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Relationship: 95

Title

The title of the KER should clearly define the two KEs being considered and the sequential relationship between them (i.e., which is upstream and which is downstream). Consequently all KER titles take the form “upstream KE leads to downstream KE”.  More help

Inhibition, Cyclooxygenase activity leads to Reduction, Prostaglandin E2 concentration

Upstream event
Upstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help
Downstream event
Downstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

This table is automatically generated upon addition of a KER to an AOP. All of the AOPs that are linked to this KER will automatically be listed in this subsection. Clicking on the name of the AOP in the table will bring you to the individual page for that AOP. More help
AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Cyclooxygenase inhibition leading reproductive failure adjacent Moderate Agnes Aggy (send email) Under Development: Contributions and Comments Welcome
Cyclooxygenase inhibition leading to acute kidney injury adjacent High High Arthur Author (send email) Under development: Not open for comment. Do not cite

Taxonomic Applicability

Select one or more structured terms that help to define the biological applicability domain of the KER. In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. Authors can indicate the relevant taxa for this KER in this subsection. The process is similar to what is described for KEs (see pages 30-31 and 37-38 of User Handbook) More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
mice Mus sp. High NCBI
rat Rattus norvegicus High NCBI
Monkey Monkey Moderate NCBI
zebra fish Danio rerio Moderate NCBI
cat Felis catus Moderate NCBI
dog Canis lupus familiaris Moderate NCBI

Sex Applicability

Authors can indicate the relevant sex for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of the User Handbook). More help
Sex Evidence
Unspecific High

Life Stage Applicability

Authors can indicate the relevant life stage for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of User Handbook). More help
Term Evidence
All life stages High

Key Event Relationship Description

Provide a brief, descriptive summation of the KER. While the title itself is fairly descriptive, this section can provide details that aren’t inherent in the description of the KEs themselves (see page 39 of the User Handbook). This description section can be viewed as providing the increased specificity in the nature of upstream perturbation (KEupstream) that leads to a particular downstream perturbation (KEdownstream), while allowing the KE descriptions to remain generalised so they can be linked to different AOPs. The description is also intended to provide a concise overview for readers who may want a brief summation, without needing to read through the detailed support for the relationship (covered below). Careful attention should be taken to avoid reference to other KEs that are not part of this KER, other KERs or other AOPs. This will ensure that the KER is modular and can be used by other AOPs. More help

There are two cyclooxygenase isoenzymes (COX-1 and -2) that are responsible for catalyzing the reaction converting arachidonic acid (AA) to various prostanoids including prostaglandins, thromboxanes, and prostacyclins(Giuliano & Warner, 2002). In 2000, Simmons et al. postulated a third COX, COX-3, which was later identified as a splice variant of COX-1(Simmons et al., 1999). The current role of COX-3 in humans is unclear but it has been shown to aid in production of PGE2 albeit to a lesser extent then COX-1 and -2 (Sharma et al., 2019). COX-1 is constitutively expressed in many tissues and aids in production of prostaglandins (PGs) for normal physiologic function. Comparatively, COX-2 expression may be induced following cell stimulation to exogenous factors (Milne et al., 2001). Both isoenzymes have been shown to catalyze PGE2 synthesis, however the majority of PGE2 synthesis is thought to be attributed to COX-2 enzymatic activity(Giuliano & Warner, 2002; Qi et al., 2006). COX catalyzes the rate limiting reaction involved in the synthesis of PGE2 in two steps, first by deoxygenation and the by reduction. Before COX can aid in PGE2 synthesis it must first be activated through a peroxidase-dependent process. A two-electron reduction of peroxide leading to heme oxidation generates an oxo-ferryl porphyrin radical cation. When an electron gets transferred to heme through oxidation, this generates a tyrosyl radical in the COX active site. The tyrosyl radical can then remove a pro-S hydrogen from carbon-13 of AA. Next, the peroxyl radical is reduced to hydrogen peroxide to form prostaglandin G2 (PGG2) which regenerates the tyrosyl radical. After initiation, the peroxidase can reduce PGG2 to the unstable prostaglandin H2 (PGH2). A secondary enzyme, prostaglandin E synthase (PGE synthase) catalyzes the oxidoreduction of PGH2 into PGE2 (Rouzer & Marnett, 2009). The mechanism of direct COX inhibition involves sterically hindering the COX active site AA binds to, inhibiting the conversion of AA to downstream PGE2 (Limongelli et al., 2010).

Evidence Supporting this KER

Assembly and description of the scientific evidence supporting KERs in an AOP is an important step in the AOP development process that sets the stage for overall assessment of the AOP (see pages 49-56 of the User Handbook). To do this, biological plausibility, empirical support, and the current quantitative understanding of the KER are evaluated with regard to the predictive relationships/associations between defined pairs of KEs as a basis for considering WoE (page 55 of User Handbook). In addition, uncertainties and inconsistencies are considered. More help
Biological Plausibility
Define, in free text, the biological rationale for a connection between KEupstream and KEdownstream. What are the structural or functional relationships between the KEs? For example, there is a functional relationship between an enzyme’s activity and the product of a reaction it catalyses. Supporting references should be included. However, it is recognised that there may be cases where the biological relationship between two KEs is very well established, to the extent that it is widely accepted and consistently supported by so much literature that it is unnecessary and impractical to cite the relevant primary literature. Citation of review articles or other secondary sources, like text books, may be reasonable in such cases. The primary intent is to provide scientifically credible support for the structural and/or functional relationship between the pair of KEs if one is known. The description of biological plausibility can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured (see page 40 of the User Handbook for further information).   More help

The concept of COX enzyme being responsible for prostaglandin production has been extensively studied since it was first proposed in the 1980s in the laboratories of Dr. Bailey and Dr. Needleman (Bailey et al., 1985; Whiteley & Needleman, 1984). Almost four decades of research has led to this mechanism being engrained in scientific literature, displayed through numerous textbook publications (Golan & Tashjian, 2012; Middendorf & Williams, 2000). Furthermore, COX enzymes are also officially referred to as prostaglandin endoperoxide synthase (PTGS), suggesting the wide acceptance of its pivotal role in prostaglandin synthesis (Jang et al., 2020). COX enzyme inhibition has been a major therapeutic target for many drugs, resulting in a vast pool of resources put towards understanding the functional mechanisms of COX isoenzyme (Ferrer et al., 2019; Turini & DuBois, 2002).COX-1 and -2 are oxidoreductase enzymes responsible for catalyzing the first two steps involved in the biosynthesis of PGE2. Initially, COXs catalyze the bis-deoxygenation of arachidonic acid (AA) to prostaglandin (PG)G2. This is followed by COX mediated reduction of PGG2 to PGH2, which is then converted to PGE2 by action of prostaglandin E synthase (PGE synthase)(Rouzer & Marnett, 2009). This mechanism of COX mediated oxidation has been well characterized by x-ray crystallography and kinetics experiments (Rouzer & Marnett, 2003; Smith et al., 2000; van der Donk et al., 2002).

Uncertainties and Inconsistencies
In addition to outlining the evidence supporting a particular linkage, it is also important to identify inconsistencies or uncertainties in the relationship. Additionally, while there are expected patterns of concordance that support a causal linkage between the KEs in the pair, it is also helpful to identify experimental details that may explain apparent deviations from the expected patterns of concordance. Identification of uncertainties and inconsistencies contribute to evaluation of the overall WoE supporting the AOPs that contain a given KER and to the identification of research gaps that warrant investigation (seep pages 41-42 of the User Handbook).Given that AOPs are intended to support regulatory applications, AOP developers should focus on those inconsistencies or gaps that would have a direct bearing or impact on the confidence in the KER and its use as a basis for inference or extrapolation in a regulatory setting. Uncertainties that may be of academic interest but would have little impact on regulatory application don’t need to be described. In general, this section details evidence that may raise questions regarding the overall validity and predictive utility of the KER (including consideration of both biological plausibility and empirical support). It also contributes along with several other elements to the overall evaluation of the WoE for the KER (see Section 4 of the User Handbook).  More help

Inhibition of COX is often measured by inhibition in prostanoid synthesis as this is the main function of the enzyme. This makes it difficult to draw a key event relationship from published data as often only inhibition of PGE2 is reported as an indirect measure of COX activity (Mirshafiey et al., 2017). This explains the lack of usable evidence for dose concordance despite COX inhibition being so widely studied and understood biologically. Furthermore, COX inhibition may not directly lead to a measurable decrease in COX expression but will still result in a decline in PGE2 synthesis as most inhibitors sterically hinder the active sight AA binds to (Nakatsugi et al.,1996). Most of the evidence directly measuring COX inhibition and PGE2 expression is available for COX-2, providing greater uncertainty for the role of COX-1 in this relationship. Inconsistencies in the data mainly surround the role PGE2 also plays in COX regulation. Some studies have reported that PGE2 also modulates COX expression, presenting uncertainty regards the sequence of key events in this relationship (Cho & Choe, 2020; Tjandrawinata & Hughes-Fulford, 1997).

Proposed study to address uncertainties:

To better evaluate the role both COX isozymes play in this KER, further experiments are required. Renal proximal tubular epithelial cells, urothelial cells and gastric epithelial cells all known to express both COX-1 and COX-2 can be exposed to a range of therapeutic doses of non-selective NSAIDs (eg. Diclofenac, ibuprofen, and naproxen) for a 24-hour period (FDA, 2018). At four-hour intervals during this period, cells can be sampled and assessed for COX-1 and COX-2 activity through use of ELISA kits and PGE2 can also be measured using ELISA or radio immunoassay kits (Li et al., 2014). Selective modulation of either isozyme in relation to PGE2 expression will clarify the role COX-1 plays in this KER and may provide temporal and dose concordance evidence as well. Furthermore, it would be beneficial to use a COX-2 knockout cell model in parallel with the previous experiment to specifically assess the role COX-1 plays in PGE2 production. It would also be beneficial to have either further studies or a systematic review assessing the role PGE2 plays in COX regulation to determine if there really is a feedback relationship occurring.

Response-response Relationship
This subsection should be used to define sources of data that define the response-response relationships between the KEs. In particular, information regarding the general form of the relationship (e.g., linear, exponential, sigmoidal, threshold, etc.) should be captured if possible. If there are specific mathematical functions or computational models relevant to the KER in question that have been defined, those should also be cited and/or described where possible, along with information concerning the approximate range of certainty with which the state of the KEdownstream can be predicted based on the measured state of the KEupstream (i.e., can it be predicted within a factor of two, or within three orders of magnitude?). For example, a regression equation may reasonably describe the response-response relationship between the two KERs, but that relationship may have only been validated/tested in a single species under steady state exposure conditions. Those types of details would be useful to capture.  More help
Time-scale
This sub-section should be used to provide information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). This can be useful information both in terms of modelling the KER, as well as for analyzing the critical or dominant paths through an AOP network (e.g., identification of an AO that could kill an organism in a matter of hours will generally be of higher priority than other potential AOs that take weeks or months to develop). Identification of time-scale can also aid the assessment of temporal concordance. For example, for a KER that operates on a time-scale of days, measurement of both KEs after just hours of exposure in a short-term experiment could lead to incorrect conclusions regarding dose-response or temporal concordance if the time-scale of the upstream to downstream transition was not considered. More help
Known modulating factors
This sub-section presents information regarding modulating factors/variables known to alter the shape of the response-response function that describes the quantitative relationship between the two KEs (for example, an iodine deficient diet causes a significant increase in the slope of the relationship; a particular genotype doubles the sensitivity of KEdownstream to changes in KEupstream). Information on these known modulating factors should be listed in this subsection, along with relevant information regarding the manner in which the modulating factor can be expected to alter the relationship (if known). Note, this section should focus on those modulating factors for which solid evidence supported by relevant data and literature is available. It should NOT list all possible/plausible modulating factors. In this regard, it is useful to bear in mind that many risk assessments conducted through conventional apical guideline testing-based approaches generally consider few if any modulating factors. More help
Known Feedforward/Feedback loops influencing this KER
This subsection should define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits? In some cases where feedback processes are measurable and causally linked to the outcome, they should be represented as KEs. However, in most cases these features are expected to predominantly influence the shape of the response-response, time-course, behaviours between selected KEs. For example, if a feedback loop acts as compensatory mechanism that aims to restore homeostasis following initial perturbation of a KE, the feedback loop will directly shape the response-response relationship between the KERs. Given interest in formally identifying these positive or negative feedback, it is recommended that a graphical annotation (page 44) indicating a positive or negative feedback loop is involved in a particular upstream to downstream KE transition (KER) be added to the graphical representation, and that details be provided in this subsection of the KER description (see pages 44-45 of the User Handbook).  More help

Domain of Applicability

As for the KEs, there is also a free-text section of the KER description that the developer can use to explain his/her rationale for the structured terms selected with regard to taxonomic, life stage, or sex applicability, or provide a more generalizable or nuanced description of the applicability domain than may be feasible using standardized terms. More help

The COX gene intron-exon arrangement is conserved across all vertebrates and is substantially conserved across most other species. There are also few structural and functional differences in the ligand binding and dimerization of COXs across species, making COX inhibition by steric hinderance widely applicable to most species while being independent of sex or lifestage (Chandrasekharan & Simmons, 2004).Specifically, COX mediated formation of PGE2 has been demonstrated in a variety of species including zebrafish (North et al., 2007; Ugwuagbo et al., 2019), dogs (King et al., 2010; Pang et al., 2014), monkeys (Markosyan & Duffy, 2009), and cats (Pelligand et al., 2015).The evidence used to construct the current KER has all been drawn from mouse (Wu et al., 1998), rat (Yu et al., 2017) or human (Caughey et al., 2001; Hazra & M Dubinett, 2007; Li et al., 2014) models providing the highest evidence for these species.

References

List of the literature that was cited for this KER description using the appropriate format. Ideally, the list of references should conform, to the extent possible, with the OECD Style Guide (OECD, 2015). More help

United States Food and Drug Administration (FDA). (2018). COX-2 Selective ( includes Bextra , Celebrex , and Vioxx ) and Non-Selective Non-Steroidal Anti- Inflammatory Drugs ( NSAIDs ). Retrieved from https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/cox-2-selective-includes-bextra-celebrex-and-vioxx-and-non-selective-non-steroidal-anti-inflammatory

Bailey, J. M., Muza, B., Hla, T., & Salata, K. (1985). Restoration of prostacyclin synthase in vascular smooth muscle cells after aspirin treatment: regulation by epidermal growth factor. Journal of Lipid Research, 26(1), 54–61. https://doi.org/https://doi.org/10.1016/S0022-2275(20)34404-7

Caughey, G. E., Cleland, L. G., Penglis, P. S., Gamble, J. R., & James, M. J. (2001). Roles of Cyclooxygenase (COX)-1 and COX-2 in Prostanoid Production by Human Endothelial Cells: Selective Up-Regulation of Prostacyclin Synthesis by COX-2. The Journal of Immunology, 167(5), 2831–2838. https://doi.org/10.4049/jimmunol.167.5.2831

Chandrasekharan, N. V, & Simmons, D. L. (2004). The cyclooxygenases. Genome Biology, 5(9), 241. https://doi.org/10.1186/gb-2004-5-9-241

Cho, W., & Choe, J. (2020). Prostaglandin E2 stimulates COX-2 expression via mitogen-activated protein kinase p38 but not ERK in human follicular dendritic cell-like cells. BMC Immunology, 21(1), 1–8. https://doi.org/10.1186/s12865-020-00347-y

Ferrer, M. D., Busquets-Cortés, C., Capó, X., Tejada, S., Tur, J. A., & Sureda*, A. P. and A. (2019). Cyclooxygenase-2 Inhibitors as a Therapeutic Target in Inflammatory Diseases. Current Medicinal Chemistry. https://doi.org/http://dx.doi.org/10.2174/0929867325666180514112124

Giuliano, F., & Warner, T. D. (2002). Origins of Prostaglandin E: Involvements of Cyclooxygenase (COX)-1 and COX-2 in Human and Rat Systems. Journal of Pharmacology and Experimental Therapeutics, 303(3), 1001 LP – 1006. https://doi.org/10.1124/jpet.102.041244

Golan, D. E., & Tashjian, A. H. (2012). Principles of pharmacology : the pathophysiologic basis of drug therapy. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins.

Hazra, S., & M Dubinett, S. (2007). Ciglitazone mediates COX-2 dependent suppression of PGE2 in human non-small cell lung cancer cells. Prostaglandins, Leukotrienes and Essential Fatty Acids, 77(1), 51–58. https://doi.org/https://doi.org/10.1016/j.plefa.2007.05.006

Jang, Y., Kim, M., & Hwang, S. W. (2020). Molecular mechanisms underlying the actions of arachidonic acid-derived prostaglandins on peripheral nociception. Journal of Neuroinflammation, 17(1), 1–27. https://doi.org/10.1186/s12974-020-1703-1

Jeffrey, J. E., & Aspden, R. M. (2007). Cyclooxygenase inhibition lowers prostaglandin E2 release from articular cartilage and reduces apoptosis but not proteoglycan degradation following an impact load in vitro. Arthritis Research & Therapy, 9(6), R129–R129. https://doi.org/10.1186/ar2346

King, J. N., Rudaz, C., Borer, L., Jung, M., Seewald, W., & Lees, P. (2010). In vitro and ex vivo inhibition of canine cyclooxygenase isoforms by robenacoxib: A comparative study. Research in Veterinary Science, 88(3), 497–506. https://doi.org/10.1016/j.rvsc.2009.11.002

Kugathas, S., Audouze, K., Ermler, S., Orton, F., Rosivatz, E., Scholze, M., & Kortenkamp, A. (2016). Effects of common pesticides on prostaglandin D2 (PGD2) inhibition in SC5 mouse sertoli cells, evidence of binding at the cox-2 active site, and implications for endocrine disruption. Environmental Health Perspectives, 124(4), 452–459. https://doi.org/10.1289/ehp.1409544

Li, M., Tan, S. Y., & Wang, X. F. (2014). Paeonol exerts an anticancer effect on human colorectal cancer cells through inhibition of PGE2 synthesis and COX-2 expression. Oncology Reports, 32(6), 2845–2853. https://doi.org/10.3892/or.2014.3543

Limongelli, V., Bonomi, M., Marinelli, L., Gervasio, F. L., Cavalli, A., Novellino, E., & Parrinello, M. (2010). Molecular basis of cyclooxygenase enzymes (COXs) selective inhibition. Proceedings of the National Academy of Sciences, 107(12), 5411 LP – 5416. https://doi.org/10.1073/pnas.0913377107

Markosyan, N., & Duffy, D. M. (2009). Prostaglandin E2 acts via multiple receptors to regulate plasminogen-dependent proteolysis in the primate periovulatory follicle. Endocrinology, 150(1), 435–444. https://doi.org/10.1210/en.2008-0591

Middendorf, P. J., & Williams, P. L. (2000, March 17). Nephrotoxicity: Toxic Responses of the Kidney. Principles of Toxicology. https://doi.org/https://doi.org/10.1002/0471231800.ch6

Milne, S. A., Perchick, G. B., Boddy, S. C., & Jabbour, H. N. (2001). Expression, Localization, and Signaling of PGE2 and EP2/EP4 Receptors in Human Nonpregnant Endometrium across the Menstrual Cycle. Journal of Clinical Endocrinology and Metabolism, 86(9), 4453–4459.

Mirshafiey, A., Taeb, M., Mortazavi-Jahromi, S. S., Jafarnezhad-Ansariha, F., Rehm, B. H. A., Esposito, E., … Matsuo, H. (2017). Introduction of β-D-mannuronic acid (M2000) as a novel NSAID with immunosuppressive property based on COX-1/COX-2 activity and gene expression. Pharmacological Reports, 69(5), 1067–1072. https://doi.org/10.1016/j.pharep.2017.04.015

Naktsugi, S., Sugimoto, N., & Furukawa, M. (1996). Effects of non-steroidal anti-inflammatory drugs on prostaglandin E2 production by cyclooxygenase-2 from endogenous and exogenous arachidonic acid in rat peritoneal macrophages stimulated with lipopolysaccharide. Prostaglandins, Leukotrienes and Essential Fatty Acids, 55(6), 451–457. https://doi.org/10.1016/S0952-3278(96)90130-1

North, T. E., Goessling, W., Walkley, C. R., Lengerke, C., Kopani, K. R., Lord, A. M., … Zon, L. I. (2007). Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature, 447(7147), 1007–1011. https://doi.org/10.1038/nature05883

Pang, L. Y., Argyle, S. A., Kamida, A., Morrison, K. O., & Argyle, D. J. (2014). The long-acting COX-2 inhibitor mavacoxib (TrocoxilTM) has anti-proliferative and pro-apoptotic effects on canine cancer cell lines and cancer stem cells in vitro. BMC Veterinary Research, 10(1), 1–11. https://doi.org/10.1186/s12917-014-0184-9

Pelligand, L., Suemanotham, N., King, J. N., Seewald, W., Syme, H., Smith, K., … Elliott, J. (2015). Effect of Cyclooxygenase(COX)-1 and COX-2 inhibition on furosemide-induced renal responses and isoform immunolocalization in the healthy cat kidney. BMC Veterinary Research, 11, 296. https://doi.org/10.1186/s12917-015-0598-z

Qi, Z., Cai, H., Morrow, J. D., & Breyer, M. D. (2006). Differentiation of Cyclooxygenase 1- and 2–Derived Prostanoids in Mouse Kidney and Aorta. Hypertension, 48(2), 323–328. https://doi.org/10.1161/01.HYP.0000231934.67549.b7

Rouzer, C. A., & Marnett, L. J. (2003). Mechanism of Free Radical Oxygenation of Polyunsaturated Fatty Acids by Cyclooxygenases. Chemical Reviews, 103(6), 2239–2304. https://doi.org/10.1021/cr000068x

Rouzer, C. A., & Marnett, L. J. (2009). Cyclooxygenases: structural and functional insights. Journal of Lipid Research, 50 Suppl(Suppl), S29–S34. https://doi.org/10.1194/jlr.R800042-JLR200

Santini, G., Patrignani, P., Sciulli, M. G., Seta, F., Tacconelli, S., Panara, M. R., … Patrono, C. (2001). The human pharmacology of monocyte cyclooxygenase 2 inhibition by cortisol and synthetic glucocorticoids. Clinical Pharmacology and Therapeutics, 70(5), 475–483. https://doi.org/10.1067/mcp.2001.119213

Sharma, S., Verma, A., Chauham, R., Kedar, M., & Kulshrestha, R. (2019). Study of Cyclooxygenase-3 on the Bases of Its Facts and Controversies. International Journal of Pharmarceutical Sciences and Research, 10(1), 387–392. https://doi.org/10.13040/IJPSR.0975-8232.10(1).387-92

Simmons, D. L., Botting, R. M., Robertson, P. M., Madsen, M. L., & Vane, J. R. (1999). Induction of an acetaminophen-sensitive cyclooxygenase with reduced sensitivity to nonsteroid antiinflammatory drugs. Proceedings of the National Academy of Sciences, 96(6), 3275 LP – 3280. https://doi.org/10.1073/pnas.96.6.3275

Smith, W. L., DeWitt, D. L., & Garavito, R. M. (2000). Cyclooxygenases: Structural, Cellular, and Molecular Biology. Annual Review of Biochemistry, 69(1), 145–182. https://doi.org/10.1146/annurev.biochem.69.1.145

Tjandrawinata, R. R., & Hughes-Fulford, M. (1997). Up-regulation of cyclooxygenase-2 by product-prostaglandin E2. Advances in Experimental Medicine and Biology, 407, 163–170.

Turini, M. E., & DuBois, R. N. (2002). Cyclooxygenase-2: A Therapeutic Target. Annual Review of Medicine, 53(1), 35–57. https://doi.org/10.1146/annurev.med.53.082901.103952

Ugwuagbo, K. C., Maiti, S., Omar, A., Hunter, S., Nault, B., Northam, C., & Majumder, M. (2019). Prostaglandin E2 promotes embryonic vascular development and maturation in zebrafish. Biology Open, 8(4), bio039768. https://doi.org/10.1242/bio.039768

Van der Donk, W. A., Tsai, A.-L., & Kulmacz, R. J. (2002). The Cyclooxygenase Reaction Mechanism. Biochemistry, 41(52), 15451–15458. https://doi.org/10.1021/bi026938h

Whiteley, P. J., & Needleman, P. (1984). Mechanism of enhanced fibroblast arachidonic acid metabolism by mononuclear cell factor. The Journal of Clinical Investigation, 74(6), 2249–2253. https://doi.org/10.1172/JCI111651

Wight, N. J., Gottesdiener, K., Garlick, N. M., Atherton, C. T., Novak, S., Gertz, B. J., … Hawkey, C. J. (2001). Rofecoxib, a COX-2 inhibitor, does not inhibit human gastric mucosal prostaglandin production. Gastroenterology, 120(4), 867–873. https://doi.org/10.1053/gast.2001.22432

Wu, D., Mura, C., Beharka, A. A., Han, S. N., Paulson, K. E., Hwang, D., & Meydani, S. N. (1998). Age-associated increase in PGE2 synthesis and COX activity in murine macrophages is reversed by vitamin E. American Journal of Physiology - Cell Physiology, 275(3 44-3). https://doi.org/10.1152/ajpcell.1998.275.3.c661

Yu, L., Yan, J., & Sun, Z. (2017). D-limonene exhibits anti-inflammatory and antioxidant properties in an ulcerative colitis rat model via regulation of iNOS, COX-2, PGE2 and ERK signaling pathways. Molecular Medicine Reports, 15(4), 2339–2346. https://doi.org/10.3892/mmr.2017.6241

Zheng, C. Y., Xiao, W., Zhu, M. X., Pan, X. J., Yang, Z. H., & Zhou, S. Y. (2012). Inhibition of cyclooxygenase-2 by tetramethylpyrazine and its effects on A549 cell invasion and metastasis. International Journal of Oncology, 40(6), 2029–2037. https://doi.org/10.3892/ijo.2012.1375