Edited by: Cheng Xue Helena Qin, Baker Heart and Diabetes Institute, Australia
Reviewed by: Agnieszka Barbara Najda, University of Life Sciences of Lublin, Poland; Zakiah Jubri, National University of Malaysia, Malaysia
*Correspondence: Ker Woon Choy,
This article was submitted to Inflammation Pharmacology, a section of the journal Frontiers in Pharmacology
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Cardiovascular diseases (CVDs) such as angina, hypertension, myocardial ischemia, and heart failure are the leading causes of morbidity and mortality worldwide. One of the major transcription factors widely associated with CVDs is nuclear factor-kappa B (NFκB). NFκB activation initiates the canonical and non-conical pathways that promotes activation of transcription factors leading to inflammation, such as leukocyte adhesion molecules, cytokines, and chemokines. Flavonoids are bioactive polyphenolic compounds found abundantly in various fruits, vegetables, beverages (tea, coffee), nuts, and cereal products with cardiovascular protective properties. Flavonoids can be classified into six subgroups based on their chemical structures: flavanones, flavones, flavonols, flavan-3-ols, isoflavones, and anthocyanidins. As NFκB inhibitors, these flavonoids may modulate the expression of pro-inflammatory genes leading to the attenuation of the inflammatory responses underlying various cardiovascular pathology. This review presents an update on the anti-inflammatory actions of flavonoids
Cardiovascular diseases (CVDs) represent the major burden of mortality and morbidity in the developed countries (
Flavonoids are plant polyphenolic compound derivatives from natural origin found in fruits, grains, vegetables, roots, bark, flowers, stems, tea, and wine (
Flavonoids are categorized into six subclasses depending on its chemical structures: flavones, flavonols, flavanones, isoflavones, flavan-3-ols, and anthocyanidins (
Flavones are found abundant in flowers, fruits, and leaves such as red peppers, celery, parsley, chamomile, mint, and ginkgo biloba (
Flavonols such as kaempferol, myricetin, quercetin, rutin, fisetin, silymarin, and isorhamnetin are ubiquitous in foods such as saffron, onions, kale, lettuce, tomatoes, apples, grapes, berries, red wine, and tea (
Flavanones widely present in all citrus fruits, which gives the bitter taste of the juice and its peel. Oranges, lemons, and grapes are rich sources of flavanones and major compounds are hesperitin, naringenin, and eriodictyol (
Isoflavones are unique in that they resemble estrogen in structure and, therefore, are classified as phytoestrogens. There are found abundantly in soy products such as tofu, roasted soy nuts, and miso (
Flavan-3-ols, also called as dihydroflavonols, include catechin, epicatechin, gallocatechin, epigallocatechin, epicatechingallate, epigallocatechingallate, and procyanidin (
Anthocyanins are rich in outer cell layers of fruits such as merlot grapes, raspberries, cranberries, red grapes, strawberries, blueberries, bilberries, and blackberries. The most commonly studied anthocyanins are cyanidin, delphinidin, malvidin, pelargonidin, and peonidin (
There are a few cellular redox pathways involved in the development of the chronic inflammatory CVD, which includes NFκB. NFκB is a transcription factor that activates inhibitor of kappa B (IκB) kinase in the cytosol upon being stimulated by inflammatory stimuli (
Mechanism of NFκB action. In inactivated state, NF-κβ, which consists of Rel and p50 proteins, is located in the cytosol complexed with the inhibitory protein Iκβα. IκB kinase (IKK) is activated by extracellular signals
The canonical NFκB pathway responds rapidly to stimuli and activates NFκB, which increases pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha (TNF-α), which results in cell apoptosis. TNF-α receptor signaling plays an important role in the canonical pathway of NFκB in cell death
A central signaling component of the non-canonical NFκB pathway is NFκB-inducing kinase, which induces p100 phosphorylation through kinase IKKα in a slow manner (
Quercetin or 3, 3′, 4′, 5, 7-pentahydroxyflvanone that falls into the category of flavonol is widely found in plants such as Ginkgo biloba,
In a clinical study involving patients with chronic systemic inflammation (CSI) in stable coronary artery disease (CAD), quercetin showed anti-inflammatory effects with reduction in indicators of CSI (
Luteolin or 3’, 4’, 5, 7-tetrahydroxyflavone is one of the most prevalent flavones widely found in fruits and vegetables such as carrots, cabbages, parsley, broccoli, celery, and apple skins (
In an
Fisetin or 3, 3c,4c,7-tetrahydroxyflavone is a bioactive molecule found in fruits such as strawberry, apple, persimmon, and grape and vegetables such as onion and cucumber (
Fisetin attenuated the development of diabetic cardiomyopathy by attenuating the expression of myocardial NFκB and the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α in the heart of diabetic rats. These result in reduction of cardiac function markers such as CK-MB, LDH, and cTn as well as normalization heart morphology (
Apigenin, a flavone, is found widely available in fruits and vegetables, such as grapefruits, oranges, celeries, and onions (
In LPS-treated macrophages, apigenin has been shown to reduce toll-like receptor 4 (TLR-4), MyD88, and p-IκB-α expression levels
Apigenin was also shown to improve cardiac dysfunction and fibrosis in diabetic cardiomyopathy. Apigenin blunted the activity of NFκB and downregulated the activity of caspase3 accompanying with decreasing oxidative stress marker, glutathione peroxidase (GSH-Px), malondialdehyde (MAD), and superoxide dismutase (SOD) (
Isoliquiritigenin is extracted from root of licorice and has been used traditionally for the treatment of inflammatory or pulmonary diseases (
Rutin is a flavonol that presents in buckwheat and citrus fruits. In a sodium fluoride-induced hypertensive rats, administration of rutin reduced blood pressure elevation by enhancing NO bioavailability
In carfilzomib-induced cardiotoxicity in rat, rutin protected against myocardial hypertrophy by upregulating IκB-α and downregulating NFκB expression, resulting in attenuation of β-myosin heavy chain, reduction in B-type natriuretic peptide mRNA expressions, and normalization of cardiac muscle fiber morphology (
In addition, rutin increased activities of Nrf, decreased activation of NFκB in human embryonic kidney reporter cell line, and preserved relaxation of fetal placental arteries derived from human chorionic plate (
In high mobility group box 1 (HMGBI)-induced inflammatory response in HUVECs, rutin attenuated NFκB and ERK1/2, which, in turn, reduced IL-6 and TNF-α levels (
In LPS-induced inflammation in HUVECs, rutin reversed barrier disruption, expression of cell adhesion molecules, and adhesion and migration of monocytes in endothelial cells. The barrier protective effects of rutin were linked to a down-regulation of TNF-α, deactivation of NFκB, and reduced phosphorylation of IκB-α (
Chrysin (5,7-dihydroxyflavone) is a flavone, which is found in the blue passion flower, honey, and propolis (
In a rat model of monocrotaline-induced pulmonary arterial hypertension (PAH), chrysin reduced right ventricular systolic pressure and mean pulmonary artery pressure. In addition to suppression of right ventricular remodeling, chrysin abolished increased expression of collagen I, collagen III, and NFκB (
In isoprenaline-induced myocardial injury in rats, chrysin relieved hemodynamic and ventricular dysfunction as well as reduced ultrastructural myocardial damage
In a rat model of myocardial infarction, fibrosis in the interstitial and perivascular regions and expression of collagen was reduced following chrysin treatment (
Genistein under the subgroup of an isoflavone [4′,5,7-trihydroxyisoflavone,5,7-dihydroxy-3-(4-hydroxyphenyl)-4-H-1-benzopyran-4-one] is primarily found in soy-based foods, legumes, and red clover. In homocysteine-induced endothelial cell inflammatory injury, genistein prevented endothelial damage
Silymarin is a flavonolignan extracted from the milk thistle. Silymarin augmented relaxation of pulmonary arteries isolated from a lung ischemia-reperfusion (I/R) injury model (
Silibinin, a major active constituent of silymarin, was able to reduce the abnormal size of cardiac myocytes and prevent hypertrophy by alleviating the production of epidermal growth factor receptor (EGFR) (
Kaempferol (3,4′,5,7-tetrahydroxyflavone) is a flavonol that is present widely in fruits, vegetables, and herbs, including grapes, tomatoes, and tea. In cardiac fibroblasts stimulated with LPS, kaempferol decreased release of pro-inflammatory cytokines by inhibiting AKT phosphorylation and NFκB activation (
Effect of flavonoids in CVDs.
No | Flavonoids | Models | Mechanisms | Reference |
---|---|---|---|---|
1 | Quercetin | Clinical study: CAD patients | ↓ NFкB, IL-1β, TNF-α, IkBα | ( |
|
↓ ERK1/2 phosphorylation, NFкB, TNF-α | ( |
||
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↓ NFкB, TNF-α, IL-1β, IL-6, AKT | ( |
||
2 | Luteolin |
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↑NO ↓ Nrf2, Kim-1, NFκB, CTnI | ( |
|
↓ NFκB, TNF-α, ↑ IκB-β | ( |
||
3 | Fisetin |
|
↓NFκB, RAGE, TNF-α, IL-6, CK-MB, LDH | ( |
|
↓NFκB, IL-1β, IL-6, TNF-α | ( |
||
4 | Apigenin |
|
↓ NFκB p65, TLR-4, MyD88, p-IκB-α ↑ ABCA1 | ( |
|
↓ NFκB, caspase3, GSH-Px, MDA, SOD | ( |
||
5 | Isoliquiriti-genin |
|
↓ NFкB, VCAM-1, E-selectin, THP-1 monocyte adhesion, IкB-α, PECAM-1 | ( |
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↓ NFкB, IL-1β and TNF-α Nrf2, | ( |
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6 | Rutin |
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↓ NFκB ↑ Nrf2 | ( |
|
↓ NFκB ↑ IκB-α | ( |
||
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↓ NFκB ↑ Nrf2 | ( |
||
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↓ NFκB, ERK1/2, TNFα, IL-6, ICAM-1, VCAM-1, E-selectin | ( |
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↓ NFκB, IκB-α, TNF-α, ICAM-1, VCAM-1, E-selectin | ( |
||
7 | Chrysin |
|
↓ p38, JNK, NFκB ↑ VEGF, AKT | ( |
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↓ NFκB | ( |
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↑ PPAR-γ ↓ NFκBp65, IκK-β, TNF-α | ( |
||
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↑ PPAR-γ ↓ NFκB, IκK-β, MMP-2, MMP-9, AP-1 | ( |
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8 | Genistein |
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↓ NFκBp65, IL-6, ICAM-1 | ( |
|
↑ PPAR-γ ↓ ERK1/2, p38, NFκB, CRP, MMP-9 | ( |
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9 | Silymarin |
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↓ NFκB, HIF-1α, iNOS, TNFα, IL-1β, IL-6 | ( |
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↓ NFκB, EGFR, IκB-α, IκKβ | ( |
||
10 | Kaempferol |
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↓ AKT, NFκBp65, TNF-α, IL-1β, IL-6, IL-18 | ( |
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↓ p38, JNK, NFκBp65, TNF-α, IL-6 | ( |
The actions of flavonoids in mitigating inflammation by modulation of NFкB offer potential agents for the treatment of CVDs. However, several of these actions reported
All authors contributed to the writing. KC, DM, and MM conceived, designed, and revised the manuscript.
This study was funded by Government Agency grant GA001-2017, MAHSA University and USIM research project code: PPPI/FPG/0118/051000/15618 Universiti Kebangsaan Malaysia and Universiti Putra Malaysia. The funding agencies played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript, which are fully the responsibilities of the authors.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The reviewer ZJ declared a shared affiliation, with no collaboration, with one of the authors, XFL, to the handling editor at time of review