Cyclopentenone Prostaglandins: Biologically Active Lipid Mediators Targeting Inflammation

Cyclopentenone prostaglandins (cyPGs) are biologically active lipid mediators, including PGA2, PGA1, PGJ2, and its metabolites. cyPGs are essential regulators of inflammation, cell proliferation, apoptosis, angiogenesis, cell migration, and stem cell activity. cyPGs biologically act on multiple cellular targets, including transcription factors and signal transduction pathways. cyPGs regulate the inflammatory response by interfering with NF-κB, AP-1, MAPK, and JAK/STAT signaling pathways via both a group of nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR-γ) dependent and PPAR-γ independent mechanisms. cyPGs promote the resolution of chronic inflammation associated with cancers and pathogen (bacterial, viral, and parasitic) infection. cyPGs exhibit potent effects on viral infections by repressing viral protein synthesis, altering viral protein glycosylation, inhibiting virus transmission, and reducing virus-induced inflammation. We summarize their anti-proliferative, pro-apoptotic, cytoprotective, antioxidant, anti-angiogenic, anti-inflammatory, pro-resolution, and anti-metastatic potential. These properties render them unique therapeutic value, especially in resolving inflammation and could be used in adjunct with other existing therapies. We also discuss other α, β -unsaturated carbonyl lipids and cyPGs like isoprostanes (IsoPs) compounds.


INTRODUCTION
Prostaglandins (PGs) are a group of lipids or oxygenated derivatives of arachidonic acid (AA) that sustain homeostatic functions and mediate the inflammatory response (Aoki and Narumiya, 2012). There are two types of PGs: conventional or classic PGs and cyclopentenone PGs (cyPGs). Examples of traditional PGs are PGD 2 , PGE 2 , prostacyclin (PGI 2 ), PGF 2α , and thromboxane A 2 (TXA 2 ), while the members of cyPGs include PGA 1 , PGA 2 , PGJ 2 , and metabolites of PGJ 2 , such as 15-Deoxy--12,14 -Prostaglandin J 2 (15d-PGJ 2 ) and 12 -PGJ 2 . As the name implies, cyPGs contain a cyclopentenone ring structure with a highly reactive α, βunsaturated carbonyl group, which can alter many proteins and their functional properties covalent attachments with thiol groups of the proteins (Straus and Glass, 2001). cyPGs are potent bioactive molecules and have a wide range of functions (Burstein, 2020). cyPGs can repress inflammatory responses, inhibit cell growth, angiogenesis, and increase apoptosis. cyPGs can interfere with virus infections and cancer development, indicating their potential to serve as therapeutic agents. This review discusses cyPGs biosynthesis, mechanism of action, functions, and their effects on virus infection and cancer development. Despite the existing knowledge, the resolving, antiviral, anti-inflammatory, and anticancer potential of cyPGs have been minimally explored and warrant further attention.
BIOSYNTHESIS OF CYCLOPENTENONE PROSTAGLANDINS (PGA 1 , PGA 2 , AND PGJ 2 AND ITS METABOLITES) AA is liberated from membrane phospholipids by the enzyme phospholipase A 2 (PLA 2 ) (Vane and Botting, 1990). Myosin, an actin-binding protein, is phosphorylated when there is an increase in intracellular calcium levels, causing PLA 2 to translocate from the cytoplasm to the intracellular membrane to access the phospholipids. Arachidonate is metabolized to PGG 2 by cyclooxygenase (COX) 1 and 2 (COX-1 and COX-2), which are contained in the endoplasmic reticulum (ER) and nuclear membranes (Vane and Botting, 1990;Hanna and Hafez, 2018) (Figure 1). PGG 2 is converted into PGH 2 by hydroxyperoxidase. Unstable PGH 2 diffuses from the ER lumen to the cytoplasm through the ER membrane. Due to its unstable nature, PGH 2 is enzymatically converted into different PGs, including PGI 2 , PGF 2 , and TXA 2 , through the action of specific PG synthases (Figure 1). When PGH 2 is acted upon by PGD 2 synthase, PGD 2 is created. PGD 2 is unstable and spontaneously undergoes non-enzymatic dehydration to yield either 15d-PGD 2 or PGJ 2 (Figure 1). Further dehydration and a 13, 14 double bond rearrangement of PGJ 2 yield 15-Deoxy--12,14 -prostaglandin J 2 (15d-PGJ 2 ) in an albumin-independent manner, while PGJ 2 dependent on serum albumin results in 12-PGJ 2 (Figueiredo-Pereira et al., 2014). PGs of the J series are synthesized in vivo as 12-PGJ 2 is a natural component of human body fluids. Its synthesis is inhibited by treatment with COX inhibitors (Hirata et al., 1988). When PGH 2 is acted upon by PGE 2 synthase, PGE 2 is formed. Dehydration of PGE 2 leads to PGA 2 Nugteren et al., 1966) (Figure 1). 15d-PGJ 2 could function in both an autocrine and paracrine manner and can be produced intracellularly and extracellularly via non-enzymatic conversion of PGD 2 (Shibata et al., 2002).

Cyclopentenone Prostaglandins in Various Diseases
15d-PGJ 2 is an immune regulator to modulate human autoimmune diseases as multiple sclerosis (MS), experimental allergic encephalomyelitis (EAE), polymyositis, Bechet's diseases, rheumatoid arthritis (RA), atopic dermatitis, systemic lupus erythematosus (SLE) (Li and Pauza, 2009), and age-related neurodegenerative diseases, including Alzheimer's (AD) and Parkinson's disease (PD) (Koharudin et al., 2011). γ T cells have been studied in context with autoimmune diseases in humans. γ T cells possess the cytotoxic activity and produce IFN-γ, tumor necrosis factor-alpha; TNF-α, and chemokines involved in recruiting monocytes and macrophages. The induction of cytokines and secretion of interleukin-17 (IL-17) contributes to inflammatory processes and promotes autoimmunity. 15d-PGJ 2 , along with rosiglitazone (Avandia), suppressed γ T cell proliferation in response and downregulated cytokine production (Li and Pauza, 2009). 15d-PGJ 2 also plays an essential regulatory role in osteosarcoma, bone FIGURE 1 | Biosynthesis of cyclopentenone prostaglandins. When the cell is activated by stressful stimuli, such as mechanical trauma, interferon, interleukin, or growth factors, the enzyme phospholipase A 2 moves from the cytoplasm to intracellular membranes to liberate arachidonic acid (AA) from the nuclear envelope or endoplasmic reticulum. AA is converted by cyclooxygenase-1 (COX-1) or cyclooxygenase-2 (COX-2) to prostaglandin G 2 (PGG 2 ), followed by hydroperoxidation of PGG 2 to PGH 2 . PGH 2 is converted to other PGH 2 metabolites such as PGD 2 , PGE 2 , PGF 2 , PGI 2 , and thromboxane A 2 (TXA 2 ) by their respective synthases. Of the metabolites, PGD 2 is dehydrated to form J 2 PGs. PGJ 2 may be located in exosomes, transport systems, or nuclear receptors to execute its function. PGE 2 is dehydrated to form PGA 2 . PGA 1 is a metabolite of linoleic acid, which is obtained through diet. metastases, and bone metabolism (Kitz et al., 2011;Kim et al., 2015).

Cyclopentenone Prostaglandins Elicit
Anti-inflammatory Responses via Regulating Transcription Factors Crucial for Inflammatory Response 15d-PGJ 2 directly inhibits multiple steps in the NF-κB signaling pathway and NF-κB-dependent gene expression (Straus et al., 2000). NF-κB represents a family of structurally related inducible transcription factors (NF-κB1; p50, NF-κB2; p52, RelA; p65, RelB, and c-Rel) located in the cytoplasm, which activates genes responsible for inflammation and innate and adaptive immunity (Senftleben et al., 2001). The NF-κB proteins are typically sequestered in the cytoplasm by a family of inhibitory proteins, including IκB family members, which sterically block the nuclear localization sequence (NLS) of NF-κB (Senftleben et al., 2001;Sun, 2017). The IκB kinase (IKK) complex is crucial for the activation of NF-κB, as it can degrade the NF-κB inhibitor IκB through phosphorylation, subsequently freeing NF-κB (Senftleben et al., 2001). NF-κB is involved in the pathogenesis of inflammatory diseases, including RA, inflammatory bowel disease (IBD), MS, atherosclerosis, SLE, type 1 diabetes, chronic obstructive pulmonary disease (COPD), and asthma (Pai and Thomas, 2008). NF-κB activation induces proinflammatory cytokines (IL-1β, IL-1, IL-2, IL-6, IL-8, and TNF-α) (Lawrence, 2009;Wang et al., 2014) and regulates inflammasome function (Guo et al., 2015) in both innate and adaptive immune cells. PGA 1 , another cyPG, is also a potent inhibitor of NF-κB activation in human cells by inhibiting phosphorylation and preventing degradation of the NF-κB inhibitor IκB-α (Rossi et al., 1997). The α, β-unsaturated carbonyl group in the cyPGs, when reactive, can undergo a Michael reaction with the cysteine nucleophile at position 179 on the IKKβ subunit of the IKK complex. This cysteine is located in the activation loop of the enzyme, and the alkylation of the cysteine inhibits the phosphorylation of the activation loop. Therefore, cyPGs inhibit IKK complex activity by directly modifying the IKKβ subunit . By doing so, the degradation IκB is inhibited, and NF-κB is unable to enter the nucleus.
15d-PGJ 2 non-specifically inhibits Signal transducer and activator of transcription (STAT) (Ji et al., 2005) and Janus kinase (JAK)-STAT signaling pathway in lymphocytes . STAT1 can be activated upon tyrosine phosphorylation by JAK1 tyrosine kinase (Mowen and David, 2000). Upon activation, STAT/STAT interactions occur immediately, and dimerized STATs can then enter the nucleus and regulate the transcription of inflammatory genes of cytokine and interferon signaling (Seif et al., 2017).

Anti-inflammatory Actions
Peroxisome proliferator-activated receptor-gamma inhibits TNFα, IL-6, inducible NO synthase (iNOS), gelatinase B, and COX-2 by acting as an antagonist to AP-1 and NF-κB (Welch et al., 2003). This inhibition mode was observed in activated macrophages expressing high levels of PPAR-γ (Ricote et al., 1998a,b;Straus et al., 2000). In general, when IFN-γ stimulated peritoneal macrophages were treated with 15d-PGJ 2 , instead of observing activated macrophages, morphological features classic of resting cells were seen (Ricote et al., 1998a,b). 15d-PGJ 2 treatment inhibited the induction of iNOS transcription by inhibiting the binding of AP-1 and NF-κB on iNOS promoter (Ricote et al., 1998a,b). Usually, iNOS is upregulated in activated macrophages accompanied by the overproduction of nitric oxide (NO), which causes inflammation (Sharma and Staels, 2007). Excess NO also induces s-nitrosylation of Sirt1, an inhibitor of p65 NF-κB, which inactivates Sirt1 and enhances pro-inflammatory response (Nakazawa et al., 2017). 15d-PGJ 2 treatment inhibits matrix metalloproteinase (MMP-9) or also called Gelatinase B in activated macrophages (Ricote et al., 1998a,b) at the transcription level. Inhibition by 15d-PGJ 2 is mediated at the level of AP-1 binding as MMP-9 transcriptional activation is dependent on AP-1 (Saarialho-Kere et al., 1993). 15d-PGJ 2 and TZDs reduced dendritic cells (DCs) stimulation with toll-like receptor (TLR) ligands via the MAP kinase and NF-κB pathways (Appel et al., 2005). In RAW264.7 cells, monocyte/macrophage-like cell lineage stimulated with LPS, a similar outcome to that of Jurkat cells was observed when treated with cyPGs (Straus et al., 2000). A different result was observed in HeLa cells, strengthening the fact that cyPGs' effect is cell type specific. Instead of inhibiting IKK complex activity, cyPGs impede the binding of NF-κB to DNA since p50 and p65 have cysteine residues at C62 and C38, respectively. Alkylation of these cysteines via the Michael reaction results in the inhibition of the binding of NF-κB to DNA (Straus et al., 2000).

ROLE OF CYCLOPENTENONE PROSTAGLANDINS DURING VIRAL INFECTIONS
Cyclopentenone Prostaglandins as Inhibitor of Viral Replication cyPGs are potent inhibitors of viral replication ( Table 2) and are effective against a wide range of viruses. These include negativestrand RNA viruses such as influenza A (Pica et al., , 2000Conti et al., 2001), Sendai virus (Amici and Santoro, 1991;Amici et al., 2001), and vesicular stomatitis virus (VSV) (Santoro et al., 1987;Pica et al., 1993); positive-strand RNA viruses such as Sindbis virus (Mastromarino et al., 1993), Poliovirus (Conti et al., 1996), and Human immunodeficiency virus-1 (Rozera et al., 1996) and DNA viruses such as herpes simplex virus (HSV) type 1 and 2 (Yamamoto et al., 1987;Amici et al., 2001). The ability of cyPGs to suppress virus production is very dramatic. In the African green monkey kidney (AGMK) cell line, replication of the Sendai virus is almost completely inhibited by 4 mg/ml of PGA 1 (Santoro et al., 1987) and by 4 mg/ml of PGJ 2 (Santoro et al., 1987) without being toxic to uninfected

Inhibition of virus cell-to-cell transmission
Human 15d-PGJ 2 Suppress NF-κB activation by inhibiting IKK complex Boisvert et al., 2008 Zika virus (ZIKV) 15d-PGJ 2 Control brain inflammation by downregulating microglial activation and by inducing apoptosis of activated microglia Bernardo and Minghetti, 2006 AGMK cells. Treatment of 6 mg/ml of 12 -PGJ 2 in Madin-Darby canine kidney cells (MDCK) infected with influenza A H1N1 (PR8) virus drastically suppressed the viral production by 95%. Simultaneously, a higher dose of 12 -PGJ 2 produced an undetectable virus yield . PGA 1 treatment also strongly inhibits the viral production of Ulster 73 (H7N1 influenza A) in LLC-monkey kidney epithelial cells (LLC-MK2), African green monkey kidney-37RC cells (AGMK-37RC), and MDCK cells (Conti et al., 2001), suggesting that cyPGs are effective against various subtypes of influenza A virus in multiple host cells. Similarly, in vivo studies have shown that PGA 1 and 16, 16-dimethyl-PGA 2 (dmPGA 2 ), a long-acting synthetic analog of PGA, in mice infected with a lethal dose of PR8 virus significantly decreases the virus titers in the lung and increases the survival rate (Santoro et al., 1987;Pica et al., 1993). In another study, the antiviral activity of the synthetic dmPGA 1 in HSV-1 and human immunodeficiency virus (HIV)-infected cells was investigated (Hughes-Fulford et al., 1992). dmPGA 1 affected HIV-1 replication in acutely infected T cells and chronically infected macrophages as assessed by a quantitative decrease in HIV-1 antigen p24 concentration (Hughes-Fulford et al., 1992). This study highlighted the unusual broad-spectrum antiviral activity of dmPGA 1 against HSV and HIV-1 and its therapeutic potential for in vivo use (Hughes-Fulford et al., 1992). Depending on the virus, cyPGs utilize various mechanisms and act on different viral cycle events to interfere with virus production. In HIV-1 infection and avian influenza, A virus infection, cyPGs prevent very early virus infection phases such as viral adsorption and penetration into target cells (Rozera et al., 1996;Carta et al., 2014). Even though antiviral action mechanisms differ between various viruses and host cell systems, the inhibition of virus replication by cyPGs is often associated with (1) alteration in viral protein synthesis and (2) alteration in viral glycoprotein glycosylation ( Table 2). PGA 1 treatment inhibited replication of Mayaro virus (MAYV) (an arbovirus endemic to certain humid forests of tropical South America) by 95% at 24 h post-infection in human epithelial type 2 (Hep-2) cells (Caldas et al., 2018). PGA 1 treatment inhibited viral structural protein synthesis by 15%, possibly via heat shock protein70 (HSP70) induction (Caldas et al., 2018).

Cyclopentenone Prostaglandins Alter Viral Protein Synthesis
Inhibition of individual virus replication by cyPGs is marked by dysregulation of viral protein synthesis ( Table 2). In influenza, A PR8 virus (a mouse-adapted H1N1 influenza virus causing severe infection in mice)-infected cells, treatment of 12 -PGJ 2 substantially decreased the synthesis of PR8 proteins such as hemagglutinin (HA), nucleoprotein (NP), and membrane protein M1 . PGA 1 could cause a significant delay in the synthesis of late viral polypeptides: HA, membrane protein M1, structural protein M2, and non-structural protein NS2 (Conti et al., 2001). Furthermore, both studies showed that inhibition or delay of viral protein synthesis is accompanied by induction of a 70 kDa host polypeptide identified as HSP70 by immunoblot analysis Conti et al., 2001). Because viral protein synthesis is repressed as long as HSP70 is present in the host cell, HSP70 seems to play an essential role in cyPGs antiviral activity.
In VSV infection, 12 -PGJ 2 can affect two distinct stages (an early stage and a late-stage) of the virus replication cycle in epithelial monkey cell lines . The inhibition of the virus at the initial stage is associated with altered viral protein synthesis. When the cells are treated with 8 mg/ml of 12 -PGJ 2 soon after virus infection, there is a dramatic decrease in VSV protein synthesis. Similar to the effect on influenza A virus replication, inhibition of VSV protein synthesis by 12 -PGJ 2 is also associated with the induction of a 74 kDa polypeptide belonging to the group of heat shock protein HSP70 . In another study, PGA 1 treatment decreased VSV proteins' production and the amount of respective viral mRNA (Bader and Ankel, 1990). This study found that PGA 1 exerts its antiviral activity at the VSV genes' primary transcription level, which leads to a reduction in viral mRNA synthesis, viral protein synthesis, and, ultimately, viral replication. To further investigate the antiviral activity of cyPGs, another study performed an RNA polymerase assay and reported that cyPGs potently inhibit VSV RNA polymerase (Parker, 1995). This inhibition correlates with the decrease in VSV replication in infected cells, indicating that cyPGs antiviral activity is due to VSV RNA polymerase inhibition.
In addition to VSV, cyPGs also exert a transcriptional block in the replication of herpes simplex virus type 1 (HSV-1) (Amici et al., 2001), HSV-2 (Yamamoto et al., 1987), and HIV-1 (Rozera et al., 1996). In HSV-1 infected human laryngeal carcinoma cells and neuroblastoma cells and HIV-1 infected colonic epithelial cells (caco-2 cells), cyPGs inhibit viral gene expression by suppressing NF-κB activation, independent of the PPAR-γ pathway (Amici et al., 2001;Boisvert et al., 2008). NF-κB is essential for many processes, including viral gene expression and, consequently, replication of viruses that contain NF-κB binding sites in their genomes. In its inactivated cytosolic form, NF-κB is bound to inhibitory IκB proteins such as IκBα. Stimuli like bacterial and viral infections increase the activity of the IKK complex, which phosphorylates IκBα, leading to ubiquitination and degradation of IκBα by proteasomes. Once NF-κB is free from IκBα, it translocates into the cell nucleus, activating the transcription of many genes, including the viral genes of HSV-1 and HIV-1 (Amici et al., 2001;Boisvert et al., 2008). Amici et al. (2001) showed that PGA 1 significantly decreases the NF-κB induction in HSV-1 infected cells by inhibiting the IKK complex.
Similarly, another study reported that the administration of PGJ 2 reduces IKK activity in HIV-1 infected cells (Boisvert et al., 2008). In both cases, suppression of IKK activity by cyPGs prevents IκBα degradation and NF-κB translocation to the nucleus. As a result, viral gene transcription and protein synthesis were repressed, leading to a significant reduction in virus production. In addition to interfering with NF-κB induction, cyPGs also target another pathway independent of NF-κB to inhibit HIV-1 replication. Kalantari et al. (2009) reported that 15d-PGJ 2 represses HIV-1 transcription by inhibiting HIV-1 transactivating protein, Tat. While the host transcriptional factor NF-κB binds to the 5 long terminal repeat (LTR) of HIV-1 to initiate transcription, viral Tat protein is recruited to an RNA stem-loop structure called transactivation response element (TAR) and is necessary for transcriptional elongation. Tat then recruits transcription elongation factor p-TEFb, which transactivates HIV LTR and allows the RNA polymerase II to continue the transcription with high processivity. 15d-PGJ 2 interferes with Tat-dependent transcriptional elongation by covalently modifying the thiol groups of Tat's cysteine residues (Kalantari et al., 2009). The resulting altered Tat protein is unable to transactivate HIV LTR in U937 human macrophages, inhibiting the transcription and replication of the virus.

Cyclopentenone Prostaglandins Alter Viral Glycoprotein Glycosylation
cyPGs can also inhibit viral replication at the post-translational level by altering the glycosylation of viral glycoproteins. This is seen in the VSV and Sendai virus ( Table 2). As mentioned earlier, 12 -PGJ 2 inhibits the VSV replication in the epithelial monkey cell line at two stages of the virus replication cycle. The inhibition at the early stage is due to a block in viral protein synthesis. Administration of 12 -PGJ 2 at a later stage (6-8 h post-infection) also leads to a decrease in virus production even though viral protein synthesis should have been completed by that time . 12 -PGJ 2 treatment started at a later stage does not affect viral protein synthesis, but it drastically decreases the glucosamine incorporation into the virus glycoprotein G without altering most cellular proteins.
Similarly, PGA 1 treatment in AGMK cells infected with the Sendai virus results in inhibition of glycosylation of viral glycoproteins hemagglutinin-neuraminidase (HN) and fusion protein (F), as indicated by the decrease in glucosamine incorporation (Santoro et al., 1987). The synthesis of nonglycosylated viral polypeptides of RNA transcriptase complex, including proteins P, NP, and matrix protein (M), are not affected by PGA 1 treatment. Likewise, 12 -PGJ 2 also markedly reduces the incorporation of glucosamine into HN and F viral glycoproteins without inhibiting the synthesis of cellular or viral proteins (Amici et al., 2001). The altered HN glycoprotein cannot insert into the cell membrane, which leads to an inhibition of virus maturation and production.
The Effect of Cyclopentenone Prostaglandins on Viral Transmission cyPGs can interfere with virus transmission via their antiproliferative activity. When PGA 1 and PGJ 2 are given to human T-cell leukemia virus type-I (HTLV-1) producing MT-2 cell line, they inhibit the growth of the cells in a dose-dependent manner (D'Onofrio et al., 1992). These cyPGs cause the cells to be arrested at the G1/S interface without detectable cellular toxicity. Another study showed that PGA 1 and PGJ 2 inhibit the proliferation of myeloid cells (K562 pluripotent stem cells, HL60 promyelocytic cells, and U937 monoblastoid cells) during early infection of HTLV-1, also in a dose-dependent manner (Lacal et al., 1994a,b). Furthermore, out of the three myeloid cell lines used in the study, the effect of growth inhibition is highest in U937 monoblastoid cells, followed by HL60 promyelocytic cells, and then K562 pluripotent stem cells. This suggests that cyPGs have a more significant antiproliferative effect on differentiated cells.
The primary mode of infection of HTLV-1 is cell-tocell transmission (Yoshida and Seiki, 1987). Furthermore, for retrovirus-like HTLV-1, integration of proviral DNA occurs after the initiation of cellular DNA synthesis in dividing cells (Varmus et al., 1979). Thus, alterations in cell proliferation and cell cycle can affect the permissiveness of recipient cells to HTLV-1. Indeed, in U937 monoblastoid cells co-cultured with virus-donor cells, PGA 1 and PGJ 2 treatments reduce the transmission of HTLV-1 (Lacal et al., 1994a,b). However, in less differentiated K562 pluripotent stem cells and HL60 promyelocytic cells, infection of recipient cells increased after cyPGs treatment antiproliferative activity is observed in these cells. This suggests that the effect of cyPGs on virus transmission is affected by cell differentiation.

The Effect of Cyclopentenone Prostaglandins on Viral Infection Induced Inflammation
Viral infections such as influenza virus, HIV-1, and respiratory syncytial virus (RSV) are characterized by excessive inflammation with the upregulation of proinflammatory cytokines and chemokines. The amount of these proinflammatory molecules correlates with the severity of illness Wesselingh et al., 1994;Hornsleth et al., 2001;Welliver et al., 2002). Given the anti-inflammatory effects of cyPGs, studies have been done to explore the possibility of utilizing cyPGs as a therapeutic agent for viral infections. In mice infected with lethal influenza infection, administration of 15d-PGJ 2 1 day after infection resulted in reduced influenza morbidity and mortality, accompanied by substantially decreased gene expression of proinflammatory cytokines (IL-6 and TNFα) and chemokines (CCL2, CCL3, CCL4, and CXCL10) via activation of PPAR-γ pathway (Cloutier et al., 2012). Similarly, 15d-PGJ 2 and other PPAR-γ agonists (ciglitazone and TGZ) can inhibit the RSV-induced release of cytokines TNF-α, GMCSF, IL-1α, IL-6, and the chemokines CXCL8 (IL-8) and CCL5 (Arnold et al., 2007). Moreover, RSV infection of the human airway epithelial cells causes an increase in expression of intercellular adhesion molecule-1 (ICAM1) on the cell surface, which enhances the adhesion of recruited immune effector cells, contributing to an intense inflammatory response and increased cytotoxicity (Wang et al., 2000;Arnold et al., 2007). Treatment of 15d-PGJ 2 and other PPAR-γ agonists results in inhibition of the upregulation of ICAM1, with the reduced cellular amount of ICAM1 mRNA (Arnold et al., 2007). This leads to a significant reduction in the adhesion of immune cells to RSV-infected cells. Also, the 15d-PGJ 2 treatment in RSVinfected cells is associated with reduced activity of NF-κB, a transcription factor essential for inflammatory responses. In HIV-infected intestinal epithelial cells, 15d-PGJ 2 also reduces the nuclear translocation of NF-κB and represses HIV-1 transcription by decreasing the activity of IKK (Boisvert et al., 2008). Overall, cyPGs can reduce the exaggerated inflammatory response associated with viral infections and great therapeutic value. PGD 2 /DP1 axis and 15d-PGJ 2 signaling contributes to the regulation of the CNS-specific response to pathogens such as neurotropic coronavirus (CoV) (Vijay et al., 2017) and acute encephalitis (Rosenberger et al., 2004), chronic demyelinating encephalomyelitis causing neurotropic virus called "MHV" (mouse hepatitis virus strain JHM) (Zheng et al., 2020).
Zika virus (ZIKV), one of the most medically relevant viral infections, affects the developing brain during pregnancy, and its connection with congenital malformations/microcephaly is well documented (de Oliveira et al., 2019). Neuroinflammation is one of the critical factors contributing to ZIKV-related microcephaly, inflammatory processes mediated by glial cells (Wen et al., 2017;Huan et al., 2018). PGD 2 , PGE 1 , PGE 2 , and PGI 2 have been correlated with neuroinflammation, protecting the CNS, and physiological responses to minimize further damage to neural tissue. Their anti-inflammatory reaction has been demonstrated in neuronal injuries (Shi et al., 2010) and neuroprotection during acute brain injury (Liang et al., 2005;An et al., 2014) 15d-PGJ 2 activates PPAR-γ by downregulating microglial activation despite the proinflammatory environment because of the neural damage (Bernardo and Minghetti, 2006).

OTHER ALPHA, BETA-UNSATURATED CARBONYL LIPIDS AND CYCLOPENTENONE ISOPROSTANES
There is another category of highly reactive electrophilic molecules, which react and modify both proteins and DNA resulting in toxicity, protein dysfunction (Sayre et al., 2006) or tissue damage and disease progression (Lee and Park, 2013). These are α, β-unsaturated aldehydes such as acrolein (ACR), 4hydroxy-2-non-enal (4-HNE), and crotonaldehyde (CRA) are the most reactive and toxic α, β-unsaturated aldehydes (Lee and Park, 2013).These induce toxicity because of depletion of cellular GSH and inactivation of antioxidant enzymes (GPx and thioredoxin; TRx) subsequently leading to ROS production, reactive nitrogen species (RNS), and free radicals (Stocker and Keaney, 2004;Lee and Park, 2013). Lipid peroxidation (LPO)-derived α, βunsaturated aldehydes play an important pathophysiological role in vascular diseases by inducing the production of various atherogenic factors, inflammatory mediators, activation of NF-κB signaling pathway, redox signaling mediators leading to cellular and tissue injury (Lee and Park, 2013).

SUMMARY AND FUTURE DIRECTIONS
There is significant evidence that cyPGs (PGA 1 , PGA 2 , and PGJ 2 ), and metabolites of PGJ 2 (15d-PGJ 2 and 12 -PGJ 2 ) can induce anti-inflammatory and antiviral effects through covalent modification reactions with their α, β-unsaturated carbonyl group. cyPGs can exert anti-inflammatory and antiviral effects in various ways depending on the host cell and pathogen type. Cell type is not the only influencer on the anti-inflammatory effects of cyPGs. The concentration of cyPGs and the length/time of exposure to cyPGs have varying anti-inflammatory and antiviral effects. Based on these factors, cyPGs can show biphasic targeting of inflammation (Garzon et al., 2011). At high doses, 15d-PGJ 2 has a dual action of stimulating anti-inflammation and anti-proliferation. Still, it can be toxic and induce both inflammation and cell proliferation at lower doses, and the biphasic pharmacodynamics has to be controlled carefully (Abbasi et al., 2016). Dose-related efficacy and safety of oral DP 2 receptor antagonists fevipiprant (QAW039), timapriprant (OC000459), and BI 671800 have been tested in patients with allergic asthma and COPD, and PGD 2 has shown anticancer effects in NSCLC (non-small cell lung carcinoma), kidney and lung fibrosis, and gastric cancer (Bateman Guerreros et al., 2017;Jandl and Heinemann, 2017;Pearson et al., 2017;Sandham et al., 2017a,b;Murillo et al., 2018;Brightling et al., 2020). Further research on outcomes based on specific concentrations is warranted. PPAR-γ antagonist (GW9662) and PPAR-γ ligands are new therapeutic targets in sepsis, hemorrhagic shock, and inflammation (Kaplan et al., 2005(Kaplan et al., , 2010Zingarelli and Cook, 2005;Chima et al., 2011). Synthetic PPAR-γ ligands rosiglitazone (Avandia) and pioglitazone have exhibited anti-inflammatory and antiviral effects in an EcoHIV mouse model that could decrease neurodegeneration. These drugs prove promising in treating HIV-1 associated neurocognitive disorders (Omeragic et al., 2020). This knowledge could significantly impact how viruses and inflammation can be treated.
The outcome of the 15d-PGJ 2 treatment depends upon its exogenously administered dose as it stimulates antiinflammation and anti-proliferation at high doses while can have toxic effects at a lower dose (Abbasi et al., 2016). Many strategies have been developed to deal with the biphasic pharmacodynamics of 15d-PGJ 2 and one of them is using a nanoemulsion (NE) composed of triolein/distearoyl phosphatidylcholine/Tween 80 at a high encapsulation ratio (>83%) allowing slow-release kinetics (Abbasi et al., 2016). NE retained a high proportion of 15d-PGJ 2 and directly delivered it to the cytosol, where proapoptotic targets are located, and could bypass cell membrane-associated targets involved in cell proliferation (Abbasi et al., 2016). NE could deliver 15d-PGJ 2 to its desired site of action, excluding undesired sites, on a subcellular level (Abbasi et al., 2016) and could be used as one of the strategies for treatment. Since the use of solid lipid nanoparticles (SLN) can improve therapeutic properties by increasing drug efficiency and availability, 15d-PGJ 2 -SLN was developed and tested for its immunomodulatory potential. The 15d-PGJ 2 -SLN formulation showed good colloidal parameters, encapsulation efficiency (96%), and stability (up to 120 days) with low hemolytic effects as compared to unloaded SLN in in vivo experiments. The 15d-PGJ 2 -SLN formulation using low concentrations reduced neutrophil migration in three inflammation models tested. 15d-PGJ 2 -SLN increased IL-10 levels and reduced IL-1β as well as IL-17 in peritoneal fluid thus highlighting the perspectives of a potent antiinflammatory system (de Melo et al., 2016). cyPGs have a wide spectrum of intracellular targets ranging from nuclear factors to mitochondria. Introduction of cyclopentenone moiety into molecules (jasmonates and chalcones) boosts their anticancer potential (Conti, 2006). Despite advancements made in the pharmacodynamics of cyPGs, a significant effort is needed to explore their unique therapeutic properties and tailor them to be used as leading anti-inflammatory, anticancer, and antiviral drugs.

AUTHOR CONTRIBUTIONS
All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.

FUNDING
We are grateful for funding support from the Center for Cancer Cell Biology, Immunology and Infection and NIH-funded grant R01CA 192970 to NS-W. The funders had no role in the design, decision to publish, or preparation of the manuscript.