Human blood platelets play a crucial role in hemostasis and thrombosis and are also involved in other biological processes, including inflammation, immunity, wound healing, cancer, and angiogenesis [2–5]. Platelets mediate complex vascular homeostasis via specific receptors, granule release, RNA transfer, and mitochondrial secretion, subsequently regulating hemostasis, infection, and innate and adaptive immunity. Activated platelets release mediators, such as 5-hydroxytryptamine (serotonin), ADP, ATP, and lysophosphatidic acid, and their hyperactivation is the causal factor for the initiation and progression of atherosclerosis and in the cardiovascular disease (CVD) [1, 2]. Atherosclerosis is the leading cause of CVD – a chronic inflammatory state in the arterial blood vessel walls with subsequent thrombus formation [3, 4]. Factors contributing to the development of atherosclerotic include increased lifespan, genetic susceptibility, adverse environment, and personal lifestyle choices such as smoking, a high-fat diet, and lack of exercise, all of which ultimately lead to plaque formation [4–6]. Regular blood platelet activity maintains hemostasis and adequate blood flow [3]. However, hyperactive platelets interact with vessel walls by shedding macro-particles, secreting adhesive growth factors, and inflammatory cytokines, interrupting blood flow and promoting a pro-thrombotic state. Activated platelets release mediators, such as 5-hydroxytryptamine (serotonin), ADP, ATP, and lysophosphatidic acid [7]. This is particularly evident in individuals with obesity, diabetes, a sedentary lifestyle, hypertension, and smokers [8–11]. Therefore, platelet activation is causal in triggering and maintaining the pro-inflammatory and pro-thrombotic state of obesity, creating a feedback loop involving adipose tissue, activated platelets, and vascular endothelium that culminates in an environment favorable for atherothrombotic vascular events [12, 13]. Hence, hyperactive platelets contribute to plaque formation and have thus been proposed as a CVD risk factor [14, 15].
Aspirin (acetylsalicylic acid) remains a cornerstone in anti-platelet treatment to prevent vascular thrombosis. However, resistance to aspirin treatment occurs in 25–30% of patients, and aspirin can also lead to several serious side effects, particularly bleedings, rendering it often unsuitable for primary CVD prevention [16–18]. In addition, other platelet inhibitors such as dipyridamole, ADP-receptor-, and glycoprotein antagonists also confer side effects, making it challenging to use them to prevent CVD. In line with this, aspirin and other anti-platelet drugs are not recommended for primary CVD prevention or in subjects with low CVD risk. Therefore, finding alternative safe anti-platelet inhibitors for those with hyperactive platelets is essential to reduce CVD risk.
There is growing interest in naturally occurring compounds with potential anti-platelet effects that lack the side effects of current anti-platelet inhibitors [18]. In line with this, nutraceuticals with anti-platelet compounds are suggested to prevent CVD [19]. Various fruits are being investigated for their cardioprotective effects due to their high polyphenol content and bioactive component profile [20]. To this end, emerging data indicate that fruit extracts may be cardioprotective via favorable modulation of the platelet-blood vessel interaction [21].
Therefore, we now systematically investigate bioactive compounds’ impact in high polyphenol-content fruits on human blood platelet aggregation. In addition, we aim to utilize the findings to characterize the mechanisms involved in this process to identify potential dietary anti-platelet components.
Dietary polyphenols have been shown to reduce platelet activation and aggregation via multiple pathways [18, 22, 23]. Plant polyphenols, such as flavonols, phenolic acids, anthocyanins, and procyanidins, are found in exceptionally high concentrations in various berries, e.g. tamarillo, and kiwano (horned melon) [24–27]. Tamarillo (Solanum betaceum Cav.) is a sub-tropical fruit known for its high nutritional value and beneficial effect on CVD, attributed to numerous phytochemicals [28]. Kiwano (Cucumis metuliferus), a fruit from the Cucurbitaceae family, also contains several polyphenols [29]. Raspberry (Rubus idaeus) is another fruit that is an excellent source of polyphenols [30]. Although these fruits contain extensive high polyphenols, their effects on platelet aggregation have not been studied. Thus, our first objective was to investigate the effects of extracts prepared from these fruits on ADP-induced platelet aggregation. Secondly, we aimed to unravel their mechanism of action on platelet activation. In this paper, we report that these fruits exhibited potent anti-platelet activity, and their anti-platelet effects can be due to benzoic acid, caffeic acid, and gallic acid. These fruits can be exploited to develop cardioprotective functional food.