Flavonoids are phenolic substances isolated from a wide range of vascular plants, with over 8000 individual compounds known. They act in plants as antioxidants, antimicrobials, photoreceptors, visual attractors, feeding repellants, and for light screening. Many studies have suggested that flavonoids exhibit biological activities, including antiallergenic, antiviral, antiinflammatory, and vasodilating actions. However, most interest has been devoted to the antioxidant activity of flavonoids, which is due to their ability to reduce free radical formation and to scavenge free radicals. The capacity of flavonoids to act as antioxidants in vitro has been the subject of several studies in the past years, and important structure-activity relationships of the antioxidant activity have been established. The antioxidant efficacy of flavonoids in vivo is less documented, presumably because of the limited knowledge on their uptake in humans. Most ingested flavonoids are extensively degraded to various phenolic acids, some of which still possess a radical-scavenging ability. Both the absorbed flavonoids and their metabolites may display an in vivo antioxidant activity, which is evidenced experimentally by the increase of the plasma antioxidant status, the sparing effect on vitamin E of erythrocyte membranes and low-density lipoproteins, and the preservation of erythrocyte membrane polyunsaturated fatty acids. This review presents the current knowledge on structural aspects and in vitro antioxidant capacity of most common flavonoids as well as in vivo antioxidant activity and effects on endogenous antioxidants.

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Flavonoids as Antioxidants

Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies

This review focuses on the role of oxidative processes in atherosclerosis and its resultant cardiovascular events. There is now a consensus that atherosclerosis represents a state of heightened oxidative stress characterized by lipid and protein oxidation in the vascular wall. The oxidative modification hypothesis of atherosclerosis predicts that low-density lipoprotein (LDL) oxidation is an early event in atherosclerosis and that oxidized LDL contributes to atherogenesis. In support of this hypothesis, oxidized LDL can support foam cell formation in vitro, the lipid in human lesions is substantially oxidized, there is evidence for the presence of oxidized LDL in vivo, oxidized LDL has a number of potentially proatherogenic activities, and several structurally unrelated antioxidants inhibit atherosclerosis in animals. An emerging consensus also underscores the importance in vascular disease of oxidative events in addition to LDL oxidation. These include the production of reactive oxygen and nitrogen species by vascular cells, as well as oxidative modifications contributing to important clinical manifestations of coronary artery disease such as endothelial dysfunction and plaque disruption. Despite these abundant data however, fundamental problems remain with implicating oxidative modification as a (requisite) pathophysiologically important cause for atherosclerosis. These include the poor performance of antioxidant strategies in limiting either atherosclerosis or cardiovascular events from atherosclerosis, and observations in animals that suggest dissociation between atherosclerosis and lipoprotein oxidation. Indeed, it remains to be established that oxidative events are a cause rather than an injurious response to atherogenesis. In this context, inflammation needs to be considered as a primary process of atherosclerosis, and oxidative stress as a secondary event. To address this issue, we have proposed an "oxidative response to inflammation" model as a means of reconciling the response-to-injury and oxidative modification hypotheses of atherosclerosis.

Role of Oxidative Modifications in Atherosclerosis

The biochemistry and medical significance of the flavonoids.

Bioactive compounds in foods: their role in the prevention of cardiovascular disease and cancer

Lipoprotein oxidation is a key early stage in the development of atherosclerosis. Oxidation of lowdensity lipoprotein (LDL) is initiated by both enzyme-mediated and non-enzymic mechanisms in vivo , and oxidized LDL has many atherogenic properties. Oxidation of LDL in vivo is likely to be influenced by local environmental factors, such as pH. The composition of LDL is also important, including such factors as antioxidant content, fatty acid composition and particle size.

Lipoprotein oxidation and atherosclerosis.

Aims To evaluate the role of novel biomarkers in early detection of acute myocardial infarction (MI) in patients admitted with acute chest pain.

Methods and results A prospective study of 664 patients presenting to two coronary care units with chest pain was conducted over 3 years from 2003. Patients were assessed on admission: clinical characteristics, ECG (electrocardiogram), renal function, cardiac troponin T (cTnT), heart fatty acid binding protein (H-FABP), glycogen phosphorylase-BB, NT-pro-brain natriuretic peptide, D-dimer, hsCRP (high sensitivity C-reactive protein), myeloperoxidase, matrix metalloproteinase-9, pregnancy associated plasma protein-A, soluble CD40 ligand. A ≥12 h cTnT sample was also obtained. MI was defined as cTnT ≥ 0.03 µg/L. In patients presenting <4 h of symptom onset, sensitivity of H-FABP for MI was significantly higher than admission cTnT (73 vs. 55%; P = 0.043). Specificity of H-FABP was 71%. None of the other biomarkers challenged cTnT. Combined use of H-FABP and cTnT (either one elevated initially) significantly improved the sensitivities of H-FABP or cTnT (85%; P ≤ 0.004). This combined approach also improved the negative predictive value, negative likelihood ratio, and the risk ratio.

Conclusion Assessment of H-FABP within the first 4 h of symptoms is superior to cTnT for detection of MI, and is a useful additional biomarker for patients with acute chest pain.

Novel biomarkers in early diagnosis of acute myocardial infarction compared with cardiac troponin T

Objective To investigate the in vivo effects of quercetin following the ingestion of fried onions. Design Five healthy volunteers, three males and two females aged between 25 and 39 y, ingested 225 g of fried onions after an overnight fast and peripheral venous blood was collected 0, 2, 4, 24 and 48 h after consumption. Quercetin in the plasma, total antioxidant capacity and susceptibility of low density lipoproteins (LDL) to oxidation were measured. Results Following the onion meal, quercetin levels increased from baseline values (28.4 +/- 1.9 ng/ml) to peak after 2 h (248.4 +/- 103.9 ng/ml), decreasing to baseline again after 24 h (P > 0.05). This was accompanied by an increase in the total antioxidant activity of the plasma from baseline (1.70 +/- 0.04 mmol/l trolox equivalents) to 1.75 +/- 0.10 mmol/l trolox equivalents after 2 h and 1.76 +/- 0.08 mmol/l trolox equivalents after 4 h. There was no significant change in the susceptibility of the plasma or the isolated LDL to oxidation over the 48 h period after consumption of the fried onions. In view of these negative findings, we isolated LDL and other lipoproteins from plasma at each time point. Quercetin was not detected in either LDL or VLDL, but was present in the HDL fraction, although this fraction also contains other proteins including albumin. Conclusions Quercetin can be absorbed in humans from dietary sources to high enough concentrations to increase the overall antioxidant activity of the plasma. Quercetin, however, has a strong affinity for protein and provides no direct protective effect during LDL oxidation.

Absorption and antioxidant effects of quercetin from onions, in man

Incremental knee extensor (KE) exercise performed at 25, 70, and 100% of single-leg maximal work rate (WRMAX) was combined with ex vivo electron paramagnetic resonance (EPR) spectroscopic detection...

https://www.physiology.org/doi/pdf/10.1152/ajpheart.00148.2004

Regulation of free radical outflow from an isolated muscle bed in exercising humans

The present study combined molecular and neuroimaging techniques to examine if free radical-mediated damage to barrier function in hypoxia would result in extracellular edema, raise intracranial pressure (ICP) and account for the neurological symptoms typical of high-altitude headache (HAH) also known as acute mountain sickness (AMS). Twenty-two subjects were randomly exposed for 18 h to 12% (hypoxia) and 21% oxygen (O2 (normoxia)) for collection of venous blood (0 h, 8 h, 15 h, 18 h) and CSF (18 h) after lumbar puncture (LP). Electron paramagnetic resonance (EPR) spectroscopy identified a clear increase in the blood and CSF concentration of O2 and carbon-centered free radicals (P<0.05 versus normoxia) subsequently identified as lipid-derived alkoxyl (LO*) and alkyl (LC*) species. Magnetic resonance imaging (MRI) demonstrated a mild increase in brain volume (7.0+/-4.8 mL or 0.6%+/-0.4%, P<0.05 versus normoxia) that resolved within 6 h of normoxic recovery. However, there was no detectable evidence for gross barrier dysfunction, elevated lumbar pressures, T2 prolongation or associated neuronal and astroglial damage. Clinical AMS was diagnosed in 50% of subjects during the hypoxic trial and corresponding headache scores were markedly elevated (P<0.05 versus non-AMS). A greater increase in brain volume was observed, though this was slight, independent of oxidative stress, barrier dysfunction, raised lumbar pressure, vascular damage and measurable evidence of cerebral edema and only apparent in the most severe of cases. These findings suggest that free-radical-mediated vasogenic edema is not an important pathophysiological event that contributes to the mild brain swelling observed in HAH.

https://journals.sagepub.com/doi/pdf/10.1038/sj.jcbfm.9600169

Jane McEneny

Papers

Lipoprotein oxidation and atherosclerosis.

Novel biomarkers in early diagnosis of acute myocardial infarction compared with cardiac troponin T

Absorption and antioxidant effects of quercetin from onions, in man

Regulation of free radical outflow from an isolated muscle bed in exercising humans

Free radical-mediated damage to barrier function is not associated with altered brain morphology in high-altitude headache