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Flavonoids and Their Disease Prevention and Treatment Potential
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Flavonoids and Their Disease Prevention and Treatment Potential

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (25 September 2020) | Viewed by 116197

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Prof. Dr. H. P. Vasantha Rupasinghe

E-Mail Website
Guest Editor
Department of Plant, Food, and Environmental Sciences, Faculty of Agriculture, Dalhousie University, Truro, NS B2N 5E3, Canada
Interests: dietary antioxidants; phytochemicals; polyphenols; flavonoids and their derivatives; chemoprevention; molecular mechanisms of action; DNA damage signaling and DNA repair; postbiotics of polyphenols
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In recent years, the interest in flavonoids as dietary bioactives to prevent human diseases, as well as their candidacy as pharmaceuticals, has been exponentially expanded. Flavonoids are a subclass of plant polyphenols that have been shown to possess numerous health-promoting properties in a wide range of investigations, from cell-based assays to epidemiological and human intervention studies.

Flavonoids are ubiquitously present in plant-based foods, traditional herbal remedies, and natural health products. Scientific evidence has strongly shown that regular intake of dietary flavonoids reduces the risk of oxidative stress- and chronic inflammation-mediated pathogenesis of human diseases, such as cardiovascular disease, certain cancers, and neurological disorders. The physiological benefits of dietary flavonoids have been demonstrated to be due to multiple mechanisms of action, including regulating redox homeostasis, epigenetic regulations, activation of survival genes and signaling pathways, regulation of mitochondrial function and bioenergetics, and modulation of inflammation response. The role of flavonoids on gut microbiota and impact of microbial metabolites of flavonoids on optimal health has begun to unravel. The complex biological activities of flavonoid molecules are due to their structural diversity. However, some flavonoids are not absorbed well, and their bioavailability could be enhanced through structural modifications and application of nanotechnology such as encapsulation.

Therefore, this Special Issue is dedicated to original research articles which cover the latest findings on the role of dietary flavonoids and their derivatives in disease prevention and treatment. Review articles could discuss the advancement of our knowledge within the mechanisms of action of specific flavonoids, the interaction of flavonoids with microbiota, the enhancement of flavonoid bioavailability and bio-efficacy, etc.

Prof. Dr. Vasantha Rupasinghe
Guest Editor

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Keywords

  • Flavonoids and their derivatives
  • Chronic and metabolic diseases
  • Prevention and treatment
  • Mechanisms of action
  • Functional foods and nutraceuticals
  • Drug discovery

Published Papers (20 papers)

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Editorial

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7 pages, 202 KiB  
Editorial
Special Issue “Flavonoids and Their Disease Prevention and Treatment Potential”: Recent Advances and Future Perspectives
by H.P. Vasantha Rupasinghe
Molecules 2020, 25(20), 4746; https://doi.org/10.3390/molecules25204746 - 16 Oct 2020
Cited by 35 | Viewed by 3572
Abstract
In recent years, the interest in flavonoids as dietary bioactives to prevent human diseases, as well as their candidacy as pharmaceutical leads, has exponentially expanded [...] Full article
(This article belongs to the Special Issue Flavonoids and Their Disease Prevention and Treatment Potential)

Research

Jump to: Editorial, Review

14 pages, 1157 KiB  
Article
Benefits of Anthocyanin-Rich Black Rice Fraction and Wood Sterols to Control Plasma and Tissue Lipid Concentrations in Wistar Kyoto Rats Fed an Atherogenic Diet
by Aneta Kopeć, Jerzy Zawistowski and David D. Kitts
Molecules 2020, 25(22), 5363; https://doi.org/10.3390/molecules25225363 - 17 Nov 2020
Cited by 3 | Viewed by 2136
Abstract
Background: This study reports on the relative effects of administrating a cyanidin-3-O-glucoside-rich black rice fraction (BRF), a standardized wood sterol mixture (WS), and a combination of both to lower plasma and target tissue lipid concentrations in Wistar Kyoto (WKY) rats [...] Read more.
Background: This study reports on the relative effects of administrating a cyanidin-3-O-glucoside-rich black rice fraction (BRF), a standardized wood sterol mixture (WS), and a combination of both to lower plasma and target tissue lipid concentrations in Wistar Kyoto (WKY) rats fed atherogenic diets. Methods: Male WKY (n = 40) rats were randomly divided into five groups, which included a nonatherogenic control diet and atherogenic diets that included a positive control and atherogenic diets supplemented with BRF or WS, respectively, and a combination of both BRF + WS. Plasma and target tissue liver, heart and aorta cholesterol, and triacylglycerides (TAG) content were also measured. Results: Rats fed atherogenic diets exhibited elevated hyperlipidemia compared to counterparts fed nonatherogenic diets (p < 0.001); this effect was mitigated by supplementing the atherogenic diets with BRF and WS, respectively (p < 0.05). Combining BRF with WS to enrich the supplement lowered cholesterol similar to the WS effect (p < 0.05) and lowered TAG characteristic to the BRF effect (p < 0.05). Conclusions: Rats fed diets containing BRF or WS effectively mitigate the hypercholesterolemia and elevated TAG induced by feeding an atherogenic diet. The benefit of adding BRF + WS together is relevant to the lipid parameter measured and is target tissue-specific. Full article
(This article belongs to the Special Issue Flavonoids and Their Disease Prevention and Treatment Potential)
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14 pages, 2488 KiB  
Article
Effects of Grape Polyphenols on the Life Span and Neuroinflammatory Alterations Related to Neurodegenerative Parkinson Disease-Like Disturbances in Mice
by Maria A. Tikhonova, Nadezhda G. Tikhonova, Michael V. Tenditnik, Marina V. Ovsyukova, Anna A. Akopyan, Nina I. Dubrovina, Tamara G. Amstislavskaya and Elena K. Khlestkina
Molecules 2020, 25(22), 5339; https://doi.org/10.3390/molecules25225339 - 16 Nov 2020
Cited by 16 | Viewed by 3092
Abstract
Functional nutrition is a valuable supplementation to dietary therapy. Functional foods are enriched with biologically active substances. Plant polyphenols attract particular attention due to multiple beneficial properties attributed to their high antioxidant and other biological activities. We assessed the effect of grape polyphenols [...] Read more.
Functional nutrition is a valuable supplementation to dietary therapy. Functional foods are enriched with biologically active substances. Plant polyphenols attract particular attention due to multiple beneficial properties attributed to their high antioxidant and other biological activities. We assessed the effect of grape polyphenols on the life span of C57BL/6 mice and on behavioral and neuroinflammatory alterations in a transgenic mouse model of Parkinson disease (PD) with overexpression of the A53T-mutant human α-synuclein. C57BL/6 mice were given a dietary supplement containing grape polyphenol concentrate (GPC—1.5 mL/kg/day) with drinking water from the age of 6–8 weeks for life. Transgenic PD mice received GPC beginning at the age of 10 weeks for four months. GPC significantly influenced the cumulative proportion of surviving and substantially augmented the average life span in mice. In the transgenic PD model, the grape polyphenol (GP) diet enhanced memory reconsolidation and diminished memory extinction in a passive avoidance test. Behavioral effects of GP treatment were accompanied by a decrease in α-synuclein accumulation in the frontal cortex and a reduction in the expression of neuroinflammatory markers (IBA1 and CD54) in the frontal cortex and hippocampus. Thus, a GP-rich diet is recommended as promising functional nutrition for aging people and patients with neurodegenerative disorders. Full article
(This article belongs to the Special Issue Flavonoids and Their Disease Prevention and Treatment Potential)
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31 pages, 5375 KiB  
Article
Antiangiogenic Activity of Flavonoids: A Systematic Review and Meta-Analysis
by Mai Khater, Francesca Greco and Helen M. I. Osborn
Molecules 2020, 25(20), 4712; https://doi.org/10.3390/molecules25204712 - 14 Oct 2020
Cited by 13 | Viewed by 4883
Abstract
An imbalance of angiogenesis contributes to many pathologies such as cancer, arthritis and retinopathy, hence molecules that can modulate angiogenesis are of considerable therapeutic importance. Despite many reports on the promising antiangiogenic properties of naturally occurring flavonoids, no flavonoids have progressed to the [...] Read more.
An imbalance of angiogenesis contributes to many pathologies such as cancer, arthritis and retinopathy, hence molecules that can modulate angiogenesis are of considerable therapeutic importance. Despite many reports on the promising antiangiogenic properties of naturally occurring flavonoids, no flavonoids have progressed to the clinic for this application. This systematic review and meta-analysis therefore evaluates the antiangiogenic activities of a wide range of flavonoids and is presented in two sections. The first part of the study (Systematic overview) included 402 articles identified by searching articles published before May 2020 using ScienceDirect, PubMed and Web of Science databases. From this initial search, different classes of flavonoids with antiangiogenic activities, related pathologies and use of in vitro and/or in/ex vivo angiogenesis assays were identified. In the second part (Meta-analysis), 25 studies concerning the antiangiogenic evaluation of flavonoids using the in vivo chick chorioallantoic membrane (CAM) assay were included, following a targeted search on articles published prior to June 2020. Meta-analysis of 15 out of the 25 eligible studies showed concentration dependent antiangiogenic activity of six compared subclasses of flavonoids with isoflavones, flavonols and flavones being the most active (64 to 80% reduction of blood vessels at 100 µM). Furthermore, the key structural features required for the antiangiogenic activity of flavonoids were derived from the pooled data in a structure activity relationship (SAR) study. All in all, flavonoids are promising candidates for the development of antiangiogenic agents, however further investigations are needed to determine the key structural features responsible for their activity. Full article
(This article belongs to the Special Issue Flavonoids and Their Disease Prevention and Treatment Potential)
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15 pages, 1568 KiB  
Article
Chalcone Methoxy Derivatives Exhibit Antiproliferative and Proapoptotic Activity on Canine Lymphoma and Leukemia Cells
by Aleksandra Pawlak, Marta Henklewska, Beatriz Hernández Suárez, Mateusz Łużny, Ewa Kozłowska, Bożena Obmińska-Mrukowicz and Tomasz Janeczko
Molecules 2020, 25(19), 4362; https://doi.org/10.3390/molecules25194362 - 23 Sep 2020
Cited by 27 | Viewed by 3307
Abstract
Chalcones are interesting candidates for anti-cancer drugs due to the ease of their synthesis and their extensive biological activity. The study presents antitumor activity of newly synthesized chalcone analogues with a methoxy group on a panel of canine lymphoma and leukemia cell lines. [...] Read more.
Chalcones are interesting candidates for anti-cancer drugs due to the ease of their synthesis and their extensive biological activity. The study presents antitumor activity of newly synthesized chalcone analogues with a methoxy group on a panel of canine lymphoma and leukemia cell lines. The antiproliferative effect of the 2′-hydroxychalcone and its methoxylated derivatives was evaluated in MTT assay after 48 h of treatment in different concentrations. The proapoptotic activity was studied by cytometric analysis of cells stained with Annexin V/FITC and propidium iodide and by measure caspases 3/7 and 8 activation. The DNA damage was evaluated by Western blot analysis of phosphorylated histone H2AX. The new compounds had selective antiproliferative activity against the studied cell lines, the most effective were the 2′-hydroxy-2″,5″-dimethoxychalcone and 2′-hydroxy-4′,6′-dimethoxychalcone. 2′-Hydroxychalcone and the two most active derivatives induced apoptosis and caspases participation, but some percentage of necrotic cells was also observed. Comparing phosphatidylserine externalization after treatment with the different compounds it was noted that the addition of two methoxy groups increased the proapoptotic potential. The most active compounds triggered DNA damage even in the cell lines resistant to chalcone-induced apoptosis. The results confirmed that the analogues could have anticancer potential in the treatment of canine lymphoma or leukemia. Full article
(This article belongs to the Special Issue Flavonoids and Their Disease Prevention and Treatment Potential)
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13 pages, 3911 KiB  
Article
Cyanidin-3-O-Glucoside-Rich Haskap Berry Administration Suppresses Carcinogen-Induced Lung Tumorigenesis in A/JCr Mice
by Madumani Amararathna, David W. Hoskin and H. P. Vasantha Rupasinghe
Molecules 2020, 25(17), 3823; https://doi.org/10.3390/molecules25173823 - 22 Aug 2020
Cited by 16 | Viewed by 3167
Abstract
In our previous study, we demonstrated that cyanidin-3-O-glucoside (C3G)-rich haskap (Lonicera caerulea L.) berry extracts can attenuate the carcinogen-induced DNA damage in normal lung epithelial cells in vitro. Here, the efficacy of lyophilized powder of whole haskap berry (C3G-HB) [...] Read more.
In our previous study, we demonstrated that cyanidin-3-O-glucoside (C3G)-rich haskap (Lonicera caerulea L.) berry extracts can attenuate the carcinogen-induced DNA damage in normal lung epithelial cells in vitro. Here, the efficacy of lyophilized powder of whole haskap berry (C3G-HB) in lowering tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, (NNK)-induced lung tumorigenesis in A/JCr mice was investigated. Three weeks after daily oral administration of C3G-HB (6 mg of C3G in 0.2 g of C3G-HB/mouse/day), lung tumors were initiated by a single intraperitoneal injection of NNK. Dietary C3G-HB supplementation was continued, and 22 weeks later, mice were euthanized. Lung tumors were visualized through positron emission tomography (PET) and magnetic resonance imaging (MRI) 19 weeks after NNK injection. Dietary supplementation of C3G-HB significantly reduced the NNK-induced lung tumor multiplicity and tumor area but did not affect tumor incidence. Immunohistochemical analysis showed reduced expression of proliferative cell nuclear antigen (PCNA) and Ki-67 in lung tissues. Therefore, C3G-HB has the potential to reduce the lung tumorigenesis, and to be used as a source for developing dietary supplements or nutraceuticals for reducing the risk of lung cancer among high-risk populations. Full article
(This article belongs to the Special Issue Flavonoids and Their Disease Prevention and Treatment Potential)
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18 pages, 6591 KiB  
Article
Flavonoid and Non-Flavonoid Compounds of Autumn Royal and Egnatia Grape Skin Extracts Affect Membrane PUFA’s Profile and Cell Morphology in Human Colon Cancer Cell Lines
by Valeria Tutino, Isabella Gigante, Rosa Anna Milella, Valentina De Nunzio, Riccardo Flamini, Mirko De Rosso, Maria Principia Scavo, Nicoletta Depalo, Elisabetta Fanizza, Maria Gabriella Caruso and Maria Notarnicola
Molecules 2020, 25(15), 3352; https://doi.org/10.3390/molecules25153352 - 23 Jul 2020
Cited by 7 | Viewed by 2730
Abstract
Grapes contain many flavonoid and non-flavonoid compounds with anticancer effects. In this work we fully characterized the polyphenolic profile of two grape skin extracts (GSEs), Autumn Royal and Egnatia, and assessed their effects on Polyunsaturated Fatty Acid (PUFA) membrane levels of Caco2 and [...] Read more.
Grapes contain many flavonoid and non-flavonoid compounds with anticancer effects. In this work we fully characterized the polyphenolic profile of two grape skin extracts (GSEs), Autumn Royal and Egnatia, and assessed their effects on Polyunsaturated Fatty Acid (PUFA) membrane levels of Caco2 and SW480 human colon cancer cell lines. Gene expression of 15-lipoxygenase-1 (15-LOX-1), and peroxisome proliferator-activated receptor gamma (PPAR-γ), as well as cell morphology, were evaluated. The polyphenolic composition was analyzed by Ultra-High-Performance Liquid Chromatography/Quadrupole-Time of Flight mass spectrometry (UHPLC/QTOF) analysis. PUFA levels were evaluated by gas chromatography, and gene expression levels of 15-LOX-1 and PPAR-γ were analyzed by real-time Polymerase Chain Reaction (PCR). Morphological cell changes caused by GSEs were identified by field emission scanning electron microscope (FE-SEM) and photomicrograph examination. We detected a different profile of flavonoid and non-flavonoid compounds in Autumn Royal and Egnatia GSEs. Cultured cells showed an increase of total PUFA levels mainly after treatment with Autumn Royal grape, and were richer in flavonoids when compared with the Egnatia variety. Both GSEs were able to affect 15-LOX-1 and PPAR-γ gene expression and cell morphology. Our results highlighted a new antitumor mechanism of GSEs that involves membrane PUFAs and their downstream pathways. Full article
(This article belongs to the Special Issue Flavonoids and Their Disease Prevention and Treatment Potential)
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10 pages, 1696 KiB  
Communication
Potential of Flavonoid-Inspired Phytomedicines against COVID-19
by Wilfred Ngwa, Rajiv Kumar, Daryl Thompson, William Lyerly, Roscoe Moore, Terry-Elinor Reid, Henry Lowe and Ngeh Toyang
Molecules 2020, 25(11), 2707; https://doi.org/10.3390/molecules25112707 - 11 Jun 2020
Cited by 112 | Viewed by 11829
Abstract
Flavonoids are widely used as phytomedicines. Here, we report on flavonoid phytomedicines with potential for development into prophylactics or therapeutics against coronavirus disease 2019 (COVID-19). These flavonoid-based phytomedicines include: caflanone, Equivir, hesperetin, myricetin, and Linebacker. Our in silico studies show that these flavonoid-based [...] Read more.
Flavonoids are widely used as phytomedicines. Here, we report on flavonoid phytomedicines with potential for development into prophylactics or therapeutics against coronavirus disease 2019 (COVID-19). These flavonoid-based phytomedicines include: caflanone, Equivir, hesperetin, myricetin, and Linebacker. Our in silico studies show that these flavonoid-based molecules can bind with high affinity to the spike protein, helicase, and protease sites on the ACE2 receptor used by the severe acute respiratory syndrome coronavirus 2 to infect cells and cause COVID-19. Meanwhile, in vitro studies show potential of caflanone to inhibit virus entry factors including, ABL-2, cathepsin L, cytokines (IL-1β, IL-6, IL-8, Mip-1α, TNF-α), and PI4Kiiiβ as well as AXL-2, which facilitates mother-to-fetus transmission of coronavirus. The potential for the use of smart drug delivery technologies like nanoparticle drones loaded with these phytomedicines to overcome bioavailability limitations and improve therapeutic efficacy are discussed. Full article
(This article belongs to the Special Issue Flavonoids and Their Disease Prevention and Treatment Potential)
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13 pages, 3963 KiB  
Article
Inhibitory Effects of Tangeretin, a Citrus Peel-Derived Flavonoid, on Breast Cancer Stem Cell Formation through Suppression of Stat3 Signaling
by Yu-Chan Ko, Hack Sun Choi, Ren Liu, Ji-Hyang Kim, Su-Lim Kim, Bong-Sik Yun and Dong-Sun Lee
Molecules 2020, 25(11), 2599; https://doi.org/10.3390/molecules25112599 - 03 Jun 2020
Cited by 20 | Viewed by 4411
Abstract
Breast cancer stem cells (BCSCs) are responsible for tumor chemoresistance and recurrence. Targeting CSCs using natural compounds is a novel approach for cancer therapy. A CSC-inhibiting compound was purified from citrus extracts using silica gel, gel filtration and high-pressure liquid chromatography. The purified [...] Read more.
Breast cancer stem cells (BCSCs) are responsible for tumor chemoresistance and recurrence. Targeting CSCs using natural compounds is a novel approach for cancer therapy. A CSC-inhibiting compound was purified from citrus extracts using silica gel, gel filtration and high-pressure liquid chromatography. The purified compound was identified as tangeretin by using nuclear magnetic resonance (NMR). Tangeretin inhibited cell proliferation, CSC formation and tumor growth, and modestly induced apoptosis in CSCs. The frequency of a subpopulation with a CSC phenotype (CD44+/CD24−) was reduced by tangeretin. Tangeretin reduced the total level and phosphorylated nuclear level of signal transducer and activator of transcription 3 (Stat3). Our results in this study show that tangeretin inhibits the Stat3 signaling pathway and induces CSC death, indicating that tangeretin may be a potential natural compound that targets breast cancer cells and CSCs. Full article
(This article belongs to the Special Issue Flavonoids and Their Disease Prevention and Treatment Potential)
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13 pages, 1433 KiB  
Article
Antiprotozoal Activity Against Entamoeba histolytica of Flavonoids Isolated from Lippia graveolens Kunth
by Ramiro Quintanilla-Licea, Javier Vargas-Villarreal, María Julia Verde-Star, Verónica Mayela Rivas-Galindo and Ángel David Torres-Hernández
Molecules 2020, 25(11), 2464; https://doi.org/10.3390/molecules25112464 - 26 May 2020
Cited by 15 | Viewed by 3391
Abstract
Amebiasis caused by Entamoeba histolytica is nowadays a serious public health problem worldwide, especially in developing countries. Annually, up to 100,000 deaths occur across the world. Due to the resistance that pathogenic protozoa exhibit against commercial antiprotozoal drugs, a growing emphasis has been [...] Read more.
Amebiasis caused by Entamoeba histolytica is nowadays a serious public health problem worldwide, especially in developing countries. Annually, up to 100,000 deaths occur across the world. Due to the resistance that pathogenic protozoa exhibit against commercial antiprotozoal drugs, a growing emphasis has been placed on plants used in traditional medicine to discover new antiparasitics. Previously, we reported the in vitro antiamoebic activity of a methanolic extract of Lippia graveolens Kunth (Mexican oregano). In this study, we outline the isolation and structure elucidation of antiamoebic compounds occurring in this plant. The subsequent work-up of this methanol extract by bioguided isolation using several chromatographic techniques yielded the flavonoids pinocembrin (1), sakuranetin (2), cirsimaritin (3), and naringenin (4). Structural elucidation of the isolated compounds was achieved by spectroscopic/spectrometric analyses and comparing literature data. These compounds revealed significant antiprotozoal activity against E. histolytica trophozoites using in vitro tests, showing a 50% inhibitory concentration (IC50) ranging from 28 to 154 µg/mL. Amebicide activity of sakuranetin and cirsimaritin is reported for the first time in this study. These research data may help to corroborate the use of this plant in traditional Mexican medicine for the treatment of dyspepsia. Full article
(This article belongs to the Special Issue Flavonoids and Their Disease Prevention and Treatment Potential)
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13 pages, 2784 KiB  
Article
Flavonoids from Acer okamotoanum Inhibit Adipocyte Differentiation and Promote Lipolysis in the 3T3-L1 Cells
by Ji Hyun Kim, Sanghyun Lee and Eun Ju Cho
Molecules 2020, 25(8), 1920; https://doi.org/10.3390/molecules25081920 - 21 Apr 2020
Cited by 17 | Viewed by 3323
Abstract
Flavonoids, quercitrin, isoquercitrin (IQ), and afzelin, were isolated from ethyl acetate fraction of Acer okamotoanum. We investigated anti-obesity effects and mechanisms of three flavonoids from A. okamotoanum in the differentiated 3T3-L1 cells. The differentiated 3T3-L1 cells increased triglyceride (TG) contents, compared with [...] Read more.
Flavonoids, quercitrin, isoquercitrin (IQ), and afzelin, were isolated from ethyl acetate fraction of Acer okamotoanum. We investigated anti-obesity effects and mechanisms of three flavonoids from A. okamotoanum in the differentiated 3T3-L1 cells. The differentiated 3T3-L1 cells increased triglyceride (TG) contents, compared with non-differentiated normal group. However, treatments of three flavonoids from A. okamotoanum decreased TG contents without cytotoxicity. In addition, they showed significant down-regulation of several adipogenic transcription factors, such as γ-cytidine-cytidine-adenosine-adenosine-thymidine/enhancer binding protein -α, -β, and peroxisome proliferator-activated receptor-γ, compared with non-treated control group. Furthermore, treatment of the flavonoids inhibited expressions of lipogenesis-related proteins including fatty acid synthase, adipocyte protein 2, and glucose transporter 4. Moreover, IQ-treated group showed significant up-regulation of lipolysis-related proteins such as adipose triglyceride lipase and hormone-sensitive lipase. In addition, flavonoids significantly activated 5′-adenosine monophosphate-activated protein kinase (AMPK) compared to control group. In particular, IQ showed higher inhibition of TG accumulation by regulation of pathways related with both adipogenesis and lipolysis, than other flavonoids. The present results indicated that three flavonoids of A. okamotoanum showed anti-obesity activity by regulation of adipocyte differentiation, lipolysis, and AMPK signaling, suggesting as an anti-obesity functional agents. Full article
(This article belongs to the Special Issue Flavonoids and Their Disease Prevention and Treatment Potential)
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13 pages, 3069 KiB  
Article
Potential Therapeutic Anti-Inflammatory and Immunomodulatory Effects of Dihydroflavones, Flavones, and Flavonols
by Cristina Zaragozá, Lucinda Villaescusa, Jorge Monserrat, Francisco Zaragozá and Melchor Álvarez-Mon
Molecules 2020, 25(4), 1017; https://doi.org/10.3390/molecules25041017 - 24 Feb 2020
Cited by 69 | Viewed by 5942
Abstract
Systemic inflammation, circulating immune cell activation, and endothelial cell damage play a critical role in vascular pathogenesis. Flavonoids have shown anti-inflammatory effects. In this study, we investigated the effects of different flavonoids on the production of pro-inflammatory interleukin (IL) 1β, 6, and 8, [...] Read more.
Systemic inflammation, circulating immune cell activation, and endothelial cell damage play a critical role in vascular pathogenesis. Flavonoids have shown anti-inflammatory effects. In this study, we investigated the effects of different flavonoids on the production of pro-inflammatory interleukin (IL) 1β, 6, and 8, and tumor necrosis factor α (TNF-α), in peripheral blood cells. Methods: We studied the whole blood from 36 healthy donors. Lipopolysaccharide (LPS)-stimulated (0.5 μg/mL) whole-blood aliquots were incubated in the presence or absence of different concentrations of quercetin, rutin, naringenin, naringin, diosmetin, and diosmin for 6 h. Cultures were centrifuged and the supernatant was collected in order to measure IL-1β, TNF-α, IL-6, and IL-8 production using specific immunoassay techniques. This production was significantly inhibited by quercetin, naringenin, naringin, and diosmetin, but in no case by rutin or diosmin. Flavonoids exert different effects, maybe due to the differences between aglycons and glucosides present in their chemical structures. However, these studies suggest that quercetin, naringenin, naringin, and diosmetin could have a potential therapeutic effect in the inflammatory process of cardiovascular disease. Full article
(This article belongs to the Special Issue Flavonoids and Their Disease Prevention and Treatment Potential)
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17 pages, 1680 KiB  
Article
Optimization of Total Phenolic and Flavonoid Contents of Defatted Pitaya (Hylocereus polyrhizus) Seed Extract and Its Antioxidant Properties
by Siti Atikah Zulkifli, Siti Salwa Abd Gani, Uswatun Hasanah Zaidan and Mohd Izuan Effendi Halmi
Molecules 2020, 25(4), 787; https://doi.org/10.3390/molecules25040787 - 12 Feb 2020
Cited by 25 | Viewed by 4957
Abstract
The present study was conducted to optimize extraction process for defatted pitaya seed extract (DPSE) adopting response surface methodology (RSM). A five-level central composite design was used to optimize total phenolic content (TPC), total flavonoid content (TFC), ferric reducing antioxidant power (FRAP), and [...] Read more.
The present study was conducted to optimize extraction process for defatted pitaya seed extract (DPSE) adopting response surface methodology (RSM). A five-level central composite design was used to optimize total phenolic content (TPC), total flavonoid content (TFC), ferric reducing antioxidant power (FRAP), and 2,2′-azino-bis (3-ethylbenzothizoline-6-sulfonic acid (ABTS) activities. The independent variables included extraction time (30–60 min), extraction temperature (40–80 °C) and ethanol concentration (60%–80%). Results showed that the quadratic polynomial equations for all models were significant at (p < 0.05), with non-significant lack of fit at p > 0.05 and R2 of more than 0.90. The optimized extraction parameters were established as follows: extraction time of 45 min, extraction temperature of 70 °C and ethanol concentration of 80%. Under these conditions, the recovery of TPC, TFC, and antioxidant activity based on FRAP and ABTS were 128.58 ± 1.61 mg gallic acid equivalent (GAE)/g sample, 9.805 ± 0.69 mg quercetin equivalent (QE)/g sample, 1.23 ± 0.03 mM Fe2+/g sample, and 91.62% ± 0.15, respectively. Ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) analysis identified seven chemical compounds with flavonoids constituting major composition of the DPSE. Full article
(This article belongs to the Special Issue Flavonoids and Their Disease Prevention and Treatment Potential)
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14 pages, 3052 KiB  
Article
The Anti-Aging Potential of Neohesperidin and Its Synergistic Effects with Other Citrus Flavonoids in Extending Chronological Lifespan of Saccharomyces Cerevisiae BY4742
by Chunxia Guo, Hua Zhang, Xin Guan and Zhiqin Zhou
Molecules 2019, 24(22), 4093; https://doi.org/10.3390/molecules24224093 - 13 Nov 2019
Cited by 32 | Viewed by 4141
Abstract
The anti-aging activity of many plant flavonoids, as well as their mechanisms of action, have been explored in the current literature. However, the studies on the synergistic effects between the different flavonoid compounds were quite limited in previous reports. In this study, by [...] Read more.
The anti-aging activity of many plant flavonoids, as well as their mechanisms of action, have been explored in the current literature. However, the studies on the synergistic effects between the different flavonoid compounds were quite limited in previous reports. In this study, by using a high throughput assay, we tested the synergistic effects between different citrus flavonoids throughout the yeast’s chronological lifespan (CLS). We studied the effect of four flavonoid compounds including naringin, hesperedin, hesperitin, neohesperidin, as well as their different combinations on the CLS of the yeast strain BY4742. Their ROS scavenging ability, in vitro antioxidant activity and the influence on the extracellular pH were also tested. The results showed that neohesperidin extended the yeast’s CLS in a concentration-dependent manner. Especially, we found that neohesperidin showed great potential in extending CLS of budding yeast individually or synergistically with hesperetin. The neohesperidin exhibited the strongest function in decreasing the reactive oxygen species (ROS) accumulation in yeast. These findings clearly indicated that neohesperidin is potentially an anti-aging citrus flavonoid, and its synergistic effect with other flavonoids on yeast’s CLS will be an interesting subject for future research of the anti-aging function of citrus fruits. Full article
(This article belongs to the Special Issue Flavonoids and Their Disease Prevention and Treatment Potential)
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13 pages, 2215 KiB  
Article
Isorhamnetin Has Potential for the Treatment of Escherichia coli-Induced Sepsis
by Anil Kumar Chauhan, Jieun Kim, Yeongjoon Lee, Pavithra K. Balasubramanian and Yangmee Kim
Molecules 2019, 24(21), 3984; https://doi.org/10.3390/molecules24213984 - 04 Nov 2019
Cited by 21 | Viewed by 3752
Abstract
Isorhamnetin is a flavonoid that is abundant in the fruit of Hippophae rhamnoides L. It is widely studied for its ability to modulate inflammatory responses. In this study, we evaluated the potential of isorhamnetin to prevent gram-negative sepsis. We investigated its efficacy using [...] Read more.
Isorhamnetin is a flavonoid that is abundant in the fruit of Hippophae rhamnoides L. It is widely studied for its ability to modulate inflammatory responses. In this study, we evaluated the potential of isorhamnetin to prevent gram-negative sepsis. We investigated its efficacy using an Escherichia coli-induced sepsis model. Our study reveals that isorhamnetin treatment significantly enhances survival and reduces proinflammatory cytokine levels in the serum and lung tissue of E. coli-infected mice. Further, isorhamnetin treatment also significantly reduces the levels of aspartate aminotransferase, alanine amino transferase and blood urea nitrogen, suggesting that it can improve liver and kidney function in infected mice. Docking studies reveal that isorhamnetin binds deep in the hydrophobic binding pocket of MD-2 via extensive hydrophobic interactions and hydrogen bonding with Tyr102, preventing TLR4/MD-2 dimerization. Notably, binding and secreted alkaline phosphatase reporter gene assays show that isorhamnetin can interact directly with the TLR4/MD-2 complex, thus inhibiting the TLR4 cascade, which eventually causes systemic inflammation, resulting in death due to cytokine storms. We therefore presume that isorhamnetin could be a suitable therapeutic candidate to treat bacterial sepsis. Full article
(This article belongs to the Special Issue Flavonoids and Their Disease Prevention and Treatment Potential)
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11 pages, 1338 KiB  
Article
Vasodilatory Effects and Mechanisms of Action of Bacopa monnieri Active Compounds on Rat Mesenteric Arteries
by Natakorn Kamkaew, Tamkeen Urooj Paracha, Kornkanok Ingkaninan, Neti Waranuch and Krongkarn Chootip
Molecules 2019, 24(12), 2243; https://doi.org/10.3390/molecules24122243 - 15 Jun 2019
Cited by 23 | Viewed by 4725
Abstract
B. monnieri extract (BME) is an abundant source of bioactive compounds, including saponins and flavonoids known to produce vasodilation. However, it is unclear which components are the more effective vasodilators. The aim of this research was to investigate the vasorelaxant effects and mechanisms [...] Read more.
B. monnieri extract (BME) is an abundant source of bioactive compounds, including saponins and flavonoids known to produce vasodilation. However, it is unclear which components are the more effective vasodilators. The aim of this research was to investigate the vasorelaxant effects and mechanisms of action of saponins and flavonoids on rat isolated mesenteric arteries using the organ bath technique. The vasorelaxant mechanisms, including endothelial nitric oxide synthase (eNOS) pathway and calcium flux were examined. Saponins (bacoside A and bacopaside I), and flavonoids (luteolin and apigenin) at 0.1–100 µM caused vasorelaxation in a concentration-dependent manner. Luteolin and apigenin produced vasorelaxation in endothelial intact vessels with more efficacy (Emax 99.4 ± 0.7 and 95.3 ± 2.6%) and potency (EC50 4.35 ± 1.31 and 8.93 ± 3.33 µM) than bacoside A and bacopaside I (Emax 83.6 ± 2.9 and 79.9 ± 8.2%; EC50 10.8 ± 5.9 and 14.6 ± 5.4 µM). Pretreatment of endothelial intact rings, with L-NAME (100 µM); an eNOS inhibitor, or removal of the endothelium reduced the relaxant effects of all compounds. In K+-depolarised vessels suspended in Ca2+-free solution, these active compounds inhibited CaCl2-induced contraction in endothelial denuded arterial rings. Moreover, the active compounds attenuated transient contractions induced by 10 µM phenylephrine in Ca2+-free medium containing EGTA (1 mM). Thus, relaxant effects occurred in both endothelial intact and denuded vessels which signify actions through both endothelium and vascular smooth muscle cells. In conclusion, the flavonoids have about twice the potency of saponins as vasodilators. However, in the BME, there is ~20 × the amount of vaso-reactive saponins and thus are more effective. Full article
(This article belongs to the Special Issue Flavonoids and Their Disease Prevention and Treatment Potential)
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Review

Jump to: Editorial, Research

16 pages, 1067 KiB  
Review
Cranberry Polyphenols and Prevention against Urinary Tract Infections: Relevant Considerations
by Dolores González de Llano, M. Victoria Moreno-Arribas and Begoña Bartolomé
Molecules 2020, 25(15), 3523; https://doi.org/10.3390/molecules25153523 - 01 Aug 2020
Cited by 54 | Viewed by 16241
Abstract
Cranberry (Vaccinium macrocarpon) is a distinctive source of polyphenols as flavonoids and phenolic acids that has been described to display beneficial effects against urinary tract infections (UTIs), the second most common type of infections worldwide. UTIs can lead to significant morbidity, [...] Read more.
Cranberry (Vaccinium macrocarpon) is a distinctive source of polyphenols as flavonoids and phenolic acids that has been described to display beneficial effects against urinary tract infections (UTIs), the second most common type of infections worldwide. UTIs can lead to significant morbidity, especially in healthy females due to high rates of recurrence and antibiotic resistance. Strategies and therapeutic alternatives to antibiotics for prophylaxis and treatment against UTIs are continuously being sought after. Different to cranberry, which have been widely recommended in traditional medicine for UTIs prophylaxis, probiotics have emerged as a new alternative to the use of antibiotics against these infections and are the subject of new research in this area. Besides uropathogenic Escherichia coli (UPEC), the most common bacteria causing uncomplicated UTIs, other etiological agents, such as Klebsiellapneumoniae or Gram-positive bacteria of Enterococcus and Staphylococcus genera, seem to be more widespread than previously appreciated. Considerable current effort is also devoted to the still-unraveled mechanisms that are behind the UTI-protective effects of cranberry, probiotics and their new combined formulations. All these current topics in the understanding of the protective effects of cranberry against UTIs are reviewed in this paper. Further progresses expected in the coming years in these fields are also discussed. Full article
(This article belongs to the Special Issue Flavonoids and Their Disease Prevention and Treatment Potential)
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29 pages, 1387 KiB  
Review
The Targeted Impact of Flavones on Obesity-Induced Inflammation and the Potential Synergistic Role in Cancer and the Gut Microbiota
by Meenakshi Sudhakaran and Andrea I. Doseff
Molecules 2020, 25(11), 2477; https://doi.org/10.3390/molecules25112477 - 27 May 2020
Cited by 25 | Viewed by 6621
Abstract
Obesity is an inflammatory disease that is approaching pandemic levels, affecting nearly 30% of the world’s total population. Obesity increases the risk of diabetes, cardiovascular disorders, and cancer, consequentially impacting the quality of life and imposing a serious socioeconomic burden. Hence, reducing obesity [...] Read more.
Obesity is an inflammatory disease that is approaching pandemic levels, affecting nearly 30% of the world’s total population. Obesity increases the risk of diabetes, cardiovascular disorders, and cancer, consequentially impacting the quality of life and imposing a serious socioeconomic burden. Hence, reducing obesity and related life-threatening conditions has become a paramount health challenge. The chronic systemic inflammation characteristic of obesity promotes adipose tissue remodeling and metabolic changes. Macrophages, the major culprits in obesity-induced inflammation, contribute to sustaining a dysregulated immune function, which creates a vicious adipocyte–macrophage crosstalk, leading to insulin resistance and metabolic disorders. Therefore, targeting regulatory inflammatory pathways has attracted great attention to overcome obesity and its related conditions. However, the lack of clinical efficacy and the undesirable side-effects of available therapeutic options for obesity provide compelling reasons for the need to identify additional approaches for the prevention and treatment of obesity-induced inflammation. Plant-based active metabolites or nutraceuticals and diets with an increased content of these compounds are emerging as subjects of intense scientific investigation, due to their ability to ameliorate inflammatory conditions and offer safe and cost-effective opportunities to improve health. Flavones are a class of flavonoids with anti-obesogenic, anti-inflammatory and anti-carcinogenic properties. Preclinical studies have laid foundations by establishing the potential role of flavones in suppressing adipogenesis, inducing browning, modulating immune responses in the adipose tissues, and hindering obesity-induced inflammation. Nonetheless, the understanding of the molecular mechanisms responsible for the anti-obesogenic activity of flavones remains scarce and requires further investigations. This review recapitulates the molecular aspects of obesity-induced inflammation and the crosstalk between adipocytes and macrophages, while focusing on the current evidence on the health benefits of flavones against obesity and chronic inflammation, which has been positively correlated with an enhanced cancer incidence. We conclude the review by highlighting the areas of research warranting a deeper investigation, with an emphasis on flavones and their potential impact on the crosstalk between adipocytes, the immune system, the gut microbiome, and their role in the regulation of obesity. Full article
(This article belongs to the Special Issue Flavonoids and Their Disease Prevention and Treatment Potential)
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12 pages, 1110 KiB  
Review
Do Aspirin and Flavonoids Prevent Cancer through a Common Mechanism Involving Hydroxybenzoic Acids?—The Metabolite Hypothesis
by Ranjini Sankaranarayanan, D. Ramesh Kumar, Janki Patel and G. Jayarama Bhat
Molecules 2020, 25(9), 2243; https://doi.org/10.3390/molecules25092243 - 10 May 2020
Cited by 15 | Viewed by 5944
Abstract
Despite decades of research to elucidate the cancer preventive mechanisms of aspirin and flavonoids, a consensus has not been reached on their specific modes of action. This inability to accurately pinpoint the mechanism involved is due to the failure to differentiate the primary [...] Read more.
Despite decades of research to elucidate the cancer preventive mechanisms of aspirin and flavonoids, a consensus has not been reached on their specific modes of action. This inability to accurately pinpoint the mechanism involved is due to the failure to differentiate the primary targets from its associated downstream responses. This review is written in the context of the recent findings on the potential pathways involved in the prevention of colorectal cancers (CRC) by aspirin and flavonoids. Recent reports have demonstrated that the aspirin metabolites 2,3-dihydroxybenzoic acid (2,3-DHBA), 2,5-dihydroxybenzoic acid (2,5-DHBA) and the flavonoid metabolites 2,4,6-trihydroxybenzoic acid (2,4,6-THBA), 3,4-dihydroxybenzoic acid (3,4-DHBA) and 3,4,5-trihydroxybenzoic acid (3,4,5-THBA) were effective in inhibiting cancer cell growth in vitro. Limited in vivo studies also provide evidence that some of these hydroxybenzoic acids (HBAs) inhibit tumor growth in animal models. This raises the possibility that a common pathway involving HBAs may be responsible for the observed cancer preventive actions of aspirin and flavonoids. Since substantial amounts of aspirin and flavonoids are left unabsorbed in the intestinal lumen upon oral consumption, they may be subjected to degradation by the host and bacterial enzymes, generating simpler phenolic acids contributing to the prevention of CRC. Interestingly, these HBAs are also abundantly present in fruits and vegetables. Therefore, we suggest that the HBAs produced through microbial degradation of aspirin and flavonoids or those consumed through the diet may be common mediators of CRC prevention. Full article
(This article belongs to the Special Issue Flavonoids and Their Disease Prevention and Treatment Potential)
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35 pages, 1953 KiB  
Review
Therapeutic Potential of Flavonoids in Pain and Inflammation: Mechanisms of Action, Pre-Clinical and Clinical Data, and Pharmaceutical Development
by Camila R. Ferraz, Thacyana T. Carvalho, Marília F. Manchope, Nayara A. Artero, Fernanda S. Rasquel-Oliveira, Victor Fattori, Rubia Casagrande and Waldiceu A. Verri, Jr.
Molecules 2020, 25(3), 762; https://doi.org/10.3390/molecules25030762 - 10 Feb 2020
Cited by 155 | Viewed by 15914
Abstract
Pathological pain can be initiated after inflammation and/or peripheral nerve injury. It is a consequence of the pathological functioning of the nervous system rather than only a symptom. In fact, pain is a significant social, health, and economic burden worldwide. Flavonoids are plant [...] Read more.
Pathological pain can be initiated after inflammation and/or peripheral nerve injury. It is a consequence of the pathological functioning of the nervous system rather than only a symptom. In fact, pain is a significant social, health, and economic burden worldwide. Flavonoids are plant derivative compounds easily found in several fruits and vegetables and consumed in the daily food intake. Flavonoids vary in terms of classes, and while structurally unique, they share a basic structure formed by three rings, known as the flavan nucleus. Structural differences can be found in the pattern of substitution in one of these rings. The hydroxyl group (–OH) position in one of the rings determines the mechanisms of action of the flavonoids and reveals a complex multifunctional activity. Flavonoids have been widely used for their antioxidant, analgesic, and anti-inflammatory effects along with safe preclinical and clinical profiles. In this review, we discuss the preclinical and clinical evidence on the analgesic and anti-inflammatory proprieties of flavonoids. We also focus on how the development of formulations containing flavonoids, along with the understanding of their structure-activity relationship, can be harnessed to identify novel flavonoid-based therapies to treat pathological pain and inflammation. Full article
(This article belongs to the Special Issue Flavonoids and Their Disease Prevention and Treatment Potential)
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