Quercetin (Que) is a flavonoid associated with high oxygen radical scavenging activity and potential neuroprotective activity against Alzheimer's disease. Que's oral bioavailability is limited by its low water solubility and extended peripheral metabolism; thus, nasal administration may be a promising alternative to achieve effective Que concentrations in the brain. The formation of Que−2-hydroxypropylated−β-cyclodextrin (Que/HP-β-CD) complexes was previously found to increase the molecule's solubility and stability in aqueous media. Que−methyl−β-cyclodextrin (Que/Me-β-CD) inclusion complexes were prepared, characterized, and compared with the Que/HP-β-CD complex using biophysical and computational methods (phase solubility, fluorescence and NMR spectroscopy, differential scanning calorimetry (DSC), and molecular dynamics simulations (MDS)) as candidates for the preparation of nose-to-brain Que's delivery systems. DSC thermograms, NMR, fluorescence spectroscopy, and MDS confirmed the inclusion complex formation of Que with both CDs. Differences between the two preparations were observed regarding their thermodynamic stability and inclusion mode governing the details of molecular interactions. Que's solubility in aqueous media at pH 1.2 and 4.5 was similar and linearly increased with both CD concentrations. At pH 6.8, Que's solubility was higher and positively deviated from linearity in the presence of HP-β-CD more than with Me-β-CD, possibly revealing the presence of more than one HP-β-CD molecule involved in the complex. Overall, water solubility of lyophilized Que/Me-β-CD and Que/HP-β-CD products was approximately 7−40 times and 14−50 times as high as for pure Que at pH 1.2−6.8. In addition, the proof of concept experiment on ex vivo permeation across rabbit nasal mucosa revealed measurable and similar Que permeability profiles with both CDs and negligible permeation of pure Que. These results are quite encouraging for further ex vivo and in vivo evaluation toward nasal administration and nose-to-brain delivery of Que.

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Quercetin, as a member of flavonoids, has emerged as a potential therapeutic agent in cardiovascular diseases (CVDs) in recent decades. In this comprehensive literature review, our goal was a critical appraisal of the pathophysiological mechanisms of quercetin in relation to the classical cardiovascular risk factors (e.g., hyperlipidemia), atherosclerosis, etc. We also assessed experimental and clinical data about its potential application in CVDs. Experimental studies including both in vitro methods and in vivo animal models mainly outline the following effects of quercetin: (1) antihypertensive, (2) hypolipidemic, (3) hypoglycemic, (4) anti-atherosclerotic, and (5) cardioprotective (suppressed cardiotoxicity). From the clinical point of view, there are human studies and meta-analyses implicating its beneficial effects on glycemic and lipid parameters. In contrast, other human studies failed to demonstrate consistent favorable effects of quercetin on other cardiometabolic risk factors such as MS, obesity, and hypertension, underlying the need for further investigation. Analyzing the reason of this inconsistency, we identified significant drawbacks in the clinical trials’ design, while the absence of pharmacokinetic/pharmacodynamic tests prior to the studies attenuated the power of clinical results. Therefore, additional well-designed preclinical and clinical studies are required to examine the therapeutic mechanisms and clinical efficacy of quercetin in CVDs.

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Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide. As a result, pharmaceutical and non-pharmaceutical interventions modifying risk factors for CVDs are a top priority of scientific research. Non-pharmaceutical therapeutical approaches, including herbal supplements, have gained growing interest from researchers as part of the therapeutic strategies for primary or secondary prevention of CVDs. Several experimental studies have supported the potential effects of apigenin, quercetin, and silibinin as beneficial supplements in cohorts at risk of CVDs. Accordingly, this comprehensive review focused critically on the cardioprotective effects/mechanisms of the abovementioned three bio-active compounds from natural products. For this purpose, we have included in vitro, preclinical, and clinical studies associated with atherosclerosis and a wide variety of cardiovascular risk factors (hypertension, diabetes, dyslipidemia, obesity, cardiac injury, and metabolic syndrome). In addition, we attempted to summarize and categorize the laboratory methods for their isolation and identification from plant extracts. This review unveiled many uncertainties which are still unexplored, such as the extrapolation of experimental results to clinical practice, mainly due to the small clinical studies, heterogeneous doses, divergent constituents, and the absence of pharmacodynamic/pharmacokinetic analyses.