Cyclopentenone prostaglandins are a subset of prostaglandins (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 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 isoprostanes viz., two cyclopentenone isoprostanes, 5,6-epoxyisoprostane E2 and 5,6-epoxisoprostane A2.

Biochemistry

In cells, COX-1 and COX-2 metabolize arachidonic acid to PGH2 which is then converted to PGE2 by any one of three isozymes, PTGES, PTGES2, and PTGES3 or, alternatively, to PGD2 by either of two enzymes, a glutathione-independent synthase termed lipocalin-type Prostaglandin D2 synthase (PTGDS or L-PGDS) and a glutathione-dependent hematopoietic-type H-PGDS or PTGDS2; the COX's also metabolizes dihomo-gamma-linolenic acid to PGH1 which is metabolized by one of the three PTGES isoenzymes to PGE1 (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:[1][2][3]

PGE2 and PGE1 are 20 carbon metabolites of arachidonic acid and dihomo-γ-linolenic acid, 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 cyclopentenone ring replacing the cyclopentanone 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[2]

The cyclopentenone 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 reactions to form covalent bonds with exposed nucleophile sites, particularly thiol residues, in diverse proteins. The reaction inactivates or reduces the activity of various functionally important target proteins and is one mechanism by which cyclopentenone PGs influence cell function.[1][2][4]

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.[1][2]

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, with 15-deoxy-Δ12,14-PGJ2 and PDJ2 exhibiting potencies comparable to PGD2 (i.e. Ki equilibrium constants ~20-45 nanomolar) and Δ12-PGJ2 having 10-fold lesser potency, at least on mouse DP2 receptor.[5][6] 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.[6] DP2 and DP1 are G protein-coupled receptors, with the DP2 receptor coupled to Gi alpha subunit-dependent depression of cellular cAMP 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.[6]

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.[7] Accordingly, further studies have focused on 15-deoxy-Δ12,14-PGJ2. This PG directly binds with and activates PPARγ thereby inducing the transcription 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, a form of cell suicide that differs from apoptosis 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.[2][4] Studies indicated the anti-inflammatory actions of the cyclopentenone prostaglandins show no or little dependency on their PPARγ-activating capacity.[8]

Covalent modification of proteins

The electrophilic centers in the cyclopentenone ring of cyclopentenone PGs form covalent bonds with exposed nucleophilic centers, primarily the sulfur atom in the thiol residues of cysteine residues. Proteomics analyses have detected 368 proteins that are covalently modified by 15-deoxy-Δ12,14-PGJ2; these include numerous plasma membrane, cell signaling, glycolytic enzyme, cytoskeletal, and Chaperone (protein)s.[9] 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.[9] This adduct formation has been studied with several functionally and/or clinically important proteins such as:

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 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, ERK2, 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, cFos, Erg-1, and cMyc or inhibiting N-Myc, Cyclin D1, Cdk4, and Insulin-like growth factor 1; and e) regulating agents such as HSP70, GPR78, Gadd153, Ubiquitin B, and Ubiquitin C which contribute to the degradation of abnormal proteins.[1][2]

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.[1][2][9] The three PGJ2 cyclopentenone prostaglandins induce apoptosis in rodent cultured neuron cells by a mechanism that involves inhibiting the Phosphoinositide 3-kinase signaling pathway; this inhibition is independent of their ability to activate PPARγ or their prostaglandin DP2 receptor.[9][16]

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; spinal cord, brain, and lung injury; injury due to ischemia in the heart, brain, kidney, and gut; and stress-induced central nervous system trauma.[2]

Rat Cerebral cortex neurons and human neuroblastoma SH-SY5Y cells become apoptotic when treated with micromolar 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 pathway of cell signaling.[16][17] 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.[16] 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 and Parkinson's disease.[9]

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 prostaglandins 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.[18]

References

  1. ^ a b c d e f g h i Surh YJ, Na HK, Park JM, Lee HN, Kim W, Yoon IS, Kim DD (2011). "15-Deoxy-Δ¹²,¹⁴-prostaglandin J₂, an electrophilic lipid mediator of anti-inflammatory and pro-resolving signaling". Biochemical Pharmacology. 82 (10): 1335–51. doi:10.1016/j.bcp.2011.07.100. PMID 21843512.
  2. ^ a b c d e f g h Straus DS, Glass CK (2001). "Cyclopentenone prostaglandins: new insights on biological activities and cellular targets". Medicinal Research Reviews. 21 (3): 185–210. doi:10.1002/med.1006.abs. PMID 11301410.
  3. ^ Rossitto M, Ujjan S, Poulat F, Boizet-Bonhoure B (2015). "Multiple roles of the prostaglandin D2 signaling pathway in reproduction". Reproduction. 149 (1): R49–58. doi:10.1530/REP-14-0381. PMID 25269616.
  4. ^ a b Shibata T (2015). "15-Deoxy-Δ¹²,¹⁴-prostaglandin J₂ as an electrophilic mediator". Bioscience, Biotechnology, and Biochemistry. 79 (7): 1044–9. doi:10.1080/09168451.2015.1012149. PMID 26011133. S2CID 6456659.
  5. ^ Hata AN, Zent R, Breyer MD, Breyer RM (2003). "Expression and molecular pharmacology of the mouse CRTH2 receptor". The Journal of Pharmacology and Experimental Therapeutics. 306 (2): 463–70. doi:10.1124/jpet.103.050955. PMID 12721327. S2CID 16771399.
  6. ^ a b c Bégué P, Quinet B, Baron S, Challier P, Fontaine JL, Lasfargues G (1989). "[Clinical and pharmacokinetic study of imipenem/cilastatin in children and newborn infants]". Pathologie-biologie. 37 (5): 485–90. PMID 2674874.
  7. ^ Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM, Evans RM (1995). "15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma". Cell. 83 (5): 803–12. doi:10.1016/0092-8674(95)90193-0. PMID 8521497.
  8. ^ a b Friedli O, Freigang S (2016). "Cyclopentenone-containing oxidized phospholipids and their isoprostanes as pro-resolving mediators of inflammation". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1862 (4): 382–392. doi:10.1016/j.bbalip.2016.07.006. PMID 27422370.
  9. ^ a b c d e f Figueiredo-Pereira ME, Corwin C, Babich J (2016). "Prostaglandin J2: a potential target for halting inflammation-induced neurodegeneration". Annals of the New York Academy of Sciences. 1363 (1): 125–37. Bibcode:2016NYASA1363..125F. doi:10.1111/nyas.12987. PMC 4801700. PMID 26748744.
  10. ^ Rossi A, Kapahi P, Natoli G, Takahashi T, Chen Y, Karin M, Santoro MG (2000). "Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IkappaB kinase". Nature. 403 (6765): 103–8. Bibcode:2000Natur.403..103R. doi:10.1038/47520. PMID 10638762. S2CID 4372129.
  11. ^ a b Wall SB, Oh JY, Diers AR, Landar A (2012). "Oxidative modification of proteins: an emerging mechanism of cell signaling". Frontiers in Physiology. 3: 369. doi:10.3389/fphys.2012.00369. PMC 3442266. PMID 23049513.
  12. ^ Kim WJ, Kim JH, Jang SK (2007). "Anti-inflammatory lipid mediator 15d-PGJ2 inhibits translation through inactivation of eIF4A". The EMBO Journal. 26 (24): 5020–32. doi:10.1038/sj.emboj.7601920. PMC 2140107. PMID 18034160.
  13. ^ Koharudin LM, Liu H, Di Maio R, Kodali RB, Graham SH, Gronenborn AM (2010). "Cyclopentenone prostaglandin-induced unfolding and aggregation of the Parkinson disease-associated UCH-L1". Proceedings of the National Academy of Sciences of the United States of America. 107 (15): 6835–40. Bibcode:2010PNAS..107.6835K. doi:10.1073/pnas.1002295107. PMC 2872412. PMID 20231490.
  14. ^ Oliva JL, Pérez-Sala D, Castrillo A, Martínez N, Cañada FJ, Boscá L, Rojas JM (2003). "The cyclopentenone 15-deoxy-delta 12,14-prostaglandin J2 binds to and activates H-Ras". Proceedings of the National Academy of Sciences of the United States of America. 100 (8): 4772–7. Bibcode:2003PNAS..100.4772O. doi:10.1073/pnas.0735842100. PMC 153631. PMID 12684535.
  15. ^ Aldini G, Domingues MR, Spickett CM, Domingues P, Altomare A, Sánchez-Gómez FJ, Oeste CL, Pérez-Sala D (2015). "Protein lipoxidation: Detection strategies and challenges". Redox Biology. 5: 253–66. doi:10.1016/j.redox.2015.05.003. PMC 4477048. PMID 26072467.
  16. ^ a b c Koma H, Yamamoto Y, Nishii A, Yagami T (2016). "15-Deoxy-Δ(12,14)-prostaglandin J2 induced neurotoxicity via suppressing phosphoinositide 3-kinase". Neuropharmacology. 113 (Pt A): 416–425. doi:10.1016/j.neuropharm.2016.10.017. PMID 27771378. S2CID 140206125.
  17. ^ Rohn TT, Wong SM, Cotman CW, Cribbs DH (2001). "15-deoxy-delta12,14-prostaglandin J2, a specific ligand for peroxisome proliferator-activated receptor-gamma, induces neuronal apoptosis". NeuroReport. 12 (4): 839–43. doi:10.1097/00001756-200103260-00043. PMID 11277593. S2CID 84937311.
  18. ^ Garza LA, Liu Y, Yang Z, Alagesan B, Lawson JA, Norberg SM, Loy DE, Zhao T, Blatt HB, Stanton DC, Carrasco L, Ahluwalia G, Fischer SM, FitzGerald GA, Cotsarelis G (2012). "Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia". Science Translational Medicine. 4 (126): 126ra34. doi:10.1126/scitranslmed.3003122. PMC 3319975. PMID 22440736.
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