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Phloretin is a flavonoid found exclusively in apples and in apple-derived products where it is present as the glucosidic form, namely, phloridzin (phloretin 2'-O-glucose). In the present study, we compared the changes in plasma and urine concentrations of these two compounds in rats fed a single meal containing 0.25% phloridzin or 0.157% phloretin (corresponding to the ingestion of 22 mg of phloretin equivalents). In plasma, phloretin was recovered mainly as the conjugated forms (glucuronided and/or sulfated) but some unconjugated phloretin was also detected. By contrast, no trace of intact phloridzin was detected in plasma of rats fed a phloridzin meal. These compounds presented different kinetics of absorption; phloretin appeared more rapidly in plasma when rats were fed the aglycone than when fed the glucoside. However, whatever compound was administered, no significant difference in the plasma concentrations of total phloretin were observed 10 h after food intake. At 24 h after the beginning of the meal, the plasma concentrations of phloretin were almost back to the baseline, indicating that this compound was excreted rapidly in urine. The total urinary excretion rate of phloretin was not affected by the forms administered, and was estimated to be 8.5 micromol/24 h in rats fed phloretin or phloridzin. Thus, 10.4% of the ingested dose was recovered in urine after 24 h. [ABSTRACT FROM AUTHOR]

Absorption and metabolism of quercetin and isoquercitrin (quercetin 3-O-glucose) were investigated in rats after in situ perfusion of jejunum plus ileum (15 nmol/min) for 30 min and compared with those of phloretin and phloridzin (phloretin 2'-O-glucose). After perfusion of the glucosides, the corresponding aglycone forms and conjugated derivatives appeared in the lumen. The conjugated metabolites were similar to those recovered after intestinal perfusion of the aglycone forms. Regardless of the aglycone or glucoside perfused, only conjugated forms were present in the mesenteric vein blood draining the perfused segment showing the importance of intestinal conjugation. The hydrolysis of glucosides was a prerequisite step before their conjugation by intestinal enzymes and their transport towards the mucosal and serosal sides. In contrast to phloridzin, lactase phloridzin hydrolase activity did not seem to be an essential pathway for isoquercitrin hydrolysis. The 3-O-glucosylation of quercetin improved the net absorption of the aglycone (P < 0.05), whereas phloretin absorption decreased when present as 2'-O-glucoside (P < 0.05). Whatever the perfused compound, the efficiency of the absorption seemed to be linked to the intestinal conjugation process and to the luminal secretion of metabolites. [ABSTRACT FROM AUTHOR]

Flavan-3-ols are the most abundant flavonoids in the human diet, but little is known about their absorption and metabolism. In this study, the absorption and metabolism of the monomeric flavan-3-ol, catechin, was investigated after the in situ perfusion of the jejunum + ileum in rats. Five concentrations of catechin were studied, ranging from 1 to 100 micromol/L. The absorption of catechin was directly proportional to the concentration, and 35 +/- 2% of the perfused catechin was absorbed during the 30-min period. Effluent samples contained only native catechin, indicating that intestinal excretion of metabolites is not a mechanism of catechin elimination. Catechin was absorbed into intestinal cells and metabolized extensively because no native catechin could be detected in plasma from the mesenteric vein. Mesenteric plasma contained glucuronide conjugates of catechin and 3'-O-methyl catechin (3'OMC), indicating the intestinal origin of these conjugates. Additional methylation and sulfation occurred in the liver, and glucuronide + sulfate conjugates of 3'OMC were excreted extensively in bile. Circulating forms were mainly glucuronide conjugates of catechin and 3'OMC. The data further demonstrate the role of the rat small intestine in the glucuronidation and methylation of flavonoids as well as the role of the liver in sulfation, methylation and biliary excretion. [ABSTRACT FROM AUTHOR]

Background: The primary treatment for lower-extremity peripheral arterial occlusive disease (PAOD) is angioplasty stenting. Its main complication is in-stent restenosis. Poor selection of stent dimensions has been identified as a factor contributing to early in-stent restenosis. The aim of this study is to determine whether the implantation of stents, selected based on arterial morphological reconstruction using a sizing software program, reduces the occurrence of in-stent restenosis. The study also aims to evaluate the potential benefits of routine preoperative sizing., Methods: Between January 2016 and December 2020, all patients treated for PAOD through scheduled angioplasty stenting in our department were included in the study. Using systematic preoperative computed tomography angiography, precise reconstruction and sizing were performed to select the ideal length and diameter of stents, resulting in the selection of a so-called IDEAL stent. During the procedure, the surgeon implanted either the IDEAL stent or a different one, named the ACTUAL stent, based on intraoperative data and/or availability. We compared the in-stent restenosis rate between IDEAL and ACTUAL stents., Results: There were no significant differences in the overall characteristics between the IDEAL and ACTUAL stent groups. The in-stent restenosis rate at 1 year was 13% (N = 28/212, P = 0.994) in the IDEAL group and 17% (N = 25/149, P = 0.994) in the ACTUAL group. Among the ACTUAL stents, a total of 19.6% of stents with a diameter mismatch when chosen based on arteriography showed a significantly higher restenosis rate during the first year of follow-up (P = 0.02)., Conclusions: Our study did not demonstrate a significant difference in 1-year restenosis rate between the IDEAL and the ACTUAL stent groups. It specifically revealed the significant impact of diameter selection on the intrastent restenosis rate during the first year of follow-up. Stents chosen based on arteriographic criteria, which exhibited diameter discordance, compared to the IDEAL stents group selected using sizing reconstructions, could be either oversized or undersized. This led to a significantly higher restenosis rate at 1 year postoperatively., (Copyright © 2024 The Author. Published by Elsevier Inc. All rights reserved.)

Introduction: Unlike paclitaxel-coated balloons, pre-clinical data comparing different paclitaxel-coated stents (PCSs) are weak. The study objective was to compare the features of the 2 main PCSs: Eluvia® (Boston Scientific, Marlborough, MA) versus ZilverPTX® (Cook Medical, Bloomington, IN)., Method: Analysis was carried out on 12 pigs divided into 2 groups: Eluvia® (n=6) and ZilverPTX® (n=6). The pigs received the PCS corresponding to their group in each external iliac artery and were paired one by one, to examine 6 different post-implantation timepoints: after 30 minutes, 6 hours, 24 hours, 3 days, 7 days, and 14 days. The paclitaxel concentration measurements and the histological analysis were carried out under blind testing on the plasma, arterial, lymph node, and muscle samples. A linear regression model and Wilcoxon Mann-Whitney test were used to study the variables., Results: The plasma paclitaxel rate decrease over 24 hours after PCS implantation was significantly different between the two groups, expressed by the correlation coefficient 0.19 (0.14-0.23; p<0.001) with an undetectable concentration at the 10th hour for Eluvia® versus 3 days for ZilverPTX®. Significantly higher paclitaxel concentrations with ZilverPTX® PCS were observed in muscle samples at each timepoint: extensor digitorum brevis 3.2 (1.17-5.23; p=0.005), biceps femoris 4.27 (2.27-6.26; p<0.001), semi-tendinosus 3.79 (1.85-5.73; p=0.001), tibialis anterior 3.0 (1.37-4.64; p=0.001), and in the femoral nodes 2.27±1.74 ng/g versus 0.14±0.13 ng/g (p<0.001). Histological analysis revealed a trend for more marked intimal inflammation in the arteries stented with ZilverPTX® (p=0.063), especially after the 7th and 14th days., Conclusion: Such a difference in the concentration of paclitaxel in the plasma, muscles, and lymph nodes between the two stents was higher than expected based on differences in device design. The clinical consequences of these results remain to be elucidated, particularly regarding the concerning presence of paclitaxel in muscles and adjacent lymph nodes., Clinical Impact: This experimental study compares 2 paclitaxel-coated stents. It demonstrates that differences in stent designs and drug features (coatings and concentrations) translate into differences in terms of concentrations of paclitaxel in the plasma, muscles, and lymph nodes. Our results favor the Eluvia® stent over the ZilverPTX® stent, although more studies are required to confirm this conclusion.

Background: Type 2 diabetes mellitus (T2DM) is a major global health issue and a significant risk factor for atherosclerosis. Atherosclerosis in T2DM patients has been associated with inflammation, insulin resistance, hyperglycemia, dyslipidemia, and oxidative stress. Identifying molecular features of atherosclerotic plaques in T2DM patients could provide valuable insights into the pathogenesis of the disease., Methods: The MASCADI (Arachidonic Acid Metabolism in Carotid Stenosis Plaque in Diabetic Patients) study aimed to investigate the increase of 2-arachidonoyl-lysophatidylcholine (2-AA-LPC) in carotid plaques from T2DM and control patients and to explore its association with plaque vulnerability as well as with blood and intra-plaque biomarkers altered during diabetes., Results: In a population of elderly, polymedicated patients with advanced stage of atherosclerosis, we found that T2DM patients had higher systemic inflammation markers, such as high-sensitivity C-reactive protein (hsCRP) and IL-1β, higher levels of oxysterols, increased triglyceride levels, and decreased HDL levels as compared to control patients. Furthermore, 2-AA-LPC was significantly enriched in plaques from diabetic patients, suggesting its potential role in diabetic atherosclerosis. Interestingly, 2-AA-LPC was not associated with systemic markers related to diabetes, such as hsCRP, triglycerides, or HDL cholesterol. However, it was significantly correlated with the levels of inflammatory markers within the plaques such as lysophospholipids and 25-hydroxycholesterol, strengthening the link between local inflammation, arachidonic acid metabolism and diabetes., Conclusion: Our study is in line with a key role for inflammation in the pathogenesis of diabetic atherosclerosis and highlights the involvement of 2-AA-LPC. Further research is needed to better understand the local processes involved in the alteration of plaque composition in T2DM and to identify potential therapeutic targets., Trial Registration: The MASCADI was registered on ClinicalTrials.gov (clinical registration number: NCT03202823)., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: We evaluated whether pre-existing brain damage may explain greater severity in cognitively-impaired patients with ischemic stroke (IS)., Methods: IS patients were retrieved from the population-based registry of Dijon, France. Pre-existing damage (leukoaraiosis, old vascular brain lesions, cortical and central brain atrophy) was assessed on initial CT-scan. Association between prestroke cognitive status defined as no impairment, mild cognitive impairment (MCI), or dementia, and clinical severity at IS onset assessed with the NIHSS score was evaluated using ordinal regression analysis. Mediation analysis was performed to assess pre-existing brain lesions as mediators of the relationship between cognitive status and severity., Results: Among the 916 included patients (mean age 76.8 ± 15.0 years, 54.3% women), those with pre-existing MCI (n = 115, median NIHSS [IQR]: 6 [2-15]) or dementia (n = 147, median NIHSS: 6 [3-15]) had a greater severity than patients without (n = 654, median NIHSS: 3 [1-9]) in univariate analysis (OR=1.69; 95% CI: 1.18-2.42, p = 0.004, and OR=2.06; 95% CI: 1.49-2.84, p < 0.001, respectively). Old cortical lesion (OR=1.53, p = 0.002), central atrophy (OR=1.41, p = 0.005), cortical atrophy (OR=1.90, p < 0.001) and moderate (OR=1.41, p = 0.005) or severe (OR=1.84, p = 0.002) leukoaraiosis were also associated with greater severity. After adjustments, pre-existing MCI (OR=1.52; 95% CI: 1.03-2.26, p = 0.037) or dementia (OR=1.94; 95% CI: 1.32-2.86, p = 0.001) remained associated with higher severity at IS onset, independently of confounding factors including imaging variables. Association between cognitive impairment and severity was not mediated by pre-existing visible brain damages., Conclusion: Impaired brain ischemic tolerance in IS patients with prior cognitive impairment could involve other mechanisms than pre-existing visible brain damage., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Purpose: Carotid artery stenting (CAS) appears as a promising alternative treatment to carotid endarterectomy for radiation therapy (RT)-induced carotid stenosis. However, this is based on a poor level of evidence studies (small sample size, primarily single institution reports, few long-term data). The purpose of this study was to report the long-term outcomes of a multicentric series of CAS for RT-induced stenosis., Methods: All CAS for RT-induced stenosis performed in 11 French academic institutions from 2005 to 2017 were collected in this retrospective study. Patient demographics, clinical risk factors, elapsed time from RT, clinical presentation and imaging parameters of carotid stenosis were preoperatively gathered. Long-term outcomes were determined by clinical follow-up and duplex ultrasound. The primary endpoint was the occurrence of cerebrovascular events during follow-up. Secondary endpoints included perioperative morbidity and mortality rate, long-term mortality rate, primary patency, and target lesion revascularization., Results: One hundred and twenty-one CAS procedures were performed in 112 patients. The mean interval between irradiation and CAS was 15 ± 12 years. In 31.4% of cases, the lesion was symptomatic. Mean follow-up was 42.5 ± 32.6 months (range 1-141 months). The mortality rate at 5 years was 23%. The neurologic event-free survival and the in-stent restenosis rates at 5 years were 87.8% and 38.9%, respectively. Diabetes mellitus (p=0.02) and single postoperative antiplatelet therapy (p=0.001) were found to be significant predictors of in-stent restenosis. Freedom from target lesion revascularization was 91.9% at 5 years., Conclusion: This study showed that CAS is an effective option for RT-induced stenosis in patients not favorable to carotid endarterectomy. The CAS was associated with a low rate of neurological events and reinterventions at long-term follow-up.

Background and Aims: Diabetes is associated with an accelerated development of atherosclerosis. Specific mechanisms related to diabetes and hyperglycemia may play a role in this process. In particular, alterations of arachidonic acid (AA) metabolism have been reported. Our main goal was to investigate for differences in the concentration of LTB4 and RvD1 as well as selected cyclooxygenase-derived mediators in carotid plaques from diabetic and non-diabetic patients. We also aimed to analyze the relationship between omega 6 and omega 3 Poly-Unsaturated Fatty acids (PUFAs) content in the plaques and the concentrations of these lipid mediators., Methods: 29 type 2 diabetic patients and 30 control patients admitted for surgical treatment of carotid stenosis were enrolled in the present study. Carotid plaques were harvested for in-depth lipidomic profiling., Results: No differences for LTB4 or other lipid mediators were observed between diabetic and non-diabetic patients. RvD1 levels were below the threshold of quantification in most of the samples. A significant correlation was found between LTB4 and 5(S)-HETE levels. Omega 3 enrichment was not significantly different between control and diabetic plaques. There was a negative correlation between DHA/AA ratio and the level of 5(S)-HETE while there was a positive association with TXB2 and PGD2 concentrations., Conclusion-Perspectives: Our results does not support the hypothesis of a specific involvement of LTB4 or COX-derived mediators in diabetic atherosclerosis. The relationship between DHA enrichment and the concentrations of specific inflammatory mediators within the plaque is of interest and will need to be confirmed in larger studies., Competing Interests: Declaration competing Interest The authors declared that they do not have anything to disclose regarding conflict of interest with respect to this manuscript., (Copyright © 2022. Published by Elsevier Ltd.)

Objective: The aim of this study was to evaluate the impact of the COVID-19 pandemic on the trends of carotid revascularization (endarterectomy [CEA], transfemoral carotid artery stenting [TFCAS]) for symptomatic and asymptomatic carotid stenosis before, during, and after the end of the first lockdown in 2020 in France., Methods: Nationwide data were provided by the French National Hospital Discharge database (Programme de Médicalisation des Systèmes d'Information). We retrospectively analyzed patients admitted for CEA or TFCAS in all French public and private hospitals during a 9-month period (January-September) in 2017, 2018, 2019, and 2020. Procedures were identified using the French Common Classification of Medical Procedures. Stenoses were considered symptomatic in the presence of stroke and/or transient ischemic attack codes (according to the International Classification of Diseases-Tenth Revision) during the stay, and asymptomatic in the absence of these codes. Hospitalization rates in 2020 were compared with the rates in the same period in the 3 previous years., Results: Between January and September 2020, 12,546 patients were hospitalized for carotid artery surgery (CEA and TFCAS) in France. Compared with the 3 previous years, there was a decrease in hospitalization rates for asymptomatic (-68.9%) and symptomatic (-12.6%) CEA procedures in April, starting at the pandemic peak concomitant with the first national lockdown. This decrease was significant for asymptomatic CEA (P < .001). After the lockdown, while CEA for asymptomatic stenosis returned to usual activity, CEA for symptomatic stenosis presented a significant rebound, up 18.52% in August compared with previous years. Lockdown also had consequences on TFCAS procedures, with fewer interventions for both asymptomatic (-60.53%) and symptomatic stenosis (-16.67%) in April., Conclusions: This study demonstrates a severe decrease for all interventions during the first peak of the COVID-19 pandemic in France. However, the trends in the postlockdown period were different for the various procedures. These data can be used to anticipate future decisions and organization for cardiovascular care., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Strategy for the acute management of minor ischemic stroke (IS) with large vessel occlusion (LVO) is under debate, especially the benefits of mechanical thrombectomy. The frequency of minor IS with LVO among overall patients is not well established. This study aimed to assess the proportion of minor IS and to depict characteristics of patients according to the presence of LVO in a comprehensive population-based setting., Methods: Patients with acute IS were prospectively identified among residents of Dijon, France, using a population-based registry (2013-2017). All arterial imaging exams were reviewed to assess arterial occlusion. Minor stroke was defined as that with a National Institutes of Health Stroke Scale (NIHSS) score of <6. Proportion of patients with LVO was estimated in the minor IS population. The clinical presentation of patients was compared according to the presence of an LVO., Results: Nine hundred seventy-one patients were registered, including 582 (59.9%) patients with a minor IS. Of these patients, 23 (4.0%) had a LVO. Patients with minor IS and LVO had more severe presentation [median 3 (IQR 2-5) vs. 2 (IQR 1-3), p = 0.001] with decreased consciousness (13.0 vs. 1.6%, p <0.001) and cortical signs (56.5 vs. 30.8%, p = 0.009), especially aphasia (34.8 vs. 15.4%, p = 0.013) and altered item level of consciousness (LOC) questions (26.1 vs. 11.6%, p = 0.037). In multivariable analyses, only NIHSS score (OR = 1.45 per point; 95% CI: 1.11-1.91, p = 0.007) was associated with proximal LVO in patients with minor IS., Conclusion: Large vessel occlusion (LVO) in minor stroke is non-exceptional, and our findings highlight the need for emergency arterial imaging in any patients suspected of acute stroke, including those with minor symptoms because of the absence of obvious predictors of proximal LVO., Competing Interests: YB reports personal fees from BMS, Pfizer, Medtronic, Amgen, Servier, NovoNordisk, and Boehringer-Ingelheim, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Duloquin, Crespy, Jakubina, Giroud, Vergely and Béjot.)

Background: There are still gaps regarding the impact of the nationwide lockdown on non-COVID-19 emergency hospitalizations. This study aims to describe the trends in hospitalizations for cardiovascular surgical emergencies in France, before, during and after the first lockdown., Materials and Methods: All adults admitted for mechanical complications of myocardial infarction (MI), aortic dissection, aortic aneurysm rupture, acute and critical limb ischemia, circulatory assistance, heart transplantation and major amputation were included. This retrospective cohort study used the French National Hospital Discharge database. The numbers of hospitalizations per month in 2020 were compared to the previous three years., Results: From January to September 2020, 94,408 cases of the studied conditions were reported versus 103,126 in the same period in 2019 (-8.5%). There was a deep drop in most conditions during the lockdown, except for circulatory assistance, which increased. After the lockdown, mechanical complications of MI and aortic aneurysm rupture increased, and cardiac transplantations declined compared with previous years., Conclusion: We confirmed a deep drop in most cardiovascular surgical emergencies during the lockdown. The post-lockdown period was characterized by a small over-recovery for mechanical complications of MI and aortic aneurysm rupture, suggesting that many patients were able to access surgery after the lockdown.

Background and Purpose: Subset of macrophages within the atheroma plaque displays a high glucose uptake activity. Nevertheless, the molecular mechanisms and the pathophysiological significance of this high glucose need remain unclear. While the role for hypoxia and hypoxia inducible factor 1α has been demonstrated, the contribution of lipid micro-environment and more specifically oxysterols is yet to be explored., Experimental Approach: Human macrophages were conditioned in the presence of homogenates from human carotid plaques, and expression of genes involved in glucose metabolism was quantified. Correlative analyses between gene expression and the oxysterol composition of plaques were performed., Key Results: Conditioning of human macrophages by plaque homogenates induces expression of several genes involved in glucose uptake and glycolysis including glucose transporter 1 (SLC2A1) and hexokinases 2 and 3 (HK2 and HK3). This activation is significantly correlated to the oxysterol content of the plaque samples and is associated with a significant increase in the glycolytic activity of the cells. Pharmacological inverse agonist of the oxysterol receptor liver X receptor (LXR) partially reverses the induction of glycolysis genes without affecting macrophage glycolytic activity. Chromatin immunoprecipitation analysis confirms the implication of LXR in the regulation of SLC2A1 and HK2 genes., Conclusion and Implications: While our work supports the role of oxysterols and the LXR in the modulation of macrophage metabolism in atheroma plaques, it also highlights some LXR-independent effects of plaques samples. Finally, this study identifies hexokinase 3 as a promising target in the context of atherosclerosis., Linked Articles: This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc., (© 2020 The British Pharmacological Society.)

Atherosclerotic carotid artery stenosis causes about 10-20% of all ischemic strokes through two main mechanisms: hemodynamic impairment in case of significant stenosis and thromboembolism from an atherosclerotic plaque regardless of the degree of stenosis. The latter is the most frequent mechanism and appear to result from embolization from a vulnerable atherosclerotic plaque or acute occlusion of the carotid artery and propagation of thrombus distally. Downstream infarcts may occur in a territory of major cerebral artery or at the most distal areas between two territories of major cerebral arteries, the so-called watershed (WS), or border zone area. Although WS infarcts, especially deep WS infarct, were historically thought to be due to hemodynamic compromise, the role of microembolism has also been documented, both mechanisms may act synergistically to promote WS infarcts. Routine and more advanced imaging techniques may provide information on the underlying mechanism involved in ipsilateral ischemic stroke. A better understanding of ischemic stroke pathogenesis in carotid stenosis may limit the use of routine non-selective shunt, whose benefit-risk balance is debated, to patients with hemodynamic impairment. After reviewing existing evidence underpinning the contribution of the two mechanisms in downstream ischemic stroke and the various imaging techniques available to investigate them, we will focus on the pathogenesis of WS infarcts that remains debated., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-20-7490). The series “Carotid Artery Stenosis and Stroke—Prevention and Treatment Part II” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Background and Purpose: Because of several methodological limitations, previous studies focusing on the prevalence of large vessel occlusion in ischemic stroke (IS) patients provided conflicting results. We evaluated the incidence of IS with a visible arterial occlusion using a comprehensive population-based registry., Methods: Patients with acute IS were prospectively identified among residents of Dijon, France, using a population-based registry (2013-2017). All arterial imaging exams were reviewed to assess arterial occlusion. Annual incidence rates of IS (first-ever and recurrent events) and IS with a visible occlusion were calculated., Results: One thousand sixty cases of IS were recorded (mean age: 76.0±15.8 years, 53.9% women). Information about arterial imaging was available in 971 (91.6%) of them, and only preexisting dementia was independently associated with having missing information (odds ratio=0.34 [95% CI, 0.18-0.65], P =0.001). Among these patients, 284 (29.2%) had a visible arterial occlusion. Occlusion site was the anterior circulation in 226 patients (23.3% of overall patients with available data) and the posterior circulation in 58 patients (6.0%). A proximal occlusion of the anterior circulation was observed in 167 patients (17.2%). The crude annual incidence rate of total IS per 100 000 was 138 (95% CI, 129-146). Corresponding standardized rates were 66 (95% CI, 50-82) to the World Health Organization and 141 (95% CI, 118-164) to the 2013 European populations. The crude annual incidence rate of IS with a visible arterial occlusion per 100 000 was 37 (95% CI, 33-41) and that of IS with a proximal occlusion of the anterior circulation was 22 (95% CI, 18-25). Corresponding standardized rates were 18 (95% CI, 10-26) and 10 (95% CI, 8-13) to the World Health Organization population, and 38 (95% CI, 26-50) and 23 (95% CI, 19-26) to the 2013 European population, respectively., Conclusions: These results will be helpful to plan the need for thrombectomy-capable stroke center resources.

Background and Purpose- The ongoing ageing population is associated with an increasing number of patients with stroke who have preexisting cognitive impairment. This study aimed to evaluate clinical severity in patients with ischemic stroke according to prestroke cognitive status. Methods- Patients with ischemic stroke were prospectively identified among residents of Dijon, France using a population-based registry (2013-2017). Prestroke cognitive status (no impairment, mild cognitive impairment [MCI], or dementia) was recorded, and severity at stroke onset was measured using the National Institutes of Health Stroke Scale (NIHSS) score. Association between prestroke cognitive status and severity was evaluated using ordinal regression analysis models in which the NIHSS score was considered as a categorical variable. Results- Among the 1048 patients (mean age, 76.3±15.2 years; 54.0% women), a greater severity was observed in those with MCI (n=132; median NIHSS: 6; interquartile range, 2-15), and those with dementia (n=164; median NIHSS: 7; interquartile range, 3-16), than in patients without cognitive impairment (n=752; median NIHSS: 3; interquartile range, 1-9). MCI (odds ratio [OR], 1.70 [95% CI, 1.21-2.38]; P =0.002) and dementia (OR, 2.24 [95% CI, 1.65-3.04]; P <0.001) were both associated with a greater severity at onset. The association was still observed after adjustment for clinical variables and proximal arterial occlusion (OR, 1.52 [95% CI, 1.02-2.28]; P =0.04 for MCI; OR, 2.16 [95% CI, 1.45-3.22]; P <0.001 dementia). Further adjustment for prestroke handicap slightly reduced the magnitude of the association (OR, 1.49 [95% CI, 0.98-2.25]; P =0.06 for MCI, and OR, 1.98 [95% CI, 1.26-3.12]; P =0.02 for dementia). The greater severity in patients with prestroke cognitive impairment was not specifically driven by a more severe impairment of either motor or language function. Conclusions- Patients with preexisting cognitive impairment suffered more severe ischemic stroke. This result could reflect a lower brain tolerance of acute ischemia. Further studies are needed to explore the underlying mechanisms that could be targeted from therapeutic perspectives focusing on neuroprotection.

Low-grade inflammation is constitutive of atherosclerosis, and anti-inflammatory therapy inhibiting interleukin-1β (IL-1β) reduces the rate of cardiovascular events. While cholesterol accumulation in atheroma plaque and macrophages is a major driver of the inflammatory process, the role of the LXR cholesterol sensors remains to be clarified. Murine and human macrophages were treated with LXR agonists for 48 h before Toll-like receptor (TLR) stimulation. Unexpectedly, we observe that, among other cytokines, LXR agonists selectively increase IL1B mRNA levels independently of TLR activation. This effect, restricted to human macrophages, is mediated by activation of HIF-1α through LXR. Accordingly, LXR agonists also potentiate other HIF-1α-dependent pathways, such as glycolysis. Treatment of human macrophages with carotid plaque homogenates also leads to induction of IL1B in an LXR-dependent manner. Thus, our work discloses a mechanism by which cholesterol and oxysterols trigger inflammation in atherosclerosis. This suggests perspectives to target IL-1β production in atherosclerotic patients., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Beyond the age of 80 years, the preventive treatment of an asymptomatic abdominal aortic aneurysm (AAA) has to be decided in light of the life expectancy which it is difficult to evaluate, but it is important to determine who in this population will benefit from it. The objective of our study was to determine the factors influencing short-term mortality and long-term survival in patients aged 80 years and older after the endovascular treatment of AAAs (EVAR)., Material and Methods: We present a retrospective analysis of the prospective databases of 4 French academic departments of vascular surgery, bringing together the data of all the patients presenting an AAA who were treated by EVAR between 1998 and 2011. Logistic regression and multivariate analysis with a Cox survival model were used to determine the factors influencing perioperative and long-term mortality. The cumulative rate of events for the measurement of survival was calculated with the technique of Kaplan-Meier., Results: We treated 345 octogenarians and 339 younger patients. The average follow-up was 40 months. Average survival was 75% at 36 months and 49% at 60 months. There was no evidence of any risk factor influencing mortality at 30 days in the octogenarians. However, chronic kidney disease (odds ratio [OR] = 3.95, P <0.001) and chronic respiratory failure (OR = 2.62, P <0.001) proved to be independent factors of a poor long-term prognosis., Conclusions: The treatment by stent graft in octogenarians is effective in the long term. The presence of an impaired renal function or respiratory failure in this population could put into question the operative indication., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: The prevalence of obesity is increasing, and its impact on the outcome of open and endovascular abdominal aortic aneurysm (AAA) repair remains unclear, particularly in the European population. We herein assessed the impact of obesity on the postoperative course for both techniques., Methods: From a database that consecutively collects all patients undergoing AAA repair; we selected all patients undergoing elective surgery for open or endovascular AAA repair, between January 2003 and December 2011. We considered obese patients (body mass index >30 kg/m(2)), overweight (25.1-30 kg/m(2)), and normal-weight patients (18.7-25 kg/m(2)), and compared mortality and/or severe complications at 30 days between obese and nonobese patients (overweight and normal weight) separately for each type of surgery by logistic regression analysis. We analyzed wound complications in the 2 groups., Results: We included 748 patients, 174 obese, and 574 nonobese patients. Obese patients were younger (P < 0.001) and were less likely to have renal failure (P < 0.001) in both techniques. Obese patients in the open repair (OR) group showed a trend toward lower mortality and/or complication rates than in nonobese patients (4.8% vs. 7.5%, P = 0.34). In contrast, in the endovascular aortic aneurysm repair (EVAR) group, obese patients showed a trend toward higher mortality and/or complication rates than nonobese patients (7.1% vs. 3.2%, P = 0.17). In multivariate analysis, obesity was not an independent predictor of outcomes in OR (P = 0.18) or in EVAR (P = 0.20). Wound complications were not higher in obese patients in OR and in EVAR., Conclusions: Obesity should not be considered an independent risk factor of death and severe complications at 30 days in either open or endovascular AAA repair. Therefore, obesity should not systematically lead to the decision to use EVAR., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Catechins are flavonoids with suggested health benefits, but are unstable during storage, processing and, after ingestion, during gut transit. We hypothesized that catechin glucosides, which occur in various plants, could be more stable than unsubstituted catechin, and additionally be deglucosylated in the gut and so act to deliver catechin in a form able to be absorbed. (+)-Catechin O-glucosides from various sources have been used in the course of this investigation. (+)-Catechin 3'-O-beta-D-glucopyranoside (C3'G), (+)-catechin 5-O-beta-D-glucopyranoside (C5G), and (+)-catechin 3-O-beta-D-glucopyranoside (C3G) were chemically synthesized. (+)-Catechin 4'-O-beta-D-glucopyranoside (C4'G) and (+)-catechin 7-O-beta-D-glucopyranoside (C7G) were prepared enzymically using preparations from lentil and barley. In general, but with some exceptions, the (+)-catechin glucosides were more stable between pH 4 and 8 than (+)-catechin, with C3'G exhibiting greatest stability. The intestinal metabolism of (+)-catechin and all (+)-catechin glucosides in the gut was determined by perfusion of rat intestine in vivo. C3'G and C5G were extensively deglycosylated in the gut, and C3'G showed greatest apparent "absorption" as calculated by the difference between effluent and influent. The results show the potential of catechin glucosides, especially C3'G, as more stable prescursors of catechin.

Rosmarinic acid (RA) was identified as one of the main components of rosemary extracts and has been ascribed to a number of health benefits. Several studies suggested that after ingestion, RA is metabolized by gut microflora into caffeic acid and derivatives. However, only limited information on the microorganisms and enzymes involved in this biotransformation is available. In this study, we investigated the hydrolysis of RA from rosemary extract with enzymes and a probiotic bacterium Lactobacillus johnsonii NCC 533. Chlorogenate esterase from Aspergillus japonicus (0.02 U/mg) hydrolyzed 90% of RA (5 mg/mL) after 2 h at pH 7.0 and 40 degrees C. Complete hydrolysis of RA (5 mg/mL) was achieved with a preparation of L. johnsonii (25 mg/mL, 3.3 E9 cfu/g) after 2 h of incubation at pH 7.0 and 37 degrees C. No hydrolysis of RA was observed after the passage of rosemary extract through the gastrointestinal tract model (GI model). Thus, RA is hydrolyzed neither chemically under the conditions of the GI model (temperature, pH, and bile salts) nor by secreted enzymatic activity (lipase and pancreatic enzymes). The addition of L. johnsonii cells to rosemary extract in the GI model resulted in substantial hydrolysis of RA (up to 99%).

The exporter ABCC2 (cMOAT, MRP2) is a membrane-bound protein on the apical side of enterocytes and hepatic biliary vessels that transports leukotriene C(4), glutathione, some conjugated bile salts, drugs, xenobiotics, and phytonutrients. The latter class includes quercetin, a bioactive flavonoid found in foods such as onions, apples, tea, and wine. There is no available three-dimensional (3D) structure of ABCC2. We have predicted the 3D structure by in silico modeling, showing that 3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid (MK571) binds most tightly to the putative binding site, and then tested the computational prediction experimentally by measuring interaction with all quercetin monoglucuronides occurring in vivo (quercetin substituted with glucuronic acid at the 3-, 3'-, 4'-, and 7-hydroxyl groups). The 4'-O-beta-D-glucuronide is predicted in silico to interact most strongly and the 3-O-beta-D-glucuronide most weakly, and this prediction is supported experimentally using binding and competition assays on ABCC2-overexpressing baculovirus-infected Sf9 cells. To test the transport in situ, we examined the effect of two ABCC2 inhibitors, MK571 and cyclosporin A, on the transport into the media of quercetin glucuronides produced intracellularly by Caco2 cells. The inhibitors reduced the amount of all quercetin glucuronides in the media. The results show that the molecular model of ABCC2 agrees well with experimentally determined ABCC2-ligand interactions and, importantly, that the interaction of ABCC2 with quercetin glucuronides is dependent on the position and nature of substitution.

Catechin is a flavonoid present in fruits, wine and cocoa products. Most foods contain the (+)-enantiomer of catechin but chocolate mainly contains ( - )-catechin, in addition to its major flavanol, ( - )-epicatechin. Previous studies have shown poor bioavailability of catechin when consumed in chocolate. We compared the absorption of ( - ) and (+)-catechin after in situ perfusion of 10, 30 or 50 micromol/l of each catechin enantiomer in the jejunum and ileum in the rat. We also assayed 23 samples of chocolate for (+) and ( - )-catechin. Samples were analyzed using HPLC with a Cyclobond I-2000 RSP chiral column. At all concentrations studied, the intestinal absorption of ( - )-catechin was lower than the intestinal absorption of (+)-catechin (p < 0.01). Plasma concentrations of ( - )-catechin were significantly reduced compared to (+)-catechin (p < 0.05). The mean concentration of ( - )-catechin in chocolate was 218 +/- 126 mg/kg compared to 25 +/- 15 mg/kg (+)-catechin. Our findings provide an explanation for the poor bioavailability of catechin when consumed in chocolate or other cocoa containing products.

Using mice deficient in hepatic cytochrome P-450 oxidoreductase (POR), which disables the liver cytochrome P-450 system, we examined the metabolism and biological response of the anticarcinogenic flavonoid, quercetin. Profiling circulating metabolites revealed similar profiles over 72 h in wild-type (WT) and POR-null (KO) mice, showing that hepatic P450 and reduced biliary secretion do not affect quercetin metabolism. Transcriptional profiling at 24 h revealed that two- to threefold more genes responded significantly to quercetin in WT compared with KO in the jejunum, ileum, colon, and liver, suggesting that hepatic P450s mediate many of the biological effects of quercetin, such as immune function, estrogen receptor signaling, and lipid, glutathione, purine, and amino acid metabolism, even though quercetin metabolism is not modified. The functional interpretation of expression data in response to quercetin (single dose of 7 mg/animal) revealed a molecular relationship between the liver and jejunum. In WT animals, amino acid and sterol metabolism was predominantly modulated in the liver, fatty acid metabolism response was shared between the liver and jejunum, and glutathione metabolism was modulated in the small intestine. In contrast, KO animals do not regulate amino acid metabolism in the liver or small intestine, they share the control of fatty acid metabolism between the liver and jejunum, and regulation of sterol metabolism is shifted from the liver to the jejunum and that of glutathione metabolism from the jejunum to the liver. This demonstrates that the quercetin-mediated regulation of these biological functions in extrahepatic tissues is dependent on the functionality of the liver POR. In conclusion, using a systems biology approach to explore the contribution of hepatic phase 1 detoxification on quercetin metabolism demonstrated the resiliency and adaptive capacity of a biological organism in dealing with a bioactive nutrient when faced with a tissue-specific molecular dysfunction.

There is good evidence from in vitro studies that green tea catechins have a role in protection against degenerative diseases. However, the concentrations used in vitro are often higher than those found in animal or human plasma, and so in vivo evidence is required to demonstrate any protective effect of catechins. This article summarizes the most interesting in vivo animal studies on the protective effects of green tea catechins against biomarkers for cancer, cardiovascular disease, and other degenerative diseases. Generally, most studies using animal models show that consumption of green tea (catechins) provides some protection, although most studies have not examined dose response. Tea catechins could act as antitumorigenic agents and as immune modulators in immunodysfunction caused by transplanted tumors or by carcinogen treatment. Green tea has antiproliferative activity in hepatoma cells and hypolipidemic activity in hepatoma-treated rats, and some studies report that it prevents hepatoxicity. It could act as a preventive agent against mammary cancer postinitiation. Nevertheless, the implications of green tea catechins in preventing metastasis have not been clearly established. Long-term feeding of tea catechins could be beneficial for the suppression of high-fat diet-induced obesity by modulating lipid metabolism, could have a beneficial effect against lipid and glucose metabolism disorders implicated in type 2 diabetes, and could also reduce the risk of coronary disease. Further investigations on mechanisms, the nature of the active compounds, and appropriate dose levels are needed.

The flavonoids (-)-epigallocatechin-3-gallate (EGCg) and (-)-epicatechin-3-gallate (ECg) are major components of green tea and show numerous biological effects. We investigated the glucuronidation of these compounds and of quercetin by microsomes. Quercetin was almost fully glucuronidated by liver microsomes after 3 h, whereas ECg and ECGg were conjugated to a lesser extent (12.2 +/- 0.2 and 7.5 +/- 0.2%, respectively). The intestinal microsomes also glucuronidated quercetin much more efficiently than ECg and EGCg. Although the rates were lower than quercetin, intestinal microsomes exhibited higher activity on the galloyl group of ECg and EGCg compared to the flavonoid ring, whereas hepatic glucuronidation was higher on the flavonoid ring of EGCg and ECg compared to the galloyl groups. The low glucuronidation rates could partially explain why these flavanols are present in plasma as unconjugated forms.

The absorption and splanchnic metabolism of different flavonoids (namely quercetin, kaempferol, luteolin, eriodictyol, genistein, and catechin) were investigated in rats after an in situ perfusion of jejunum plus ileum (14 nmol/min). Net transfer across the brush border ranged widely according to the perfused compound (from 78% for kaempferol to 35% for catechin). This variation seems linked to the lipophilicity of a given flavonoid rather than to its three-dimensional structure. Except for catechin, conjugated forms of perfused flavonoids were also detected in the intestinal lumen, but the extent of this secretion depended on the nature of the perfused compounds (52% for quercetin to 11% for genistein). For some of the perfused aglycones, biliary secretion was an important excretion route: 30% of the perfused dose for genistein but only 1% for catechin. Thus the splanchnic metabolism of flavonoid is controlled by several factors: 1) the efficiency of their transfer through the brush border, 2) the intensity of the intestinal secretion of conjugates toward the mucosal and serosal sides, respectively, and 3) the biliary secretion of conjugates. These data suggested that the splanchnic metabolism of perfused flavonoids depends on the nature of the compound considered, which in turn influences their availability for peripheral tissues.

The physiologic importance of ferulic acid (FA), and notably its antioxidant properties, depends upon its availability for absorption and subsequent interaction with target tissues. Because FA is widely present in cereals, the aim of the present study was to investigate its intestinal and hepatic metabolism in rats by in situ intestinal perfusion model (from 10 to 50 nmol/min), and its bioavailability in supplemented diets (from 10 to 250 micromol/d) or in a complex cereal matrix, i.e., whole flours from Valoris (Triticum aestivum) or Duriac (T. durum) cultivars and bran or white flour from the Valoris cultivar. In perfused rat intestine, net FA absorption was proportional to the perfused dose (R2 = 0.997); once absorbed, FA was completely recovered as conjugated forms in plasma and bile secretion (representing 5-7% of the perfused dose). In rats fed FA-enriched semipurified diets, FA absorption was quite efficient because approximately 50% of the ingested dose was recovered in urine. This extensive elimination by kidneys limited FA accumulation in plasma (typically 1 micromol/L in rats fed 50 micromol FA/d). In contrast, in rats fed cereal diets providing 56-81 micromol FA/d, urine excretion was 90-95% lower than in rats fed FA-enriched semipurified diets, and plasma concentrations were approximately 0.2-0.3 micromol/L. Thus, the cereal matrix appears to severely limit FA bioavailability. This inherently low bioavailability of FA in cereals likely reflects FA association with the fiber fraction through cross-linking with arabinoxylans and lignins.

Absorption and metabolism of quercetin, isoquercitrin (quercetin 3-O-glucose), and rutin (quercetin 3-O-glucose-rhamnose) were investigated in rats after in situ gastric administration (15 micromol/L) for 30 min. At the end of the experiment, 38% of the initial dose of quercetin had disappeared. Quercetin was rapidly absorbed by the stomach, and was recovered in the bile 20 min after infusion (4.07 +/- 0.10 micromol/L). The administration of rutin and isoquercitrin indicated that these glycosides were not hydrolyzed nor absorbed by this tissue. In conclusion, when flavonols are present in the diet as aglycons, they could be partly absorbed in the stomach, in contrast to their glycosidic forms which are not absorbed.

Several studies suggest that polyphenols might exert a protective effect against osteopenia. The present experiment was conducted to observe the effects of rutin (quercetin-3-O-glucose rhamnose) on bone metabolism in ovariectomized (OVX) rats. Thirty 3-month-old Wistar rats were used. Twenty were OVX while the 10 controls were sham-operated (SH). Among the 20 OVX, for 90 days after surgery 10 were fed the same synthetic diet as the SH or OVX ones, but 0. 25% rutin (OVX + R) was added. At necropsy, the decrease in uterine weight was not different in OVX and OVX + R rats. Ovariectomy also induced a significant decrease in both total and distal metaphyseal femoral mineral density, which was prevented by rutin consumption. Moreover, femoral failure load, which was not different in OVX and SH rats, was even higher in OVX + R rats than in OVX or SH rats. In the same way, on day 90, both urinary deoxypyridinoline (DPD) excretion (a marker for bone resorption) and calciuria were higher in OVX rats than in OVX + R or SH rats. Simultaneously, plasma osteocalcin (OC) concentration (a marker for osteoblastic activity) was higher in OVX + R rats than in SH rats. High-performance liquid chromatography (HPLC) profiles of plasma samples from OVX + R rats revealed that mean plasma concentration of active metabolites (quercetin and isorhamnetin) from rutin was 9.46+/-1 microM, whereas it was undetectable in SH and OVX rats. These results indicate that rutin (and/or its metabolites), which appeared devoid of any uterotrophic activity, inhibits ovariectomy-induced trabecular bone loss in rats, both by slowing down resorption and increasing osteoblastic activity.

The effect of the nature of the sugar moiety on quercetin absorption has been investigated in rats. Four groups of rats received an experimental meal containing 20 mg of quercetin equivalents, supplied as quercetin, quercetin 3-O-beta-glucoside, quercetin 3-O-beta-rhamnoside or rutin. Four hours after the meal, the metabolites identified in hydrolysed plasma were identical in all groups (3'- and 4'-methylquercetin). However, the total concentration of metabolites was markedly different: 11.2+/-1.8, 2.5+/-2.0 and 33.2+/-3.5 microM for the quercetin, rutin, and quercetin 3-glucoside meals respectively. After quercetin 3-rhamnoside consumption, we failed to detect any metabolites in the plasma. These data suggest that the 3-O-glucosylation improves the absorption of quercetin in the small intestine, whereas the binding of a rhamnose to the aglycone markedly depresses it. Additional experiments have shown that the higher plasma levels measured after quercetin 3-glucoside meal compared to the quercetin meal were maintained throughout the 24-hour period following the meal. Using a multi-electrode coulometric detection, together with suitable chromatographic conditions, we were able to distinguish between the conjugated and the glycosylated forms. Thus, we clearly showed the absence of quercetin 3-O-beta-glucoside in the plasma from rats fed a diet containing this glucoside. This result suggests that quercetin 3-O-beta-glucoside is hydrolysed before or during its intestinal absorption.

A large number of flavonoids, mostly O-glycosides, are found in foods of plant origin. The bound sugar moiety is known to influence their bioavailability. We examined here the effect of the nature of the sugar on the absorption of the glycosides. Four groups of rats (n = 6) received a meal containing 20 mg of quercetin equivalents supplied as aglycone, quercetin 3-glucoside, quercetin 3-rhamnoside or rutin. Plasma were hydrolysed by a beta-glucuronidase/sulfatase and analyzed by HPLC coupled to UV detection at 370 nm. Four hours after the beginning of the meal, the quercetin metabolites present in plasma were identical in all groups but their total concentrations were quite different. With pure quercetin the circulating levels were 1.7 +/- 1.8 microM, but this level was three fold higher when quercetin was supplied as quercetin 3-glucoside (33.2 +/- 3.5 microM). By contrast, the plasma concentrations of quercetin metabolites was quite low with the rutin meal (about 3 microM) and undetectable after the quercetin 3-rhamnoside meal. These data suggest that the 3-O-glucosylation improves the absorption of quercetin in the small intestine, whereas the binding of a rhamnose or of a glucose-rhamnose moiety to the aglycone markedly depressed its absorption. Additionnal experiments have shown that the higher plasma levels measured after the meal containing quercetin 3-glucoside compared to quercetin were maintained throughout a 24 hour period following the meal. In conclusion, the nature of the glycosylation markedly influences the efficiency of quercetin absorption in rats. Quercetin 3-glucose can be absorbed in the small intestine and is better absorbed than quercetin itself. By contrast, glycosides containing a rhamnose moiety could not be absorbed in the small intestine.

Rutin and quercetin absorption and metabolism were investigated in rats after in situ perfusion of jejunum plus ileum (15 nmol/min). In contrast to rutin, a high proportion of quercetin (two-thirds) disappeared during perfusion, reflecting extensive transfer into the intestinal wall. Net quercetin absorption was not complete (2.1 nmol/min), inasmuch as 52% were reexcreted in the lumen as conjugated derivatives (7.7 nmol/min). Enterohepatic recycling contribution of flavonoids was excluded by catheterization of the biliary duct before perfusion. After a 30-min perfusion period, 0.71 microM of quercetin equivalents were detected in plasma, reflecting a significant absorption from the small intestine. The differential hydrolysis of effluent samples by glucuronidase and/or sulfatase indicates that the conjugated forms released in the lumen were 1) glucuronidated derivatives of quercetin and of its methoxylated forms (64%) and 2) sulfated form of quercetin (36%). In vitro quercetin glucuronides synthetized using jejunal and ileal microsomal fractions were similar to those recovered in the effluent of perfusion. These data suggest that glucuronidation and sulfatation take place in intestinal cells, whereas no glucurono-sulfoconjugates could be detected in the effluent. The present work shows that a rapid quercetin absorption in the small intestine is very effective together with its active conjugation in intestinal cells.

Quercetin is one of the most widely distributed flavonoids present in fruits and vegetables. The present experiments were performed on rats adapted for 3 wk to a semipurified diet supplemented with 0.2% quercetin. The major part of the circulating metabolites of quercetin (91.5%) are glucurono-sulfo conjugates of isorhamnetin (3'-O-methyl quercetin; 89.1 +/- 2.1 microM) and of quercetin (14.7 +/- 1.7 microM); the minor part (8.5%) is constituted by glucuronides of quercetin and its methoxylated forms (9.6 +/- 2.3 microM). Conjugated dienes formation, resulting from Cu2+-catalyzed oxidation of rat very low density lipoproteins + low density lipoproteins (LDL), was effectively inhibited in vitro by conjugated metabolites of quercetin. These metabolites appeared to be four times more potent than trolox in inhibiting LDL oxidation. Moreover, the plasma from rats adapted to a diet containing 0.2% quercetin exhibited a total antioxidant status markedly higher than that of control rats (+60%). This study shows that ubiquitous quercetin is conjugated in vivo, yielding metabolites that exhibit antioxidant properties. Thus the health benefits of flavonoids in foods can be due to the antioxidant properties of their metabolites.