Strategy to Improve the Oral Pharmacokinetics of Cyclin-Dependent Kinase 4/6 Inhibitors: Enhancing Permeability and CYP450 Inhibition by a Natural Bioenhancer.

Palbociclib and ribociclib an orally bioavailable, potent cyclin-dependent kinase 4/6 inhibitors, with low oral bioavailability due to substrate specificity towards CYP3A and P-glycoprotein. Thus, current research aims to examine the effect of a bioenhancer (naringin), on oral pharmacokinetics of palbociclib and ribociclib. Naringin's affinity for CYP3A4 and P-glycoprotein was studied using molecular docking; its impact on palbociclib/ribociclib CYP3A metabolism and P-glycoprotein-mediated efflux was examined using in vitro preclinical models; and its oral pharmacokinetics in rats were assessed following oral administration of palbociclib/ribociclib in presence of naringin (50 and 100 mg/kg). Naringin binds optimally to both proteins with the highest net binding energy of - 1477.23 and - 1607.47 kcal/mol, respectively. The microsomal intrinsic clearance of palbociclib and ribociclib was noticeably reduced by naringin (5-100 µM), by 3.0 and 2.46-folds, respectively. Similarly, naringin had considerable impact on the intestinal transport and efflux of both drugs. The pre-treatment with 100 mg/kg naringin increased significantly (p < 0.05) the oral exposure of palbociclib (2.0-fold) and ribociclib (1.95-fold). Naringin's concurrent administration of palbociclib and ribociclib increased their oral bioavailability due to its dual inhibitory effect on CYP3A4 and P-glycoprotein; thus, concurrent naringin administration may represent an innovative strategy for enhancing bioavailability of cyclin-dependent kinase inhibitors.

Dietary Flavonoids: Mitigating Air Pollution's Cardiovascular Risks.

Air pollution significantly impacts cardiovascular health, yet pollution reduction strategies in cardiovascular disease prevention remain limited. Dietary flavonoids show promise in protecting cardiovascular health, but their potential to mitigate air-pollution-induced risks is unexplored. This study investigates this research gap. Following PRISMA-ScR guidelines, literature from 2014-2024 was searched across MedLine/PubMed, ScienceDirect, and MDPI databases. Of 463 identified studies, 53 were eligible for analysis based on PICO criteria. Findings revealed significant impacts of air pollution on cardiovascular health, including increased disease risks and mortality. Flavonoid intake demonstrated protective effects against these risks. Flavonoid mechanisms include improved endothelial function, antioxidant and anti-inflammatory effects, blood pressure regulation, antiplatelet effects, cardioprotection, and enhanced lipid and glucose metabolism. Higher flavonoid intake was consistently associated with reduced cardiovascular risks. While reducing pollution remains crucial, promoting flavonoid-rich diets is a promising complementary strategy. Public health initiatives should raise awareness about these benefits. Further research on direct interactions between flavonoid intake and air pollution exposure is needed. Current evidence supports integrating dietary interventions into broader strategies to reduce air pollution's cardiovascular impacts.

Intestinal absorption mechanism and nutritional synergy promotion strategy of dietary flavonoids: transintestinal epithelial pathway mediated by intestinal transport proteins.

Dietary flavonoids exhibit a variety of physiological functions in regulating glucose and lipid metabolism, improving cardiovascular function, and enhancing stress resistance. However, poor intestinal absorption limits their health benefits. Previous studies on improving the absorption efficiency of flavonoids have focused on targeted release, enhanced gastrointestinal stability and prolonged retention time in digestive tract. But less attention has been paid to promoting the uptake and transport of flavonoids by intestinal epithelial cells through modulation of transporter protein-mediated pathways. Interestingly, some dietary nutrients have been found to modulate the expression or function of transporter proteins, thereby synergistically or antagonistically affecting flavonoid absorption. Therefore, this paper proposed an innovative regulatory strategy known as the "intestinal transport protein-mediated pathway" to promote intestinal absorption of dietary flavonoids. The flavonoid absorption mechanism in the intestinal epithelium, mediated by intestinal transport proteins, was summarized. The functional differences between the uptake transporter and efflux transporters during flavonoid trans-intestinal cellular transport were discussed. Finally, from the perspective of nutritional synergy promotion of absorption, the feasibility of promoting flavonoid intestinal absorption by regulating the expression/function of transport proteins through dietary nutrients was emphasized. This review provides a new perspective and developing precise dietary nutrient combinations for efficient dietary flavonoid absorption.

Mechanistic insight into the mode of inhibition of dietary flavonoids; targeting macrophage migration inhibitory factor.

Introduction: The Macrophage Migration Inhibitory Factor (MIF), a key pro-inflammatory mediator, is responsible for modulating immune responses. An array of inflammatory and autoimmune diseases has been linked to the dysregulated activity of MIF. The significance in physiological as well as pathophysiological phenomena underscores the potential of MIF as an attractive target with pharmacological relevance. Extensive research in past has uncovered a number of inhibitors, while the ISO-1, or (S, R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester being recognized as a benchmark standard so far. Recent work by Yang and coworkers identified five promising dietary flavonoids, with superior activity compared to the standard ISO-1. Nevertheless, the exact atomic-level inhibitory mechanism is still elusive. Methods: To improve the dynamic research, and rigorously characterize, and compare molecular signatures of MIF complexes with ISO-1 and flavonoids, principal component analysis (PCA) was linked with molecular dynamics (MD) simulations and binding free energy calculations. Results: The results suggest that by blocking the tautomerase site these small molecule inhibitors could modify the MIF activity by disrupting the intrinsic dynamics in particular functional areas. The stability matrices revealed the average deviation values ranging from 0.27-0.32 nm while the residue level fluctuations indicated that binding of the selected flavonoids confer enhanced stability relative to the ISO-1. Furthermore, the gyration values extracted from the simulated trajectories were found in the range of 1.80-1.83 nm. Discussion: Although all the tested flavonoids demonstrated remarkable results, the one obtained for the potent inhibitors, particularly Morin and Amentoflavone exhibited a good correlation with biological activity. The PCA results featured relatively less variance and constricted conformational landscape than others. The stable ensembles and reduced variation in turns might be the possible reasons for their outstanding performance documented previously. The results from the present exploration provide a comprehensive understanding of the molecular complexes formed by flavonoids and MIF, shedding light on their potential roles and impacts. Future studies on MIF inhibitors may benefit from the knowledge gathered from this investigation.

Nailfold Capillaroscopy: A Comprehensive Review on Its Usefulness in Both Clinical Diagnosis and Improving Unhealthy Dietary Lifestyles.

Since the 1970s, the utility of nailfold capillaroscopy (NFC) in diagnosing rheumatological disorders such as systemic sclerosis has been well established. Further studies have also shown that NFC can detect non-rheumatic diseases such as diabetes, glaucoma, dermatitis, and Alzheimer disease. In the past decade, nailfold capillary morphological changes have also been reported as symptoms of unhealthy lifestyle habits such as poor diet, smoking, sleep deprivation, and even psychological stress, all of which contribute to slow blood flow. Therefore, studying the relationships between the morphology of nailfold capillaries and lifestyle habits has a high potential to indicate unhealthy states or even pre-disease conditions. Simple, inexpensive, and non-invasive methods such as NFC are important and useful for routine medical examinations. The present study began with a systematic literature search of the PubMed database followed by a summary of studies reporting the assessment of morphological changes detected by NFC, and a comprehensive review of NFC's utility in clinical diagnosis and improving unhealthy dietary lifestyles. It culminates in a summary of dietary and lifestyle health promotion strategy, assessed based on NFC and other related measurements that indicate healthy microvascular blood flow and endothelial function.

The associations between dietary flavonoids intake and risk of depressive symptom in diabetic patients: Data from NHANES 2007-2008, 2009-2010, and 2017-2018.

BACKGROUND: The increasing incidence of depressive symptoms in diabetic patients contributes to the global burden of disease, but few epidemiological studies have evaluated the relationship between dietary flavonoids intake and depressive symptoms in diabetic patients in American adults. OBJECTIVE: This study intended to evaluate the associations of dietary flavonoids intake and depressive symptoms in diabetic patients in American adults. METHODS: We conducted a cross-sectional analysis of 1993 adults aged ≥20 years old who participated in the 2007-2008, 2009-2010, and 2017-2018 National Health and Nutrition Examination Surveys (NHANES). Chi-square test and independent-sample t-test were used to compare subjects' characteristics. Logistic regression model was further used to analyze the relationship between dietary flavonoid intake and depressive symptoms in diabetic patients. Restricted cubic spline (RCS) analysis was used to investigate the non-linear relationship between dietary flavonoid intake and the prevalence of depressive symptoms in diabetic patients. The weighted quartile sum (WQS) regression was used to analyze the effect of 29 flavonoids monomers. RESULTS: The results showed that the total flavonoid intake in the third quartile (OR, 0.635; 95 % CI,0.419-0.962; P, 0.032) was significantly associated with a reduced risk of depressive symptoms in diabetic patients compared with the lowest quartile. And there was a U-shaped association between dietary flavonoid intake and risk of depressive symptoms in diabetic patients. Top contributors of flavonoid monomers were eriodictyol, naringenin, and theaflavin-3'-gallate, accounting for a percentage of 30.83 %, 22.17 %, and 6.92 %, respectively. CONCLUSION: Moderate (56.07-207.12 mg/day) dietary flavonoid intake was associated with a reduced risk of depressive symptoms in diabetic patients. The important flavonoid monomers were eriodictyol, naringenin, and theaflavin-3'-gallate.

Ceiba pentandra ethyl acetate extract improves doxorubicin antitumor outcomes against chemically induced liver cancer in rat model: a study supported by UHPLC-Q-TOF-MS/MS identification of the bioactive phytomolecules.

Hepatocellular carcinoma (HCC) is a prevalent cancer worldwide. Late-stage detection, ineffective treatments, and tumor recurrence contribute to the low survival rate of the HCC. Conventional chemotherapeutic drugs, like doxorubicin (DOX), are associated with severe side effects, limited effectiveness, and tumor resistance. To improve therapeutic outcomes and minimize these drawbacks, combination therapy with natural drugs is being researched. Herein, we assessed the antitumor efficacy of Ceiba pentandra ethyl acetate extract alone and in combination with DOX against diethylnitrosamine (DENA)-induced HCC in rats. Our in vivo study significantly revealed improvement in the liver-function biochemical markers (ALT, AST, GGT, and ALP), the tumor marker (AFP-L3), and the histopathological features of the treated groups. A UHPLC-Q-TOF-MS/MS analysis of the Ceiba pentandra ethyl acetate extract enabled the identification of fifty phytomolecules. Among these are the dietary flavonoids known to have anticancer, anti-inflammatory, and antioxidant qualities: protocatechuic acid, procyanidin B2, epicatechin, rutin, quercitrin, quercetin, kaempferol, naringenin, and apigenin. Our findings highlight C. pentandra as an affordable source of phytochemicals with possible chemosensitizing effects, which could be an intriguing candidate for the development of liver cancer therapy, particularly in combination with chemotherapeutic drugs.

The association of dietary total flavonoids and their subclasses with the risk of type 2 diabetes: a prospective cohort study.

BACKGROUND: Data from mechanistic studies suggest flavonoids may benefit glucose metabolism, but their associations with type 2 diabetes (T2D) remain unclear. This study examined the prospective associations of dietary intake of total, classes, and individual flavonoids, as well as their source foods, with T2D in the CArdioVascular disease Association Study (CAVAS). METHODS: A total of 16,666 Korean men and women were enrolled at baseline, and 953 were newly diagnosed with T2D over a median follow-up of 5.96 years. Intake of flavonoids was cumulatively averaged using all food frequency questionnaires before the censoring events. A Poisson regression model was used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (CIs). RESULTS: Women with higher total flavonoid, flavonol, isoflavone, and proanthocyanidin intake had a lower risk of T2D (fourth vs. first quartile, IRR 0.62; 95% CI 0.44-0.89; P for linearity and non-linearity < 0.05 for total flavonoids), while in men, flavanones, anthocyanins, and proanthocyanidins, but not total flavonoids, were inversely associated with T2D risk (all P interaction for sex > 0.05). The key source foods contributing to flavonoid intake were also different between men and women, except for apples: tangerines and strawberries in men and green leafy vegetables and soy products in women. CONCLUSIONS: A higher intake of total flavonoids, particularly from vegetables, soybeans, and apples, may be associated with lower risk of T2D in women. However, flavonoids from fruits, rather than total flavonoids, may be inversely associated in men. The association between flavonoid intake and the risk of T2D may be contingent upon the dietary sources of flavonoids consumed.

Aflatoxin B1-induced redox imbalance in the hippocampus and cerebral cortex of male Wistar rats is accompanied by altered cholinergic, indoleaminergic, and purinergic pathways: Abatement by dietary rutin.

The neurotoxic impact of dietary exposure to aflatoxin B1 (AFB1) is well documented in experimental studies. Rutin is a phytochemical with prominent anti-inflammatory and antioxidant activities. There is an information gap on the influence of rutin on AFB1-induced neurotoxicity. This study investigated the influence of rutin on neurobehavioral and biochemical abnormalities in male Wistar rats (six weeks old) orally treated with AFB1 (0.75, and 1.5 mg/kg body weight) or co-administered with rutin (50 mg/kg) for 30 uninterrupted days. Results indicate that AFB1-induced depression-like behavior by Tail Suspension Test (TST) and cognitive impairment by Y-maze was abated following rutin co-administration. Abatement of AFB1-induced decreases in acetylcholinesterase (AChE) activity, and increased antioxidant status, by rutin was accompanied by a marked reduction in oxidative stress markers and increased hydrolysis of the purinergic molecules in the cerebral cortex and hippocampus of rats. Additionally, rutin co-treatment abrogated AFB1-mediated elevation of interleukin-6 (IL-6), nitric oxide (NO) levels, and activity of myeloperoxidase (MPO). Correspondingly, rutin co-treatment lowered the activity and immunocontent of immunosuppressive indoleamine 2, 3-dioxygenase (IDO). Further, rutin co-treatment prevented histological injuries in the cerebral cortex and hippocampus. In conclusion, abatement of AFB1-induced neurobehavioral abnormalities by rutin involves the mechanisms of anti-inflammatory, antioxidant, and regulation of cholinergic, purinergic, and indoleaminergic pathways in rats.

Transmembrane behaviors and quantitative structure-activity relationship of dietary flavonoids in the presence of intestinal digestive products from different carbohydrate sources based on in vitro and in silico analysis.

Bioavailability plays a key role for flavonoids to exert their bioactivities. This study investigated the transmembrane transport behavior and structure-activity of dietary flavonoids. Results showed that the apparent permeability coefficients of some flavonoids could be significantly increased when digestion products from rice flour (RD) or wheat flour (WD) are present (p < 0.05), especially in the WD, potentially due to higher reducing sugar (p < 0.05). 3D-QSAR revealed that the hydrogen bond acceptor groups at positions 5 and 6 of ring A, small-volume groups at position 3', hydrophobic groups at position 4', and large-volume groups at position 5' of ring B increased the transmembrane transport of flavonoids in the WD. A hydrogen bond donor group at position 4' of ring B enhanced the transmembrane transport of flavonoid compounds in the RD. These findings contribute to our comprehensive understanding of flavonoid absorption within the context of intestinal carbohydrate digestion.

Unlocking the Power of Onion Peel Extracts: Antimicrobial and Anti-Inflammatory Effects Improve Wound Healing through Repressing Notch-1/NLRP3/Caspase-1 Signaling.

Onion peels are often discarded, representing an unlimited amount of food by-products; however, they are a valuable source of bioactive phenolics. Thus, we utilized UPLC-MS/MS to analyze the metabolomic profiles of red (RO) and yellow (YO) onion peel extracts. The cytotoxic (SRB assay), anti-inflammatory (Griess assay), and antimicrobial (sensitivity test, MIC, antibiofilm, and SP-SDS tests) properties were assessed in vitro. Additionally, histological analysis, immunohistochemistry, and ELISA tests were conducted to investigate the healing potential in excisional skin wound injury and Candida albicans infection in vivo. RO extract demonstrated antibacterial activity, limited skin infection with C. albicans, and improved the skin's appearance due to the abundance of quercetin and anthocyanin derivatives. Both extracts reduced lipopolysaccharide-induced nitric oxide release in vitro and showed a negligible cytotoxic effect on MCF-7 and HT29 cells. When extracts were tested in vivo for their ability to promote tissue regeneration, it was found that YO peel extract had the greatest impact. Further biochemical analysis revealed that YO extract suppressed NLRP3/caspase-1 signaling and decreased inflammatory cytokines. Furthermore, YO extract decreased Notch-1 levels and boosted VEGF-mediated angiogenesis. Our findings imply that onion peel extract can effectively treat wounds by reducing microbial infection, reducing inflammation, and promoting tissue regeneration.

Association of Dietary Flavonoid Intake with Serum Cotinine Levels in the General Adult Population.

Cotinine, the primary metabolite of nicotine, can be utilized as a marker for active smoking and as an indicator of exposure to secondhand smoke. However, the direct relationship between dietary flavonoid intake and serum cotinine levels remains a subject of ongoing investigation. In this study, we utilized data from the National Health and Nutrition Examination Survey (NHANES) 2007-2010 and 2017-2018 to assess the association between dietary flavonoid intake and serum cotinine levels in adults through multiple linear regression analysis. A weighted quantile sum (WQS) regression model was used to assess the association of the mixture of six dietary flavonoids with serum cotinine levels in adults, which could represent the overall effect of the mixture of six dietary flavonoids. We also conducted stratified analyses by smoke status to explore multiple linear regression associations between different flavonoid intake and serum cotinine levels. A total of 14,962 adults were included in the study. Compared to the group with the lowest dietary flavonoid intake, total flavonoid intake in the second (ß = -0.29 [-0.44, -0.14]), third (ß = -0.41 [-0.58, -0.24]), and highest groups (ß = -0.32 [-0.49, -0.16]) was inversely related to the levels of serum cotinine after adjusting the full model. An RCS model showed that when the total dietary flavonoid intake was less than 99.61 mg/day, there was a negative linear association between dietary flavonoid intake and the serum cotinine. The WQS regression model also showed that the intake of a mixture of six dietary flavonoids was significantly negatively correlated with serum cotinine levels (ß = -0.54 [-0.61, -0.46], p <0.01), with anthocyanins having the greatest effect (weights = 32.30%). Our findings imply a significant correlation between dietary flavonoid intake and serum cotinine levels among adults. The consumption of a combination of six dietary flavonoids was consistently linked to lower serum cotinine levels, with anthocyanins displaying the most pronounced impact.

The Role of Diet and Nutrition in Allergic Diseases.

Allergic diseases are a set of chronic inflammatory disorders of lung, skin, and nose epithelium characterized by aberrant IgE and Th2 cytokine-mediated immune responses to exposed allergens. The prevalence of allergic diseases, including asthma, allergic rhinitis, and atopic dermatitis, has increased dramatically worldwide in the past several decades. Evidence suggests that diet and nutrition play a key role in the development and severity of allergic diseases. Dietary components can differentially regulate allergic inflammation pathways through host and gut microbiota-derived metabolites, therefore influencing allergy outcomes in positive or negative ways. A broad range of nutrients and dietary components (vitamins A, D, and E, minerals Zn, Iron, and Se, dietary fiber, fatty acids, and phytochemicals) are found to be effective in the prevention or treatment of allergic diseases through the suppression of type 2 inflammation. This paper aims to review recent advances in the role of diet and nutrition in the etiology of allergies, nutritional regulation of allergic inflammation, and clinical findings about nutrient supplementation in treating allergic diseases. The current literature suggests the potential efficacy of plant-based diets in reducing allergic symptoms. Further clinical trials are warranted to examine the potential beneficial effects of plant-based diets and anti-allergic nutrients in the prevention and management of allergic diseases.

The Therapeutic Potential of Natural Dietary Flavonoids against SARS-CoV-2 Infection.

The exploration of non-toxic and cost-effective dietary components, such as epigallocatechin 3-gallate and myricetin, for health improvement and disease treatment has recently attracted substantial research attention. The recent COVID-19 pandemic has provided a unique opportunity for the investigation and identification of dietary components capable of treating viral infections, as well as gathering the evidence needed to address the major challenges presented by public health emergencies. Dietary components hold great potential as a starting point for further drug development for the treatment and prevention of SARS-CoV-2 infection owing to their good safety, broad-spectrum antiviral activities, and multi-organ protective capacity. Here, we review current knowledge of the characteristics-chemical composition, bioactive properties, and putative mechanisms of action-of natural bioactive dietary flavonoids with the potential for targeting SARS-CoV-2 and its variants. Notably, we present promising strategies (combination therapy, lead optimization, and drug delivery) to overcome the inherent deficiencies of natural dietary flavonoids, such as limited bioavailability and poor stability.

Construction of a QSAR Model Based on Flavonoids and Screening of Natural Pancreatic Lipase Inhibitors.

Pancreatic lipase (PL) is a key hydrolase in lipid metabolism. Inhibition of PL activity can intervene in obesity, a global sub-health disease. The natural product is considered a good alternative to chemically synthesized drugs due to its advantages, such as low side effects. However, traditional experimental screening methods are labor-intensive and cost-consuming, and there is an urgent need to develop high-throughput screening methods for the discovery of anti-PL natural products. In this study, a high-throughput virtual screening process for anti-PL natural products is provided. Firstly, a predictable anti-PL natural product QSAR model (R2train = 0.9444, R2test = 0.8962) were developed using the artificial intelligence drug design software MolAIcal based on genetic algorithms and their conformational relationships. 1068 highly similar (FS > 0.8) natural products were rapidly enriched based on the structure-activity similarity principle, combined with the QSAR model and the ADMET model, for rapid prediction of a total of five potentially efficient anti-PL natural products (IC50pre < 2 µM). Subsequently, molecular docking, molecular dynamics simulation, and MMGBSA free energy calculation were performed to not only reveal the interaction of candidate novel natural products with the amino acid residues of PL but also to validate the stability of these novel natural compounds bound to PL. In conclusion, this study greatly simplifies the screening and discovery of anti-PL natural products and accelerates the development of novel anti-obesity functional foods.

Food matrix-flavonoid interactions and their effect on bioavailability.

Flavonoid compounds exhibit a wide range of health benefits as plant-derived dietary components. Typically, co-consumed with the food matrix,they must be released from the matrix and converted into an absorbable form (bioaccessibility) before reaching the small intestine, where they are eventually absorbed and transferred into the bloodstream (bioavailability) to exert their biological activity. However, a large number of studies have revealed the biological functions of individual flavonoid compounds in different experimental models, ignoring the more complex but common relationships established in the diet. Besides, it has been appreciated that the gut microbiome plays a crucial role in the metabolism of flavonoids and food substrates, thereby having a significant impact on their interactions, but much progress still needs to be made in this area. Therefore, this review intends to comprehensively investigate the interactions between flavonoids and food matrices, including lipids, proteins, carbohydrates and minerals, and their effects on the nutritional properties of food matrices and the bioaccessibility and bioavailability of flavonoid compounds. Furthermore, the health effects of the interaction of flavonoid compounds with the gut microbiome have also been discussed. HIGHLIGHTSFlavonoids are able to bind to nutrients in the food matrix through covalent or non-covalent bonds.Flavonoids affect the digestion and absorption of lipids, proteins, carbohydrates and minerals in the food matrix (bioaccessibility).Lipids, proteins and carbohydrates may favorably affect the bioavailability of flavonoids.Improved intestinal flora may improve flavonoid bioavailability.

Flavonoids and gastrointestinal health: single molecule for multiple roles.

Diet can be considered as one of the pivotal factors in regulating gastrointestinal health, and polyphenols widely distributed in human daily diet. The polyphenols and their metabolites playing a series of beneficial effects in human gastrointestinal tract that can regulate of the gut microbiota, increase intestinal barrier function, repair gastrointestinal mucosa, reduce oxidative stress, inhibit the secretion of inflammatory factors and regulating immune function, and their absorption and biotransformation mainly depend on the activity of intestinal microflora. However, little is known about the two-way interaction between polyphenols and intestinal microbiota. The objective of this review is to highlight the structure optimization and effect of flavonoids on intestinal flora, and discusses the mechanisms of dietary flavonoids regulating intestinal flora. The multiple effects of single molecule of flavonoids, and inter-dependence between the gut microbiota and polyphenol metabolites. Moreover, the protective effects of polyphenols on intestinal barrier function, and effects of interaction between plant polyphenols and macromolecules on gastrointestinal health. This review provided valuable insight that may be useful for better understanding the mechanism of the gastrointestinal health effects of polyphenols, and provide a scientific basis for their application as functional food.

Possible mechanism of flavonoids regulating intestinal flora.Flavonoids optimize the structure and composition of gut microbiota.Polyphenol improve intestinal barrier function.Interaction between polyphenols and macromolecules improves gastrointestinal healthThe two-way interaction between flavonoids and intestinal microflora to improve bioavailability.

Structural insights and shedding light on preferential interactions of dietary flavonoids with G-quadruplex DNA structures: A new horizon.

G-quadruplex, a structurally unique structure in nucleic acids present all throughout the human genome, has sparked great attention in therapeutic investigations. Targeting G-quadruplex structure is a new strategy for the drug development. Flavonoids are found in almost all dietary plant-based beverages and food products; therefore, they are ingested in significant proportions through the human diet. Although synthetically developed drug molecules are used vigorously but they have various adverse effects. While on the other hand, nature supplies chemically unique scaffolds in the form of distinct dietary flavonoids that are easily accessible, less poisonous, and have higher bioavailability. Because of their great pharmacological effectiveness and minimal cytotoxicity, such low molecular weight compounds are feasible alternatives to synthetic therapeutic medicines. Therefore, from a drug-development point of view, investigation on screening the binding capabilities of quadruplex-interactive small natural compounds like dietary flavonoids are expected to be highly effective, with a particular emphasis on the selectivity towards polymorphic G-quadruplex structures. In this respect, quadruplexes have scintillated research into their potential interaction with these dietary flavonoids. The purpose of this review is to offer an up-to-date close-up look at the research on their interaction with structurally varied dietary flavonoids with the goal of providing newer perspectives to construct novel therapeutic agents for next-generation disease managements.

Genistein and Procyanidin B2 Reduce Carcinogen-Induced Reactive Oxygen Species and DNA Damage through the Activation of Nrf2/ARE Cell Signaling in Bronchial Epithelial Cells In Vitro.

Cancer is one of the leading causes of death worldwide. Chemotherapy and radiation therapy are currently providing the basis for cancer therapies, although both are associated with significant side effects. Thus, cancer prevention through dietary modifications has been receiving growing interest. The potential of selected flavonoids in reducing carcinogen-induced reactive oxygen species (ROS) and DNA damage through the activation of nuclear factor erythroid 2 p45 (NF-E2)-related factor (Nrf2)/antioxidant response element (ARE) pathway was studied in vitro. Dose-dependent effects of pre-incubated flavonoids on pro-carcinogen 4-[(acetoxymethyl)nitrosamino]-1-(3-pyridyl)-1-butanone (NNKAc)-induced ROS and DNA damage in human bronchial epithelial cells were studied in comparison to non-flavonoids. The most effective flavonoids were assessed for the activation of Nrf2/ARE pathway. Genistein, procyanidin B2 (PCB2), and quercetin significantly suppressed the NNKAc-induced ROS and DNA damage. Quercetin significantly upregulated the phosphorylated protein kinase B/Akt. PCB2 significantly upregulated the activation of Nrf2 and Akt through phosphorylation. Genistein and PCB2 significantly upregulated the phospho-Nrf2 nuclear translocation and catalase activity. In summary, genistein and PCB2 reduced the NNKAc-induced ROS and DNA damage through the activation of Nrf2. Further studies are required to understand the role of dietary flavonoids on the regulation of the Nrf2/ARE pathway in relation to carcinogenesis.

A Review on Dietary Flavonoids as Modulators of the Tumor Microenvironment.

The tumor microenvironment (TME) is the local environment where malignant cells strive and survive, composed of cancer cells and their surroundings, regulating essential tumor survival, and promotion functions. Dietary flavonoids are abundantly present in common vegetables and fruits and exhibit good anti-cancer activities, which significantly inhibit tumorigenesis by targeting TME constituents and their interaction with cancer cells. This review aims to synthesize information concerning the modulation of TME by dietary flavonoids, as well as to provide insights into the molecular basis of its potential anti-tumor activities, with an emphasis on its ability to control intracellular signaling cascades that regulate the TME processes, involving cell proliferation, invasion and migration, continuous angiogenesis, and immune inflammation. This study will provide a theoretical basis for the development of the leading compound targeting TME for anti-cancer therapies from these dietary flavonoids.