Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Ronan Lordan
 + 3812 word(s) 3812 2021-12-01 10:26:31 |
2 format correction
Peter Tang
 Meta information modification 3812 2021-12-02 02:55:40 |

Video Upload Options

Do you have a full video?
Send video materials Upload full video

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Lordan, R. Platelet-Activating Factor Inhibitors as Therapeutics and Preventatives. Encyclopedia. Available online: https://encyclopedia.pub/entry/16650 (accessed on 27 July 2024).
Lordan R. Platelet-Activating Factor Inhibitors as Therapeutics and Preventatives. Encyclopedia. Available at: https://encyclopedia.pub/entry/16650. Accessed July 27, 2024.
Lordan, Ronan. "Platelet-Activating Factor Inhibitors as Therapeutics and Preventatives" Encyclopedia, https://encyclopedia.pub/entry/16650 (accessed July 27, 2024).
Lordan, R. (2021, December 01). Platelet-Activating Factor Inhibitors as Therapeutics and Preventatives. In Encyclopedia. https://encyclopedia.pub/entry/16650
Lordan, Ronan. "Platelet-Activating Factor Inhibitors as Therapeutics and Preventatives." Encyclopedia. Web. 01 December, 2021.
Platelet-Activating Factor Inhibitors as Therapeutics and Preventatives
Edit
This entry is adapted from the peer-reviewed paper 10.3390/molecules24234414

Platelet-activating factor (PAF) refers to the classical structure reported in 1979, which is a pro-inflammatory phospholipid mediator. PAF mediates a wide variety of cellular functions and cell–cell interactions. 

platelet-activating factor inflammation cardiovascular disease cell signalling phospholipids

1. Platelet-Activating Factor

Since its discovery, the structure of platelet-activating factor (PAF) also known as PAF-acether or AGEPC (acetyl-glyceryl-ether-phosphorylcholine) has been identified as a phosphoglycerylether lipid mediator involved in diverse physiological and pathophysiological processes. It seems apparent that PAF has different physiological roles in animals, plants, and monocellular organisms. It is considered the most potent lipid mediator known to date [1][2]. Previous to the 1970s, lipid mediators were thought to be generally derived from phospholipids. However, PAF was the first intact phospholipid mediator to demonstrate autacoid or messenger functions [3]. PAF was initially considered one molecule, which is commonly referred to as the classical PAF. However, now it is understood that there are a large number of structurally related phospholipids or PAF analogues that are dissimilar in structure to PAF that interact with the PAF-receptor (PAF-R) and belong to the ‘PAF family’, collectively known as PAF-like lipids (PAFLL). For the purpose of this review, PAF refers to the classical structure reported in 1979, which is responsible for most of the known biological effects and is thought to be the most potent PAF molecule. PAF mediates a wide variety of cellular functions and cell–cell interactions. Therefore, PAF is involved in several physiological processes including apoptosis, physiological inflammation, wound healing, reproduction, angiogenesis, long-term potentiation, and potentially retrograde signaling [4][5][6][7]. However, PAF is also a potent pro-inflammatory mediator that is implicated in a variety of conditions and chronic diseases such as cancer, renal diseases, cerebrovascular and central nervous system disorders, allergies, asthma, infections, and cardiovascular diseases (CVD) [5][8][9][10][11][12][13]. PAF is known to carry out its broad pathophysiological actions at concentrations as low as 10−12 M and almost always by 10−9M as an intercellular messenger [14]. In evolutionary terms, many ether lipids were replaced over time by their esterified analogues; however, PAF and other minor phosphoglycerylether molecules were conserved in various organisms due to their important biological roles [15].

2. The Discovery and Structural Elucidation of the Platelet-Activating Factor

2.1. The Discovery of the Platelet-Activating Factor

PAF was first introduced into the literature in 1966 when Barbaro and Zvaifler described a substance that caused antigen induced histamine release from rabbit platelets producing antibodies in passive cutaneous anaphylaxis [16]. Almost four years later, Henson described a ‘soluble factor’ released from leukocytes that induced vasoactive amine release in platelets. Further observations by Siraganuan and Osler [17] described the existence of a diluted substance that had the capacity to cause platelet activation. A year later Jacques Benveniste and colleagues elaborated on the findings of the previous two studies and described a novel factor that induced aggregation and secretion of platelets, which participated in a leukocyte-dependent histamine release from rabbit platelets [18]. Hence, the term platelet-activating factor (PAF) was coined because of the initial observations of its effects on platelets [18]. It was later discerned that PAF was a lipid-like molecule [19]. It is recalled that to study PAF Benveniste prepared a measure of PAF from 100 L of hog blood, which resulted in a 100 L solution from which 1 µL was sufficient to induce platelet aggregation, indicating its high level of potency [20]. However, this amount of PAF was too low to use techniques at the time such as mass spectrometry or magnetic resonance that might determine the structure of the bioactive compound [20]. Despite the lack of structural data, Benveniste and others had determined several of the physical characteristics of PAF. They determined that it was a lipid compound, it could bind to albumin, and it migrated between lysolecithin and sphingomyelin in thin-layer chromatography separation, all properties of which were similar to that of lysophosphatidylcholine. The compound was also affected by several phospholipases (PLA2, PLC, and PLD) but resistant to others (sphingomyelinase C and PLA1), indicating that indeed it had a phospholipid type structure [20][21]. Studies began to discern that PAF was implicated in IgE anaphylaxis [22] and many of the properties of PAF released during IgE anaphylaxis began to be elucidated [23]. Furthermore, the role of PAF in platelet aggregation was beginning to be further understood by June 1979 [24].

2.2. Structural Elucidation of the Platelet-Activating Factor

Following several experiments with phospholipases, etc. the structure of PAF was thought to be 2-acyl-sn-glycero-3-phosphocholine (1-lysophosphatidylcholine) [25], but owing to acyl chain migration this molecule was known for its instability and did not demonstrate the biological properties corresponding to PAF [20][26]. Around that time, several other structures were interrogated, and many researchers were involved in discussions as reviewed by Chap [20]. However, on the 10th of October 1979, Constantinos Demopoulos, Neal Pinckard, and Donald Hanahan, from San Antonio Texas published the structure of PAF (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) under the name AcGEPC (Acetyl-glyceryl-ether-phosphocholine), which was shown to have biological activities indistinguishable from that of naturally generated rabbit PAF (Figure 1) [27]. The researchers realised that the AcGEPC they synthesised was indeed the same structure as naturally occurring PAF. Interestingly, nineteen days after the Demopoulos, Pinckard, and Hanahan [27] publication, the same structure was reported by a group led by Fred Snyder who were assessing the properties of an isolated compound in the kidney that was responsible for peculiar biological activity, which was known by them as the antihypertensive polar renomedullary lipid (APRL) [28]. These studies were followed by an article by Benveniste who subsequently proposed the name PAF-acether [29]. Later articles confirmed that synthetically produced PAF initiated identical biological effects to the PAF molecules responsible for IgE-induced systemic anaphylaxis [30], which also caused similar vascular, cardiovascular, and respiratory problems associated with anaphylaxis in rabbits [31] and baboons [32]. In addition, platelets were not required to induce anaphylactic shock in rabbits when injected with synthetic PAF, indicating for the first time that PAF acts via a receptor [33].
/media/item_content/202112/61a8276815703molecules-24-04414-g001.png
Figure 1. The structure of platelet-activating factor (PAF): (A) PAF space fill model data from [34] and (B) PAF structural model.
Hanahan and colleagues formally confirmed the structure of PAF in 1980 using mass spectrometry and simplified their abbreviation of the molecules name to AGEPC [35]. Likewise, Benveniste and colleagues simplified the name of the PAF precursor to lyso-PAF [36]. As many researchers were working with PAF at the same time, it is reported that there were conflicting attitudes between the groups with reference to what the name of the molecule should be. Furthermore, Chap described the difficulty encountered by Benveniste who was unfortunate not to have elucidated the structure of PAF previous to the other groups [20]. Considering that we now know PAF exhibits a vast diversity of actions and the fact that a myriad of other molecules can activate platelets, it seems ironic that the name PAF is a misnomer [37] that has remained in the literature.
However, that was not the end of Benveniste’s role in determining some of the properties of PAF. Indeed, Benveniste and colleagues provided the first evidence that platelets synthesise PAF [38] and they determined the subcellular localisation of PAF biosynthesis in human neutrophils [39]. However, Benveniste’s important role in the discovery of PAF may be overshadowed by his later controversial research that led to major scientific scandals [20][40][41] that are not the subject of this review. The very first account of the discovery of PAF and its various properties was published in Nature in 1980 by Cusack [42]. The intensive and dedicated research of many scientists involved in the discovery and structural elucidation of PAF in the 70s and 80s set in motion a research field that is ever growing to this day, which has had profound implications to medical research.

3. The Importance of Platelet-Activating Factor Research

PAF is implicated in various physiological processes and a multitude of pathophysiological processes. However, the critical feature of PAF physiologically and in disease is that the biological effects of PAF can be modulated by diet, lifestyle, and environmental factors [5][43][44][45][46]. This means that PAF could be a potential therapeutic target for many chronic diseases [5][8][10] and thus PAF is of significant importance and value to researchers across several disciplines. While this review discusses many of these events, not all of PAF’s roles are discussed due to the vast accumulation of research published around PAF in the last forty years. In the last two years alone there has been over 2000 articles published in relation to PAF. This review specifically focuses on some of the emerging PAF-related research trends over the last decade. In particular, this article discusses the most contentious issues of PAF research such as the role of the PAF metabolic enzymes in physiological and inflammatory processes and the role of PAF in various chronic diseases, such as disorders of the central nervous system (CNS), CVD, and cancer. These diseases have major health implications for patients and are an enormous burden to healthcare globally. Indeed, some of the research highlighted in this article may lead to ground-breaking discoveries that enhance our understanding of cell signaling, inflammation, and disease.
After the elucidation of the structure of PAF in 1979, there was much motivation in the development of research in the field that from 1983 lead to several congresses being organised entirely focused on PAF research. These congresses were held every three years worldwide until 2004 (Table 1). After 21 years, PAF research became interdisciplinary and grew and expanded to virtually all areas of biochemistry and medicine. The congresses stopped being organised as much of the research surrounding PAF were disseminated at various international conferences. However, attempts have been made to reignite these congresses as recent as February 2015 in Tokyo Japan, where PAF communications were presented in special sessions at the ‘6th International Conference on Phospholipase A2 and Lipid Mediators’ [47].
Table 1. International conferences of platelet-activating factor (PAF).

Title

Date

Location

1st International Symposium on Platelet-Activating Factor and Structurally Related Ether-Lipids

26–29 June 1983

Paris, France

2nd International Conference on Platelet-Activating Factor and Structurally Related Ether-Lipids

26–29 October 1986

Gatlinburg, Tennessee, USA

3rd International Conference on Platelet-Activating Factor and Structurally Related Ether-Lipids

8–12 May 1989

Tokyo, Japan

4th International Congress on Platelet-Activating Factor and Related Lipid Mediators

22–25 September 1992

Snowbird, Utah, USA

5th International Congress on Platelet-Activating Factor and Related Lipid Mediators

12–16 September 1995

Berlin, Germany

6th International Congress on Platelet-Activating Factor and Related Lipid Mediators

21–24 September 1998

New Orleans, Louisiana, USA

7th International Congress on Platelet-Activating Factor and Related Lipid Mediators

24–27 September 2001

Tokyo, Japan

8th International Congress on Platelet-Activating Factor and Related Lipid Mediators

6–9 October 2004

Berlin, Germany

6th International Conference on Phospholipase A2 and Lipid Mediators

10–12 February 2015

Tokyo, Japan

4. The Potential Use of Platelet-Activating Factor Inhibitors as Therapeutics and Preventatives of Disease

Research into potential physiological and therapeutic ways of suppressing PAF activity demonstrated that endogenous or ingested PAF inhibitors could inhibit the actions of PAF [10][48]. Endogenous inhibitors of PAF have been identified in humans [49], many of which were identified as cardiolipins [50][51]. As a consequence of discovering that the body circulated PAF antagonists, it was thought that the absence of circulating antagonists could result in increased PAF activity [5]. Therefore, the potential role of PAF inhibitors in disease prevention and treatment has been of significant interest over the last three decades. Initial indications in the early 1980s demonstrated that PAF release from leukocytes could be modulated pharmacologically [52]. This was followed by studies using pharmacological compounds such as ticlopidine and calmodulin to study PAF-induced platelet aggregation [53][54]. At that time it was also shown that methanolic extracts of garlic bulbs exhibited inhibition of various platelet agonists including PAF [55]. This seems to be the first time in the literature that compounds originating from food were reported to have inhibited PAF-induced platelet aggregation. This was a significant finding as it demonstrated the existence of not only pharmacological therapeutics, but potentially dietary sources of PAF inhibitors also.
Around this period of PAF research there was a large increase in the number of published research relating to the discovery of PAF antagonists of natural and synthetic origin for which we now know of several hundred natural and synthetic PAF inhibitor molecules in existence [14]. In particular, researchers were investigating the potential use of compounds known as ginkgolides isolated from the Ginkgo biloba tree; a tree native to China, the existence of which dates back over 270 million years [56].
There are several ways to classify PAF inhibitors including if they are of natural of synthetic origin, they can be classified by their various chemical structures, and they can be classified by their interaction with the PAF-R, e.g., specific and non-specific inhibitors [57]. In terms of their structures, PAF inhibitors can be PAF analogues such as polar lipids, or there are molecules that are dihydropyridines, nitrogen heterocyclic compounds, phenolics, and other various natural medicinal compounds [57][58][59].
Along with being classified into compounds of natural or synthetic origin, PAF inhibitors can be characterised into two main classes according to their specificity: non-specific and specific inhibitors. Non-specific PAF inhibitors are compounds that inhibit certain processes in the PAF-induced signal transduction pathways such as calcium channel blockers, G-protein inhibitors, intracellular calcium chelators, etc. [14]. Various non-specific PAF inhibitors were crucial to identifying the individual steps of PAF-related signal transduction pathways. However, their pharmacological value is limited due to their low specificity [60][61][62][63]. By contrast, specific PAF inhibitors competitively or noncompetitively bind with the PAF-R. These types of inhibitors may have potential therapeutic value [5][14].

4.1. PAF Inhibitors of Synthetic Origin

The initial synthetic PAF inhibitor compounds such as CV-3988 [64][65], CV-6209 [66], RO 19-3704 [67], and ONO-6240 [68] were structurally similar to PAF. In fact CV-3988 a thiazolium derivative was a zwitterionic species that was the first synthetic antagonist of the PAF-R [64]. Later inhibitors replaced the glycerol backbone with cyclic structures such as SRI 63-441 [69], SRI 63-073 [70], UR-11353 [71], and CL-184,005 [72]. Subsequently, other PAF antagonists were developed that had no structural similarity to PAF. These antagonists were composed of heterocyclic structures that were characterised by sp2 nitrogen atom that interacted with the PAF-R as a hydrogen bond acceptor [57]. Many of these were derivatives of imidazolyl that lead to the development of lexipafant [73] and modipafant [74], thiazolidine derivatives such as SM-10661 [75], pyrrolothiazole-related antagonists such as tulopafant [76], and hetrazepine derivatives like WEB-2086 and WEB-2170 [77]. There are a plethora of synthetic PAF-R antagonists including psychotropic triazolobenzodiazepines [78], L-652,731 [79], and various examples of inorganic metal complexes [59][80]. However, it was later discovered that some of these antagonists were not orally active and some had toxicity issues [81][82], thus they had limited therapeutic value [83].
Clinical trials were conducted for several of these inhibitors, which demonstrated their tolerability and safety, but there were issues with their efficacy; juxtaposed, there were several trials that indicated positive outcomes following PAF-R antagonism. The inhibitors and their target diseases or disorders are outlined in Table 2.
Table 2. A list of some of the major synthetic PAF antagonists assessed against several conditions in clinical trials.

PAF-R Antagonist

Target Disease or Disorder

Outcome

Reference

Lexipafant

Cognitive impairment complications as a result of coronary artery bypass graft

No significant reduction in cognitive impairment

[84]

Myocardial infarction

No significant effect on streptokinase-induced hypotension in myocardial infarction patients

[85]

Sepsis

No significant affect in patients with severe sepsis

[86]

Organ failure related to pancreatitis

No significant amelioration of systemic inflammatory response syndrome in pancreatitis-induced organ failure

[87]

Modipafant

Asthma

No significant effect against chronic asthma

[74]
 

Asthma

No significant effect in early or late responses to allergens

[88]

Responses to inhaled PAF

Potent inhibition of airway and neutrophil responses to PAF with a duration of up to 24 h and a reduction of secondary eicosanoid production in response to inhaled PAF

[89]

SR27417A

SR27417A

Asthma

Modest inhibitory effects against asthma

[90][91],

Ulcerative colitis

No evidence of efficacy in the treatment of acute ulcerative colitis

[92]

WEB 2086

Asthma

No attenuation of early of late allergen-induced responses or airway hyperresponsiveness

[93]

UVB-induced dermatitis

Significant inhibition of UVB light-induced erythema

[94]

BN 50730

Rheumatoid arthritis

Ineffective in the treatment of rheumatoid arthritis

[95]

BN 52021

Pulmonary function in the early post ischaemic graft function in clinical lung transplantation

Improvement of alveoloarterial oxygen difference and a reduction of PAF levels

[96]

Ro 24-238

Psoriasis

No significant effects reported

[97]

TCV-309

Septic shock

No significant difference in adverse events or mortality. A substantial reduction of organ dysfunction and morbidity associated with septic shock was reported

[98]

Levocetirizine

Chronic idiopathic urticaria

Reduction of urticarial activity score

[99]

Rupatadine

Chronic idiopathic urticaria

Reduction of urticarial activity score but not as effective as levocetirizine

[99][100]
 

Allergic rhinitis and allergies

Significant effects against both conditions as demonstrated in the comprehensive review by Mullol et al.

[101]

Y-24180

Asthma

Improvement of bronchial hyperresponsiveness in patients with asthma

[102]
Notably, some molecules exhibit dual antagonistic properties towards PAF and other inflammatory mediators. For instance, rupatadine is both an antagonist of the PAF-R and the histamine H(1) receptor [103], whereas LDP-392 can target both PAF and 5-lipoxygenase [104]. Likewise, common statins targeting CVD [105][106] and antiretrovirals targeting human immunodeficiency virus (HIV) [107][108] also exhibit anti-PAF pleiotropic effects. Indeed, various other molecules can inhibit both PAF and inducible nitric oxide synthase induction (iNOS) [109] or thromboxane synthases [110].
Finally, apart from the various compounds presented in Table 2, research has investigated the use of various inorganic metal complexes including other structurally related and structurally dissimilar PAF-R antagonists [57]. The authors recommend the following comprehensive reviews for further information on various synthetic and inorganic metal complexes with PAF-R antagonistic properties, their structures, synthesis, and biological effects [111][57][83][101].

4.2. PAF Inhibitors of Natural Origin

Extracts from Ginkgo biloba were some of the first PAF inhibitors of natural origin to be discovered. Several studies by Pierre Braquet and colleagues demonstrated that one compound in particular, BN 2021, was a highly specific competitive PAF antagonist. Several related ginkgolides also exhibited inhibitory properties against PAF [112][113][114][115][116][117]. Indeed, several other researchers at the time discovered anti-PAF properties in other natural isolates of Chinese medicinal herbs such as phomactin A, kadsurenone, and various xanthones [118][119][120][121][122]. In fact, the discovery that compounds from garlic bulbs possess anti-PAF activity stimulated interest in the exploration of natural compounds for anti-PAF activity [55].
By 1996, several molecules had been discovered with PAF-like activity as reviewed by Demopoulos [123]. Further experimentation uncovered that a neutral glycerylether lipid without an acetyl group from pine pollen exhibited biological activity against PAF [124]. Consequently, it was deduced that other lipid extracts could potentially inhibit PAF-induced platelet aggregation. This led to a series of studies investigating food lipid extracts starting around 1993, which initially lead to the discovery of PAF antagonists in the polar lipid fractions of olive oil [125], honey and wax [126], milk and yoghurt [127], mackerel (Scomber scombrus) [128], and wine [129] before the turn of the century. These studies deduced that mainly polar lipids such as glycerophospholipids and glycolipids exhibited potent inhibition against PAF-induced platelet aggregation through competitive binding to the PAF-R. As this research field developed it was noted that many of the compounds discovered that exhibited anti-PAF activity were also constituents of foods of the Mediterranean diet [5][130][131]. Therefore, these constituents may be responsible for the observed beneficial effects of consuming the Mediterranean diet [5][130][131]. Indeed, later research demonstrated that polar lipid extracts of olive oil, olive pomace, and fish could also affect many of the PAF metabolic enzymes both in vitro and in vivo [132][133][134]. These extracts were able to aid in the re-equilibration of PAF levels with beneficial outcomes against models of chronic inflammation.
Research into the effect of lipids on PAF activity and PAF metabolism is still being explored today in the pursuit of finding natural ways to prevent the pro-inflammatory signaling of PAF. It is now known that many foods, beverages, and other natural sources including food industry by-products are rich in PAF antagonists [58][135]. However, there have been several critical discoveries in vivo that suggest that PAF inhibitors of natural origin may help prevent diseases such as CVD. In studies in vivo, olive oil, olive oil polar lipids extracts, and olive oil neutral lipids extracts were administered to rabbits consuming an atherogenic diet. It was demonstrated that rabbits consuming olive oil or olive oil polar lipid extracts had more beneficial physiological and biochemical changes as a result of increased plasma levels of PAF-AH, less oxidation in the plasma, a reduction of atherosclerotic lesion thickness, and retention of vessel wall elasticity, thus impeding atherosclerosis development [136]. These results were corroborated in a subsequent study that found that polar lipid extracts of olive oil and olive pomace can impede early atherosclerosis development through reducing platelet sensitivity to PAF and reducing atherosclerotic lesion thickness [137]. A later follow-up study in rabbits demonstrated that olive pomace polar lipid extracts were equipotent to simvastatin in preventing the progression of atherogenesis [138].
It was questioned whether other polar lipid extracts of natural origin could exhibit the same effects. Therefore, two studies of similar design demonstrated anti-atherogenic effects when rabbits consumed polar lipids extracted from fish (seabream, Sparus aurata) in a model of hypercholesterolaemia. These studies demonstrated that fish polar lipids could also reduce platelet aggregation, reduce atherosclerotic lesion size, and increase HDL levels in rabbits [139] along with modulating PAF metabolism leading to lower PAF levels and activity in rabbit blood [134]. Representative optic micrographs (×100) of the aortic wall of these rabbits are presented in Figure 2. These images demonstrate that rabbits consuming an atherogenic diet supplemented with fish polar lipids leads to a reduction of atherosclerotic lesion width (b) versus a control group that consumed only an atherogenic diet (a) [139].
/media/item_content/202112/61a82789875b5molecules-24-04414-g004.png
Figure 2. Representative optic micrographs ×100 of aortic wall cross-sections stained with hematoxylin and eosin obtained from the two rabbit experimental groups. Atherosclerotic lesions appear as foam cells between the arrows. Each tissue sample was approximately 5 µm thick. (a) Group A (atherogenic diet) and (b) group B (atherogenic diet enriched with seabream polar lipids). Reproduced with permission from Nasopoulou et al. [139].
However, after discovering that polar lipids could inhibit PAF in vitro and in vivo, the question remained whether these compounds of natural origin could affect human health? It is now known that there have been some promising nutritional trials that indicate that PAF antagonists in wine may affect platelet aggregation and metabolism postprandially in humans [43][140]. In people with metabolic syndrome, consumption of meals including wild plants of the Mediterranean diet rich in PAF inhibitors postprandially reduced PAF-induced platelet aggregation [141]. Other results from dietary intervention studies have shown that the administration of traditional Mediterranean diet meals [142][143] to either normal volunteers or individual’s with type II diabetes mellitus (who have a predisposition to CVD) resulted in the characteristic lower PAF activity in blood (measured as PAF-induced platelet aggregability), which correlates with inhibition of atherogenesis according to experiments [136].
Likewise, dietary supplements can reduce PAF-induced platelet aggregation and increase PAF catabolism in healthy humans [144]. These studies collectively indicate that consumption of PAF antagonists from foods and nutraceuticals may benefit the consumer by reducing the pro-inflammatory effects of PAF either through inhibition of PAF/PAF-R signaling or by influencing the metabolic enzymes of PAF.
Considering, the potential use of dietary polar lipids for the prevention of CVD, several recent studies have discovered PAF antagonists in various fish species and by-products of the fishing industry including salmon fillet and head, minced boarfish, and herring [145][146][147], and other foods such as sheep and goat meat [148], milk and fermented dairy products [149][150][151][152], and beer and brewing by-products [153][154]. Future research in this area aims to develop novel functional foods and nutraceuticals that incorporate these bioactive polar lipid extracts for the prevention of CVD and other inflammation-related diseases. For more extensive reviews of the anti-inflammatory and antithrombotic properties of various food polar lipids the authors suggest the following literature [155][58].

References

  1. Demopoulos, C.A. State of lipid research in greece. Euro. J. Lipid Sci. Technol. 2000, 102, 665–666.
  2. Demopoulos, C.A. Biological activity of lipids of pine pollen on platelet aggregation in correlation with the platelet activating factor. In Proceedings of the second international conference on platelet-activating factor and structurally related alkyl ether lipids, Gatlinburg, TN, USA, 26–29 October 1986.
  3. Prescott, S.M.; Zimmerman, G.A.; Stafforini, D.M.; McIntyre, T.M. Platelet-activating factor and related lipid mediators. Annu. Rev. Biochem. 2000, 69, 419–445.
  4. Maclennan, K.M.; Smith, P.F.; Darlington, C.L. Platelet-activating factor in the cns. Prog. Neurobiol. 1996, 50, 585–596.
  5. Tsoupras, A.; Lordan, R.; Zabetakis, I. Inflammation, not cholesterol, is a cause of chronic disease. Nutrients 2018, 10, 604.
  6. Suvarna, Y.; Maity, N.; Shivamurthy, M.C. Emerging trends in retrograde signaling. Mol. Neurobiol. 2016, 53, 2572–2578.
  7. Birkl, D.; Quiros, M.; García-Hernández, V.; Zhou, D.W.; Brazil, J.C.; Hilgarth, R.; Keeney, J.; Yulis, M.; Bruewer, M.; García, A.J.; et al. TNF-α promotes mucosal wound repair through enhanced platelet activating factor receptor signaling in the epithelium. Mucosal Immunol. 2019, 12, 909–918.
  8. Lordan, R.; Tsoupras, A.; Zabetakis, I. The potential role of dietary platelet-activating factor inhibitors in cancer prevention and treatment. Adv. Nutr. 2019, 10, 148–164.
  9. da Silva-Jr, I.; Chammas, R.; Lepique, A.; Jancar, S. Platelet-activating factor (PAF) receptor as a promising target for cancer cell repopulation after radiotherapy. Oncogenesis 2017, 6, e296.
  10. Demopoulos, C.A.; Karantonis, H.C.; Antonopoulou, S. Platelet-activating factor — a molecular link between atherosclerosis theories. Eur. J. Lipid Sci. Technol. 2003, 105, 705–716.
  11. Palur Ramakrishnan, A.V.K.; Varghese, T.P.; Vanapalli, S.; Nair, N.K.; Mingate, M.D. Platelet activating factor: A potential biomarker in acute coronary syndrome? Cardiovasc. Ther. 2017, 35, 64–70.
  12. Yost, C.C.; Weyrich, A.S.; Zimmerman, G.A. The platelet activating factor (PAF) signaling cascade in systemic inflammatory responses. Biochimie 2010, 92, 692–697.
  13. Tsoupras, A.B.; Chini, M.; Tsogas, N.; Fragopoulou, E.; Nomikos, T.; Lioni, A.; Mangafas, N.; Demopoulos, C.A.; Antonopoulou, S.; Lazanas, M.C. Anti-platelet-activating factor effects of highly active antiretroviral therapy (HAART): A new insight in the drug therapy of hiv infection? Aids Res. Hum. Retrovir. 2008, 24, 1079–1086.
  14. Antonopoulou, S.; Nomikos, T.; Karantonis, H.; Fragopoulou, E.; Demopoulos, C.A. PAF, a potent lipid mediator. In Bioactive phospholipids: Role in inflammation and atherosclerosis; Tselepis, A.D., Ed.; Transworld Research Network: Kerala, India, 2008; pp. 85–134.
  15. Kulikov, V.; Muzya, G. Ether lipids and platelet-activating factor: Evolution and cellular function. Biochem. Biokhimiia 1997, 62, 1103–1108.
  16. Barbaro, J.F.; Zvaifler, N.J. Antigen induced histamine release from platelets of rabbits producing homologous PGA antibody. Proc. Soc. Exp. Biol. Med. 1966, 122, 1245–1247.
  17. Siraganian, R.P.; Osler, A.G. Destruction of rabbit platelets in the allergic response of sensitized leukocytes: I. Demonstration of a fluid phase intermediate. J. Immunol. 1971, 106, 1244–1251.
  18. Benveniste, J.; Henson, P.M.; Cochrane, C.G. Leukocyte-dependent histamine release from rabbit platelets: The role of IGE, basophils, and a platelet-activating factor. J. Exp. Med. 1972, 136, 1356–1377.
  19. Benveniste, J. Platelet-activating factor, a new mediator of anaphylaxis and immune complex deposition from rabbit and human basophils. Nature 1974, 249, 581–582.
  20. Chap, H. Forty five years with membrane phospholipids, phospholipases and lipid mediators: A historical perspective. Biochimie 2016, 125, 234–249.
  21. Slotboom, A.J.; de Haas, G.H.; Bonsen, P.P.M.; Burbach-Westerhuis, G.J.; van Deenen, L.L.M. Hydrolysis of phosphoglycerides by purified lipase preparations i. Substrate-, positional- and stereo-specificity. Chem. Phys. Lipids 1970, 4, 15–29.
  22. Henson, P.M.; Pinckard, R.N. Basophil-derived platelet-activating factor (PAF) as an in vivo mediator of acute allergic reactions: Demonstration of specific desensitization of platelets to PAF during IGE-induced anaphylaxis in the rabbit. J. Immunol. 1977, 119, 2179–2184.
  23. Pinckard, R.N.; Farr, R.S.; Hanahan, D.J. Physicochemical and functional identity of rabbit platelet-activating factor (PAF) released in vivo during IGE anaphylaxis with PAF released in vitro from IGE sensitized basophils. J. Immunol. 1979, 123, 1847–1857.
  24. Chignard, M.; Le Couedic, J.; Tence, M.; Vargaftig, B.; Benveniste, J. The role of platelet-activating factor in platelet aggregation. Nature 1979, 279, 799–800.
  25. Benveniste, J.; Le Couedic, J.P.; Polonsky, J.; Tence, M. Structural analysis of purified platelet-activating factor by lipases. Nature 1977, 269, 170–171.
  26. De Haas, G.H.; Van Deenen, L.L.M. Structural identification of isomeric lysolecithins. Biochim. Biophys. Lipids Lipid Metab. 1965, 106, 315–325.
  27. Demopoulos, C.; Pinckard, R.; Hanahan, D.J. Platelet-activating factor. Evidence for 1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine as the active component (a new class of lipid chemical mediators). J. Biol. Chem. 1979, 254, 9355–9358.
  28. Blank, M.L.; Snyder, F.; Byers, L.W.; Brooks, B.; Muirhead, E.E. Antihypertensive activity of an alkyl ether analog of phosphatidylcholine. Biochem. Biophys. Res. Commun. 1979, 90, 1194–1200.
  29. Benveniste, J.; Tence, M.; Varenne, P.; Bidault, J.; Boullet, C.; Polonsky, J. Semi-synthese et structure proposde du facteur activant les plaquettes (PAF): Paf-acether, un alkyl ether analogue de la lysophosphatidylcholine. C R. Acad. Sci. Paris 1979, 289D, 1037–1040.
  30. Mcmanus, L.M.; Hanahan, D.; Demopoulos, C.; Pinckard, R. Pathobiology of the intravenous infusion of acetyl glyceryl ether phosphorylcholine (AGEPC), a synthetic platelet-activating factor (PAF), in the rabbit. J. Immunol. 1980, 124, 2919–2924.
  31. Halonen, M.; Palmer, J.D.; Lohman, I.C.; McManus, L.M.; Pinckard, R.N. Respiratory and circulatory alterations induced by acetyl glyceryl ether phosphorylcholine, a mediator of ige anaphylaxis in the rabbit. Am. Rev. Respir. Dis. 1980, 122, 915–924.
  32. Pinckard, R.N.; O’Rourke, R.A.; Crawford, M.H.; Grover, F.S.; McManus, L.M.; Ghidoni, J.J.; Storrs, S.B.; Olson, M.S. Complement localization and mediation of ischemic injury in baboon myocardium. J. Clin. Investig. 1980, 66, 1050–1056.
  33. Halonen, M.; Palmer, J.D.; Lohman, I.C.; McManus, L.M.; Pinckard, R.N. Differential effects of platelet depletion on the physiologic alterations of ige anaphylaxis and acetyl glyceryl ether phosphorylcholine infusion in the rabbit. Am. Rev. Resp. Dis. 1981, 124, 416–421.
  34. National Center for Biotechnology Information. Pubchem Database, Platelet-Activating Factor, cid = 108156. Available online: https://pubchem.ncbi.nlm.nih.gov/compound/Platelet-activating-factor (accessed on 17 October 2019).
  35. Hanahan, D.J.; Demopoulos, C.; Liehr, J.; Pinckard, R. Identification of platelet activating factor isolated from rabbit basophils as acetyl glyceryl ether phosphorylcholine. J. Biol. Chem. 1980, 255, 5514–5516.
  36. Polonsky, J.; Tencé, M.; Varenne, P.; Das, B.C.; Lunel, J.; Benveniste, J. Release of 1-O-alkylglyceryl 3-phosphorylcholine, O-deacetyl platelet-activating factor, from leukocytes: Chemical ionization mass spectrometry of phospholipids. Proc. Natl. Acad. Sci. USA 1980, 77, 7019–7023.
  37. Valone, F. Quantifying platelet-activating factor in biologic systems. J. Allergy Clin. Immunol. 1993, 91, 551–552.
  38. Chap, H.; Mauco, G.; Simon, M.F.; Benveniste, J.; Douste-Blazy, L. Biosynthetic labelling of platelet activating factor from radioactive acetate by stimulated platelets. Nature 1981, 289, 312–314.
  39. Ribbes, G.; Ninio, E.; Fontan, P.; Record, M.; Chap, H.; Benveniste, J.; Douste-Blazy, L. Evidence that biosynthesis of platelet-activating factor (PAF-acether) by human neutrophils occurs in an intracellular membrane. Febs Lett. 1985, 191, 195–199.
  40. Pincock, S. Jacques benveniste. Lancet 2004, 364, 1660.
  41. Watts, G. Jacques benveniste. BMJ 2004, 329, 1290.
  42. Cusack, N.J. Platelet-activating factor. Nature 1980, 285, 193.
  43. Argyrou, C.; Vlachogianni, I.; Stamatakis, G.; Demopoulos, C.A.; Antonopoulou, S.; Fragopoulou, E. Postprandial effects of wine consumption on platelet-activating factor metabolic enzymes. Prostaglandins Other Lipid Mediat. 2017, 130, 23–29.
  44. Marathe, G.K.; Johnson, C.; Billings, S.D.; Southall, M.D.; Pei, Y.; Spandau, D.; Murphy, R.C.; Zimmerman, G.A.; McIntyre, T.M.; Travers, J.B. Ultraviolet B radiation generates platelet-activating factor-like phospholipids underlying cutaneous damage. J. Biol. Chem. 2005, 280, 35448–35457.
  45. Zabetakis, I.; Lordan, R.; Tsoupras, A. The Impact of Nutrition and Statins on Cardiovascular Diseases, 1st ed.; Elsevier: London, UK, 2019; 348p.
  46. Platelet-Activating Factor as an Effector for Environmental Stressors. Available online: https://link.springer.com/chapter/10.1007/164_2019_218. (accessed on 17 October 2019).
  47. Proceeding of the PAF communications, 6th International Conference on Phospholipase A2 and Lipid Mediators, Tokyo, Japan, 10–12 February 2015; Available online: https://www.bioweb.ne.jp/mid_meeting/stg_info/id_16774/ (accessed on 2 December 2019).
  48. Woodard, D.S.; Ostrom, K.K.; McManus, L.M. Lipid inhibitors of platelet-activating factor (PAF) in normal human plasma. J. Lipid Mediat. Cell Signal. 1995, 12, 11–28.
  49. Macpherson, J.L.; Kemp, A.; Rogers, M.; Mallet, A.I.; Toia, R.F.; Spur, B.; Earl, J.W.; Chesterman, C.N.; Krilis, S.A. Occurrence of platelet-activating factor (PAF) and an endogenous inhibitor of platelet aggregation in diffuse cutaneous mastocytosis. Clin. Exp. Immunol. 1989, 77, 391–396.
  50. Antonopoulou, S.; Demopoulos, C.A.; Iatrou, C. Blood cardiolipin in haemodialysis patients. Its implication in the biological action of platelet-activating factor. Int. J. Biochem. Cell Biol. 1996, 28, 43–51.
  51. Tsoukatos, D.; Demopoulos, C.A.; Tselepis, A.D.; Moschidis, M.C.; Donos, A.; Evangelou, A.; Benveniste, J. Inhibition by cardiolipins of platelet-activating factor-induced rabbit platelet activation. Lipids 1993, 28, 1119–1124.
  52. Bussolino, F.; Benveniste, J. Pharmacological modulation of platelet-activating factor (paf) release from rabbit leucocytes. I. Role of camp. Immunology 1980, 40, 367–376.
  53. Lecrubier, C.; Conard, J.; Horellou, M.H.; Samama, M. Study of platelet aggregation induced by platelet activating factor (PAF) after administration of ticlopidine or aspirin. Agents Actions 1983, 13, 77–80.
  54. Levy, J.V. Calmodulin antagonist w-7 inhibits aggregation of human platelets induced by platelet activating factor. Proc. Soc. Exp. Biol. Med. 1983, 172, 393–395.
  55. Apitz-Castro, R.; Cabrera, S.; Cruz, M.R.; Ledezma, E.; Jain, M.K. Effects of garlic extract and of three pure components isolated from it on human platelet aggregation, arachidonate metabolism, release reaction and platelet ultrastructure. Thromb. Res. 1983, 32, 155–169.
  56. Isah, T. Rethinking ginkgo biloba l.: Medicinal uses and conservation. Pharm. Rev. 2015, 9, 140–148.
  57. Papakonstantinou, V.D.; Lagopati, N.; Tsilibary, E.C.; Demopoulos, C.A.; Philippopoulos, A.I. A review on platelet activating factor inhibitors: Could a new class of potent metal-based anti-inflammatory drugs induce anticancer properties? Bioinorg. Chem. Appl. 2017, 2017.
  58. Lordan, R.; Nasopoulou, C.; Tsoupras, A.; Zabetakis, I. The anti-inflammatory properties of food polar lipids. In Bioactive Molecules in Food; Mérillon, J.M., Ramawat, K.G., Eds.; Springer International Publishing: Cham, Switzerland, 2018; pp. 1–34.
  59. Sioriki, E.; Lordan, R.; Nahra, F.; van hecke, K.; Zabetakis, I.; Nolan, S.P. In vitro anti-atherogenic properties of n-heterocyclic carbene aurate(I) compounds. ChemMedChem 2018, 13.
  60. Honda, Z.-I.; Ishii, S.; Shimizu, T. Platelet-activating factor receptor. J. Biochem. 2002, 131, 773–779.
  61. Ishii, S.; Shimizu, T. Platelet-activating factor (PAF) receptor and genetically engineered paf receptor mutant mice. Prog. Lipid Res. 2000, 39, 41–82.
  62. Chao, W.; Olson, M.S. Platelet-activating factor: Receptors and signal transduction. Biochem. J. 1993, 292 Pt 3, 617–629.
  63. Hwang, S.B. Specific receptors of platelet-activating factor, receptor heterogeneity, and signal transduction mechanisms. J. Lipid Mediat. 1990, 2, 123–158.
  64. Terashita, Z.-I.; Tsushima, S.; Yoshioka, Y.; Nomura, H.; Inada, Y.; Nishikawa, K. Cv-3988 - a specific antagonist of platelet activating factor (PAF). Life Sci. 1983, 32, 1975–1982.
  65. Valone, F.H. Inhibition of binding of the platelet-activating factor agepc to platelets by the AGEPC analog rac-3-(n-n-octadecylcarbamoyloxy)-2-methoxypropyl 2-thiazolioethyl phosphate (CV-3988). Biochem. Biophys. Res. Commun. 1985, 126, 502–508.
  66. Terashita, Z.; Imura, Y.; Takatani, M.; Tsushima, S.; Nishikawa, K. CV-6209, a highly potent antagonist of platelet activating factor in vitro and in vivo. J. Pharm. Exp. 1987, 242, 263–268.
  67. D’Humières, S.; Russo-Marie, F.; Boris Vargaftig, B. PAF-acether-induced synthesis of prostacyclin by human endothelial cells. Eur. J. Pharm. 1986, 131, 13–19.
  68. Toyofuku, T.; Kubo, K.; Kobayashi, T.; Kusama, S. Effects of ONO-6240, a platelet-activating factor antagonist, on endotoxin shock in unanesthetized sheep. Prostaglandins 1986, 31, 271–281.
  69. Handley, D.A.; Tomesch, J.C.; Saunders, R.N. Inhibition of PAF-induced systemic responses in the rat, guinea pig, dog and primate by the receptor antagonist SRI 63–441. Thromb. Haemost. 1986, 55, 040–044.
  70. Saunders, R.N.; Handley, D.A. Platelet-activating factor antagonists. Annu. Rev. Pharm. Toxicol. 1987, 27, 237–255.
  71. Merlos, M.; Gómez, L.A.; Giral, M.; Vericat, M.L.; García-Rafanell, J.; Forn, J. Effects of paf-antagonists in mouse ear oedema induced by several inflammatory agents. Br. J. Pharm. 1991, 104, 990–994.
  72. Wissner, A.; Carroll, M.L.; Green, K.E.; Kerwar, S.S.; Pickett, W.C.; Schaub, R.E.; Torley, L.W.; Wrenn, S.; Kohler, C.A. Analogues of platelet activating factor. 6. Mono-and bis-aryl phosphate antagonists of platelet activating factor. J. Med. Chem. 1992, 35, 1650–1662.
  73. Kingsnorth, A.N.; Galloway, S.W.; Formela, L.J. Randomized, double-blind phase II trial of lexipafant, a platelet-activating factor antagonist, in human acute pancreatitis. Br. J. Surg. 1995, 82, 1414–1420.
  74. Kuitert, L.M.; Angus, R.M.; Barnes, N.C.; Barnes, P.J.; Bone, M.F.; Chung, K.F.; Fairfax, A.J.; Higenbotham, T.W.; O’Connor, B.J.; Piotrowska, B. Effect of a novel potent platelet-activating factor antagonist, modipafant, in clinical asthma. Am. J. Respir. Crit. Care Med. 1995, 151, 1331–1335.
  75. Komuro, Y.; Imanishi, N.; Uchida, M.; Morooka, S. Biological effect of orally active platelet-activating factor receptor antagonist SM-10661. Mol. Pharm. 1990, 38, 378–384.
  76. O’Hair, D.P.; Roza, A.M.; Komorowski, R.; Moore, G.; McManus, R.P.; Johnson, C.P.; Adams, M.B.; Pieper, G.M. Tulopafant, a paf receptor antagonist, increases capillary patency and prolongs survival in discordant cardiac xenotransplants. J. Lipid Mediat. 1993, 7, 79–84.
  77. Casals-Stenzel, J.; Heuer, H.O. Use of WEB 2086 and WEB 2170 as platelet-activating factor antagonists. In Methods Enzymol; Murphy, R.C., Fitzpatrick, F.A., Eds.; Academic Press: Cambridge, MA, USA, 1990; Volume 187, pp. 455–465.
  78. Kornecki, E.; Ehrlich, Y.; Lenox, R. Platelet-activating factor-induced aggregation of human platelets specifically inhibited by triazolobenzodiazepines. Science 1984, 226, 1454–1456.
  79. Hwang, S.B.; Lam, M.H.; Biftu, T.; Beattie, T.R.; Shen, T.Y. Trans-2,5-bis-(3,4,5-trimethoxyphenyl) tetrahydrofuran. An orally active specific and competitive receptor antagonist of platelet activating factor. J. Biol. Chem. 1985, 260, 15639–15645.
  80. Tsoupras, A.B.; Papakyriakou, A.; Demopoulos, C.A.; Philippopoulos, A.I. Synthesis, biochemical evaluation and molecular modeling studies of novel rhodium complexes with nanomolar activity against platelet activating factor. J. Inorg. Biochem. 2013, 120, 63–73.
  81. Arnout, J.; van Hecken, A.; De Lepeleire, I.; Miyamoto, Y.; Holmes, I.; De Schepper, P.; Vermylen, J. Effectiveness and tolerability of CV-3988, a selective paf antagonist, after intravenous administration to man. Br. J. Clin. Pharm. 1988, 25, 445–451.
  82. Hsieh, K.H. Effects of PAF antagonist, bn52021, on the PAF-, methacholine-, and allergen-induced bronchoconstriction in asthmatic children. Chest 1991, 99, 877–882.
  83. Gómez, F.P.; Rodriguez-Roisin, R. Platelet-activating factor antagonists. Biodrugs 2000, 14, 21–30.
  84. Taggart, D.P.; Browne, S.M.; Wade, D.T.; Halligan, P.W. Neuroprotection during cardiac surgery: A randomised trial of a platelet activating factor antagonist. Heart 2003, 89, 897–900.
  85. Taylor, R.; Fatovich, D.; Hitchcock, T.; Morrison, C.; Curtis, L. Platelet-activating factor antagonism and streptokinase-induced hypotension in clinical acute myocardial infarction. Clin. Sci. 2001, 100, 601–607.
  86. Suputtamongkol, Y.; Intaranongpai, S.; Smith, M.D.; Angus, B.; Chaowagul, W.; Permpikul, C.; Simpson, J.A.; Leelarasamee, A.; Curtis, L.; White, N.J. A double-blind placebo-controlled study of an infusion of lexipafant (platelet-activating factor receptor antagonist) in patients with severe sepsis. Antimicrob. Agents Chemother. 2000, 44, 693–696.
  87. Johnson, C.D.; Kingsnorth, A.N.; Imrie, C.W.; McMahon, M.J.; Neoptolemos, J.P.; McKay, C.; Toh, S.K.C.; Skaife, P.; Leeder, P.C.; Wilson, P.; et al. Double blind, randomised, placebo controlled study of a platelet activating factor antagonist, lexipafant, in the treatment and prevention of organ failure in predicted severe acute pancreatitis. Gut 2001, 48, 62–69.
  88. Kuitert, L.M.; Hui, K.P.; Uthayarkumar, S.; Burke, W.; Newland, A.C.; Uden, S.; Barnes, N.S. Effect of the platelet-activating factor antagonist UK-74,505 on the early and late response to allergen. Am. Rev. Respir. Dis. 1993, 147, 82–86.
  89. O’Connor, B.J.; SUden, S.; Carty, T.J.; Eskra, J.D.; Barnes, P.J.; Chung, K.J. Inhibitory effect of uk,74505, a potent and specific oral platelet activating factor (PAF) receptor antagonist, on airway and systemic responses to inhaled paf in humans. Am. J. Respir. Crit. Care Med. 1994, 150, 35–40.
  90. Evans, D.J.; Barnes, P.J.; Cluzel, M.; O’Connor, B.J. Effects of a potent platelet-activating factor antagonist, SR27417a, on allergen-induced asthmatic responses. Am. J. Respir. Crit. Care Med. 1997, 156, 11–16.
  91. Gomez, F.; Roca, J.; Barbera, J.; Chung, K.; Peinado, V.; Rodriguez-Roisin, R. Effect of a platelet-activating factor (PAF) antagonist, SR27417a, on paf-induced gas exchange abnormalities in mild asthma. Eur. Respir. J. 1998, 11, 835–839.
  92. Stack, W.A.; Jenkins‡, D.; Vivet§, P.; Hawkey*, C.J. Lack of effectiveness of the platelet-activating factor antagonist SR27417a in patients with active ulcerative colitis: A randomized controlled trial. Gastroenterology 1998, 115, 1340–1345.
  93. Freitag, A.; Watson, R.M.; Matsos, G.; Eastwood, C.; O’Byrne, P.M. Effect of a platelet activating factor antagonist, WEB 2086, on allergen induced asthmatic responses. Thorax 1993, 48, 594–598.
  94. Baltás, E.; Trach, V.; Dobozy, A.; Kemény, L. Platelet-activating factor antagonist WEB 2086 inhibits ultraviolet-B radiation-induced dermatitis in the human skin. Ski. Pharm. Physiol. 2003, 16, 259–262.
  95. Hilliquin, P.; Chermat-Izard, V.; Menkes, C.J. A double blind, placebo controlled study of a platelet activating factor antagonist in patients with rheumatoid arthritis. J. Rheumatol. 1998, 25, 1502–1507.
  96. Wittwer, T.; Grote, M.; Oppelt, P.; Franke, U.; Schaefers, H.-J.; Wahlers, T. Impact of PAF antagonist BN 52021 (ginkolide b) on post-ischemic graft function in clinical lung transplantation. J. Heart Lung Transplant. 2001, 20, 358–363.
  97. Elders, M.E.; Gerritsen, M.J.P.; Van De Kerkhof, P.C.M. The effect of topical application of the platelet-activating factor-antagonist, RO 24–0238, in psoriasis vulgaris—a clinical and immunohistochemical study. Clin. Exp. Derm. 1994, 19, 453–457.
  98. Poeze, M.; Froon, A.H.; Ramsay, G.; Buurman, W.A.; Greve, J.W. Decreased organ failure in patients with severe sirs and septic shock treated with the platelet-activating factor antagonist TCV-309: A prospective, multicenter, double-blind, randomized phase II trial. TCV-309 septic shock study group. Shock 2000, 14, 421–428.
  99. Johnson, M.; Kwatra, G.; Badyal, D.K.; Thomas, E.A. Levocetirizine and rupatadine in chronic idiopathic urticaria. Int. J. Derm. 2015, 54, 1199–1204.
  100. Mullol, J.; Bousquet, J.; Bachert, C.; Canonica, W.G.; Gimenez-Arnau, A.; Kowalski, M.L.; Marti-Guadano, E.; Maurer, M.; Picado, C.; Scadding, G.; et al. Rupatadine in allergic rhinitis and chronic urticaria. Allergy 2008, 63 (Suppl. 87), 5–28.
  101. Mullol, J.; Bousquet, J.; Bachert, C.; Canonica, G.W.; Giménez-Arnau, A.; Kowalski, M.L.; Simons, F.E.R.; Maurer, M.; Ryan, D.; Scadding, G. Update on rupatadine in the management of allergic disorders. Allergy 2015, 70, 1–24.
  102. Hozawa, S.; Haruta, Y.; Ishioka, S.; Yamakido, M. Effects of a PAF antagonist, Y-24180, on bronchial hyperresponsiveness in patients with asthma. Am. J. Respir. Crit. Care Med. 1995, 152, 1198–1202.
  103. Saint-Martin, F.; Dumur, J.P.; Pérez, I.; Izquierdo, I.; French Rupatadine-Rhinitis Study Group. A randomized, double-blind, parallel-group study, comparing the efficacy and safety of rupatadine (20 and 10 mg), a new PAF and H1 receptor-specific histamine antagonist, to loratadine 10 mg in the treatment of seasonal allergic rhinitis. J. Investig. Allergol. Clin. Immunol. 2004, 14, 34–40.
  104. Qian, C.; Hwang, S.B.; Libertine-Garahan, L.; Eckman, J.B.; Cai, X.; Scannell, R.T.; Yeh, C.G. Anti-inflammatory activities of LDP-392, a dual paf receptor antagonist and 5-lipoxygenase inhibitor. Pharm. Res. 2001, 44, 213–220.
  105. Sultan, S.; D’Souza, A.; Zabetakis, I.; Lordan, R.; Tsoupras, A.; Kavanagh, E.P.; Hynes, N. Chapter 6 - statins: Rationale, mode of action, and side effects. In The Impact of Nutrition and Statins on Cardiovascular Diseases; Zabetakis, I., Lordan, R., Tsoupras, A., Eds.; Academic Press: London, UK, 2019; pp. 171–200.
  106. Tsantila, N.; Tsoupras, A.B.; Fragopoulou, E.; Antonopoulou, S.; Iatrou, C.; Demopoulos, C.A. In vitro and in vivo effects of statins on platelet-activating factor and its metabolism. Angiology 2011, 62, 209–218.
  107. Chini, M.; Tsoupras, A.B.; Mangafas, N.; Tsogas, N.; Papakonstantinou, V.D.; Fragopoulou, E.; Antonopoulou, S.; Gargalianos, P.; Demopoulos, C.A.; Lazanas, M.C. Effects of haart on platelet-activating factor metabolism in naive HIV-infected patients I: Study of the tenofovir-df/emtricitabine/efavirenz haart regimen. Aids Res. Hum. Retrovir. 2012, 28, 766–775.
  108. Chini, M.; Tsoupras, A.B.; Mangafas, N.; Tsogas, N.; Papakonstantinou, V.D.; Fragopoulou, E.; Antonopoulou, S.; Gargalianos, P.; Demopoulos, C.A.; Lazanas, M.C. Effects of highly active antiretroviral therapy on platelet activating factor metabolism in naive HIV-infected patients: II) study of the abacavir/lamivudine/efavirenz haart regimen. Int. J. Immunopathol. Pharm. 2012, 25, 247–258.
  109. Hussaini, I.M.; Yi-Hua, Z.; Lysiak, J.J.; Shen, T.Y. Dithiolane analogs of lignans inhibit interferon-γ and lipopolysaccharide-induced nitric oxide production in macrophages. Acta Pharm. Sin. 2000, 21, 897–904.
  110. Fujita, M.; Seki, T.; Inada, H.; Shimizu, K.; Takahama, A.; Sano, T. Novel agents combining platelet activating factor (PAF) receptor antagonist with thromboxane synthase inhibitor (TXSI). Bioorg. Med. Chem. Lett. 2002, 12, 771–774.
  111. Hyland, I.K.; O’Toole, R.F.; Smith, J.A.; Bissember, A.C. Progress in the development of platelet-activating factor receptor (PAFR) antagonists and applications in the treatment of inflammatory diseases. Chem. Med. Chem. 2018, 13, 1873–1884.
  112. Braquet, P. Treatment and prevention of PAF-acether-induced sickness by a new series of highly specific inhibitors. Gb Pat. 1984, 8, 418–424.
  113. Touvay, C.; Etienne, A.; Braquet, P. Inhibition of antigen-induced lung anaphylaxis in the guinea-pig by BN 52021 a new specific PAF-acether receptor antagonist isolated from ginkgo biloba. Agents Actions 1986, 17, 371–372.
  114. Braquet, P.G.; Spinnewyn, B.; Braquet, M.; Bourgain, R.; Taylor, J.E.; Etienne, A.; Drieu, K. BN 52021 and related compounds: A new series of highly specific PAF-acether receptor antagonists isolated from Ginkgo biloba L. Blood Vessel 1985, 16, 558–572.
  115. Papakonstantinou, V.D. Ginkgo biloba and its anti-inflammatory value as a medical tool. Hellenic J. Atherosclerosis 2013, 4, 109–115.
  116. Braquet, P. Proofs of involvement of PAF-acether in various immune disorders using BN 52021 (ginkgolide b): A powerful PAF-acether antagonist isolated from Ginkgo biloba L. Adv. Prostaglandin. Thromboxane. Leukot. Res. 1986, 16, 179–198.
  117. Bourgain, R.H.; Maes, L.; Andries, R.; Braquet, P. Thrombus induction by endogenic PAF-acether and its inhibition by Ginkgo biloba extracts in the guinea pig. Prostaglandins 1986, 32, 142–144.
  118. Shen, T.Y.; Hwang, S.B.; Chang, M.N.; Doebber, T.W.; Lam, M.H.; Wu, M.S.; Wang, X.; Han, G.Q.; Li, R.Z. Characterization of a platelet-activating factor receptor antagonist isolated from haifenteng (piper futokadsura): Specific inhibition of in vitro and in vivo platelet-activating factor-induced effects. Proc. Nat. Acad. Sci. USA 1985, 82, 672–676.
  119. Koltai, M.; Braquet, P.G. Platelet-activating factor antagonists. Clin. Rev. Allergy 1994, 12, 361–380.
  120. Lee, I.S.; Jung, K.Y.; Oh, S.R.; Kim, D.S.; Kim, J.H.; Lee, J.J.; Lee, H.-K.; Lee, S.-H.; Kim, E.-H.; Cheong, C. Platelet-activating factor antagonistic activity and 13c NMR assignment of pregomisin and chamigrenal fromschisandra chinensis. Arch. Pharm. Res. 1997, 20, 633–636.
  121. Zeng, H.-W.; Jiang, Y.-Y.; Cai, D.-G.; Bian, J.; Long, K.; Chen, Z.-L. Piperbetol, methylpiperbetol, piperol a and piperol b: A new series of highly specific PAF receptor agonists from piper betle. Planta Med. 1997, 63, 296–298.
  122. Jantan, I.; Juriyati, J.; Warif, N.A. Inhibitory effects of xanthones on platelet activating factor receptor binding in vitro. J. Ethnopharmacol. 2001, 75, 287–290.
  123. Demopoulos, C.A.; Antonopoulou, S. A discovery trip to compounds with PAF-like activity. Adv. Exp. Med. Biol. 1996, 416, 59–63.
  124. Siafaka-Kapadai, A.; Demopoulos, C.A.; Andrikopoulos, N.K. Biological activity of lipids of pine pollen on platelet aggregation in correlation with the platelet activating factor. Biochem. Int. 1986, 12, 33–41.
  125. Koussissis, S.G.; Semidalas, C.E.; Antonopoulou, S.; Kapoulas, V.M.; Demopoulos, C.A.; Kalyvas, V. Paf antagonists in foods: Isolation and identification of paf antagonists in virgin olive oil. Rev. Française Des Corps Gras 1993, 40, 323–327.
  126. Koussissis, S.G.; Semidalas, C.E.; Hadzistavrou, E.C.; Kalyvas, V.G.; Antonopoulou, S.; Demopoulos, C.A. Paf antagonists in foods: Isolation and identification of PAF antagonists in honey and wax. Rev. Française Des Corps Gras 1994, 41, 127–132.
  127. Antonopoulou, S.; Semidalas, C.E.; Koussissis, S.; Demopoulos, C.A. Platelet-activating factor (PAF) antagonists in foods: A study of lipids with paf or anti-paf-like activity in cow’s milk and yogurt. J. Agric. Food Chem. 1996, 44, 3047–3051.
  128. Rementzis, J.; Antonopoulou, S.; Argyropoulos, D.; Demopoulos, C.A. Biologically active lipids from S. scombrus. In Platelet-Activating Factor and Related Lipid Mediators 2: Roles in Health and Disease; Nigam, S., Kunkel, G., Prescott, S.M., Eds.; Springer: Boston, MA, USA, 1996; pp. 68–72.
  129. Fragopoulou, E.; Nomikos, T.; Antonopoulou, S.; Mitsopoulou, C.A.; Demopoulos, C.A. Separation of biologically active lipids from red wine. J. Agric. Food Chem. 2000, 48, 1234–1238.
  130. Tierney, A.; Lordan, R.; Tsoupras, A.; Zabetakis, I. Chapter 8 - diet and cardiovascular disease: The Mediterranean diet. In The Impact of Nutrition and Statins on Cardiovascular Diseases; Zabetakis, I., Lordan, R., Tsoupras, A., Eds.; Academic Press: London, UK, 2019; pp. 267–288.
  131. Detopoulou, P.; Demopoulos, C.; Karantonis, H.; Antonopoulou, S. Mediterranean diet and its protective mechanisms against cardiovascular disease: An insight into platelet activating factor (PAF) and diet interplay. Ann. Nutr. Disord. 2015, 2, 1–10.
  132. Tsoupras, A.B.; Fragopoulou, E.; Nomikos, T.; Iatrou, C.; Antonopoulou, S.; Demopoulos, C.A. Characterization of the de novo biosynthetic enzyme of platelet activating factor, ddt-insensitive cholinephosphotransferase, of human mesangial cells. Mediat. Inflamm. 2007, 2007, 27683.
  133. Tsoupras, A.B.; Fragopoulou, E.; Iatrou, C.; Demopoulos, C.A. In vitro protective effects of olive pomace polar lipids towards platelet activating factor metabolism in human renal cells. Curr. Top. Nutraceutical Res. 2011, 9, 105.
  134. Nasopoulou, C.; Tsoupras, A.B.; Karantonis, H.C.; Demopoulos, C.A.; Zabetakis, I. Fish polar lipids retard atherosclerosis in rabbits by down-regulating PAF biosynthesis and up-regulating PAF catabolism. Lipids Health Dis. 2011, 10, 1–18.
  135. Karantonis, H.C.; Tsantila, N.; Stamatakis, G.; Samiotaki, M.; Panayotou, G.; Antonopoulou, S.; Demopoulos, C.A. Bioactive polar lipids in olive oil, pomace and waste byproducts. J. Food Biochem. 2008, 32, 443–459.
  136. Karantonis, H.C.; Antonopoulou, S.; Perrea, D.N.; Sokolis, D.P.; Theocharis, S.E.; Kavantzas, N.; Iliopoulos, D.G.; Demopoulos, C.A. In vivo antiatherogenic properties of olive oil and its constituent lipid classes in hyperlipidemic rabbits. Nutr. Metab. Cardiovasc. Dis. 2006, 16, 174–185.
  137. Tsantila, N.; Karantonis, H.C.; Perrea, D.N.; Theocharis, S.E.; Iliopoulos, D.G.; Antonopoulou, S.; Demopoulos, C.A. Antithrombotic and antiatherosclerotic properties of olive oil and olive pomace polar extracts in rabbits. Mediat. Inflamm. 2007, 2007.
  138. Tsantila, N.; Karantonis, H.C.; Perrea, D.N.; Theocharis, S.E.; Iliopoulos, D.G.; Iatrou, C.; Antonopoulou, S.; Demopoulos, C.A. Atherosclerosis regression study in rabbits upon olive pomace polar lipid extract administration. Nutr. Metab. Cardiovasc. Dis. 2010, 20, 740–747.
  139. Nasopoulou, C.; Karantonis, H.C.; Perrea, D.N.; Theocharis, S.E.; Iliopoulos, D.G.; Demopoulos, C.A.; Zabetakis, I. In vivo anti-atherogenic properties of cultured gilthead sea bream (Aparus aurata) polar lipid extracts in hypercholesterolaemic rabbits. Food Chem. 2010, 120, 831–836.
  140. Xanthopoulou, M.N.; Kalathara, K.; Melachroinou, S.; Arampatzi-Menenakou, K.; Antonopoulou, S.; Yannakoulia, M.; Fragopoulou, E. Wine consumption reduced postprandial platelet sensitivity against platelet activating factor in healthy men. Eur. J. Nutr. 2016, 56, 1485–1492.
  141. Fragopoulou, E.; Detopoulou, P.; Nomikos, T.; Pliakis, E.; Panagiotakos, D.B.; Antonopoulou, S. Mediterranean wild plants reduce postprandial platelet aggregation in patients with metabolic syndrome. Metabolism 2012, 61, 325–334.
  142. Antonopoulou, S.; Fragopoulou, E.; Karantonis, H.C.; Mitsou, E.; Sitara, M.; Rementzis, J.; Mourelatos, A.; Ginis, A.; Phenekos, C. Effect of traditional greek Mediterranean meals on platelet aggregation in normal subjects and in patients with type 2 diabetes mellitus. J. Med. Food 2006, 9, 356–362.
  143. Karantonis, H.C.; Fragopoulou, E.; Antonopoulou, S.; Rementzis, J.; Phenekos, C.; Demopoulos, C.A. Effect of fast-food Mediterranean-type diet on type 2 diabetics and healthy human subjects’ platelet aggregation. Diabetes Res. Clin. Pr. 2006, 72, 33–41.
  144. Gavriil, L.; Detopoulou, M.; Petsini, F.; Antonopoulou, S.; Fragopoulou, E. Consumption of plant extract supplement reduces platelet activating factor-induced platelet aggregation and increases platelet activating factor catabolism: A randomised, double-blind and placebo-controlled trial. Br. J. Nutr. 2019, 1–10.
  145. Tsoupras, A.; Lordan, R.; Demuru, M.; Shiels, K.; Saha, S.K.; Nasopoulou, C.; Zabetakis, I. Structural elucidation of irish organic farmed salmon (Salmo salar) polar lipids with antithrombotic activities. Mar. Drugs 2018, 16, 176.
  146. Tsoupras, A.; O’Keeffe, E.; Lordan, R.; Redfern, S.; Zabetakis, I. Bioprospecting for antithrombotic polar lipids from salmon, herring, and boarfish by-products. Foods 2019, 8, 416.
  147. Tsoupras, A.; Lordan, R.; Shiels, K.; Saha, S.K.; Nasopoulou, C.; Zabetakis, I. In vitro antithrombotic properties of salmon (Salmo salar) phospholipids in a novel food-grade extract. Mar. Drugs 2019, 17, 62.
  148. Poutzalis, S.; Lordan, R.; Nasopoulou, C.; Zabetakis, I. Phospholipids of goat and sheep origin: Structural and functional studies. Small Rumin. Res. 2018, 167, 39–47.
  149. Megalemou, K.; Sioriki, E.; Lordan, R.; Dermiki, M.; Nasopoulou, C.; Zabetakis, I. Evaluation of sensory and in vitro anti-thrombotic properties of traditional greek yogurts derived from different types of milk. Heliyon 2017, 3, e00227.
  150. Lordan, R.; Walsh, A.M.; Crispie, F.; Finnegan, L.; Demuru, M.; Tsoupras, A.; Cotter, P.D.; Zabetakis, I. Caprine milk fermentation enhances the antithrombotic properties of cheese polar lipids. J. Funct. Foods 2019, 61, 103507.
  151. Lordan, R.; Walsh, A.M.; Crispie, F.; Finnegan, L.; Cotter, P.D.; Zabetakis, I. The effect of ovine milk fermentation on the antithrombotic properties of polar lipids. J. Funct. Foods 2019, 54, 289–300.
  152. Lordan, R.; Zabetakis, I. Invited review: The anti-inflammatory properties of dairy lipids. J. Dairy Sci. 2017, 100, 4197–4212.
  153. Lordan, R.; O’Keeffe, E.; Dowling, D.; Mullally, M.; Heffernan, H.; Tsoupras, A.; Zabetakis, I. The in vitro antithrombotic properties of ale, lager, and stout beers. Food Biosci. 2019, 28, 83–88.
  154. Lordan, R.; O’Keeffe, E.; Tsoupras, A.; Zabetakis, I. Total, neutral, and polar lipids of brewing ingredients, by-products and beer: Evaluation of antithrombotic activities. Foods 2019, 8, 171.
  155. Lordan, R.; Tsoupras, A.; Zabetakis, I. Phospholipids of animal and marine origin: Structure, function, and anti-inflammatory properties. Molecules 2017, 22, 1964.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Medicine, Research & Experimental
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Ronan Lordan
View Times: 450
Revisions: 2 times (View History)
Update Date: 02 Dec 2021
Table of Contents
    1000/1000
    Hot Most Recent
    Video Production Service
    Feedback