2.2.1. Wine and its by-products phenolic bioactives with antioxidant, anti-inflammatory and anti-thrombotic beneficial properties
Phenolic compounds are the most abundant bioactive components in wine [
1,
2,
3,
4,
32,
43,
44], and are primarily present in the seeds and skins of grapes, except for hydroxycinnamic acids which are found in lesser amounts in the flesh [
1,
22,
23,
36,
37,
42]. The high number of factors influencing phytochemical composition and content leads to a very wide range of phenolic content. In general, red grape varietals have more phenolic compounds than white grape varieties, and the red vinification process, which includes longer maceration durations, supports nearly total extraction. Vineyard interventions similarly may have a significant impact on grape phenolic compositions. Different phenolic compositions can also be observed among different wine varieties, The estimated overall polyphenolic composition in red wines ranges from 1531 and 3192 mg of gallic acid equivalents (GAE) per liter, with white wine having a phenolic composition between 210 and 402 GAE/L [
43], while the remaining wineries’ by-products like grape pomace contain also valuable amounts of phenolic compounds, the main classes of which are shown in
Table 1 (expressed in GAE/L) [
16,
22,
23,
33,
34,
35,
36,
37,
38,
39,
40,
41,
42].
Such phenolic compounds of both wine and grape pomace can be divided into two main groups, flavonoids, and non-flavonoids [
36,
42,
43,
44,
45]. The structures of the most characteristic classes and compounds of these two groups of phenolics are shown in
Figure 1. Flavonoids attribute to 85% of the phenolic constituents in red wine and are primarily present in the skins of grapes, as well as in wineries’ by-products (wine) and by-products (grape pomace) too, while they comprise mainly by flavan-3-ols, anthocyanins, and flavonols (
Figure 1). Flavan-3-ols include monomers like catechin, epicatechin, and polymers (polyphenols) like proanthocyanidins [
1,
2,
3,
4,
36,
37,
42,
43,
44]. Flavanols, catechins and epicatechins, are the most complicated subclass of flavonoids that contribute to the different sensory qualities and structure of wines, by interacting with proline-rich proteins in the mouth to produce an astringent sensation and bitter taste [
30]. In the non-flavonoids group of phenolic compounds, several phenolic acids (cinnamic/hydroxycinnamic acids and benzoic/hydroxybenzoic acids), phenolic aldehydes, volatile simple phenolics, stilbenes, tannins and coumarins are classified (
Figure 1) [
36,
37,
42,
43,
44,
45,
46].
Apart from their role on the organoleptic characteristics of wine, a plethora of studies have indicated that phenolic compounds are associated with the health benefits of moderate consumption of wine, as well as with the potential use of wineries’ by-products as a sustainable source of functional compounds, since such phenolic compounds have exhibited potent antioxidant, anti-inflammatory and antithrombotic properties, with the most bioactive ones being the flavonols, flavanols, and anthocyanins from the flavonoids and resveratrol from the non-flavonoids [
1,
2,
3,
4,
5,
6,
22,
23,
25,
30,
32,
33,
34,
35,
36,
37,
38,
39,
40,
41,
42,
43,
44,
45,
46,
47,
48,
49,
50,
51,
52,
53]. The health-promoting effects of wine and wineries by-products’ phenolic compounds was initially attributed on their strong antioxidant capacity [
1,
4,
20,
21,
32,
36,
37,
38,
39,
40,
41,
43,
51,
52,
53,
54,
55]. It has also been proposed that the greater the polyphenolic content, the greater the antioxidant activity [
1]. Phenolic bioactives like stilbenes, flavonoids and flavan-3-ols derivatives of wine, can cross cell membranes and effectively demonstrate their antioxidant potential through the reduction in reactive oxygen species (ROS) within cells [
54].
The antioxidant activity of wine flavonoids is linked to their ability to scavenge of free radicals, which reduces the vulnerability of low-density lipoprotein (LDL) to oxidation and prevents the manifestation of endothelial dysfunction and atherosclerosis as a result [
51,
53,
54,
55,
56]. Intake of moderate wine consumption with a meal can significantly enhance plasma total antioxidant capacity (TAC) and counteract oxidative lipid damage and the activation of NF-κB signaling [
55], suggesting that the antioxidant effects of moderate wine consumption, influenced by the presence of wine polyphenols. Additionally, red wine and its polyphenolic constituents, play an essential role in CVD prevention by means of its antioxidant, antithrombotic, anti-inflammatory and antiatherogenic properties [
1,
2,
3,
4,
30,
43,
48,
49,
50,
51].
This is not surprising since the important pathophysiological processes of our body, oxidative stress, inflammation and thrombosis are intertwined, and if any of them and/or all of these processes is/are unregulated, then it/they can contribute to the unregulation of the other ones, promoting thus a vicious cycle of a continuous induction of oxidative stress and thrombo-inflammatory manifestations, which can conclude to the onset and development of several chronic disorders, including atherosclerosis, CVD, insulin resistance, hypertension and cancer [
6,
7,
9,
24,
43,
56]. This process can be impeded through the incorporation of wine and wineries’ by-products bioactive phenolic compounds in the diet, which promote not only anti-oxidant but also a plethora of anti-inflammatory health benefits [
1,
2,
3,
4,
5,
6,
7,
14,
18,
19,
20,
25,
30,
42,
43,
44,
46,
48,
49,
50,
53,
56]. Even though wine and wineries’ by-products phenolics are not essential nutrients, they can contribute to health through several pleiotropic effects, and subsequently they also do not fit in the classic and rigorous pharmacological definitions, as they can be modified by organisms before they interact with targets, can have different targets depending on their concentration, and do not have a univocal pharmacological mechanism of action [
42,
43,
46]. Therefore, a reductionist approach or studying of one single mechanism of action should not be followed with respect to the benefits of wine and wineries’ by-products phenolics, because this can limit their classification as only being free radical scavengers and antioxidants, while they possess manifold mechanisms of actions, including anti-inflammatory actions [
43].
More specifically, the polyphenolic composition of wine and wineries’ by-products is of significance in terms of the associated anti-inflammatory and antioxidant actions that attribute to the greater antioxidant serum activity, increased resistance of LDL peroxidation and thus inhibition of LDL oxidation, stimulation of the level of high-density lipoprotein (HDL), the promotion of vasorelaxation, the inhibition of platelet aggregation and lowering of platelet sensitization and adhesiveness, as well as the inhibition of the activities and synthesis of inflammatory mediators like PAF and cytokines, as well as a plethora of anti-inflammatory effects on several inflammatory genes, mediators, receptors, adhesive molecules, signaling pathways and thrombo-inflammatory manifestations [
1,
2,
3,
4,
5,
6,
7,
14,
16,
18,
19,
20,
22,
23,
25,
30,
33,
38,
42,
43,
44,
46,
48,
49,
50,
53,
56,
58,
59,
60,
61]
Thus, the moderate consumption of wine is not only linked with an increase in antioxidant capacity, but it is also interlinked with anti-inflammatory beneficial effects and a reduction in pro-inflammatory markers [
1,
2,
4,
5,
6,
18,
19,
20,
25,
30,
43,
48,
49,
50,
56,
60,
61], which have been attributed to its phenolic compounds. Moreover, according to recent literature, the mode of action by which polyphenols exert their beneficial properties appears to involve the interplay between molecular signaling pathways and regulators of cellular actions involved in inflammation [
2,
4,
5,
6,
18,
30,
42,
43,
48,
49,
50,
59]. Both flavonoids and non flavonoids have exhibited such benefits, while differences on the effects of compounds from each group have also been reported [
2,
3,
30,
43]
The different interactions that wine flavonoids may have with key biological targets are linked to the unique structure of each and their structure activity relationships are crucial for the health protective properties of wine and grape pomace based products against several diseases such as CVD, cancer, obesity, neurodegenerative diseases, diabetes, allergies and osteoporosis [
4,
22,
23]. Moreover, several studies have clearly revealed the anti-inflammatory protective effects of flavonoids of wine on health, by lessening the risk of the development and onset of inflammation-related chronic disorders [
2,
4,
18,
30,
43,
44,
48,
49,
50,
59]. In addition, pleiotropic anti-inflammatory benefits on vascular health have also been observed in trials based on monomeric or polymeric flavonoids [
62]. Furthermore, consumption of polymeric flavonoids like procyanidins (polyphenols that are polymers of catechin and/or epicatechin units) within a diet is correlated to the reduced risk of developing type 2 diabetes (T2D) and CVD [
63].
Apart from flavan-3-ols and flavonols, anthocyanins are also one of the most important water-soluble flavonoid pigments in nature, with grapes being amongst the fruits with the highest concentration in anthocyanins [
22,
23,
42]. Subsequently, anthocyanins are found in red wine and especially in red wine’s grape pomace wastes, and in lesser amounts in white wines and their grape pomaces [
22,
23,
42]. Pharmacokinetics studies has shown indication that anthocyanins are rapidly absorbed into the bloodstream shortly after consumption, as well as their positive implication and essential role in the prevention of a variety of diseases, including cancer, neurodegenerative disorders and CVD through anti-inflammatory activities and improvement of the immune system [
4,
30,
42,
48,
49].
Among the non-flavonoids’ group of phenolic compounds in grapes, wine and grape pomace, a plethora of studies have highlighted the anti-oxidant and anti-inflammatory health benefits and preventative-therapeutic properties of resveratrol [
1,
2,
3,
5,
6,
7,
18,
42,
43,
44,
50,
64,
65,
66,
67]. The benefits of resveratrol have been documented since 90’s as the main bioactive component of wine (concentrations of 0.1–14.3 mg/L), when Drs. Michel de Lorgeril and Serge Renaud talked about the “French Paradox”, the observation of an unusually low rate of heart disease among Southern French people who drink a lot of red wine, despite a high saturated fat diet, and the theoretically inhibitory effects of wine consumption against lipid peroxidation, in the “60 Minutes” CBS show [
43,
64,
66]. At the time the “free radical/antioxidant hypothesis” was in full swing and it was commonplace to believe that eating and drinking (poly)phenols would scavenge free radicals and prevent their noxious effects, for example by inhibiting LDL oxidation [
43,
64].
This granted red wine (poly)phenols, namely resveratrol, immediate popularity not only as a possible explanation for the “French paradox,”, but also trigger the vast amount of well-funded research [
43,
64,
66]. From then, several studies have highlighted resveratrol as a pan-assay interference compound, hence linking to a wide variety of signaling pathways. Subsequently, resveratrol’s usage as a nutraceutical and a therapeutic agent for a variety of disorders has been extensively investigated in
in vitro,
ex vivo and
in vivo studies in animal models and humans, as well as in preclinical and clinical trials as a natural molecule. Accumulating evidence suggests that resveratrol is a highly pleiotropic molecule that modulates numerous targets and molecular functions [
65,
66,
67,
68,
69,
70,
71,
72,
73,
74]. Epidemiological studies indicate that the Mediterranean diet, rich in resveratrol, is associated with a reduced risk of atherosclerosis. Resveratrol is believed to decrease circulating low-density lipoprotein cholesterol levels, reduce cardiovascular disease risk; it reduces lipid peroxidation, platelet aggregation and oxidative stress [
65,
66,
67,
68,
69,
70,
71,
72,
73,
74].
For example, resveratrol’s ability to protect against inflammation and oxidative stress occurs via nuclear erythroid 2-related factor 2 (Nrf2) signaling pathway [
75]. Moreover, the cardio-protective anti-inflammatory effects of resveratrol have been demonstrated at nutritionally relevant concentrations, by decreasing the over expression of intercellular and vascular cell adhesion molecules, as it inhibits the induced by inflammatory cytokines activation of coronary arterial endothelial cells, such as the inhibition of tumor necrosis factor (TNF)-α-induced nuclear factor Kappa B (NF-Κb) activation of these cells and the subsequent expression of inflammatory genes [
68,
76,
77]. Thus, resveratrol supplementation may partially protect against CVD especially during the early atherosclerotic phase by its anti-inflammatory effects, as well as by reducing circulating levels of important chemotactic chemokines, such as the monocyte chemoattractant protein-1 (MCP-1/CCL2) and macrophage inflammatory protein-1 alpha (MIP-1α/CCL3), which regulate migration and infiltration of monocytes/macrophages and are induced and involved in various diseases [
68,
76].
Resveratrol has also improved the TNF-α-induced endothelial dysfunction during the interaction of Caco-2 cells and endothelium [
78]. Apart from the inhibitory effect of resveratrol on the actions of inflammatory cytokines, resveratrol is also associated with the reduction of the levels of pro-inflammatory cytokines, such as interleukin (IL)-1 and TNF-α, which are related to the pathologies of cancer and CVD [
79]. The anti-cancer potential of resveratrol was also demonstrated by the induced autophagic cell death and reduction in cell viability found in oral cancer cells but absent from normal cells [
80]. Several other very recent studies within 2023 have also indicated the anti-tumor effects of resveratrol and other wine phenolics, through their (pro-)apoptotic and immune-regulatory effects [
6,
50,
80,
81,
82,
83,
84,
85,
86,
87], while it has also previously been reported that resveratrol suppresses tumor metastasis by its effects on platelets and by inhibiting platelet-mediated angiogenic responses, and thus resveratrol is a potential therapeutic drug for the prevention of tumor metastasis by interrupting the platelet-tumor cell amplification loop [
87].
Resveratrol and other phenolics from wine and grape pomace exhibit a plethora of beneficial effects by affecting platelet functions [
12,
14,
16,
18,
22,
23,
30,
42,
43,
50,
65,
66,
67,
68,
69,
70,
71,
72,
73,
74,
87,
88,
89,
90,
91]. These effects can take place through several mechanisms, while similar mechanisms exist also in several other cells and tissues, in which resveratrol acts beneficially. For example, resveratrol, and wine and grape pomace phenolics in general have shown strong cardioprotective properties and anti-inflammatory protection against chronic disorders by strongly inhibiting platelet aggregation and the activation and sensitization of platelets induced by the activities and release of thrombotic and inflammatory mediators, such as PAF, thrombin, collagen, fibrinogen, arachidonic acid (AA), Thromboxane A2 (TxA2), TxB2, ADP and epinephrine, and thus by exhibiting potent anti-inflammatory and antithrombotic protection against inflammation and thrombosis related chronic disorders [
12,
14,
16,
18,
22,
23,
30,
42,
43,
50,
65,
66,
67,
68,
69,
70,
71,
72,
73,
74,
87,
88,
89,
90,
91].
For example, resveratrol-induced inhibition of platelet metabolism and TXA2 release may lead to a reduction of platelet function and thrombus formation in patients with type 2 diabetes, and thus resveratrol may be beneficial to prevent vascular complications as a future complementary treatment in aspirin-resistant diabetic patients [
88]. More specifically, resveratrol reduced collagen-induced thrombi by over 50%, in both the blood of healthy and diabetic patients, TXA2 release by 38% in healthy platelets and by 79% in diabetic platelets. Resveratrol also reduced the activities of enzymes responsible for glycolysis and oxidative metabolism in the platelets of both groups [
88]. Such effects of resveratrol on platelets appear to be mediated through cyclooxygenase-1 (COX-1) repression, which results in decreased TxA2 production and thus inhibition of platelet aggregation, rather than through cyclooxygenase-2 (COX-2) that synthesizes prostacyclins as antiplatelet factors in vascular endothelium [
69]. Resveratrol can reduce platelet aggregation by forming stable complexes in platelet COX-1 channels, as well as by inhibiting the arachidonate-dependent synthesis of inflammatory agents, such as TXB2, hydroxyheptadecatrienoate, and 12-hydroxyeicosatetraenoate [
69,
89].
Moreover, resveratrol inhibits thrombin-induced platelet aggregation through decreasing Ca2+ release from its stores and inhibiting store-operated Ca2+ influx into platelets [
91], while it has also been proposed that resveratrol may inhibit platelet aggregation induced by epinephrine and other mediators by increasing NO production [
70]. In addition the antiplatelet effect of resveratrol, and subsequently its antithrombotic and anti-inflammatory benefits, both
in vitro and
in vivo, has also been attributed to its potential to modulate gene/protein expression of tissue factor (TF) and its functions, since TF that can be produced by several cells and especially under inflammatory cytokines induction, is a well-known thromboplastin, which activates thrombosis through binding to and further stimulation of coagulation factor VII as a principle initiator of extrinsic coagulation cascade [
69].
Furthermore, recent studies have outlined that resveratrol can target and activate AMP-activated protein kinase (AMPK), having an important role in reducing fat accumulation, cholesterol synthesis, and inflammatory cytokines, while it can also activate-stimulate at an amplitude of ~10-fold the mammalian versions of the sirtuin family of proteins, SIRT1, and subsequently all the pathways regulated by SIRT1, which deacetylates histones and non-histone proteins, such as transcription factors, and thus affects important processes like metabolism, stress resistance, cell survival, cellular senescence, inflammation-immune function, endothelial functions, and circadian rhythms [
66,
67,
68]. Stimulation of SIRT1 and AMPK boosts the eNOS activity in human coronary arterial endothelial cells and increases NO production and mitochondrial biogenesis, which triggers vasodilation and decreases atherosclerosis [
68], while the activation of SIRT1 by resveratrol seems to protect against disorders such as improper metabolic regulation, inflammation, and cell cycle abnormalities [
66].
Interestingly, resveratrol-induced activation of SIRT1 downregulates the expression of the receptor of PAF (PAFR) on platelets via proteosomal and lysosomal pathways, and that this downregulation inhibits platelet aggregation in vitro and pulmonary thrombus formation in vivo [
88]. It has also been proposed that resveratrol might improve cardiovascular health by affecting the gene expression for producing PAFs [
69].
In addition, resveratrol has also been found to reduce the levels of PAF by inhibiting its synthesis and thus reducing the inflammatory status [
5,
6,
7,
92]. For example, resveratrol has inhibited PAF-synthesis in human mesangial cells [
5], as well as in U-937 macrophages under inflammatory conditions [
92], suggesting a potential antitumor effect of resveratrol [
6], as well as protective effects against several PAF-associated inflammatory and thrombotic chronic diseases [
7].
Resveratrol content in wines varies from 0.43 to 62.65 µM, and depends on several factors such as grape variety, climate and winemaking process. Resveratrol is highly absorbed in the intestine, presents low bioavailability and is rapidly excreted, while consumption of pure resveratrol at doses higher than those present in wines results in a low content of this compound in plasma. These findings may challenge the common idea that resveratrol is the main phenolic compound associated with cardioprotective effect. Consequently, other stilbenes and other phenolic compounds present in wines such as flavonoids, have also been proposed to act beneficially [
70]. Astringin is another stilbene for which early reports have shown promising results, citing anti-oxidant activity and a free radical scavenging ability more potent than resveratrol, while other natural and synthetic analogues/derivatives of resveratrol have also been extensively studied for enhanced beneficial effects against inflammation, thrombosis and associated disorders [
66,
67,
68,
69,
71,
72,
93,
94,
95].
The majority of the reviewed phytochemicals in wine and grape pomace require relatively high doses to be active on several cells and tissues
in vitro and these doses may further increase when plasma is present, for instance in case of resveratrol. As Professor Visioli et al (2020) have highlighted, animal studies often employ very high doses of grape/wine (poly)phenols, such as resveratrol, with results that cannot be readily transferred to humans, who would need to ingest several grams of extracts to replicate the same effects, while discrepancies between animal and human effects and potential toxicity of high doses of resveratrol have also been recently reviewed [
43]. Therefore, the current high dosing is one of the drawbacks for the testing of such compounds for possible therapeutical intervention [
4,
43,
74].
Several phenolic compounds are very weak (if at all effective)
in vivo direct antioxidants, while for kinetic reasons they do not scavenge free radicals and their bioavailability is generally so low that they contribute very little to the integrated cellular antioxidant machinery, which is mostly composed of enzymes [
43]. Thus, other limitations are the often unclear bioavailability and metabolic absorption of the phytochemicals and of their metabolites, the pharmacokinetic profile in blood and non-platelet effects, which for the cardiovascular system may be positive or negative [
4,
43,
74]. There is still a gap between the knowledge of wine flavonoids bioavailability and their health-promoting effects The beneficial effects of dietary phenolic compounds are affected by their low intestinal absorption as well as their differential bioavailability and interactions with plasma and gut microbiota that generates broad shifts in the plasma metabolome and gut microbiota composition [
4,
26,
43,
74,
96,
97,
98,
99,
100,
101]. It is estimated that the small intestine only absorbs 5-10% of consumed dietary polyphenols following enzymatic glycosylation. The remaining dietary polyphenols enter the colon intact and undergo degradation by the gut microbiota yielding simple phenolic acids that are absorbed into the bloodstream [
96]. Thus, it is apparent that the gut microbiota facilitates the bioaccumulation of polyphenols and their associated metabolites
Hence, the molecular forms of phenolic compounds that contribute to health benefits are not limited to those ingested but also include their associated metabolites created in vivo by the intestinal microbiota. Lately, plenty of researchers correctly use (poly)phenols’ metabolites in their in vitro studies, focusing on low-molecular weight (LMW) polyphenol-related components consisting of free anthocyanins, free proanthocyanins, pyranoanthocyanins as well as smaller amounts of phenolic acids and resveratrol. The hurdle here is the difficulty of synthesizing such metabolites, which are often produced by the organism in different forms, while the relatively recent discovery of microbiota-synthesized metabolites amplifies the list of potential biologically-active molecules produced by the body after the ingestion of (poly)phenol-rich foods [
43]. Therefore, more
in vivo results as well as studies focused on phenolic metabolites are still required. Moreover, it is also necessary to better understand how biological interactions (with microbiota and cells, enzymes or general biological systems) could interfere with phenolics’ bioavailability. Nevertheless, the moderate consumption of red wine is positively correlated with the beneficial modulation of gut microbiota [
100]. The ability of red wine consumption to balance the growth of select gut microbiota in humans indicates the potential probiotic benefits linked to the incorporation of red wine polyphenols into the diet. For example, resveratrol plays a significant role in the regulation of the gut microbiome, protection of the intestinal barrier and in the inhibition of intestinal inflammation [
96,
97,
98,
99,
100,
101].
In addition, the acquired knowledge on effects of certain phytochemicals, as platelet-inhibiting and anti-inflammatory compounds, can be employed for the further selection and chemical modification of these in the design of effective antiplatelet and anti-inflammatory drugs. In other words, those phytochemical compounds with a proven effect on platelets, thrombus formation and inflammation can trigger new ways for drug discovery. This could develop into new antiplatelet and anti-inflammatory drugs, and also to potentiate the action of current antiplatelet drugs, as several of the phytochemicals seem to have priming effects on platelets. Interestingly, combinations of wine and grape pomace phytochemicals with other bioactives present can have synergistic effects on platelets and inflammatory signaling, which will further enhance the priming.
2.2.2. Bioactive lipid compounds of wine and wineries’ by-products
Apart from the plentiful phenolics, several other bioactive compounds have also been identified in wine and wineries’ by-products, such as their bio-functional lipid bioactives. The lipids present in grapes/yeast undergo chemical modification throughout the fermentation process with the most bioactive lipids being derived at the final wine product. Even though wine contains lower amounts of lipids compared to grapes and the remaining grape pomace, still for the last 20 years Prof. C.A. Demopoulos and colleagues (Prof. Antonopoulou SA, Dr. Fragopoulou E, Dr. Nomikos T, Dr. Tsoupras A, et al) have highlighted that the wine amphiphilic polar lipids, such as several phospholipids and especially glycolipids (
Figure 2), originating from the grapes, yeasts and wine must, as well as due to the fermentation process, are highly bioactive and have exhibited strong anti-inflammatory, antithrombotic and anti-atherogenic cardioprotection [
7,
8,
9,
10,
11,
12,
13,
14,
18,
19,
20]. Grape pomace has also been found to contain similar bioactive polar lipids along with its rich content on phenolics. Such bioactive polar lipids usually contain bio-functional unsaturated fatty acids (UFA) within their structures in a combination that usually favors an anti-inflammatory potential [
7,
8,
9,
10,
11,
16,
17,
22].
Such UFA are usually the monounsaturated fatty acid (MUFA) oleic acid (OA; 18:1 omega-9) and the long-chain polyunsaturated fatty acids (PUFA), linoleic acid (LA: 18:2-omega-6), gamma linoleic acid (GLA; 18:3 omega-6) and alpha linolenic acid (ALA; 18:3 omega-3) [
16] (
Figure 2A). UFA have shown on their own strong anti-inflammatory and antithrombotic properties against several inflammatory and thrombotic mediators, including PAF, promoting an anti-inflammatory potential and health benefits against several inflammation-related disorders [
7,
102,
103,
104,
105,
106,
107]. UFA control cell fluidity, the attachment of certain enzymes to cell membranes, and the transmission of signals and other metabolic activities. They are involved in the manufacture of eicosanoids, leukotrienes, prostaglandins, and resolvins, which have anti-inflammatory, anti-arrhythmic, and anti-aggregatory properties [
102]. Several of them promote cardiovascular health, and others increase visual function and cognition in newborns and adults [
102].
Similarly, grape seed oils are high value by-products for the extraction of bioactives from grape pomace [
108]. The seeds consist of up to 20% oil, which is rich in UFA [
109]. Inversely, the grape seed oil has a low polyphenol content, which can be traced to the hydrophilic nature of these compounds [
110]. The most abundant fatty acid in grape seed oil is LA, but the nutritional role of this omega-6 UFA has grown progressively complex throughout years of study, with important functions in regulating inflammatory cellular processes. In contrast, the omega-3 fatty acids, such as ALA, perform opposing effects with well known cardioprotective effects and anti-inflammatory characteristics, reducing thromboxane synthesis and PAF, and demonstrating immense potential in inhibition of pro-inflammatory cytokine synthesis [
7,
102,
106,
107]. Thus, despite the suggestions of the possible health benefits of LA, the anti-inflammatory effect of grape seed oil with regards to its high UFA and LA content remains to be seen [
111].
Nevertheless, more research has recently been contacted on the polar lipid bioactives of wine and grape pomace [
7,
8,
9,
10,
11,
12,
13,
14,
15,
16,
17,
18,
19,
20,
21,
22]. Polar lipids are amphiphilic biomolecules and important structural elements for all cells in nature, with a plethora of diverse bioactivities. Polar lipids generally contain two fatty acids usually esterified or rarely etherified to a glycerol- or a sphingosine-based backbone, and a phosphorus functional group for phospholipids or a sugar for glycolipids that is linked to a head group (
Figure 2B). Bioactive polar lipids with UFA in their structures (usually at the
sn2 position of their glycerol/sphingosine backbone), such as polar lipids with OA and/or ALA (
Figure 2B), possess higher bioavailability of their UFA throughout the body, due to their amphiphilic properties, while most importantly polar lipids themselves possess strong anti-inflammatory and antithrombotic properties against several mediators and inflammatory pathways, by a variety of mechanisms of actions (
Figure 4), with promising health benefits against atherosclerosis and CVD, cancer and metastatic procedures, renal and neurodegenerative disorders, persistent infections and associated inflammatory manifestations, allergy and asthma, sepsis, etc. [
6,
7,
11,
14,
18,
22,
102].
For example, such bioactive polar lipids have modulated or even reduced the formation of atherosclerotic plaques, by inhibiting the activities and reducing the levels of the inflammatory and thrombotic mediator, PAF, and its atherogenic effects [
7]. Since the thrombotic and inflammatory pathways of PAF are implicated in several chronic disorders, including cancer, atherosclerosis and CVD [
6,
7,
24], the inhibition of PAF activities and the reduction of its levels by wine and grape pomace polar lipid bioactives further suggest their anti-atherogenic, cardioprotective and anti-tumor potential [
6,
7,
8,
9,
10,
11,
12,
13,
14,
15,
16,
17,
18,
19,
20,
21,
22].
Apart from modulating PAF-metabolism towards reduced PAF-levels, such bioactive polar lipids from wine, wine-must, yeasts and grape pomace have also inhibited the inflammatory and thrombotic pathways of both PAF and thrombin, while they have reduced the platelet sensitivity, activation and aggregation induced by well-established platelet agonists, collagen, and ADP [
7,
8,
9,
10,
11,
12,
13,
14,
15,
16,
17,
18,
19,
20,
21,
22,
112]. It seems that the anti-inflammatory and anti-thrombotic anti-PAF properties of these polar lipid bioactives occur either through affecting beneficially PAF-metabolism towards reduction of its levels of homeostatic ones and/or through inhibiting the binding of PAF on its receptor and thus inhibiting PAF-related inflammatory and thrombotic pathways and activities (
Figure 3), and subsequently reducing the risk for PAF-associated inflammatory chronic disorders such as atherosclerosis, CVD, and cancer [
6,
7,
11,
14,
18,
22,
102].
Moreover, apart from the strong anti-inflammatory and anti-thrombotic properties of the whole structures of such bioactive polar lipids, it has also been proposed that once the rich in UFA polar lipids have surpassed the intestine barrier and are bound to and transferred from plasma lipoproteins to the cell-membranes of all tissues, there a cytoplasmic phospholipase A2 (PLA2) releases their UFA content from their structure of these membrane bound polar lipids, while the released UFA interacts with several inflammatory pathways, genes and signaling, such as the eicosanoids pathways (COX-enzymes), for reducing and resolving inflammation and the inflammatory cell-response (
Figure 3) [
6,
7,
102]. Based on these findings, several trials have been conducted based on the effects of the consumption of wine or of grape pomace extracts rich phenolics and bioactive polar lipids on thrombo-inflammatory mediators like PAF, on inflammatory cytokines’ release and on metabolic and oxidative stress responses [
12,
13,
15,
19,
20,
21].
Overall, the benefits of wine consumption and of grape pomace extracts are not only attributed to their phenolic content but also to other microconstituents like their bioactive lipid compounds, and especially in their glycolipids, phospholipids and their UFAs, as well as by the synergism of all these bioactives. Although bioavailable amounts of the antioxidant wine and grape pomace polyphenols have little to do with a proposed in vivo protection against oxidative stress, they still play a crucial role as primary antioxidants against oxidation of lipids, including PL and UFA compounds, in several natural sources, foods, beverages, cosmetics, and lipid extracts [
113]. In extracts of several sources, a very substantial improvement in oxidative stability, bioavailability, and preservation of the bioactivities of phenolics, UFA and polar phenolic compounds can be achieved by a co-presence and synergism of all these polar compounds. Subsequently, the presence of phenolic compounds in PL extracts from any type of wine and/or grape pomace, seem to facilitate the preservation of the bioactivities of the protected PL compounds. Thus, the synergism of such wine and grape pomace bioactive compounds, which can ameliorate the oxidative stress response and inhibit the activities and/or reduce the levels of thrombo-inflammatory mediators like PAF and thrombin, seem to explain the potential of an extract rich in such polar organic bioactives, rather than of just one molecule like resveratrol, for the prevention/reduction of risk of several inflammation and thrombosis associated chronic disorders [
6,
7,
10,
11,
14,
18,
22].