Novel insights into the pharmacology of flavonoids.
TL;DR: The most recent developments in flavonoid – and related polyphenolic compounds – pharmacology are discussed, with particular emphasis on very recent data, most of which are published in Phytotherapy Research, which highlight new aspects.
Abstract: Flavonoids are widely distributed secondary metabolites and currently consumed in large amounts in the daily diet. In this article, some of the most recent developments in flavonoid - and related polyphenolic compounds - pharmacology are discussed, with particular emphasis on very recent data, most of which are published in Phytotherapy Research, which highlight new aspects in flavonoid anti-inflammatory, antilipidemic, antihyperglycemic, antiviral, hepatoprotective, gastric antiulcer, cardioprotective, neuroprotective, antioxidant and anticancer actions. These updated data confirm the well-established diverse beneficial pharmacological actions and might support the perspective for a therapeutic use.
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TL;DR: New findings showed that the antioxidant activity of Hsd/Hst was not only limited to its radical scavenging activity, but it augmented the antioxidant cellular defenses via the ERK/Nrf2 signaling pathway as well.
Abstract: Inflammation and oxidative stress are two major causes of various life-threatening diseases. Hesperidin (Hsd) and its aglycone, hesperetin (Hst), are two flavonoids from citrus species that have numerous biological properties, particularly antioxidant and anti-inflammatory. New findings showed that the antioxidant activity of Hsd/Hst was not only limited to its radical scavenging activity, but it augmented the antioxidant cellular defenses via the ERK/Nrf2 signaling pathway as well. Various in vitro and in vivo studies have been conducted to evaluate Hsd, its metabolites, or its synthetic derivatives at reducing inflammatory targets including NF-κB, iNOS, and COX-2, and the markers of chronic inflammation. In this review, new findings regarding the molecular targets of Hsd and Hst in the reduction of oxidative stress are discussed. Also, in the anti-inflammatory section, we provide a summary of significant investigations concerning the mechanisms of action based on the studied inflammation models.
587 citations
Cites background from "Novel insights into the pharmacolog..."
...However, a large number of studies have been published since then describing its new pharmacological activities, molecular targets, and mechanisms of action (Chiba et al., 2014; Romano et al., 2013)....
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TL;DR: Isobolographic analysis of the interaction between myricetin and apigenin or morin showed that both of them exhibited synergistic effects at low concentrations and tended to exhibit additive or antagonistic interaction at high concentrations.
Abstract: Inhibition of α-glucosidase activity may suppress postprandial hyperglycemia. The inhibition kinetic analysis showed that apigenin reversibly inhibited α-glucosidase activity with an IC50 value of (10.5 ± 0.05) × 10–6 mol L–1, and the inhibition was in a noncompetitive manner through a monophasic kinetic process. The fluorescence quenching and conformational changes determined by fluorescence and circular dichroism were due to the formation of an α-glucosidase–apigenin complex, and the binding was mainly driven by hydrophobic interactions and hydrogen bonding. The molecular simulation showed that apigenin bound to a site close to the active site of α-glucosidase, which may induce the channel closure to prevent the access of substrate, eventually leading to the inhibition of α-glucosidase. Isobolographic analysis of the interaction between myricetin and apigenin or morin showed that both of them exhibited synergistic effects at low concentrations and tended to exhibit additive or antagonistic interaction a...
207 citations
TL;DR: In vitro antiviral experiments showed that baicalin as the main metabolite of baicalein exerting in vitro anti-DENV activity, and showed anti-adsorption effect with IC50 = 18.07 ± 0.2 μg/ml.
Abstract: Baicalin, a flavonoid derived from Scutellaria baicalensis, is the main metabolite of baicalein released following administration in different animal models and human. We previously reported the antiviral activity of baicalein against dengue virus (DENV). Here, we examined the anti-DENV properties of baicalin in vitro, and described the inhibitory potentials of baicalin at different steps of DENV-2 (NGC strain) replication. Our in vitro antiviral experiments showed that baicalin inhibited virus replication at IC50 = 13.5 ± 0.08 μg/ml with SI = 21.5 following virus internalization by Vero cells. Baicalin exhibited virucidal activity against DENV-2 extracellular particles at IC50 = 8.74 ± 0.08 μg/ml and showed anti-adsorption effect with IC50 = 18.07 ± 0.2 μg/ml. Our findings showed that baicalin as the main metabolite of baicalein exerting in vitro anti-DENV activity. Further investigations on baicalein and baicalin to deduce its antiviral therapeutic effects are warranted.
199 citations
TL;DR: The main inhibition mechanism of ka Kempferol on XO activity may be due to the insertion of kaempferol into the active site of XO occupying the catalytic center of the enzyme to avoid the entrance of the substrate and inducing conformational changes ofXO.
Abstract: Xanthine oxidase (XO), a key enzyme in purine catabolism, is widely distributed in human tissues. It can catalyze xanthine to generate uric acid and cause hyperuricemia and gout. Inhibition kinetics assay showed that kaempferol inhibited XO activity reversibly in a competitive manner. Strong fluorescence quenching and conformational changes of XO were found due to the formation of a kaempferol-XO complex, which was driven mainly by hydrophobic forces. The molecular docking further revealed that kaempferol inserted into the hydrophobic cavity of XO to interact with some amino acid residues. The main inhibition mechanism of kaempferol on XO activity may be due to the insertion of kaempferol into the active site of XO occupying the catalytic center of the enzyme to avoid the entrance of the substrate and inducing conformational changes of XO. In addition, luteolin exhibited a stronger synergistic effect with kaempferol than did morin at the lower concentration.
199 citations
TL;DR: The results indicated that apigenin significantly inhibited LPS-induced production of pro-inflammatory cytokines, such as IL-6, IL-1β, and TNF-α through modulating multiple intracellular signaling pathways in macrophages.
Abstract: Background: Apigenin is a non-toxic natural flavonoid that is abundantly present in common fruits and vegetables. It has been reported that apigenin has various beneficial health effects such as anti-inflammation and chemoprevention. Multiple studies have shown that inflammation is an important risk factor for atherosclerosis, diabetes, sepsis, various liver diseases, and other metabolic diseases. Although it has been long realized that apigenin has anti-inflammatory activities, the underlying functional mechanisms are still not fully understood. Methodology and Principal Findings: In the present study, we examined the effect of apigenin on LPS-induced inflammatory response and further elucidated the potential underlying mechanisms in human THP-1-induced macrophages and mouse J774A.1 macrophages. By using the PrimePCR array, we were able to identify the major target genes regulated by apigenin in LPS-mediated immune response. The results indicated that apigenin significantly inhibited LPS-induced production of pro-inflammatory cytokines, such as IL-6, IL-1b, and TNF-a through modulating multiple intracellular signaling pathways in macrophages. Apigenin inhibited LPS-induced IL-1b production by inhibiting caspase-1 activation through the disruption of the NLRP3 inflammasome assembly. Apigenin also prevented LPS-induced IL-6 and IL-1b production by reducing the mRNA stability via inhibiting ERK1/2 activation. In addition, apigenin significantly inhibited TNF-a and IL-1binduced activation of NF-kB. Conclusion and Significance: Apigenin Inhibits LPS-induced Inflammatory Response through multiple mechanisms in macrophages. These results provided important scientific evidences for the potential application of apigenin as a therapeutic agent for inflammatory diseases.
187 citations
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TL;DR: Western medicine has not yet used flavonoids therapeutically, even though their safety record is exceptional, and suggestions are made where such possibilities may be worth pursuing.
Abstract: Flavonoids are nearly ubiquitous in plants and are recognized as the pigments responsible for the colors of leaves, especially in autumn. They are rich in seeds, citrus fruits, olive oil, tea, and red wine. They are low molecular weight compounds composed of a three-ring structure with various substitutions. This basic structure is shared by tocopherols (vitamin E). Flavonoids can be subdivided according to the presence of an oxy group at position 4, a double bond between carbon atoms 2 and 3, or a hydroxyl group in position 3 of the C (middle) ring. These characteristics appear to also be required for best activity, especially antioxidant and antiproliferative, in the systems studied. The particular hydroxylation pattern of the B ring of the flavonoles increases their activities, especially in inhibition of mast cell secretion. Certain plants and spices containing flavonoids have been used for thousands of years in traditional Eastern medicine. In spite of the voluminous literature available, however, Western medicine has not yet used flavonoids therapeutically, even though their safety record is exceptional. Suggestions are made where such possibilities may be worth pursuing.
4,663 citations
"Novel insights into the pharmacolog..." refers background in this paper
...Flavonoids also modulate the function of inflammatory cells such as lymphocytes, natural killer cells, monocytes, neutrophils, mast cells and macrophages (Middleton et al., 2000)....
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...Flavonoids display a remarkable array of biochemical and pharmacological actions which are suggestive of anti-inflammatory effects and modulation of the immune system (Middleton et al., 2000)....
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...Flavonoids are low molecular weight phenolic compounds, secondarymetabolites found in fruits, vegetables, nuts, seeds, herbs, spices, stems and flowers as well as in tea and red wine (Middleton et al., 2000)....
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TL;DR: Several high-quality investigations have examined the relationship between flavonoid structure and antibacterial activity and these are in close agreement, and future studies may allow the development of a pharmacologically acceptable antimicrobial agent or class of agents.
3,630 citations
TL;DR: This review summarizes available data on these beneficial effects of flavonoids and suggests that the compounds may possess significant antihepatotoxic, antiallergic, anti-inflammatory, antiosteoporotic and even antitumor activities.
1,291 citations
"Novel insights into the pharmacolog..." refers background in this paper
...Flavonoids occur both in the free state and as glycosides and exert several important pharmacological actions of potential clinical interest (Di Carlo et al., 1999; Samuelsson, 1999)....
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TL;DR: The aim of this review is to discuss both the antioxidant and prooxidant effects of flavonoids.
1,152 citations
"Novel insights into the pharmacolog..." refers background in this paper
...Since then, a great number of biological effects has been ascribed to flavonoids (Prasad et al., 2010; Amado et al., 2011; Hanrahan et al., 2011; Procházková et al., 2011; Dajas, 2012)....
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TL;DR: This review summarizes the known mechanisms involved in the anti-inflammatory activity of flavonoids and the implications of these effects on the protection against cancer and cardiovascular disease.
Abstract: Chronic inflammation is being shown to be increasingly involved in the onset and development of several pathological disturbances such as arteriosclerosis, obesity, diabetes, neurodegenerative diseases and even cancer. Treatment for chronic inflammatory disorders has not been solved, and there is an urgent need to find new and safe anti-inflammatory compounds. Flavonoids belong to a group of natural substances occurring normally in the diet that exhibit a variety of beneficial effects on health. The anti-inflammatory properties of flavonoids have been studied recently, in order to establish and characterize their potential utility as therapeutic agents in the treatment of inflammatory diseases. Several mechanisms of action have been proposed to explain in vivo flavonoid anti-inflammatory actions, such as antioxidant activity, inhibition of eicosanoid generating enzymes or the modulation of the production of proinflammatory molecules. Recent studies have also shown that some flavonoids are modulators of proinflammatory gene expression, thus leading to the attenuation of the inflammatory response. However, much work remains to be done in order to achieve definitive conclusions about their potential usefulness. This review summarizes the known mechanisms involved in the anti-inflammatory activity of flavonoids and the implications of these effects on the protection against cancer and cardiovascular disease.
889 citations
"Novel insights into the pharmacolog..." refers background in this paper
...These include antioxidant activity, inhibition of eicosanoid generating enzymes, reduction of the production of proinflammatory molecules as well as modulation of proinflammatory genes expression (García-Lafuente et al., 2009)....
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