*2.2. Plant-Derived Compounds*

Among natural polyphenols, flavonoids are present in most plants, having antioxidant activity. Phenols and flavonoids can directly scavenge reactive oxygen species (ROS) as a result of their ability to donate hydrogen atoms or electrons. Every plant contains a unique combination of phytochemicals, which can cause different beneficial effects in individuals. Green tea, grapes, apples, ginkgo biloba, soybean, turmeric, berries and onions are rich in flavonoids and are used as natural food supplements. Many studies also confirmed the protective effects of polyphenol antioxidants against diabetic vascular complications [53–56], such as the effects of green tea and cocoa polyphenols on endothelial dysfunction in patients with DM, red-wine polyphenols on microvascular dysfunction and citrus-fruit consumption on vascular protection [57,58]. Virgin olive oil rich in polyphenols has a cardioprotective effect suggested with a consumption between 20 and 30 g/day [59]. The ingestion of 40 g of dark chocolate in 22 heart transplant subjects improved coronary circulation and decreased platelet adhesion 2 h after supplementation [60,61]. However, the heterogeneity of the results does not allow one to make a definitive evaluation on chocolate's usefulness in DM [62]. A randomized, double-blind, placebo-controlled cross-over trial is in development to investigate whether cocoa flavanols improve blood pressure and vascular reactivity in patients with T2DM [63]. Overall, the European Food Safety Authority (EFSA) stated that 200 mg daily of cocoa flavanols (10 g of high-flavanol dark chocolate) could be beneficial for endothelium-dependent vasodilation in healthy populations [64]. Therefore, there are several epidemiological studies and various prospective clinical trials suggesting that a diet rich in polyphenols reduces the risk of incurring in cardiovascular diseases, but a clinical evaluation of specific phenols is lacking.

The present proposal focused on the study of the activity of five selected plant-derived polyphenolic compounds in the treatment of vascular damage, especially linked to hyperglycemia. With this aim in mind, the selected polyphenols investigated were baicalein, curcumin, mangiferin, quercetin and resveratrol (Figure 1). Of course, to plan a factual intervention against vascular damage, particularly with respect to PAD, known risk factors, including smoking, hyperglycemia, hypertension, dyslipidemia, chronic kidney disease and depression, should be identified and limited as much as possible.

**Figure 1.** Chemical structure of the considered polyphenols.
