3.4.2. Activity: Preclinical Studies

Quercetin shows prominent antioxidant potential and is considered an effective freeradical scavenger mainly based on several in vitro studies [154–156]. The antioxidant activity of quercetin is believed to be linked to the regulation of GSH levels [150]; moreover, the hydroxyl groups on the side phenyl ring of the molecule can bind to amino acid residues of key enzymes, such as acetylcholinesterase and butyrylcholinesterase, both linked to oxidative properties. Quercetin also increases the levels of endogenous antioxidant enzymes, e.g., catalase, GSH peroxidase and superoxide dismutase. More specifically, considering the vascular effects, quercetin induces the vasodilation of isolated rat arteries [157–159] and, in vivo, antihypertensive effects on rats fed with a high-fat, high-sucrose diet [158] and in spontaneously hypertensive animals, without effect in normotensive animals [160]. Generally, this flavonoid showed antiangiogenic activity in several experimental models [161–163].

The protective effect of quercetin against the activation of ER stress was attributed to the upregulation of markers, such as the 78 kDa glucose-regulated protein (GRP78), a molecular chaperone, and the C/EBP-homologous protein (CHOP) in unresolved diabetic and experimental ER-stress conditions [164]. Furthermore, quercetin pretreatment decreased the expression of tunicamycin-induced ER-stress markers in HUVECs [164]. In another study, mitochondrial-targeted quercetin activities were observed to be a mechanism of protection against neurodegenerative diseases [165]. Quercetin has been reported to protect against hydrogen peroxide-induced pheochromocytoma cell neurodegeneration [166].

In general, quercetin has shown anti-inflammatory action in several experimental models, mainly through mechanisms that inhibit NF–κB and cofactors in the chromatin of proinflammatory genes [167]. Quercetin also increases glucose uptake from the blood by inducing the glucose transporter GLUT4, and promotes glucose storage by the liver [156,168].

### 3.4.3. Activity: Clinical Studies

Few trials have examined the effect of quercetin supplementation on blood pressure, with discordant results; however, generally, a reduction in systolic blood pressure both in healthy subjects and hypertensive patients has been reported [169–172]. Recently, a metaanalysis showed significant s in both systolic and diastolic blood pressure with quercetin supplementation; the treatments ranged from 4 to 10 weeks, with doses ≥500 mg/day [173]. Another meta-analysis showed a significant reduction in blood pressure and, furthermore, for participants receiving quercetin for at least 8 weeks, a decrease in triglycerides in trials with a parallel design [174]. A double-blinded, placebo-controlled cross-over study conducted on 93 overweight or obese subjects aged 25 to 65 years with metabolic syndrome traits showed that quercetin administered at 150 mg/day (6-week-treatment period) reduced systolic blood pressure and plasma oxidized-LDL levels in overweight subjects with a high-CVD-risk phenotype [171].

In the scientific literature, no clinical studies have been reported on the use of quercetin in the treatment of PAD.

#### 3.4.4. Safety Profile

Egert et al. reported that daily supplementation with 150 mg of quercetin/day, administered orally to volunteer subjects with a high-CVD-risk phenotype for 6 weeks, was safe [171]. In general, the clinical studies reported that the orally administered quercetin use was safe and well-tolerated [173,174].

Quercetin per se has few adverse effects reported in VigiBase [95]; a total of 45 unwanted effects are described, mainly in the Americas and Europe. Nervous system disorders (e.g., dizziness and headache), respiratory disorders (e.g., dyspnea), pruritus and drug interaction are the most recurrent effects [95]. Nevertheless, in general, moderate doses of quercetin are described as safe.

#### *3.5. Resveratrol*

#### 3.5.1. Chemistry and Sources

Resveratrol is a stilbene derivative (3,5,4 –trihydroxystilbene) occurring both as *trans*and *cis*-isomers that are present in a variable percentage in several natural sources, the *trans*form being the most abundant and mainly responsible for the cardiovascular effects [175]. Resveratrol is a phytoalexin (a class of antimicrobials synthesized by plants under pathogen infection) found in many plant foods. Its presence is well-known in red grapes (skin) and red wine, but even in tea and berries and also in various medicinal plants (e.g., *Polygonum* spp. roots) used in popular medicine as treatments for allergic and inflammatory diseases [176].
