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Biosynthesis and Biological Activities of Flavonoids

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

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 39138

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Special Issue Editors

Prof. Dr. Katia Petroni

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Guest Editor

Department of BioSciences, Università degli Studi di Milano, Milan, Italy
Interests: flavonoids; anthocyanins; nutrigenomics; cardioprotection; obesity
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Grażyna Budryn

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Guest Editor

Institute of Food Technology and Analysis, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Stefanowskiego 4/10, 90-924 Lodz, Poland
Interests: phytocompounds; phenolic compounds; bioactive peptides; in vitro digestion; bioavailability and absorption of nutrients; food protection and safety; food packaging and storage

Dr. Malgorzata Zakłos-Szyda

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Institute of Molecular and Industrial Biotechnology, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Stefanowskiego 2/22, 90-537 Lodz, Poland
Interests: phytocompounds; phenolic compounds; animal cell culture; cell signaling; nuclear receptors; apoptosis; cytoprotection; lipid and carbohydrates metabolism
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

Flavonoids are a family of plant secondary metabolites and are widely acknowledged for their beneficial effects on human health. Many epidemiological, preclinical and clinical studies have highlighted their protective effects against many chronic diseases, including cancer and cardiovascular and neurodegenerative diseases. Flavonoid biosynthesis and its regulation have been extensively studied in different plant species. However, novel findings on the regulation of specific branches controlling modifications of flavonoid aglycones (e.g. glycosylation, methylation, acylation etc.) are increasingly emerging. Modifications of flavonoid aglycones also impact the biological activity of flavonoids. This Special Issue is dedicated to manuscripts focused on dietary flavonoids, their derivatives and related biological activities, with a special emphasis on the biosynthesis and structural features of flavonoids, their specific mechanism of action and health benefits against chronic diseases.

Prof. Dr. Katia Petroni
Prof. Dr. Grażyna Budryn
Dr. Malgorzata Zakłos-Szyda
Guest Editors

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Keywords

Flavonoids and their derivatives
Biological activity
Health benefits
Chronic diseases
Mechanisms of action
Functional foods and nutraceuticals
Flavonoid biosynthesis

Published Papers (9 papers)

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Research

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19 pages, 2866 KiB

Open AccessArticle

Oxidative Transformation of Dihydroflavonols and Flavan-3-ols by Anthocyanidin Synthase from Vitis vinifera

by Jia-Rong Zhang, Claudine Trossat-Magnin, Katell Bathany, Luc Negroni, Serge Delrot and Jean Chaudière

Molecules 2022, 27(3), 1047; https://doi.org/10.3390/molecules27031047 - 3 Feb 2022

Cited by 5 | Viewed by 2087

Abstract

Twelve polyphenols from three distinct families (dihydroflavonols, flavan-3-ols, and flavanones) were studied as potential substrates of anthocyanidin synthase from Vitis vinifera (VvANS). Only flavan-3-ols of (2R,3S) configuration having either a catechol or gallol group on ring B are accepted as substrates. Only dihydroflavonols of (2R,3R) configuration are accepted as substrates, but a catechol or gallol group is not mandatory. Flavanones are not substrates of VvANS. HPLC and MS/MS analyses of the enzymatic products showed that the VvANS-catalyzed oxidative transformation of (+)-dihydroflavonols, such as dihydroquercetin, dihydrokaempferol and dihydromyricetin, leads only to the corresponding flavonols. Among the flavan-3-ols recognized as substrates, (+)-gallocatechin was only transformed into delphinidin by VvANS, whereas (+)-catechin was transformed into three products, including two major products that were an ascorbate–cyanidin adduct and a dimer of oxidized catechin, and a minor product that was cyanidin. Data from real-time MS monitoring of the enzymatic transformation of (+)-catechin suggest that its products are all derived from the initial C₃-hydroxylation intermediate, i.e., a 3,3-gem-diol, and their most likely formation mechanism is discussed. Full article

(This article belongs to the Special Issue Biosynthesis and Biological Activities of Flavonoids)

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17 pages, 3601 KiB

Open AccessArticle

Expression Profiling of Flavonoid Biosynthesis Genes and Secondary Metabolites Accumulation in Populus under Drought Stress

by Umair Ahmed, Muhammad Junaid Rao, Cheng Qi, Qi Xie, Hamza Armghan Noushahi, Muhammad Yaseen, Xueping Shi and Bo Zheng

Molecules 2021, 26(18), 5546; https://doi.org/10.3390/molecules26185546 - 13 Sep 2021

Cited by 40 | Viewed by 3796

Abstract

Flavonoids are key secondary metabolites that are biologically active and perform diverse functions in plants such as stress defense against abiotic and biotic stress. In addition to its importance, no comprehensive information has been available about the secondary metabolic response of Populus tree, especially the genes that encode key enzymes involved in flavonoid biosynthesis under drought stress. In this study, the quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed that the expression of flavonoid biosynthesis genes (PtPAL, Pt4-CL, PtCHS, PtFLS-1, PtF3H, PtDFR, and PtANS) gradually increased in the leaves of hybrid poplar (P. tremula × P. alba), corresponding to the drought stress duration. In addition, the activity and capacity of antioxidants have also increased, which is positively correlated with the increment of phenolic, flavonoid, anthocyanin, and carotenoid compounds under drought stress. As the drought stress prolonged, the level of reactive oxygen species such as hydrogen peroxide (H₂O₂) and singlet oxygen (O₂⁻) too increased. The concentration of phytohormone salicylic acid (SA) also increased significantly in the stressed poplar leaves. Our research concluded that drought stress significantly induced the expression of flavonoid biosynthesis genes in hybrid poplar plants and enhanced the accumulation of phenolic and flavonoid compounds with resilient antioxidant activity. Full article

(This article belongs to the Special Issue Biosynthesis and Biological Activities of Flavonoids)

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28 pages, 4328 KiB

Open AccessArticle

Phenolics-Rich Extracts of Dietary Plants as Regulators of Fructose Uptake in Caco-2 Cells via GLUT5 Involvement

by Małgorzata Zakłos-Szyda, Nina Pietrzyk, Agnieszka Kowalska-Baron, Adriana Nowak, Katarzyna Chałaśkiewicz, Marcin Ratajewski, Grażyna Budryn and Maria Koziołkiewicz

Molecules 2021, 26(16), 4745; https://doi.org/10.3390/molecules26164745 - 5 Aug 2021

Cited by 7 | Viewed by 3211

Abstract

The latest data link the chronic consumption of large amounts of fructose present in food with the generation of hypertension and disturbances in carbohydrate and lipid metabolism, which promote the development of obesity, non-alcoholic fatty liver disease, insulin resistance, and type 2 diabetes. This effect is possible after fructose is absorbed by the small intestine cells and, to a lesser extent, by hepatocytes. Fructose transport is dependent on proteins from the family of glucose transporters (GLUTs), among which GLUT5 selectively absorbs fructose from the intestine. In this study, we examined the effect of four phenolic-rich extracts obtained from A. graveolens, B. juncea, and M. chamomilla on fructose uptake by Caco-2 cells. Extracts from B. juncea and M. chamomilla most effectively reduced fluorescent fructose analogue (NBDF) accumulation in Caco-2, as well as downregulated GLUT5 protein levels. These preparations were able to decrease the mRNA level of genes encoding transcription factors regulating GLUT5 expression-thioredoxin-interacting protein (TXNIP) and carbohydrate-responsive element-binding protein (ChREBP). Active extracts contained large amounts of apigenin and flavonols. The molecular docking simulation suggested that some of identified phenolic constituents can play an important role in the inhibition of GLUT5-mediated fructose transport. Full article

(This article belongs to the Special Issue Biosynthesis and Biological Activities of Flavonoids)

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22 pages, 4559 KiB

Open AccessArticle

The Effect of Simulated In Vitro Digestion on Biological Activity of Viburnum opulus Fruit Juices

by Nina Pietrzyk, Małgorzata Zakłos-Szyda, Małgorzata Redzynia and Anna Podsędek

Molecules 2021, 26(13), 4086; https://doi.org/10.3390/molecules26134086 - 4 Jul 2021

Cited by 1 | Viewed by 3560

Abstract

In the present study, an in vitro digestion method has been used to assay the influence of the physiological conditions in the mouth, stomach, and intestine on the stability and activity in different cell models of the main phenolic compounds from Viburnum opulus fresh juice (FJ), phenolic-rich juice (PJ), and the bioavailable fractions (DFJ and DPJ). The data obtained indicate that the V. opulus samples achieved after in vitro digestion had an influence on cellular glucose and lipid metabolism. The bioavailable fraction of both digested juices stimulated glucose uptake and decreased lipid accumulation by L6 myoblasts and HepG2 hepatocytes. Both DFJ and DPJ reduced the secretion of inflammatory cytokines by 3T3-L1 adipocytes: interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Simultaneously, DFJ and DPJ enhanced oxidative stress in MIN6 cells and decreased glucose-stimulated insulin secretion (GSIS). UPLC–MS analysis revealed qualitative and quantitative changes in hydroxycinnamic acids. In particular, the content of chlorogenic acid decreased drastically; its content in the bioavailable fraction was almost 7 times and 30 times lower than in the FJ and PJ, respectively. Our results suggested that although the phenolic compounds of V. opulus juices undergo transformation during digestion, they are still potent antioxidant agents with biological activity. Full article

(This article belongs to the Special Issue Biosynthesis and Biological Activities of Flavonoids)

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12 pages, 869 KiB

Open AccessArticle

Toxicological Screening of Four Bioactive Citroflavonoids: In Vitro, In Vivo, and In Silico Approaches

by Rolffy Ortiz-Andrade, Jesús Alfredo Araujo-León, Amanda Sánchez-Recillas, Gabriel Navarrete-Vazquez, Avel Adolfo González-Sánchez, Sergio Hidalgo-Figueroa, Ángel Josabad Alonso-Castro, Irma Aranda-González, Emanuel Hernández-Núñez, Tania Isolina Coral-Martínez, Juan Carlos Sánchez-Salgado, Victor Yáñez-Pérez and M. A. Lucio-Garcia

Molecules 2020, 25(24), 5959; https://doi.org/10.3390/molecules25245959 - 16 Dec 2020

Cited by 13 | Viewed by 2789

Abstract

Many studies describe different pharmacological effects of flavonoids on experimental animals and humans. Nevertheless, few ones are confirming the safety of these compounds for therapeutic purposes. This study aimed to investigate the preclinical safety of naringenin, naringin, hesperidin, and quercetin by in vivo, in vitro, and in silico approaches. For this, an MTT-based cytotoxicity assay in VERO and MDCK cell lines was performed. In addition, acute toxicity was evaluated on Wistar rats by OECD Guidelines for the Testing of Chemicals (Test No. 423: Acute Oral Toxicity-Class Method). Furthermore, we used the ACD/Tox Suite to predict toxicological parameters such as hERG channel blockade, CYP450 inhibition, and acute toxicity in animals. The results showed that quercetin was slightly more cytotoxic on cell lines (IC₅₀ of 219.44 ± 7.22 mM and 465.41 ± 7.44 mM, respectively) than the other citroflavonoids. All flavonoids exhibited an LD₅₀ value > 2000 mg/kg, which classifies them as low-risk substances as OECD guidelines established. Similarly, predicted LD⁵⁰ was LD₅₀ > 300 to 2000 mg/kg for all flavonoids as acute toxicity assay estimated. Data suggests that all these flavonoids did not show significant toxicological effects, and they were classified as low-risk, useful substances for drug development. Full article

(This article belongs to the Special Issue Biosynthesis and Biological Activities of Flavonoids)

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Review

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43 pages, 11805 KiB

Open AccessReview

Antibacterial Effects of Flavonoids and Their Structure-Activity Relationship Study: A Comparative Interpretation

by Nur Farisya Shamsudin, Qamar Uddin Ahmed, Syed Mahmood, Syed Adnan Ali Shah, Alfi Khatib, Sayeed Mukhtar, Meshari A. Alsharif, Humaira Parveen and Zainul Amiruddin Zakaria

Molecules 2022, 27(4), 1149; https://doi.org/10.3390/molecules27041149 - 9 Feb 2022

Cited by 121 | Viewed by 8993

Abstract

According to the latest report released by the World Health Organization, bacterial resistance to well-known and widely available antibacterial drugs has become a significant and severe global health concern and a grim challenge to tackle in order to cure infections associated with multidrug-resistant pathogenic microorganisms efficiently. Consequently, various strategies have been orchestrated to cure the severe complications related to multidrug-resistant bacteria effectively. Some approaches involved the retardation of biofilm formation and multidrug-resistance pumps in bacteria as well as the discovery of new antimicrobial agents demonstrating different mechanisms of action. In this regard, natural products namely alkaloids, terpenoids, steroids, anthraquinone, flavonoids, saponins, tannins, etc., have been suggested to tackle the multidrug-resistant bacterial strains owing to their versatile pharmacological effects. Amongst these, flavonoids, also known as polyphenolic compounds, have been widely evaluated for their antibacterial property due to their tendency to retard the growth of a wide range of pathogenic microorganisms, including multidrug-resistant bacteria. The hydroxylation of C5, C7, C3′, and C4′; and geranylation or prenylation at C6 have been extensively studied to increase bacterial inhibition of flavonoids. On the other hand, methoxylation at C3′ and C5 has been reported to decrease flavonoids’ antibacterial action. Hence, the latest information on the antibacterial activity of flavonoids is summarized in this review, with particular attention to the structure–activity relationship of this broad class of natural compounds to discover safe and potent antibacterial agents as natural products. Full article

(This article belongs to the Special Issue Biosynthesis and Biological Activities of Flavonoids)

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20 pages, 1258 KiB

Open AccessReview

Botanical, Phytochemical, Anti-Microbial and Pharmaceutical Characteristics of Hawthorn (Crataegus monogyna Jacq.), Rosaceae

by Federico Martinelli, Anna Perrone, Sanaz Yousefi, Alessio Papini, Stefano Castiglione, Francesco Guarino, Angela Cicatelli, Mitra Aelaei, Neda Arad, Mansour Gholami and Seyed Alireza Salami

Molecules 2021, 26(23), 7266; https://doi.org/10.3390/molecules26237266 - 30 Nov 2021

Cited by 27 | Viewed by 6228

Abstract

Hawthorn (Crataegus monogyna Jacq.) is a wild edible fruit tree of the genus Crataegus, one of the most interesting genera of the Rosaceae family. This review is the first to consider, all together, the pharmaceutical, phytochemical, functional and therapeutic properties of C. monogyna based on numerous valuable secondary metabolites, including flavonoids, vitamin C, glycoside, anthocyanin, saponin, tannin and antioxidants. Previous reviews dealt with the properties of all species of the entire genera. We highlight the multi-therapeutic role that C. monogyna extracts could have in the treatment of different chronic and degenerative diseases, mainly focusing on flavonoids. In the first part of this comprehensive review, we describe the main botanical characteristics and summarize the studies which have been performed on the morphological and genetic characterization of the C. monogyna germplasm. In the second part, the key metabolites and their nutritional and pharmaceutical properties are described. This work could be an essential resource for promoting future therapeutic formulations based on this natural and potent bioactive plant extract. Full article

(This article belongs to the Special Issue Biosynthesis and Biological Activities of Flavonoids)

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18 pages, 1719 KiB

Open AccessReview

Antioxidant Metabolites in Primitive, Wild, and Cultivated Citrus and Their Role in Stress Tolerance

by Muhammad Junaid Rao, Songguo Wu, Mingzheng Duan and Lingqiang Wang

Molecules 2021, 26(19), 5801; https://doi.org/10.3390/molecules26195801 - 24 Sep 2021

Cited by 22 | Viewed by 3284

Abstract

The genus Citrus contains a vast range of antioxidant metabolites, dietary metabolites, and antioxidant polyphenols that protect plants from unfavorable environmental conditions, enhance their tolerance to abiotic and biotic stresses, and possess multiple health-promoting effects in humans. This review summarizes various antioxidant metabolites such as organic acids, amino acids, alkaloids, fatty acids, carotenoids, ascorbic acid, tocopherols, terpenoids, hydroxycinnamic acids, flavonoids, and anthocyanins that are distributed in different citrus species. Among these antioxidant metabolites, flavonoids are abundantly present in primitive, wild, and cultivated citrus species and possess the highest antioxidant activity. We demonstrate that the primitive and wild citrus species (e.g., Atalantia buxifolia and C. latipes) have a high level of antioxidant metabolites and are tolerant to various abiotic and biotic stresses compared with cultivated citrus species (e.g., C. sinensis and C. reticulata). Additionally, we highlight the potential usage of citrus wastes (rag, seeds, fruit peels, etc.) and the health-promoting properties of citrus metabolites. Furthermore, we summarize the genes that are involved in the biosynthesis of antioxidant metabolites in different citrus species. We speculate that the genome-engineering technologies should be used to confirm the functions of candidate genes that are responsible for the accumulation of antioxidant metabolites, which will serve as an alternative tool to breed citrus cultivars with increased antioxidant metabolites. Full article

(This article belongs to the Special Issue Biosynthesis and Biological Activities of Flavonoids)

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20 pages, 2187 KiB

Open AccessReview

Protein Adducts and Protein Oxidation as Molecular Mechanisms of Flavonoid Bioactivity

by P. Matthew Joyner

Molecules 2021, 26(16), 5102; https://doi.org/10.3390/molecules26165102 - 23 Aug 2021

Cited by 22 | Viewed by 3919

Abstract

There are tens of thousands of scientific papers about flavonoids and their impacts on human health. However, despite the vast amount of energy that has been put toward studying these compounds, a unified molecular mechanism that explains their bioactivity remains elusive. One contributing factor to the absence of a general mechanistic explanation of their bioactivity is the complexity of flavonoid chemistry in aqueous solutions at neutral pH. Flavonoids have acidic protons, are redox active, and frequently auto-oxidize to produce an array of degradation products including electrophilic quinones. Flavonoids are also known to interact with specificity and high affinity with a variety of proteins, and there is evidence that some of these interactions may be covalent. This review summarizes the mechanisms of flavonoid oxidation in aqueous solutions at neutral pH and proposes the formation of protein-flavonoid adducts or flavonoid-induced protein oxidation as putative mechanisms of flavonoid bioactivity in cells. Nucleophilic residues in proteins may be able to form covalent bonds with flavonoid quinones; alternatively, specific amino acid residues such as cysteine, methionine, or tyrosine in proteins could be oxidized by flavonoids. In either case, these protein-flavonoid interactions would likely occur at specific binding sites and the formation of these types of products could effectively explain how flavonoids modify proteins in cells to induce downstream biochemical and cellular changes. Full article

(This article belongs to the Special Issue Biosynthesis and Biological Activities of Flavonoids)

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