Δ12,14-PGJ2; this effect appears due to the ability of 15-d-Δ12,15-PGJ2 to inhibit the
Phosphoinositide 3-kinase Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
pathway of cell signaling. The direct injection of 15-d-Δ12,14-PGJ2 into the hippocampus proved to impair contextual memory retrieval in rats, again apparently acting by inhibiting the Phosphoinositide 3-kinase pathway. Based on these and other studies, the overproduction of cyclopentenone prostaglandins by the brain has been suggested to contribute to the neuron injury observed in various rodent models of neurodegenerative diseases and therefore may be relevant to the development and/or progression of the neuron injury occurring in human diseases such as
Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
and Parkinson's disease.


Human studies

15d-Δ12,14-PGJ2 and its PGD2 precursor have been demonstrated to suppress hair growth in studies of mouse and human follicular explant culture models; further studies examining the content of these two prostaglanidns in normal and balding tissue of mice and humans have implicated PGD2 and to a much lesser extent 15d-Δ12,Δ14-PGJ2 in the development of
male pattern baldness Pattern hair loss (also known as androgenetic alopecia (AGA)) is a hair loss condition that primarily affects the top and front of the scalp. In male-pattern hair loss (MPHL), the hair loss typically presents itself as either a receding front ha ...
.


References

{{Transient receptor potential channel modulators Prostaglandins Anti-inflammatory agents