Ethanol-Induced Hepatic Ferroptosis Is Mediated by PERK-Dependent MAMs Formation: Preventive Role of Quercetin.

SCOPE: Iron deposition is frequently observed in alcoholic liver disease (ALD), which indicates a potential role of ferroptosis in its development. This study aims to explore the effects of quercetin on ferroptosis in ALD and elucidates the underlying mechanism involving the formation of mitochondria-associated endoplasmic reticulum membranes (MAMs) mediated by protein kinase RNA-like endoplasmic reticulum kinase (PERK). METHODS AND RESULTS: C57BL/6J mice are fed either a regular or an ethanol-containing liquid diet (with 28% energy form ethanol) with or without quercetin supplementation (100 mg kg-1 BW) for 12 weeks. Ethanol feeding or treatment induced ferroptosis in mice and AML12 cells, which is associated with increased MAMs formation and PERK expression within MAMs. Quercetin attenuates these changes and protects against ethanol-induced liver injury. The antiferroptotic effect of quercetin is abolished by ferroptosis inducers, but mimicked by ferroptosis inhibitors and PERK knockdown. The study demonstrates that PERK structure, rather than its kinase activity (transfected with the K618A site mutation that inhibits kinase activity-ΔK plasmid or protein C terminal knockout-ΔC plasmid of PERK), mediates the enhanced MAMs formation and ferroptosis during the ethanol exposure. CONCLUSION: Quercetin ameliorates ethanol-induced liver injury by inhibiting ferroptosis via modulating PERK-dependent MAMs formation.

Ultrasound-mediated host-guest self-assembly between different dietary fatty acids and sodium caseinate and their complexes improving the water dispersibility, stability, and bioaccessibility of quercetin.

Quercetin (QUE) sufferred from poor processing adaptability and absorbability, hindering its application as a dietary supplement in the food industry. In this study, fatty acids (FAs)-sodium caseinate (NaCas) ligand complexes carriers were fabricated to improve the aqueous dispersibility, storage/thermal stability, and bioaccessibility of QUE using an ultrasound method. The results indicated that all six selected common dietary FAs formed stable hydrophilic complexes with NaCas and the FAs-NaCas complexes achieved an encapsulation efficiency greater than 90 % for QUE. Furthermore, the introduction of FAs enhanced the binding affinity between NaCas and QUE, but did not change the binding mode (static bursting) and types of intermolecular forces (mainly hydrogen bonding). In addition, a distinct improvement was discovered in the storage stability (>2.37-fold), thermal processing stability (>32.54 %), and bioaccessibility (>2.37-fold) of QUE. Therefore, the FAs-NaCas ligand complexes could effectively protect QUE to minimize degradation as fat-soluble polyphenol delivery vehicles.

Accumulation of the bitter substance quercetin mediated by the overexpression of a novel seed-specific gene FtRDE2 in Tartary buckwheat.

Tartary buckwheat (Fagopyrum tataricum) is frequently employed as a resource to develop health foods, owing to its abundant flavonoids such as rutin. However, the consumption of Tartary buckwheat (TB) is limited in food products due to the strong bitterness induced by the hydrolysis of rutin into quercetin. This transformation is facilitated by the degrading enzyme (RDE). While multiple RDE isoenzymes exist in TB, the superior coding gene of FtRDEs has not been fully explored, which hinders the breeding of TB varieties with minimal bitterness. Here, we found that FtRDE2 is the most abundant enzyme in RDE crude extracts, and its corresponding gene is specifically expressed in TB seeds. Results showed that FtRDE2 has strong rutin hydrolysis activity. Overexpression of FtRDE2 not only significantly promoted rutin hydrolysis and quercetin accumulation but also dramatically upregulated genes involved in the early phase of flavonoid synthesis (FtPAL1、FtC4H1、Ft4CL1, FtCHI1) and anthocyanin metabolism (FtDFR1). These findings elucidate the role of FtRDE2, emphasizing it as an endogenous factor contributing to the bitterness in TB and its involvement in the metabolic regulatory network. Moreover, correlation analysis revealed a positive relationship between the catalytic activity of RDE extracts and the expression level of FtRDE2 during seed germination. In summary, our results suggest that FtRDE2 can serve as a promising candidate for the molecular breeding of a TB variety with minimal bitterness.

UGT89AC1-mediated quercetin glucosylation is induced upon herbivore damage and enhances Camellia sinensis resistance to insect feeding.

Quercetin is a key flavonol in tea plants (Camellia sinensis (L.) O. Kuntze) with various health benefits, and it often occurs in the form of glucosides. The roles of quercetin and its glucosylated forms in plant defense are generally not well-studied, and remain unknown in the defense of tea. Here, we found higher contents of quercetin glucosides and a decline of the aglucone upon Ectropis grisescens (E. grisescens) infestation of tea. Nine UGTs were strongly induced, among which UGT89AC1 exhibited the highest activity toward quercetin in vitro and in vivo. The mass of E. grisescens larvae that fed on plants with repressed UGT89AC1 or varieties with lower levels of UGT89AC1 was significantly lower than that of larvae fed on controls. Artificial diet supplemented with quercetin glucoside also reduced the larval growth rate, whereas artificial diet supplemented with free quercetin had no significant effect on larval growth. UGT89AC1 was located in both the cytoplasm and nucleus, and its expression was modulated by JA, JA-ILE, and MeJA. These findings demonstrate that quercetin glucosylation serves a defensive role in tea against herbivory. Our results also provide novel insights into the ecological relevance of flavonoid glycosides under biotic stress in plants.

Effects of Dietary Components on Mast Cells: Possible Use as Nutraceuticals for Allergies?

Allergic diseases affect an estimated 30 percent of the world's population. Mast cells (MC) are the key effector cells of allergic reactions by releasing pro-inflammatory mediators such as histamine, lipid mediators, and cytokines/chemokines. Components of the daily diet, including certain fatty acids, amino acids, and vitamins, as well as secondary plant components, may have effects on MC and thus may be of interest as nutraceuticals for the prevention and treatment of allergies. This review summarizes the anti-inflammatory effects of dietary components on MC, including the signaling pathways involved, in in vitro and in vivo models. Butyrate, calcitriol, kaempferol, quercetin, luteolin, resveratrol, curcumin, and cinnamon extract were the most effective in suppressing the release of preformed and de novo synthesized mediators from MC or in animal models. In randomized controlled trials (RCT), vitamin D, quercetin, O-methylated epigallocatechin gallate (EGCG), resveratrol, curcumin, and cinnamon extract improved symptoms of allergic rhinitis (AR) and reduced the number of inflammatory cells in patients. However, strategies to overcome the poor bioavailability of these nutrients are an important part of current research.

A Mango Leaf Extract (Zynamite®) Combined with Quercetin Has Exercise-Mimetic Properties in Human Skeletal Muscle.

Zynamite PX®, a mango leaf extract combined with quercetin, enhances exercise performance by unknown molecular mechanisms. Twenty-five volunteers were assigned to a control (17 males) or supplementation group (8 males, receiving 140 mg of Zynamite® + 140 mg quercetin/8 h for 2 days). Then, they performed incremental exercise to exhaustion (IE) followed by occlusion of the circulation in one leg for 60 s. Afterwards, the cuff was released, and a 30 s sprint was performed, followed by 90 s circulatory occlusion (same leg). Vastus lateralis muscle biopsies were obtained at baseline, 20 s after IE (occluded leg) and 10 s after Wingate (occluded leg), and bilaterally at 90 s and 30 min post exercise. Compared to the controls, the Zynamite PX® group showed increased basal protein expression of Thr287-CaMKIIδD (2-fold, p = 0.007) and Ser9-GSK3ß (1.3-fold, p = 0.005) and a non-significant increase of total NRF2 (1.7-fold, p = 0.099) and Ser40-NRF2 (1.2-fold, p = 0.061). In the controls, there was upregulation with exercise and recovery of total NRF2, catalase, glutathione reductase, and Thr287-CaMKIIδD (1.2-2.9-fold, all p < 0.05), which was not observed in the Zynamite PX® group. In conclusion, Zynamite PX® elicits muscle signaling changes in resting skeletal muscle resembling those described for exercise training and partly abrogates the stress kinases responses to exercise as observed in trained muscles.

Anti-inflammatory effects of Allium cepa L. peel extracts via inhibition of JAK-STAT pathway in LPS-stimulated RAW264.7 cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Allium cepa L. (A. cepa) is one of the oldest cultivated plants in the world. A. cepa has been used in traditional folk medicine to treat inflammatory disease in several regions, such as Palestine and Serbia. A. cepa peel has a higher content of flavonoids, such as quercetin, than the edible parts. These flavonoids alleviate inflammatory diseases. However, the anti-inflammatory effects of A. cepa peel extract-obtained using various extraction methods-and their underlying mechanisms require further investigation. AIM OF THE STUDY: Although research to find safe anti-inflammatory substances in various natural products has been actively conducted for many years, it is important to continue identifying potential anti-inflammatory effects in natural materials. The purpose of this study was to investigate the ethnopharmacological properties of the A. cepa peel extract, whose efficacy when obtained through different extraction methods and underlying action mechanisms is not well known. The present study specifically aimed to observe the anti-inflammatory effects of the A. cepa peel extracts obtained using various extraction methods and the related detailed mechanisms of A. cepa peel extracts in lipopolysaccharide (LPS)-induced RAW264.7 cells. MATERIALS AND METHODS: The total flavonoid content of the A. cepa peel extracts was determined the diethylene glycol colorimetric method and measured using a calibration curve prepared using quercetin as a standard solution. The antioxidant activity was evaluated using the ABTS assay, and cytotoxicity was measured using the MTT assay. NO production was measured using Griess reagent. Protein levels were measured by western blotting, and mRNA expression was measured by RT-qPCR. Secreted cytokines were analyzed using ELISA or cytokine arrays. In the GSE160086 dataset, we calculated Z-scores for individual genes of interest and displayed using a heat map. RESULTS: Of the three A. cepa peel extracts obtained using different extraction methods, the A. cepa peel 50% EtOH extract (AP50E) was the most effective at inhibiting LPS-induced nitric oxide (NO) and inducible nitric oxide synthase (iNOS). Furthermore, AP50E significantly reduced the levels of pro-inflammation cytokines interleukin (IL)-1α, IL-1ß, IL-6, and IL-27. Additionally, AP50E directly inhibited the Janus kinase-signaling transducer and activator of transcription (JAK-STAT) pathway. CONCLUSIONS: These results showed that AP50E exhibited an anti-inflammatory effect in LPS-induced RAW264.7 mouse macrophages by directly inhibiting JAK-STAT signaling. Based on these findings, we propose AP50E as a potential candidate for the development of preventive or therapeutic agents against inflammatory diseases.

Virtual screening and antimicrobial evaluation for identification of natural compounds as the prospective inhibitors of antibacterial drug resistance targets in Staphylococcus aureus.

Infectious diseases have remained a burgeoning cause of death and disability since long. Staphylococcus aureus (S. aureus) is a severe bacterial pathogen causing nosocomial and community infections. It exhibits widespread resistance to antibiotics posing a significant threat to their efficacy. For combating this challenge, different strategies may include modifying existing antibiotics, developing new antibacterial agents, and combining treatments with resistance mechanism inhibitors. Resistance in S. aureus occurs through horizontal gene transfer or chromosomal mutations. Acquisition mechanisms involve enzymatic modification, efflux, target bypass, and drug displacement. Mutations can impact drug targets, activate efflux pumps, or alter cell wall composition to impede drug access. Overcoming S. aureus resistance requires innovative approaches to preserve antibiotic effectiveness. The present study involves the virtual screening of phytochemicals of diverse chemical classes from Zinc database against the antibiotic resistant targets of S. aureus like ß-Lactamase, Penicillin Binding Protein 2a (PBP2a), Dihydrofolate reductase (DHFR), DNA gyrase, Multidrug ABC transporter SAV1866, Undecaprenyl diphosphate synthase (UPPS), etc. Thymol, eugenol, gallic acid, l-ascorbic acid, curcumin, berberine and quercetin were identified as potential molecules based on their docking score, binding interactions. These molecules were further analyzed for the ADMET and drug likeness properties using pkCSM, SwissADME and Qikprop tools. Further in vitro evaluation of these molecules against antibiotic-resistant strains of S. aureus, both alone and in combination with antibiotics revealed significant findings. Curcumin demonstrated the lowest MIC values (31.25-62.5 µg/ml) when tested individually. Thymol, berberine, and quercetin displayed MIC values within the range of 125-250 µg/ml, while eugenol and gallic acid exhibited MIC values ranging from 500 to 1000 µg/ml. Notably, thymol exhibited potent synergy with all four antibiotics against clinical isolates of S. aureus, with Fractional inhibitory concentration index (FICI) values consistently below 0.5, highlighting its exceptional antibacterial activity, especially in combination with amoxicillin.

Anti-Inflammatory Effect of Ethanolic Extract from Tabebuia rosea (Bertol.) DC., Quercetin, and Anti-Obesity Drugs in Adipose Tissue in Wistar Rats with Diet-Induced Obesity.

Obesity is characterized by the excessive accumulation of fat, which triggers a low-grade chronic inflammatory process. Currently, the search for compounds with anti-obesogenic effects that help reduce body weight, as well as associated comorbidities, continues. Among this group of compounds are plant extracts and flavonoids with a great diversity of action mechanisms associated with their beneficial effects, such as anti-inflammatory effects and/or as signaling molecules. In the bark of Tabebuia rosea tree, there are different classes of metabolites with anti-inflammatory properties, such as quercetin. Therefore, the present work studied the effect of the ethanolic extract of T. rosea and quercetin on the mRNA of inflammation markers in obesity compared to the drugs currently used. Total RNA was extracted from epididymal adipose tissue of high-fat diet-induced obese Wistar rats treated with orlistat, phentermine, T. rosea extract, and quercetin. The rats treated with T. rosea and quercetin showed 36 and 31% reductions in body weight compared to the obese control, and they likewise inhibited pro-inflammatory molecules: Il6, Il1b, Il18, Lep, Hif1a, and Nfkb1 without modifying the expression of Socs1 and Socs3. Additionally, only T. rosea overexpressed Lipe. Both T. rosea and quercetin led to a reduction in the expression of pro-inflammatory genes, modifying signaling pathways, which led to the regulation of the obesity-inflammation state.

Quercetin serves as the major component of Xiang-lian Pill to ameliorate ulcerative colitis via tipping the balance of STAT1/PPARγ and dictating the alternative activation of macrophage.

ETHNOPHARMACOLOGICAL RELEVANCE: The traditional Chinese herbal formula, Xiang-lian Pill (XLP), is commonly prescribed for ulcerative colitis (UC) patients to relieve their clinical symptom. Nonetheless, the underlying cellular and molecular mechanisms of XLP's anti-UC effect remain incompletely understood. AIM OF THE STUDY: To evaluate the therapeutic effect and elucidate the possible working mechanisms of XLP in UC treatment. The major active component of XLP was also characterized. MATERIALS AND METHODS: Colitis was induced in C57BL/6 mice with 3% dextran sulfate sodium (DSS) dissolved in drinking water for 7 consecutive days. The UC mice were grouped and treated with XLP (3640 mg/kg) or vehicle orally during the procedure of DSS induction. Mouse body weight, disease activity index (DAI) score and colon length were recorded. Histopathological changes and inflammatory cell infiltration were evaluated by pathological staining and flow cytometric analysis (FACS). Network pharmacology, bioinformatic analysis, widely targeted and targeted metabolomics analysis were performed to screen the potential effective ingredients and key targets. Bone marrow derived macrophages (BMDMs), peripheral blood mononuclear cells (PBMCs), RAW264.7 and THP-1 cells were used to dissect the anti-inflammatory effect of XLP. RESULTS: Oral administration of XLP ameliorated DSS induced mouse colitis, as evidenced by reduced DAI and colonic inflammatory destruction. FACS results demonstrated that XLP treatment effectively restored immune tolerance in colon, inhibited the generation of monocyte derived macrophages and skewed macrophage polarization into M2 phenotype. Network pharmacology analysis suggested that innate effector modules related to macrophage activation comprise the major targets of XLP, and the counter-regulatory STAT1/PPARγ signaling possibly serves as the critical downstream pathway. Subsequent experiments unveiled an imbalance of STAT1/PPARγ signaling in monocytes derived from UC patients, and validated that XLP suppressed LPS/IFN-γ induced macrophage activation (STAT1 mediated) but facilitated IL-4 induced macrophage M2 polarization (PPARγ dependent). Meanwhile, our data showed that quercetin served as the major component of XLP to recapitulate the regulatory effect on macrophages. CONCLUSION: Our findings revealed that quercetin serves as the major component of XLP that regulates macrophage alternative activation via tipping the balance of STAT1/PPARγ, which provides a mechanistic explanation for the therapeutic effect of XLP in UC treatment.

Quercetin protects against iron overload-induced osteoporosis through activating the Nrf2/HO-1 pathway.

AIMS: Eucommia is the tree bark of Eucommia japonica, family Eucommiaceae. In traditional Chinese medicine, Eucommia is often used to treat osteoporosis. Quercetin (QUE), a major flavonoid extract of Eucommia japonica, has been reported to have anti-osteoporosis effects. However, there are no studies reporting the mechanism of QUE in the treatment of iron overload-induced osteoporosis. This study set out to investigate the therapeutic effects of QUE against iron overload-induced bone loss and its potential molecular mechanisms. MATERIALS AND METHODS: In vitro, MC3T3-E1 cells were used to study the effects of QUE on osteogenic differentiation, anti-apoptosis and anti-oxidative stress damage in an iron overload environment (FAC 200 µM). In vivo, we constructed an iron overload mouse model by injecting iron dextrose intraperitoneally and assessed the osteoprotective effects of QUE by Micro-CT and histological analysis. KEY FINDINGS: In vitro, we found that QUE increased the ALP activity of MC3T3-E1 cells in iron overload environment, promoted the formation of bone mineralized nodules and upregulated the expression of Runx2 and Osterix. In addition, QUE was able to reduce FAC-induced apoptosis and ROS production, down-regulated the expression of Caspase3 and Bax, and up-regulated the expression of Bcl-2. In further studies, we found that QUE activated the Nrf2/HO-1 signaling pathway and attenuated FAC-induced oxidative stress damage. The results of the in vivo study showed that QUE was able to reduce iron deposition induced by iron dextrose and attenuate bone loss. SIGNIFICANCE: Our results suggested that QUE protects against iron overload-induced osteoporosis by activating the Nrf2/HO-1 signaling pathway.

Effects of covalent conjugation with quercetin and its glycosides on the structure and allergenicity of Bra c p from bee pollen.

Profilin family members are potential pan-allergens in foods, presenting public health hazards. However, studies on the allergenicity modification of profilin allergens are limited. Herein, quercetin and its glycosides (isoquercitrin and rutin) were applied to modify the allergenicity of a profilin allergen (Bra c p) from Brassica campestris bee pollen. Results showed that only quercetin can be closely covalently bound to Bra c p among the three, and the binding site was located at the Cys98 residue. After covalently conjunction, the relative content of α-helix structure in Bra c p was reduced by 40.05%, while random coil was increased by 42.89%; moreover, the Tyr and Phe residues in Bra c p were masked. These structural changes could alter the conformational antigenic epitopes of Bra c p, resulting in its allergenicity reduction. Our findings might provide a technical foundation for reducing the allergenicity of bee pollen and foods containing profilin family allergens.

Cytotoxicity of quercetin is related to mitochondrial respiration impairment in Saccharomyces cerevisiae.

Quercetin is a flavonol ubiquitously present in fruits and vegetables that shows a potential therapeutic use in non-transmissible chronic diseases, such as cancer and diabetes. Although this phytochemical has shown promising health benefits, the molecular mechanism behind this compound is still unclear. Interestingly, quercetin displays toxic properties against phylogenetically distant organisms such as bacteria and eukaryotic cells, suggesting that its molecular target resides on a highly conserved pathway. The cytotoxicity of quercetin could be explained by energy depletion occasioned by mitochondrial respiration impairment and its concomitant pleiotropic effect. Thereby, the molecular basis of quercetin cytotoxicity could shed light on potential molecular mechanisms associated with its health benefits. Nonetheless, the evidence supporting this hypothesis is still lacking. Thus, this study aimed to evaluate whether quercetin supplementation affects mitochondrial respiration and whether this is related to quercetin cytotoxicity. Saccharomyces cerevisiae was used as a study model to assess the effect of quercetin on energetic metabolism. Herein, we provide evidence that quercetin supplementation: (1) decreased the exponential growth of S. cerevisiae in a glucose-dependent manner; (2) affected diauxic growth in a similar way to antimycin A (complex III inhibitor of electron transport chain); (3) suppressed the growth of S. cerevisiae cultures supplemented with non-fermentable carbon sources (glycerol and lactate); (4) promoted a glucose-dependent inhibition of the basal, maximal, and ATP-linked respiration; (5) diminished complex II and IV activities. Altogether, these data indicate that quercetin disturbs mitochondrial respiration between the ubiquinone pool and cytochrome c, and this phenotype is associated with its cytotoxic properties.

Effects of Dried Onion Powder and Quercetin on Obesity-Associated Hepatic Menifestation and Retinopathy.

Onion (Allium cepa L.), rich in flavonoids (particularly quercetin), reportedly has anti-obesity properties, but the underlying mechanisms and associated health issues remain unclear. In this study, we compared the effects of dried onion powder (DO) with that of quercetin on high-fat diet (HFD)-induced obesity, nonalcoholic fatty liver disease, and retinal neovascularization. Briefly, rats (n = 9-10 per group) were divided into control, HFD alone (43% fat), HFD + DO (1% DO), HFD + 5DO (5% DO, w/w), and HFD + quercetin (180 mg/kg). After 12 weeks, body fat, markers of metabolism, fatty liver, steatohepatitis, and retinopathy were analyzed. The results revealed that DO and 5DO dose-dependently suppressed body weight, visceral and subcutaneous fat accumulation, and epididymal adipocyte in HFD-fed rats. DO also decreased HFD-induced ALT, AST, free fatty acid, glucose, proinflammatory cytokines, and oxidative stress. DO and 5DO groups had lower triglycerides, total cholesterol, proinflammatory cytokine levels, and ACC-α (a fatty acid synthesis-associated enzyme) expression but higher hepatic antioxidant enzyme activities and fecal lipids. 5DO exhibited better or similar efficacy to quercetin. Both 5DO and quercetin increased fecal levels of acetic acid and butyric acid similarly. They also reduced lipid peroxidation of the eye, retinal adiposity, and neovascularization. However, quercetin resulted in a more apparent decrease in regulation of the Raf/MAPK pathway than DO in eye specimens. Conclusively, DO suppresses visceral, subcutaneous, and liver fat accumulation better than quercetin likely due to higher fecal fat excretion and lower oxidative stress, proinflammatory cytokine levels, and ACC-α expression. Quercetin regulating signal pathways is better than DO at reducing retinal adiposity and neovascularization.

Flavanones from Erythrina crista-galli Twigs and Their Antioxidant Properties Determined through In Silico and In Vitro Studies.

Flavonoids are a secondary metabolite group with various bioactivities, such as antioxidants. They are rich in the genus Erythrina, such as Erythrina crista-galli. This research aims to isolate and characterize flavonoids from the twigs of E. crista-galli and determine their antioxidant properties through in silico and in vitro assays. The ethyl acetate extract of E. crista-galli twigs were separated by column chromatography and characterized using spectroscopic methods. Density functional theory (DFT) calculations were performed on the isolated flavonoids and the reference compounds (ascorbic acid and quercetin) to obtain global descriptive parameters and a donor-acceptor map (DAM). We successfully isolated lupinifolin (1) and citflavanone (2) for the first time from E. crista-galli, along with lonchocarpol A (3), which has been discovered previously. The DAM suggests that these flavanones are good antiradicals with effective electron donors. However, they tend to be electron acceptors in methanol. The frontier molecular orbital analysis implies that lupinifolin (1) is a better antiradical than the other flavanones. The DPPH assays show that lupinifolin (1) has the highest antioxidant (antiradical) activity, with an IC50 value of 128.64 ppm. The in silico studies showed similar trends to the in vitro assays using the DPPH method.

Chlorogenic Acid and Quercetin in a Diet with Fermentable Fiber Influence Multiple Processes Involved in DSS-Induced Ulcerative Colitis but Do Not Reduce Injury.

Ulcerative colitis (UC) patients often avoid foods containing fermentable fibers as some can promote symptoms during active disease. Pectin has been identified as a more protective fermentable fiber, but little has been done to determine the interaction between pectin and bioactive compounds present in foods containing that fiber type. Quercetin and chlorogenic acid, two bioactives in stone fruits, may have anti-cancer, anti-oxidant, and anti-inflammatory properties. We hypothesized that quercetin and chlorogenic acid, in the presence of the fermentable fiber pectin, may suppress the expression of pro-inflammatory molecules, alter the luminal environment, and alter colonocyte proliferation, thereby protecting against recurring bouts of UC. Rats (n = 63) received one of three purified diets (control, 0.45% quercetin, 0.05% chlorogenic acid) containing 6% pectin for 3 weeks before exposure to dextran sodium sulfate (DSS, 3% for 48 h, 3x, 2 wk separation, n = 11/diet) in drinking water to initiate UC, or control (no DSS, n = 10/diet) treatments prior to termination at 9 weeks. DSS increased the fecal moisture content (p < 0.05) and SCFA concentrations (acetate, p < 0.05; butyrate, p < 0.05). Quercetin and chlorogenic acid diets maintained SLC5A8 (SCFA transporter) mRNA levels in DSS-treated rats at levels similar to those not exposed to DSS. DSS increased injury (p < 0.0001) and inflammation (p < 0.01) scores, with no differences noted due to diet. Compared to the control diet, chlorogenic acid decreased NF-κB activity in DSS-treated rats (p < 0.05). Quercetin and chlorogenic acid may contribute to the healthy regulation of NF-κB activation (via mRNA expression of IκΒα, Tollip, and IL-1). Quercetin enhanced injury-repair molecule FGF-2 expression (p < 0.01), but neither diet nor DSS treatment altered proliferation. Although quercetin and chlorogenic acid did not protect against overt indicators of injury and inflammation, or fecal SCFA concentrations, compared to the control diet, their influence on the expression of injury repair molecules, pro-inflammatory cytokines, SCFA transport proteins, and NF-κB inhibitory molecules suggests beneficial influences on major pathways involved in DSS-induced UC. Therefore, in healthy individuals or during periods of remission, quercetin and chlorogenic acid may promote a healthier colon, and may suppress some of the signaling involved in inflammation promotion during active disease.

The important role of glycerophospholipid metabolism in the protective effects of polyphenol-enriched Tartary buckwheat extract against alcoholic liver disease.

Alcoholic liver disease (ALD) is a mounting public health problem with significant medical, economic and social burdens. Tartary buckwheat (F. tataricum (L.) Gaertn, bitter buckwheat) is a kind of healthy and nutritious food, which has been demonstrated to protect against ALD, but the underlying mechanism has not been fully studied. Herein, we aimed to elucidate the beneficial effects of Tartary buckwheat extract (mainly composed of polyphenols including rutin, quercetin, kaempferol and kaempferol-3-O-rutinoside) in terms of lipid metabolism with the aid of lipidomic analysis. In our study, we employed C57BL/6J mice and a Lieber-DeCarli alcohol liquid diet to construct an ALD model and found that Tartary buckwheat extract was able to prevent ALD-induced histopathological lesions, liver injury and abnormal plasma lipid levels. These beneficial effects might be attributed to the regulation of energy metabolism-related genes (SIRT1, LKB1 and AMPK), lipid synthesis-related genes (ACC, SREBP1c and HMGR) and lipid oxidation-related genes (PPARα, CPT1 and CPT2). In addition, lipidomic profiling and KEGG pathway analysis showed that glycerophospholipid metabolism contributed the most to elucidating the regulatory mechanism of Tartary buckwheat extract. In specific, chronic ethanol intake reduced the level of phosphatidylcholines (PC) and increased the level of phosphatidylethanolamines (PE) in the liver, resulting in a decrease in the PC/PE ratio, which could be all significantly restored by Tartary buckwheat extract intervention, indicating that the Tartary buckwheat extract might regulate PC/PE homeostasis to exert its lipid-lowering effect. Overall, we demonstrated that Tartary buckwheat extract could prevent ALD by modulating hepatic glycerophospholipid metabolism, providing the theoretical basis for its further exploitation as a medical plant or nutritional food.

Lowering effect of combined sweet potato and onion intake on plasma quercetin concentration and underlying mechanism involving intestinal ß-glucosidase activity.

A combined intake of cooked sweet potato and fried onion in humans was found to suppress the increase of plasma quercetin metabolite concentration. Experiments using rat ß-glucosidase indicated that excess carbohydrate digestion products, especially glucose-containing saccharides, interfere with the deglycosylation of quercetin glucosides during intestinal epithelial uptake. Combined meals of sweet potato and onion may lower the bioavailability of onion quercetin glucosides.

Quercetin Mitigates Cisplatin-Induced Oxidative Damage and Apoptosis in Cardiomyocytes through Nrf2/HO-1 Signaling Pathway.

Cisplatin is massively used to treat solid tumors. However, several severe adverse effects, such as cardiotoxicity, are obstacles to its clinical application. Cardiotoxicity may lead to congestive heart failure and even sudden cardiac death in patients receiving cisplatin. Therefore, finding a novel therapeutic strategy for the prevention of cisplatin-induced cardiotoxicity is urgent. Quercetin is a flavonol compound that can be found in dietary fruits and vegetables. The antioxidant function and anti-inflammatory capacity of quercetin have been reported. However, whether quercetin could protect against cisplatin-caused apoptosis and cellular damage in cardiomyocytes is still unclear. H9c2 cardiomyocytes were treated with cisplatin (40 µM) for 24 h to induce cellular damage with or without quercetin pretreatment. We found that quercetin activates Nrf2 and HO-1 expression, thereby mitigating cisplatin-caused cytotoxicity in H9c2 cells. Quercetin also increases SOD levels, maintains mitochondrial function, and reduces oxidative stress under cisplatin stimulation. Quercetin attenuates cisplatin-induced apoptosis and inflammation in H9c2 cardiomyocytes; however, these cytoprotective effects were diminished by silencing Nrf2 and HO-1. In conclusion, this study reports that quercetin has the potential to antagonize cisplatin-caused cardiotoxicity by reducing ROS-mediated mitochondrial damage and inflammation via the Nrf2/HO-1 and p38MAPK/NF-[Formula: see text]Bp65/IL-8 signaling pathway. This study provided the theoretical basis and experimental proof for the clinical application of quercetin as a new effective strategy to relieve chemotherapy-induced cardiotoxicity.

Plant-Derived Catechols Are Substrates of TonB-Dependent Transporters and Sensitize Pseudomonas aeruginosa to Siderophore-Drug Conjugates.

Pseudomonas aeruginosa is an opportunistic pathogen responsible for acute and chronic infections in immunocompromised hosts. This organism is known to compete efficiently against coinfecting microorganisms, due in part to the secretion of antimicrobial molecules and the synthesis of siderophore molecules with high affinity for iron. P. aeruginosa possess a large repertoire of TonB-dependent transporters for the uptake of its own, as well as xenosiderophores released from other bacteria or fungi. Here, we show that P. aeruginosa is also capable of utilizing plant-derived polyphenols as an iron source. We found that exclusively plant-derived phenols containing a catechol group (i.e., chlorogenic acid, caffeic acid, quercetin, luteolin) induce the expression of the TonB-dependent transporters PiuA or PirA. This induction requires the two-component system PirR-PirS. Chlorogenic acid in its Fe(III)-loaded form was actively transported by PiuA and PirA and supported growth under iron-limiting conditions. Coincidentally, PiuA and PirA are also the main TonB transporters for the recently approved siderophore-drug conjugate cefiderocol. Surprisingly, quercetin supplementation increased the susceptibility of P. aeruginosa to siderophore-drug conjugates, due to induction of piuA and pirA expression mediated by the PirR-PirS two-component system. These findings suggest a potential novel therapeutic application for these biologically active dietary polyphenols. IMPORTANCE Iron is an essential element for living organisms. Most bacteria synthesize species-specific iron chelators, called siderophores, able to capture iron from their host or the environment. Pseudomonas aeruginosa, an opportunistic pathogen, produces two endogenous siderophores but is able to acquire iron also via xenosiderophores, produced by other bacteria or fungi, using a set of conserved TonB transporters. Here, we show that P. aeruginosa is also able to use plant metabolites, like quercetin and chlorogenic acid, as siderophores. These metabolites possess an iron-chelating catechol group and are recognized and transported by the TonB transporters PirA and PiuA. Since these transporters also promote the specific uptake of siderophore-drug conjugates, P. aeruginosa exposed to these plant catechols becomes hypersusceptible to this novel class of antibiotics. This unexpected finding suggests a potential therapeutic application for quercetin and chlorogenic acid, which were mainly investigated for their antioxidant and anti-inflammatory properties.