Low Dietary Flavonoid Consumption Is Associated to Severe Inflammatory Bowel Disease.

Background and Aims: Associations between diet habits and inflammatory bowel disease (IBD) have been widely described. Flavonoids are taken with vegetables, fruits, and green tea. Because of barrier-protective and anti-inflammatory effects, flavonoid consumption (FC) may influence the severity of IBD. The aim of this study was to reveal the role of FC in the course and severity of IBD. Methods: A prospective cohort study including 204 IBD patients (Crohn's disease n = 126, ulcerative colitis n = 78) was conducted between 2016 and 2021. FC was calculated using questionnaires. In addition to standard activity scores and different treatments, a "severity index" was related to individual FC. Differences between groups and odds ratios were analyzed. Results: Inverse correlation (r = -0.0549; P = .01) between FC and severity of IBD was found. Patients were assigned to 3 different severity index ranges: mild, moderate, and severe disease. FC of patients with severe disease (331 ± 330 mg/week) was less than FC of patients with mild (1404 ± 1086 mg/ week) disease (P < .001). The risk of IBD patients with low FC (1000 mg/week) experiencing overall severe disease was 17 times increased (P < .001) compared to patients with high FC (>1000 mg/week). Patients with UC and low FC had a 9.6-times higher risk for disease progression (P < .001). Conclusion: Consumption of dietary flavonoids and the overall severity of IBD are inversely correlated. Patients with mild diseases consume higher amounts of flavonoids than patients with severe diseases. Low dietary flavonoids were related to a considerable risk of severe IBD.

Differential effects of dietary polyphenols on oral pharmacokinetics of cyclin-dependent kinase inhibitors in rats: a mechanistic framework for in vitro-in vivo extrapolation.

OBJECTIVES: Cyclin-dependent kinase inhibitors are subject to rapid first-pass metabolism, and their oral absorption is hindered by intestinal CYP3A4 and P-gp. The present study investigates the impact of dietary polyphenols on the oral pharmacokinetics of palbociclib and ribociclib, considering their potential as modulators of CYP3A4 and P-gp. METHODS: Therefore, potential inhibitory effects of dietary polyphenols on drug metabolism and efflux of these drugs were investigated using molecular docking; in vitro preclinical assay using rat liver microsomes and Caco-2 cell monolayers; in vivo, pharmacokinetic parameters were determined in rats pretreated with dietary polyphenols. KEY FINDINGS: Curcumin and quercetin have the highest binding affinities to the PXR's AF-2 region cluster. Curcumin and quercetin significantly inhibited both intestinal efflux and CYP3A4-mediated metabolism of palbociclib and ribociclib (P < .05). In rats pretreated with curcumin, Cmax of palbociclib exhibited a 5.13% increase, while the AUC0-24h of ribociclib showed a significant increase of 18.83% (P < .05). Quercetin administration, notably, impedes the pharmacokinetics of palbociclib. However, the pharmacokinetics of ribociclib remains unaffected by quercetin. CONCLUSIONS: In conclusion, the utilization of curcumin as a bioenhancer can enhance the bioavailability of dual substrates of P-gp and CYP3A4.

The activity comparison of six dietary flavonoids identifies that luteolin inhibits 3T3-L1 adipocyte differentiation through reducing ROS generation.

Mitochondrial reactive oxygen species (ROS)generation plays an essential role in the process of adipocyte differentiation and is involved in the development of obesity and associated metabolic diseases. Various dietary flavonoids possess the substantial anti-adipogenic activity. However, it is unclear whether these flavonoids inhibit adipocyte differentiation by reducing ROS generation. In this study, the effects of six common dietary flavonoids on adipocyte differentiation were assessed in 3T3-L1 cells. The flavonoids with the same backbone of 5,7-dihydroxylflavone, including flavones apigenin, chrysin, luteolin and flavonols kaempferol, myricetin, quercetin, dose-dependently inhibited 3T3-L1 adipocyte differentiation, suggesting an associated hierarchy of inhibitory capability: luteolin > quercetin > myricetin > apigenin/kaempferol > chrysin. Meanwhile, six flavonoids were found to inhibit adipogenic gene expression and the early stage of adipocyte differentiation. Among the tested flavonoids, luteolin significantly reduced both intracellular and mitochondrial ROS generation during adipocyte differentiation. Further, luteolin treatment depressed the elevation of H2O2 concentration in the early stage of 3T3-L1 differentiation and reversed the facilitated effects of exogenous H2O2 on 3T3-L1 adipocyte differentiation and ROS generation. Altogether, the activity comparison of six dietary flavonoids identifies that luteolin inhibits 3T3-L1 adipocyte differentiation through reducing ROS generation, elucidating a new mechanism underlying the anti-adipogenic actions of flavonoids.

Protective Effects of Chrysin against Cyclophosphamide-Induced Cardiotoxicity in Rats: A Biochemical and Histopathological Approach.

Mounting evidences have indicated that cyclophosphamide (CyC)a potent anticancer and cytotoxic agent is associated with various organ and systemic toxicities and the cytotoxic effects observed after administration of CyC still challenges its clinical use. Chrysin (Chy) is a dietary flavonoid with prevailing antioxidant and anti-inflammatory properties. This study evaluated the protective properties of Chy against CyC-induced cardiotoxicity in rats. The animals were orally treated with Chy (25 and 50 mg/kg/day) for 35 days and exposed to CyC (i. p., 100 mg/kg) once a week for four weeks. The results indicated that CyC caused significant cardiotoxicity as manifested by notable increases in heart weight, cardiac function biomarkers such as lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), troponin T and aspartate transaminase (AST). In addition, cardiac malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α), interleukin 1ß (IL1 ß) and interleukin 6 (IL-6) levels were considerably increased. Meanwhile, cardiac antioxidant enzymes activities such as superoxide dismutase (SOD) and catalase (CAT), as well as glutathione (GSH) level were suppressed, while H&E stained histopathological assessment showed marked alterations in cardiac tissues. CyC also significantly lowered red blood cells (RBC) and white blood cells (WBC) parameters, whereas treatment with Chy significantly restored the altered biochemical and histopathological features. Conclusively, aforementioned results inferred that Chy offered cardioprotective potentials against CyC-induced cardiotoxicity which may be due to its antioxidant, and anti-inflammatory properties.

Dietary flavonoid intake and risk of esophageal squamous cell carcinoma: A population-based case-control study.

OBJECTIVES: The aim of this population-based case-control study was to investigate the association between dietary consumption of the total flavonoids, subclasses, and specific flavonoids and the risk of esophageal squamous cell carcinoma (ESCC) among adults in a high-risk area of China. METHODS: We recruited 820 ESCC participants and 863 control participants from Yanting County. Dietary flavonoids were assessed using a validated 76-item food frequency questionnaire. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using logistic regression after considering potential confounders. RESULTS: Comparing the highest and lowest intake quartiles, we observed a negative association of ESCC risk with consumption of isoflavones (OR = 0.34, 95% CI = 0.23-0.50, P for trend < 0.001), daidzein (OR = 0.31, 95% CI = 0.21-0.45, P for trend < 0.001), genistein (OR = 0.34, 95% CI = 0.23-0.50, P for trend < 0.001), and glycitein (OR = 0.32, 95% CI = 0.22-0.48, P for trend < 0.001) after adjustment for potential confounders. A more pronounced negative association was observed when comparing the third quartile, rather than the fourth, with the lowest quartile for consumption of anthocyanidins (OR = 0.58, 95% CI = 0.42-0.80, P for trend = 0.004), delphinidin (OR = 0.57, 95% CI = 0.41-0.78, P for trend = 0.004), and cyanidin (OR = 0.48, 95% CI = 0.35-0.66, P for trend = 0.003) after considering potential confounders. Consumption of total flavonoids, flavones, flavonols, and six other specific flavonoids (quercetin, myricetin, kaempferol, luteolin, apigenin, and peonidin) was not associated with ESCC risk. CONCLUSIONS: The results suggest that increased dietary intake of isoflavones and moderate consumption of anthocyanidins were associated with a decreased risk of ESCC. Future nutritional guidelines may emphasize foods or supplements rich in specific isoflavones and anthocyanidins for ESCC chemoprevention.

Long-term dietary flavonoid intake and risk of Alzheimer disease and related dementias in the Framingham Offspring Cohort.

BACKGROUND: Findings from existing prospective observational studies on the protective associations of flavonoid intake and the risk of Alzheimer disease and related dementias (ADRD) are inconsistent largely due to limitations of these studies. OBJECTIVES: To examine the prospective relation between total and 6 classes of dietary flavonoid intake and risk of ADRD and Alzheimer disease (AD) while addressing limitations of earlier observational studies. METHODS: We used data from the Framingham Heart Study Offspring Cohort exams 5 through 9. Participants were ADRD-free with a valid FFQ at baseline. Flavonoid intakes were updated at each exam to represent the cumulative average intake across the 5 exams, and were expressed as percentile categories of intake (≤15th, >15th to 30th, >30th to 60th, >60th) to handle their nonlinear relation with ADRD and AD. Cox proportional hazards regression was used to estimate the HRs for the association between the flavonoid intakes and incidence of ADRD and AD. RESULTS: Over an average follow-up of 19.7 y in 2801 participants (mean baseline age = 59.1 y; 52% females), there were 193 ADRD events of which 158 were AD. After multivariate and dietary adjustments, individuals with the highest (>60th percentile) intakes of flavonols, anthocyanins, and flavonoid polymers had a lower risk of ADRD relative to individuals with the lowest intakes (≤15th percentile), with HRs (95% CI; P-trend) of 0.54 (0.32, 0.90; P = 0.003) for flavonols, 0.24 (0.15, 0.39; P < 0.001) for anthocyanins, and 0.58 (0.35, 0.94; P = 0.03) for flavonoid polymers. The same pattern of associations was seen with AD for flavonols and anthocyanins but not for flavonoid polymers. CONCLUSIONS: Our findings imply that higher long-term dietary intakes of flavonoids are associated with lower risks of ADRD and AD in US adults.

Beneficial Effects of Kaempferol after Developmental Traumatic Brain Injury Is through Protection of Mitochondrial Function, Oxidative Metabolism, and Neural Viability.

Oxidative energy metabolism is depressed after mild/moderate traumatic brain injury (TBI) during early development, accompanied by behavioral debilitation and secondary neuronal death. A TBI metabolome analysis revealed broad effects with a striking impact on energy metabolism. Our studies on mitochondrial modulators and their effects on brain function have shown that kaempferol, a stimulator of the mitochondrial Ca2+ uniporter channel (mCU), enhanced neural and neurovascular activity in the normal brain and improved stimulus-induced brain activation and behavior after TBI during early development. Because kaempferol enhances mitochondrial Ca2+ uptake and cycling, with protective effects after TBI, we tested the hypothesis that kaempferol treatment during the acute/subacute stage after TBI (0-72 h) acted on mitochondria in improving TBI outcome. Developmental age rats (P31) underwent TBI and were treated with vehicle or kaempferol (1 mg/kg intraperitoneally) in three doses at 1, 24, and 48 h after TBI. Brains were harvested at 72 h and subjected to liquid chromatography mass spectrometric measurements. Decrease in pyruvate and tricarboxylic acid (TCA) cycle flux were observed in the untreated and vehicle-treated group, consistent with previously established energy metabolic decline after TBI. Kaempferol improved TCA cycle flux, maintained mitochondrial functional integrity as observed by decreased acyl carnitines, improved neural viability as evidenced by higher N-acetyl aspartate levels. The positive outcomes of kaempferol on metabolic profile corresponded with improved sensorimotor behavior.

Recent Trends in Potential Therapeutic Applications of the Dietary Flavonoid Didymin.

Didymin (isosakuranetin 7-O-rutinoside) is an orally bioactive dietary flavonoid glycoside first found in citrus fruits. Traditionally, this flavonoid has long been used in Asian countries as a dietary antioxidant. Recent studies have provided newer insights into this pleiotropic compound, which could regulate multiple biological activities of many important signaling molecules in health and disease. Emerging data also presented the potential therapeutic application of dietary flavonoid glycoside didymin against cancer, neurological diseases, liver diseases, cardiovascular diseases, and other diseases. In this review, we briefly introduce the source and extraction methods of didymin, and summarize its potential therapeutic application in the treatment of various diseases, with an emphasis on molecular targets and mechanism that contributes to the observed therapeutic effects. The dietary flavonoid didymin can be used to affect health and disease with multiple therapeutic targets, and it is anticipated that this review will stimulate the future development of this potential dietary medicine.

Phloretin as a Potent Natural TLR2/1 Inhibitor Suppresses TLR2-Induced Inflammation.

Toll-like receptor 2 (TLR2) responses are involved in various inflammatory immune disorders. Phloretin is a naturally occurring dietary flavonoid that is abundant in fruit. Here, we investigated whether the anti-inflammatory activity of phloretin is mediated through TLR2 pathways, and whether phloretin acts as an inhibitor of TLR2/1 heterodimerization using the TLR2/1 agonist Pam3CSK4. We tested the effects of phloretin on tumor necrosis factor (TNF)-α production induced by various TLRs using known TLR-specific agonists. Phloretin significantly inhibited Pam3CSK4-induced TRL2/1 signaling in Raw264.7 cells compared to TLR signaling induced by the other agonists tested. Therefore, we further tested the effects of phloretin in human embryonic kidney (HEK) 293-hTLR2 cells induced by Pam3CSK4, and confirmed that phloretin has comparable inhibition of TLR2/1 heterodimerization to that induced by the known TLR2 inhibitor CU-CPT22. Moreover, phloretin reduced the secretion of the inflammatory cytokines TNF-α and interleukin (IL)-8 in Pam3CSK4-induced HEK293-hTLR2 cells, whereas it did not significantly reduce these cytokines under Pam2CSK4-induced activation. Western blot results showed that phloretin significantly suppressed Pam3CSK4-induced TLR2 and NF-κB p65 expression. The molecular interactions between phloretin and TLR2 were investigated using bio-layer interferometry and in silico docking. Phloretin bound to TLR2 with micromolar binding affinity, and we proposed a binding model of phloretin at the TLR2⁻TLR1 interface. Overall, we confirmed that phloretin inhibits the heterodimerization of TLR2/1, highlighting TLR2 signaling as a therapeutic target for treating TLR2-mediated inflammatory immune diseases.