Inflammation that causes endothelial dysfunction seems to be the key causative underlying mechanistic player, at the molecular and cellular level, for the onset and development of subsequent inflammation-related chronic disorders such as atherosclerosis and subsequent CVD, ischemic and renal disorders, cancer metastasis, diabetes, infections, and comorbidities [ 8 , 57 , 58 , 59 , 60 , 61 , 62 ]. For example, in cases of dyslipidaemia, increased cholesterol levels are not the causative agent or the underlying biochemical mechanism responsible for endothelial dysfunction and atherosclerosis development.
The accumulation of excess plasma LDL cholesterol is addressed by the innate immune system as an undesired event. Therefore, an inflammatory response at the endothelial wall is promoted to reduce the threat by the removal of excess LDL and oxidised-LDL Ox-LDL cholesterol from the blood stream to the subendothelium, where they are engulfed by comigrated monocytes for final removal [ 63 , 64 ].
During chronic inflammatory diseases, inflammation and infections can also induce a variety of alterations in lipid metabolism, including decreases in serum HDL cholesterol, increases in triglycerides, lipoprotein a , and LDL levels. These changes of the lipid levels may initially dampen inflammation or fight infection; however, the sustained inflammation can contribute to the increased risk of atherosclerosis [ 65 ].
In addition to affecting serum lipid levels, inflammation also adversely effects lipoprotein function; LDL is more easily oxidised, as the ability of HDL to prevent the oxidation of LDL is diminished, while several steps in the reverse cholesterol transport pathway are also adversely affected during inflammation.
The greater the severity of the underlying inflammatory disease, the more consistently these abnormalities in lipids and lipoproteins are observed [ 65 ]. Thus, it is not serum cholesterol and lipoproteins that influence the endothelium but the inflammatory response that affects the well integrity and functionality of the endothelium. Apart from the effects of inflammation on plasma lipids, it is now well established that more important soluble and cellular immune factors associated with chronic inflammation can promote inflammation-related endothelial dysfunction and atherogenesis, either during dyslipidaemia or independently of dyslipidaemia [ 66 ].
Even though atherosclerosis and CVD were previously viewed as lipid storage disorders, we now recognise that inflammation drives much of endothelial dysfunction and mechanisms of clinical complications with these diseases and related comorbidities, such as sepsis [ 67 , 68 ], human immunodeficiency virus HIV infection [ 69 , 70 , 71 , 72 , 73 , 74 ], periodontal diseases [ 75 , 76 , 77 ], kidney disorders [ 78 , 79 , 80 , 81 ], healthy ageing, and inflammatory autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, independently of traditional cardiovascular risk factors such as serum lipid levels [ 66 , 82 , 83 ].
The consequence of chronic inflammation is endothelial dysfunction that sets in, and we can define it as an integrated marker of the damage to arterial walls by classic risk factors. Endothelial dysfunction is usually characterised by an inflammation-related milieu acting on leukocytes and endothelial cells, through an interplay with other immune cells such as T lymphocytes, mast cells, dendritic cells DC , and platelets [ 57 , 58 , 66 , 84 , 85 ].
Other linked events include the increased generation of reactive oxygen species ROS , the increased oxidation of LDL cholesterol, and the reduction of protective nitric oxide levels. Therefore, the mechanistic pathways and key players implicated in the inflammatory crosstalk taking place throughout the onset, development, and progression of chronic diseases is of great importance, in order to unravel putative preventive and therapeutic targets with less side effects.
The inverse effects of the Med-diet with chronic diseases is mostly related to the pleiotropic effects and interplay of its food constituents on all these inflammation-related pathways; following a Mediterranean dietary pattern leads to the reduction of several inflammatory mediators and biomarkers related to the endothelial functionality, such as decreases in hsCRP, IL-6, and intracellular adhesion molecule-1 ICAM-1 [ 27 ]. PAF is a potent lipid inflammatory mediator with pleiotropic effects that are implicated in several chronic diseases [ 57 ].
The classic PAF molecule is characterised by an alkyl ether linkage at the sn -1 position, an acetyl group at the sn -2 position, and a phosphocholine group at the sn -3 position of glycerol backbone 1-O-alkyl sn -acetyl-glycerophosphocholine, [ 86 ] Figure 1 A. These three structural features are all equally important requisites for the optimal biological activity of PAF, mediated by its stereospecific binding to its specific receptor [ 87 , 88 ].
Because of the ether linkage at the sn -1 position, the classic molecule of PAF is an unusual lipid, as such moieties are not common in animals, nor is it common to find the acetic acid esterified directly to glycerol at the sn -2 position. Thus, it seems that PAF was chosen by evolution to participate in specific functions in several of our cells, tissues, organs, and throughout the body. PAF was the first intact phospholipid known to have messenger functions by binding to a specific receptor on the cell membrane, and not simply via physicochemical effects on the plasma membrane of the target cell [ 79 ].
A Typical structure of classic platelet-activating factor PAF molecule [ 86 ]. B Representative structures of bioactive polar lipids PL towards the PAF inflammatory pathways B , which have been identified in several foods of the Mediterranean diet [ 56 ]. The molecular composition of PAF varies depending on different species and cell types.
Related PAF-like lipids include, for example, the acyl-phosphatidylcholine-PAFs with a short chain acyl group at the sn -2 position , ethanolamine-PAFs, inositol-PAFs, oxidised alkyl-acyl phosphatidyl glycerophosphocholines [ 90 , 91 ], and hydroxyl-alkyl acyl phospholipids [ 76 , 77 ]. PAF, in general, play a vital role in various physiological processes such as mediation of normal inflammatory responses, regulation of blood circulation and pressure, regulation of coagulation responses, glycogen degradation, brain function, reproduction, foetal implantation, lung maturation, initiation of parturition, and exocrine gland functions [ 92 ].
However, PAF can be regarded as both a friend, since it is presumed to have evolved as part of a protective mechanism in the innate host defence system, but also as a foe, because of its involvement in uncontrolled inflammation-related pathological conditions [ 93 ].
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When present in excess, PAF has been implicated in the pathogenesis of several inflammation-related chronic disorders [ 57 ]; thus, its synthesis, distribution, and degradation are all strictly controlled, as would be predictable for such a potent molecule with a wide range of diverse actions.
Species identity, differentiated by heterogeneity in linkage, degree of unsaturation, and carbon chain length of the alkyl or acyl chains at the sn -1 and sn -2 position, partially dictates signalling specificity by eliciting various signal transduction pathways following PAF-R activation [ 94 , 95 ]. The PAF-R is constitutively present on platelets, leukocytes, and endothelial cells, and further expression may be induced by appropriate stimuli.
PAF-R is highly expressed by cells within the innate immune and cardiovascular systems [ 96 ], pointing to a role for PAF and PAF-like molecules as pleiotropic communicators in plasma [ 97 ]. Role of PAF, PAF-R, and its related pathways in the inflammatory cascades and in the pathogenesis of inflammation-related chronic disorders; increased PAF levels by pro-inflammatory stimuli and binding of PAF on its receptor, PAF-R, on the membranes of several cell types can lead to intracellular cascades and a PAF cycle-related amplification of the initial stimuli A and in numerous cell responses according to each cell type B , which can lead to endothelial dysfunction and the onset and progression of inflammation-related chronic diseases.
Under normal circumstances, homeostatic levels of PAF present in plasma and biological tissue seem to be regulated by a balance of its biosynthetic and catabolic enzymatic pathways [ 57 ]. PAF is synthesised throughout the body by the specific stimulation of various cell types such as platelets, macrophages, monocytes, eosinophils, basophils, and endothelial cells.
PAF is mostly produced in the blood, lungs, kidney, myocardium, brain, liver, skin, saliva, retina, uterus, and embryo [ 56 , 99 , ]. PAF levels result from enzymatic biosynthesis, non-enzymatic oxidative synthesis, and enzymatic catabolism, while bioactive microconstituents of the Med-diet beneficially affect these pathways. The remodelling enzymatic pathway of PAF biosynthesis involves remodelling of a membrane lipid constituent a long-chain fatty acyl residue in sn -2 is replaced with an acetyl residue , and it has been proposed that this pathway is periodically involved in the acute pro-inflammatory production of PAF under activation of several cells during inflammation [ ].
LPCAT2 is highly expressed in inflammatory cells, and, depending upon the inflammatory stimulus used to activate the cells, PAF is produced within seconds, minutes, or hours following stimulation. The de novo enzymatic pathway of PAF biosynthesis is similar but distinct to the biosynthesis of phosphatidylcholine, since a phosphocholine function is transferred to alkyl acetyl glycerol. This pathway has been initially reported as the pathway responsible for the constitutive production of PAF basal levels. Thus, the regulation of the biosynthetic pathways of PAF seems to be more complicated than was initially thought, while both PAF biosynthetic routes are correlated with well-established inflammatory and immunological biomarkers i.
Apart from its enzymatic biosynthetic pathways, PAF and PAF-like lipids can also be produced through non-enzymatic synthesis by oxidation of other lipids during oxidative stress [ , ]. Vice versa, PAF and PAF-like lipids can also stimulate the production of ROS and nitrogenous species such as reactive nitrogen species RNS during oxidative and nitrosative stress in inflammation-induced endothelial dysfunction and atherosclerosis [ 89 ]. These enzymes, PAF-AH, are produced largely by hepatocytes and macrophages, and are widely distributed in human plasma, blood cells, and a variety of tissues.
Intracellular PAF-AH type I exists in the cytoplasm of many probably all types of mammalian cells and tissues [ ]. It is thus suggested that PAF-AH II functions as an antioxidant phospholipase that plays a protective role also against oxidative stress [ , ]. Under normal conditions, plasma and tissue levels of PAF are tightly regulated by its metabolic pathways. Increased PAF levels at the site of inflammation can activate several cell types through its receptor.
This leads to the initiation of a broad spectrum of PAF effects depending on the cell type and tissue, which is achieved through the production and release of various downstream mediators, such as PAF itself and several other mediators of inflammation such as eicosanoids, cytokines i. The interconnected crosstalk between PAF, pro-inflammatory upstream mediators that induce PAF production, and PAF-induced downstream mediators seems to be interrelated during inflammatory manifestations and inflammation-related chronic diseases.
These pathways serve as one of the main junctions between many inflammatory cascades that ultimately lead to endothelium dysfunction and inflammation-related disorders such as atherosclerosis, CVD, renal disorders, cerebrovascular, central nervous system CNS disorders, metastatic angiogenesis during cancer, sepsis, and several other chronic disorders Figure 2 B [ 57 , 58 , 78 , 89 , ]. Cardiovascular diseases CVD are the leading cause of death worldwide. It is estimated that 49 million people are now living with the disease in the European Union alone [ ]. Atherosclerosis is a slow progressive disease in which lesions or plaques form in large and medium-sized arteries, consisting of necrotic cores, calcified regions, accumulated modified lipids, migrated smooth muscle cells SMC , foam cells, endothelial cells, and several leukocyte subtypes.
Monocytes, circulating blood precursors of tissue macrophages, and myeloid-derived DC influence plaque development following recruitment into the intima and differentiation to foam cells. In contrast to the previous notions concerning the passive accumulation of lipids in macrophages during the formation of foam cells, it is now clear that there are more complex inflammatory mechanisms acting on monocytes, macrophages, platelets, several other leucocyte subtypes, and endothelial cells that seem to promote atherosclerosis via pro-inflammatory foam cell formation [ 66 ].
Persistent and unresolved inflammation at the vascular wall gives rise to inappropriate platelet and leukocyte recruitment at the endothelium. The inflammatory interplay and crosstalk between these cells and endothelial cells, facilitated by several inflammatory mediators, initiates the cascades that induce chronic inflammatory manifestations at the vascular wall, which counteracts the homeostatic inflammatory response, leading to endothelial dysfunction and initiation of proatherogenic events that lead to atherogenesis and atherosclerosis [ ].
PAF is one of the main junctions between several inflammatory pathways cytokines, oxidative stress, eicosanoids, etc. Therefore, PAF is implicated in all stages of atherosclerosis, from the initiation of atherogenesis all the way through to plaque formation, development, instability, and rupture [ 58 , 89 , , ]. Thus, PAF can further propagate oxidative stress, through the oxidation of LDL and the reduction of NO bioavailability, but mostly by acting as a potent chemotactic factor for other human cells that exhibit its receptor on their membranes, such as monocytic and granulocytic leukocytes of the innate and adaptive immune system, endothelial cells, etc.
Following these activations, a number of mediators are released by these activated cells e. The PAF pathway downstream products can further contribute to the propagation of atherosclerosis. Molecules of the selectin family mediate interactions between platelets and leukocytes, with the endothelium allowing leukocytes and platelets to roll along the vascular endothelium wall.
Platelet binding of the endothelium seems to precede the appearance of leukocytes in plaques and induces bidirectional expression of adhesion molecules and the production of monocyte attracting chemokines, such as PAF that plays a central role in cytokine-induced monocyte adherence to endothelium [ 58 , 89 , , ].
Activated platelets that adhere to the inflamed endothelium may enhance leukocyte recruitment, activation, and transmigration, thereby enhancing the inflammatory processes underlying atherosclerosis [ ]. PAF and Leukotriene B4 LTB4 , derived by activated platelets, leukocytes or endothelium, but also thrombin through PAF and LTB4 pathways , can propagate the activation of platelets and the subsequent activation and adhesion of leucocytes through the interplay of chemokines and their receptors [ ].
An important aspect of this platelet-leucocyte interplay is the diversity of leukocytes recruited by vessel wall adherent platelets, such as the platelet-mediated recruitment of neutrophils, monocytes, DC, T-lymphocytes, B-lymphocytes, and NK-cells to endothelium [ ]. In addition, platelets regulate neutrophil activation through the generation of PAF as a chemoattractant pro-inflammatory lipid [ ]. Activated endothelial cells and platelets generate considerable amounts of PAF, which act cooperatively with other extracellular stimuli to induce full integrin activation and leukocyte arrest [ 58 , 89 , ].
However, whether PAF mostly originates from activated platelets, endothelial cells or leukocytes are not well defined yet [ ]. PAF, other vasoactive compounds, angiogenic compounds, and pro-inflammatory mediators, such as arachidonic acid metabolites, histamine, cytokines, chemokines, and proteolytic enzymes, can also be released by mast cells that accumulate in the human arterial intima and adventitia during atherosclerotic plaque progression, and thus aggravate atherogenesis [ 8 ].
Cytokines produced by mast cells may be activated by pro-inflammatory stimuli, including cytokines, hypercholesterolemia, and hyperglycaemia, and trigger the endothelial expression of adhesion molecules such as P-selectin, VCAM-1, and chemokines such as PAF that mediate the recruitment and adhesion of leukocytes [ 8 ]. Similar to other chemoattractants, PAF has been detected in circulation; however, this molecule is mostly cell membrane-associated and operates in a paracrine manner on the G-protein coupled receptors of neighbouring cells [ 58 , 89 , ].
Thus, PAF is also a main player in juxtacrine signalling and adhesion of leukocytes to other cells, and has also been shown to regulate firm neutrophil adhesion on the surface of immobilised spread platelets [ , ]. The level of platelet stimulation impacts directly on neutrophil adhesion to platelets monolayer, upon which neutrophil activity is spatially regulated by PAF generation [ 58 , 89 , ]. Platelets and activated neutrophils act jointly to induce expression of adhesion molecules, permeability changes, and limit the bioavailability of nitric oxide, altogether aggravating endothelial dysfunction and facilitating subsequent monocyte plaque recruitment [ ].
In the aortic lumen, endothelial cells have been activated by the aforementioned PAF-implicated downstream manifestations, leading to increased endothelium permeability and endothelial dysfunction. Subsequent abnormal recruitment, migration, and infiltration of monocytes then take place in the intima and subintima. Within the intima, monocytes secrete lipoprotein-binding proteoglycans, resulting in increased accumulation of modified LDL, which sustains inflammation.
In addition, once in the intima, differentiation factors such as the macrophage colony-stimulating factor M-CSF differentiate pro-inflammatory monocytes into inflammatory type macrophages that ingest modified lipoprotein to become foam cells [ 59 , ]. Emerging evidence suggests that the role of monocytes and macrophages in atherosclerosis is not simply that of a passive acceptor of lipids [ 66 ].
Apart from their phagocytic roles, macrophages can also instruct or be instructed by other immune cells by producing various immune effector molecules and by acting as antigen-presenting cells APC. Plaque-related macrophages can have many phenotypes and functions depending on the stage of the disease; several monocyte subtypes exist, and subsequently several pro-inflammatory and anti-inflammatory macrophage subtypes also exist, while macrophages can rapidly adapt their phenotype and consequently their function in response to changes of the microenvironment and intracellular signalling pathways [ ].
After appropriate activation, macrophages can exhibit a pro-inflammatory phenotype that can further activate endothelial cells, which in turn triggers further blood monocyte recruitment [ , ]. Thus, upon activation, the pro-inflammatory subtype of macrophages and foam cells produce inflammatory cytokines and chemokines that enhance inflammation and further regulate monocyte and T cell infiltration [ 59 , ].
Macrophages express a myriad of receptors including G-protein coupled receptors such as PAF-R, through which they scan their environment for activation or polarisation signals, e. Several autacoid molecules of the microenvironment, such as PAF and its receptor, play a significant role in the pro-inflammatory activation of macrophages by oxidative stress and in the uptake of Ox-LDL by macrophages [ ], since Ox-LDL contains inflammatory PAF-like oxidised phospholipids that mimic PAF and interact with these cells [ ].
In addition, autacoids such as PAF and PAF-like molecules in Ox-LDL also play a significant role in the cytoskeletal reorganisation of these cells during differentiations [ ], as macrophages engulf and retain large molecules such as Ox-LDL, oxidised phospholipids, and blood cells, which have also migrated into the intima and sub-intima.
The macrophages become lipid-loaded foam cells through phagocytosis, scavenger-receptor mediated uptake, and pinocytosis; the macrophages become lipid-loaded foam cells [ 58 ]. This process is outlined in Figure 4. A schematic of the key role of PAF in the onset, progression, and expansion of atherosclerotic plaques and their subsequent cardiovascular disorders.
Atherosclerotic events take place in four discrete stages IIa — IV as follows: I Under normal conditions, blood cells roll within the blood stream during physiological blood circulation. Leukocytes scavenge the endothelium by weak adhesion on it and after rolling, return to the blood stream. IIb Binding of PAF to its receptor on the membranes of these cells further induces the PAF cycle-related amplification of the initial inflammatory stimuli, which is achieved through the expression of inflammation-related genes and the subsequent production and release of various downstream mediators, such as PAF itself and several other mediators of inflammation including eicosanoids, cytokines, growth factors, further oxidative stress ROS, RNS, Ox-LDL, and Ox-PL , and selectins and integrins in the membranes of activated endothelial cells and leukocytes.
III If unresolved, the PAF cycle-related inflammatory activation of endothelial cells leads to tight adhesion of leukocytes on the activated endothelium and subsequent migration of these leukocytes and Ox-LDL to the subendothelium. There, the crosstalk of key-junction inflammatory mediators such as PAF within the developing plaque microenvironment, with a panel of inflammatory cells of both the innate and adaptive immune system, favours inflammatory phenotypes in these cells and perpetuates a continuous inflammatory milieu, leading to the differentiation of monocytes to macrophages, which engulf Ox-LDL and further transform to foam cells; thus, facilitating the onset, increase, and expansion of atherosclerotic plaque.
IV Although plaques can grow to a sufficiently large size to compromise blood flow, most of their clinical complications are attributable to arterial occlusion due to plaque erosion or rupture. Vulnerable plaques are typically large, with a necrotic core covered by a thin fibrous cap, and they contain high levels of inflammatory immune cells.
Gradually accumulating foam cells die in the intima due to inflammation-induced apoptosis, and when not promptly disposed of, become necrotic, progressively leading to the formation of a thrombogenic and pro-inflammatory necrotic core with cholesterol crystals. In addition, the thin layer of the fibrous cap easily ruptures due to PAF-related inflammatory and atherothrombotic stimuli. Thus, as the plaque continues to develop, it can become unstable and rupture, leading to major cardiovascular event.
Under atherosclerotic conditions, the role of DC is to take up atherosclerosis-specific antigens, which become locally activated, and migrate out of the plaque towards either local draining or distant lymph nodes, where they induce protective anti-inflammatory T cell activation and proliferation. However, apart from their role in directing different T and B cell subsets, not all their functions have been fully elucidated or understood. The above PAF effects on DC perpetuate local inflammation, decrease the activation of anti-inflammatory T-lymphocytes, and thus further increase plaque growth.
Lymphocytes, particularly T-lymphocytes, are also recruited to the vessel wall by mechanisms such as monocyte recruitment; thus, they are present in atherosclerotic lesions in parallel with macrophages, but in lower amounts. PAF and other platelet-related inflammatory mediators, such as thromboxane A 2 , serotonin, and histamine, also display Th1 cell-regulatory effects towards the Th1 response that promotes the progression of atherosclerosis and diverse effects on Th2 response [ ]. Activated platelets produce a significant amount of TxA 2 , which inhibits Th1 proliferation and cytokine production [ ], while they also express PAF-R, and PAF can enhance Th1 cytokine production [ , ].
PAF can also promote differentiation of Th17 cells that are present in atherosclerotic lesions, which can induce cytokine production by these cells. However, the role of Th17 also remains controversial, as both atherogenic, as well as atheroprotective, effects have been reported [ 59 ]. These events lead to an expansion of atherosclerotic plaque burden and perpetuation of the pathogenic T-cell response. Overall, there is intricate interplay and crosstalk between a panel of inflammatory cells of both the innate and adaptive immune system. When key-junction inflammatory mediators within the developing plaque microenvironment are increased, there is favour towards inflammatory phenotypes in these cells, which perpetuates a continuous inflammatory milieu, leading to further increase and expansion of the atherosclerotic plaque.
Subsequently, the intimal thickness increases, and blood flow is eventually impaired. Gradually accumulating foam cells die in the intima through inflammation induced apoptosis. When these cells are not promptly disposed of they become necrotic, progressively leading to the formation of a thrombogenic and pro-inflammatory necrotic core containing cholesterol crystals [ 58 ]. During plaque growth and expansion, SMC migrate from the media to the intima and proliferate, forming a fibrous cap from extracellular matrix deposition, where activated lymphocytes and calcium deposits are found.
Although plaques can grow to a sufficiently large size to compromise blood flow, most of their clinical complications are attributable to arterial occlusion due to plaque erosion or rupture. Vulnerable plaques are typically large with a necrotic core covered by a thin fibrous cap and contain high levels of inflammatory immune cells [ ]. The thin fibrous cap easily ruptures, as there are areas of the plaque where few SMC are present, and macrophages exist in abundance. This is because inflammatory cells cause the death of SMC, which are the main source of collagen that produce and maintain the fibrous cap.
As the plaque continues to develop it can become unstable and rupture, leading to a major cardiovascular event such as myocardial infarction, stroke, or congestive heart failure, depending on the location of the rupture. Plaque rupture occurs under inflammatory cascades and atherothrombosis through an interplay of platelet-leukocyte aggregates. Upon vessel injury i.
Such platelet secretory components include membrane ligands and several chemokines such as PAF that play a role in further recruitment of leukocytes, additional platelets, or other blood cells to the vessel wall [ ]. Platelet adhesion under conditions of high shear stress, which occurs in stenotic atherosclerotic arteries, is central to the development of arterial thrombosis.
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Therefore, precise control of platelet adhesion must occur to maintain blood fluidity and to prevent thrombotic complications [ ]. Outcomes from multiple animal model experiments and several clinical studies have also outlined the crucial role of PAF in atherosclerosis due to its elevated levels and its inflammatory interplay and crosstalk with several cells in the pathogenesis of cardiovascular disorders. PAF-R antagonists have been tested with promising results [ , , , , , , ], however the most prominent beneficial outcomes against atherosclerosis development and CVD were found when food-derived PAF inhibitors such as those present in the foods of the Med-diet.
These molecules beneficially inhibit PAF activities and modulate its metabolism towards homeostatic PAF levels [ , , , , , , ].
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Many of these components are present in olive oil, wine, fish, and dairy products Table 1. Interestingly, the administration of polar lipid extracts from fish or olive oil to hypercholesterolemic rabbits lead to the regression of atherosclerotic plaques [ , , , , ]. Thus, by targeting inflammation, the cause of these disorders through non-toxic approaches such as the Med-diet and by not targeting single risk factors such as hypercholesterolaemia seems to provide preventive and protective beneficial results against atherosclerosis and CVD. Studies on the beneficial impact of microconstituents from foods of the Mediterranean diet, such as polar lipids and vitamins, towards inflammation-related disorders, through their effects on the PAF pathways and metabolism.
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New blood vessel formation penetrating solid tumours seems to be required for their growth and metastasis. Production of PAF and overexpression of PAF-R are implicated in the tumour-endothelium interplay during cancer growth, invasion, and metastasis in several types of cancer [ 57 , , , , ]. It is not yet fully understood whether the initial levels of PAF in the tumour microenvironment originate from migrated inflammatory circulating cells as a response, or by activated endothelial cells in the vessels neighbouring tumours, or by the tumour cells themselves.
Therefore, LPCAT1 seems to contribute to tumour growth and metastasis in these types of cancer [ , ]. In addition cigarette smoking, a classic risk factor for several cancers, contributes to metastatic disease via production of PAF and PAF-like molecules in lung tumours [ ], while smoking related inhibition of breast cancer cell PAF-AH results in PAF accumulation and a subsequent increase in cell motility, tumour growth, and metastasis [ , ].
These cascades, in coordination with angiogenic cytokines and growth factors, enhance the initial signal and induce morphological alterations and cellular activities such as growth proliferation and motility, expression of adhesion molecules, extracellular matrix breakdown, migration, and endothelium reorder that leads to the formation of distinct neoplastic vessels in the tumour microenvironment [ 57 ]. All of the above result in the onset and development of tumour-induced angiogenesis and metastasis [ 57 ]. In addition, PAF and PAF-like molecules are in part transported by tumour-derived extracellular vesicles, which play an important role in intercellular communication through PAF-R expressed by a variety of microenvironmental cells and endothelial cells, favouring metastasis [ ].
Apart from its crucial role in cancer metastasis, which has been extensively reviewed [ 57 ], recent outcomes have demonstrated that PAF is also implicated in immunosuppression-related cancer induced by UV-irradiation, in which UV-induced production of PAF and PAF-like molecules and the expression of PAF-R activates systemic immune suppression and delays DNA repair [ 93 ]. On the other hand, PAF and its receptor have been beneficially associated with cell survival during radiotherapy or chemotherapy, by proliferative signals on the surviving cells that are induced by apoptotic cells.
These signals take place through mechanisms dependent on the activation of PAF-R related pathways of NF-kB, such as up-regulation of anti-apoptotic factors and decrease of the cytotoxic effect of chemotherapeutic agents, thereby contributing to cell survival [ ]. However, recent studies have demonstrated that during cancer therapies i. In several cancer types, PAF through the NF-kB pathway controls the expression of genes that take part in processes that lead to metastatic angiogenesis on one hand, while on the other hand it results in apoptosis of cancer cells, during the immune response and haematopoiesis during chemotherapies and radiotherapies [ 57 ].
It seems that PAF is a unique growth regulator with apparently diverse functions; PAF, like NF-kB, seems to promote distinct biological processes, and these dual actions of PAF may relate to the point of action in the cell cycle [ 57 ]. The timing, space, and quantity of its production play a significant role in the malignant or beneficial direction of its effects. Understanding how conditions and factors that control timing, location of activity, and the quantity of PAF levels and how these relate to the metabolic enzymes of PAF is of great importance.
PAF-R antagonists have exhibited promising results in vitro and in vivo as anti-angiogenic molecules in several cancer cells and tumours, but also by reducing persistent pain during cancers [ 57 , , , ]. In addition, the combination of chemotherapy and classic PAF-R antagonists seems to reduce the tumour volume and cause higher tumour regression when compared to each treatment alone [ , ]. Recently, synthetic glycosylated alkyl-phospholipids that act as PAF agonists and antagonists have exhibited promising antiproliferative outcomes and are now regarded as and can be new class of anti-tumour drugs [ ].
PAF has been characterised as one of the main inflammatory mediators implicated in renal pathophysiology [ ]. Production of PAF in the kidney can potentially be attributed to infiltrating inflammatory cells, but mostly to resident renal cells such as the mesangial cells of glomeruli [ 81 , ]. In the kidney, PAF-R mRNA is ubiquitously expressed, and a gradient of its expression levels seems to exist; it is higher in the renal cortex, lesser in the outer medulla, and much lesser in the inner medulla, while within the nephron, the glomerulus demonstrates the highest PAF-R expression [ 78 ].
PAF infusion affects renal hemodynamics and glomerular permeability, resulting in changes in filtration rate and proteinuria [ 78 ]. Apart from the physiological effects of PAF, its increased levels and overexpression of PAF-R in kidney are involved in the pathogenesis and progression of renal damage and acute renal failure [ 78 , , , ]. Thus, PAF is implicated in antibody- and complement-mediated glomerular injury, in antithymocyte antibody-induced glomerular damage and other experimental models of immune renal damage, and in patients with lupus nephritis and IgA nephropathy [ 78 ].
PAF participates in the development of kidney graft dysfunction, namely, transplant rejection chronic transplant nephropathy and immunosuppressive drug-mediated nephrotoxicity [ 78 ]. PAF is also implicated in drug-related renal damage of different causes, such as cyclosporin A, glycerol, gentamicin, and cisplatin [ 78 ]. However, the most important role of PAF in renal dysfunction is its implication in the onset and progression of glomerulosclerosis, a renal disorder that shares common features with atherosclerosis and can lead to organ failure.
It has been proposed that PAF might be one of the chemokines released by mesangial cells that mediate their communication with podocytes. All of these molecular events potentially culminate in the development of glomerulosclerosis and fibrosis, which are key feature of progressive renal disease, regardless of the primary cause [ 78 , , ]. In addition, PAF promotes inflammatory infiltration of the glomerulus, since it functions as a chemoattractant, and it increases adhesion of polymorphonuclear leukocytes and monocytes to mesangial cells through integrins [ 78 ].
PAF increases the expression of the LDL-receptor and scavenger receptors in mesangial cells, and thus causes an increased uptake of lipids and their accumulation in mesangial cells, leading to the formation of foam cells, which is an important stage of glomerulosclerosis and a key factor that participates in the initiation and progression of lipid-mediated renal injury [ 78 , ]. Several PAF-R antagonists have been used in several of the aforementioned renal disorders with promising results [ 78 , ].
As reducing dietary cholesterol levels may be ineffective, such outcomes have further supported the notion of using full-fat products such as dairy products and non-low-fat products, since the full-fat dairy products exhibit higher bioavailability of high-value nutrients such as bioactive polar lipids and vitamin D, which both possess strong anti-inflammatory and protective properties [ 3 ]. When present at normal concentrations, PAF is a modulator of many CNS processes, ranging from long-term potentiation to neuronal differentiation [ , ].
PAF accumulation in CNS diseases exacerbates the inflammatory response and pathological consequences, while application of PAF inhibitors or PAF-R antagonists significantly reduces inflammation, protects cells, and improves the recovery of neural functions by blocking the PAF pathway [ , , ]. Several PAF inhibitors of natural origin have also exhibited beneficial outcomes in CNS disorders, especially ginkgolides that are derived from Ginkgo biloba [ , ]. However, further studies are required to establish the mechanisms surrounding how a healthy diet can improve systemic inflammation associated with the PAF pathway and CNS disorders.
Anaphylaxis is defined as a severe, life-threatening, systemic or general, immediate reaction of hypersensitivity, with repeatable symptoms caused by a dose of stimulus that is well tolerated by healthy persons [ , ]. Recently, PAF and PAF-AH have been reported as clinically valuable biomarkers of anaphylaxis [ ], since PAF produced and released by mast cells, basophils, neutrophils, eosinophils, fibroblasts, platelets, endothelial cells, and even cardiac muscle cells plays an important role in anaphylaxis and several other allergic reactions, from allergic rhinitis to asthmatic complications [ 67 , , , , , , , ].
PAF increases the production of eicosanoids, ROS, cytokines, growth factors, platelet-derived growth factor PDGF , RANTES, and degranulation of eosinophils, while it also acts as a chemoattractant for these cells, and, via integrins, it increases their adhesion to vascular endothelium. Thus, exposure of mast cells to PAF leads to the induction of specific functions in these cells such as degranulation of their granules via neuropeptides and PAF-dependent release of histamine.
In fact, the greater the levels of PAF in mast cells microenvironment, the more enhanced the release of histamine. At the same time, PAF-activated myocardial mast cells locally release factors responsible for cardiac dysfunction and hypotension that occur in severe anaphylactic reactions [ , ]. Increased levels of PAF correlate with the severity of allergic systemic reactions. The protective role of PAF-AH in reducing PAF levels is usually highly diminished through allergic reactions [ , ], while administration of recombinant PAF-AH in animal models exhibited protective results and reduced mortality due to anaphylactic reactions [ ], implying that modulation of PAF metabolism towards homeostatic PAF levels can also provide beneficial outcomes in these disorders too.
In addition, specific PAF-R inhibitors have been used in several allergy-related disorders [ ], and even specific anti-allergic drugs were designed and are currently used according to their anti-PAF effects [ , ], while combination of PAF inhibitors with other therapies such as antihistamines provided better outcomes [ , , , ].
However, further studies are required to establish the potential of a healthy diet to improve systemic inflammation associated with the PAF pathway and allergic complications. Inflammatory and immune responses are central to protecting against most infectious agents. However, the pathogenesis and tissue damage after infection are not usually related to the direct action microorganisms and of their replication, but instead to altered immune and inflammatory responses triggered following contact with the pathogen.
Many diseases develop as an adverse consequence of an imbalanced inflammatory response; thus, chronic and unresolved infections are usually accompanied by chronic and unresolved inflammatory manifestations and comorbidities [ ]. PAF and PAF-like molecules are implicated in inflammatory manifestations occurring in several infections [ , ], such as HIV [ 69 , 70 , 71 , 72 , 73 , 74 , 85 ], leishmaniosis [ ], periodontitis [ 75 , 76 , 77 ], or even in sepsis [ 67 , ]. The most common coexistent diseases associated with chronic infections are CVD, CNS disorders, and tumour malignancies, which are usually promoted by increased levels of PAF and PAF-related continuous and unresolved inflammation [ 57 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 85 , ].
In addition, PAF seems to act in synergy with infectious agents to initiate and propagate the disease process, i. Several PAF inhibitors have been used in infectious diseases with promising results, mostly in relation to their deterioration of the PAF-related chronic inflammatory manifestations [ 67 , 71 , 74 , 85 , , , , , ].
However, in the case of severe sepsis, clinical trials using recombinant human PAF-AH or PAF-R antagonists failed to reduce the mortality of severe septic patients, although a substantial reduction in organ dysfunction was achieved [ ]. Drugs administrated in such infectious pathologies have also been thoroughly screened for potential dual actions against both the infectious agent and PAF activities and synthesis. Several antiretrovirals and their combinations in highly active antiretroviral therapy have been found to exhibit beneficial outcomes in HIV infected patients through their capabilities to inhibit PAF activities and to influence PAF metabolism towards reduction of PAF levels in vitro and in vivo, while similar outcomes have also been found for several antibiotics [ 68 , 69 , 71 , 73 ].
Nevertheless, inhibition of PAF activities and modulation of PAF metabolism towards homeostatic PAF levels seem to be useful therapeutic targets with which to interfere with inflammatory damage that follows an infection, and thus they may reduce the risk of several comorbidities in infectious disorders. Although there are several studies published on the importance of a healthy diet for infection prevention, further studies are required to establish the potential role of healthy eating to improve systemic inflammation associated with the PAF pathway and related complications during chronic infections.
Several PAF inhibitors have been used in these inflammation-related diseases with promising results [ , , , , , ].
These effects were mostly due to the deterioration of PAF-related chronic inflammatory manifestations present in these disorders. For example, the consumption of components of the Med-diet or a traditional Greek Mediterranean diet can reduce PAF-related inflammatory outcomes such as platelet activity in patients suffering from type II diabetes mellitus and metabolic syndrome, but also in healthy subjects. This has been attributed to the presence of PAF inhibitors among other possible effects, and these effects can occur over a short period of time [ , , ].
In addition, the use of probiotics has exhibited beneficial effects against necrotising enterocolitis [ ]; this is unsurprising, as fermented dairy products, which are also components of the Med-diet, are rich in PAF inhibitors and have also exhibited beneficial outcomes in several inflammation-related intestine dysfunctions [ 3 ].
Common junctions in the mechanistic crosstalk of inflammatory mediators, signalling pathways, and cellular interactions that occur during chronic and unresolved inflammatory manifestations seem to be promising therapeutic targets for the prevention and treatment of inflammation-related chronic diseases. Drug-based therapeutic interventions targeting inflammatory mediators such as cytokines i. However, such approaches can sometimes provide undesirable effects and may leave the individual immunocompromised and at a greater risk of infections, since disruption of the physiological balance seems to be a risky strategy [ , ], which is clearly behind the multifaceted effects of such mediators.
On the other hand, since PAF and its related inflammatory cascades belong to the most vital joint mechanistic pathways of inflammation-related chronic disorders, the exploration of possible therapeutic approaches targeting PAF and its related pathways may provide better outcomes. Notably, the uptake of such dietary polar lipids seems to beneficially affect the functionality of HDL lipoproteins, especially in atherosclerotic conditions.
These HDL-associated activities contribute to the maintenance of endothelial cell homeostasis, which protects the cardiovascular system [ ]. Plasma PAF-AH is also found in atherosclerotic lesions, since it comigrates there along with the lipoproteins i. Thus, during inflammatory cascades that cause increased PAF levels, this isoform of PAF-AH LpPLA 2 seems to be activated as a homeostatic mechanism to downregulate these events by downregulating the levels of PAF and oxidised phospholipids as a terminator signal [ ].
Because of that, but also because of the activities of the oxidised sub products of PAF-AH actions in LDL oxidised phospholipids, the use of plasma PAF-AH as an atherogenic biomarker and therapeutic target has been debated [ , ]. The focus has been placed on increasing HDL levels as one of the main goals of dietary interventions and drug administration for cardioprotection [ ].
This is in agreement with the beneficial in vitro and in vivo effects of several dietary polar lipids, especially on PAF metabolism and HDL biofunctionality [ 56 ]. Therefore, it is important to recognise that foods of the Med-diet such as fruit and vegetables are high in chemical constituents, many of which are regarded as powerful antioxidants, such as vitamins A, C, and E [ ]. Despite positive findings from in vitro studies, clinical trials have consistently failed to show a benefit for the use of antioxidants, as associations between plasma concentrations of antioxidant vitamins and protection against CVD have proved elusive, and large interventional trials have failed to conclusively show any benefit of their administration [ , , , ].
Despite this, the European prospective investigation into cancer and nutrition EPIC Norfolk study found that increased plasma concentrations of vitamin C were inversely associated with CVD-related mortality and all-cause mortality. However, a meta-analysis has shown that vitamin C supplementation did not reduce cardiovascular events; thus, the antioxidant effects of vitamin C were not responsible for the beneficial effects of increased consumption of fruit and vegetables [ ].
A large-scale, year study found that diets rich in vitamin C were associated with a lower incidence of stroke, but no coronary heart disease in the elderly [ ]. Considering these findings, it may be the case that vitamin C may not be the active agent that induced the effects witnessed in the Norfolk study, but although eating fruit and vegetables will increase plasma vitamin C levels, the effects observed may be through other fruit- and vegetable-derived nutrients [ ], or synergism between multiple nutrients that affect different mechanisms including inflammation through the mechanisms of the PAF pathways [ ].
The bioavailability of vitamins, phenolic compounds, and other antioxidants is often cited as the main reason that in vitro and ex vivo studies do not seem to agree [ ]. For instance, some antioxidants such as phenolic compounds are effectively screened out by the gut of rapidly metabolised and excreted [ ]. Plasma concentrations of phenolic compounds are typically in the nanomolar range—too low to have a direct impact on antioxidant capacity [ ]. Further research is required to elucidate the effects of certain biomolecules against ROS and inflammatory pathways.
Overall, the protective outcomes of the adoption of Med-diet towards chronic diseases seem to be associated with the pleiotropic beneficial effects of its bioactive microconstituents that are not only limited to increasing plasma-HDL levels, functionality, and providing better stability against oxidation, but mainly on their effects on the levels, activities, and metabolism of key-inflammatory mediators such as PAF [ 56 , 57 ].
However, more in vivo results are needed in several chronic disorders and their inflammation-related manifestations in order to further support these findings. In this review, we clarify the roles of risk factors, such as plasma cholesterol and the importance of causative agents for chronic diseases, namely chronic and unresolved inflammation and its manifestations.
Instead of cholesterol, targeting and treatment of inflammation will lead to lower side effects in chronic disorders. The overall outcomes and the extensive paradigms of the beneficial effects of the Mediterranean diet against the inflammatory milieu, without any reported side effects so far, have radically shifted attention away from the lipid-centric hypotheses and the subsequent trends for targeting cholesterol towards more effective approaches against inflammation, which is the causative factors of chronic diseases.
Therefore, the causative role of inflammation in the onset and progression of several chronic disorders is summarised with respect to the role of PAF and its related inflammatory cascades, which seem to serve as common junctions of the inflammatory milieu. The coexistence of several risk factors seems to upstream pro-inflammatory stimuli i.
Common junctions, such as PAF and its related inflammatory pathways, seem to be promising therapeutic targets for the prevention and treatment of the onset and progression of inflammation-related chronic diseases, particularly CVD. Implementation of healthy lifestyle choices based on appropriate dietary interventions and exercise have exhibited beneficial outcomes and health benefits, without noticeable side effects.
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Adoption of dietary patterns such as the Med-diet provides bioactive food microconstituents with pleiotropic beneficial effects that are not limited to decreasing co-absorption of cholesterol and increasing plasma HDL levels and functionality, but mainly by providing better stability against oxidation and inflammation. Therefore, microconstituents such as polar lipids and vitamins present in foods of the Med-diet beneficially affect the levels, activities, and metabolism of key inflammatory mediators implicated in chronic diseases, including the PAF pathway, towards reducing inflammation and acquiring homeostasis, which can lead to reduced risk of inflammation-related chronic disorders.
Nature has provided us with a wide range of dietary weapons, which, if appropriately combined in dietary patterns such as the Med-diet, can beneficially contribute to improving our quality of life, health, and life expectancy by equilibrating the inflammatory milieu to normal levels and thus preventively reducing the risk of inflammation-related chronic disorders. National Center for Biotechnology Information , U.
Journal List Nutrients v. Published online May Author information Article notes Copyright and License information Disclaimer. Received Apr 23; Accepted May 9. This article has been cited by other articles in PMC. Abstract Since the Seven Countries Study, dietary cholesterol and the levels of serum cholesterol in relation to the development of chronic diseases have been somewhat demonised. Keywords: cardiovascular disease, atherosclerosis, inflammation, platelet-activating factor, oxidised lipoproteins, cholesterol, chronic diseases.
Introduction 1. Biological Significance of Cholesterol—Circulating Blood Cholesterol Cholesterol, an unsaturated alcohol of the steroid family, is essential for the normal function of all animal cells. Cholesterol Levels: Demonising a Risk Factor but Not the Causative Mechanisms of Chronic Diseases Several modifiable and non-modifiable risk factors genetic, environmental, nutrition, and lifestyle, etc. Revisiting the Lipid Hypothesis: Outcomes of the Mediterranean Diet against Inflammation Previous epidemiological and observational studies, such as the SCS in which the lipid hypothesis was mostly based, have been re-evaluated.
Re-Discovering Chronic Inflammation as the Cause for Chronic Diseases Inflammation is a physiological reaction of the innate immune system that maintains a constant internal milieu while being exposed to continuously changing environmental pressures, irrespective of whether the initial causes originate from mechanical, physical, chemical, infectious, immunological, or reactive natural traumatic injury or metabolic dysfunction. PAF Structure and Physiological Roles PAF is a potent lipid inflammatory mediator with pleiotropic effects that are implicated in several chronic diseases [ 57 ].
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Open in a separate window. Figure 1. Figure 2. PAF Levels Result from Enzymatic Biosynthesis, Non-Enzymatic Oxidative Synthesis, and Enzymatic Catabolism Under normal circumstances, homeostatic levels of PAF present in plasma and biological tissue seem to be regulated by a balance of its biosynthetic and catabolic enzymatic pathways [ 57 ].
Figure 3. Figure 4. The Overgrowth and Instability of Plaques and Subsequent Acute Cardiovascular Events During plaque growth and expansion, SMC migrate from the media to the intima and proliferate, forming a fibrous cap from extracellular matrix deposition, where activated lymphocytes and calcium deposits are found.
Table 1 Studies on the beneficial impact of microconstituents from foods of the Mediterranean diet, such as polar lipids and vitamins, towards inflammation-related disorders, through their effects on the PAF pathways and metabolism. The Role of PAF in Allergies and Asthma Anaphylaxis is defined as a severe, life-threatening, systemic or general, immediate reaction of hypersensitivity, with repeatable symptoms caused by a dose of stimulus that is well tolerated by healthy persons [ , ].
Targeting the PAF Pathways and Metabolism — Beneficial Outcomes of the Mediterranean Diet Common junctions in the mechanistic crosstalk of inflammatory mediators, signalling pathways, and cellular interactions that occur during chronic and unresolved inflammatory manifestations seem to be promising therapeutic targets for the prevention and treatment of inflammation-related chronic diseases. Conclusions In this review, we clarify the roles of risk factors, such as plasma cholesterol and the importance of causative agents for chronic diseases, namely chronic and unresolved inflammation and its manifestations.
The studies thus far have been small, retrospective analyses, and they haven't taken into account other factors that could contribute to such fractures, including general ill health. But given what we know about the effects of bisphosphonates on bone remodeling, the findings seem plausible. In the short term, slowing bone resorption increases bone density. But in the long run, it may impair new bone formation and reduce the bone's ability to repair microscopic cracks from normal wear and tear. There's some evidence in animal studies that Fosamax can inhibit microdamage repair. Over time, such microdamage might accumulate and cause a fracture.
Also, while bone breakdown is suppressed, the mineralization process continues, potentially resulting in "hypermineralized" bone, which may be more brittle and less resilient to wear and tear. This is all largely speculative, as no studies have produced empirical evidence that such mechanisms actually lead to fractures. Merck, the manufacturer of Fosamax, says it will undertake further study of the drug's effects on bone. And the FDA and Merck will continue monitoring for adverse events. In the meantime, it's important not to overreact.
Fosamax has a proven capacity to prevent fractures — and the disability and death that can accompany them. By , according to the National Osteoporosis Foundation NOF , as many as 12 million Americans will have osteoporosis, and over 40 million will have osteopenia low bone mass. Most experts believe that when Fosamax is used appropriately, its benefits greatly outweigh the risks. Clinicians diagnose osteoporosis by measuring bone mineral density with a technique known as dual-energy x-ray absorptiometry DXA.
DXA results are used to calculate a statistical measure called a T-score. Experts recommend that a woman with osteoporosis defined by a T-score of —2. Women with osteopenia — a T-score between —1. The World Health Organization has developed the Fracture Risk Assessment Tool FRAX , an online calculator that estimates an individual's year risk of having a hip fracture or other major fracture available at www. Currently, there's no consensus on how long you should take a bisphosphonate medication.
Regular checkups and appropriate care can help most girls and women lead healthy, independent lives. Signs and symptoms of Turner syndrome may vary among girls and women with the disorder. For some girls, the presence of Turner syndrome may not be readily apparent, but in other girls, a number of physical features and poor growth are apparent early. Signs and symptoms can be subtle, developing slowly over time, or significant, such as heart defects.
Prenatal ultrasound of a baby with Turner syndrome may show:. The most common signs in almost all girls, teenagers and young women with Turner syndrome are short stature and ovarian insufficiency due to ovarian failure that may have occurred by birth or gradually during childhood, the teen years or young adulthood. Signs and symptoms of these include:.
Sometimes it's difficult to distinguish the signs and symptoms of Turner syndrome from other disorders. It's important to get a prompt, accurate diagnosis and appropriate care. See your doctor if you have concerns about physical or sexual development.
Most people are born with two sex chromosomes. Boys inherit the X chromosome from their mothers and the Y chromosome from their fathers. Girls inherit one X chromosome from each parent. In girls who have Turner syndrome, one copy of the X chromosome is missing, partially missing or altered. The missing or altered X chromosome of Turner syndrome causes errors during fetal development and other developmental problems after birth — for example, short stature, ovarian insufficiency and heart defects.
Physical characteristics and health complications that arise from the chromosomal error vary greatly. The loss or alteration of the X chromosome occurs randomly.