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Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

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Open Access   Full Text Article                                                                                                                                                                    Review Article 

Anti-Inflammatory Properties of Quercetin: A Review

*^{, 1}Chibuzo Carole Nweze, ²WandooTseaa & ³Ini Patrick Ekpe

^1,2 Department of Biochemistry and Molecular Biology, Nasarawa State University, Keffi, Nigeria

³ Department of Biochemistry, Faculty of Natural and Applied Sciences, Veritas University Abuja, Nigeria

Introduction 

An organism’s ability to fight infection and heal damage depends on its metabolic and immune systems. Inflammation is a self-protecting measure taken when the body experiences damaging or troublesome stimuli¹. An inflammatory response is a defense mechanism in higher organisms to protect them from infection and injury. Its purpose is to localize and eliminate the injurious agent and to remove damaged tissue components so that the body can begin to heal. The normal inflammatory response relies upon metabolic support, and energy redistribution, particularly the mobilization of stored lipid, plays an important role in fighting infection during the acute-phase response¹. These events are controlled by a host of extracellular mediators and regulators, including cytokines, growth factors, eicosanoids (prostaglandins, leukotrines, etc), complement and peptides². The aim of this process is removing of the injured cells, pathogens, or other adverse stimuli, while beginning the treatment procedure. Inflammatory conditions are not essentially equal to infection. Infection is usually resulted from a viral, bacterial, or fungal source, but inflammatory processes include the reaction of the human body toward healing itself. Inflammation can be linked to a wide range of diseases such as allergy, cancer, Alzheimer’s disease and many others².

Mechanism of Inflammatory Response

Inflammation involves a cascade of events. The first step of an inflammatory response involves the detection of an infection signal or damaged tissues which is mediated by the pathogen-associated molecular patterns (PAMPs) that recognize molecules expressed by the pathogens and the damage-associated molecular patterns (DAMPs) that recognize cells committed to death¹. Thisleads to the activation of the immune system via interaction with pattern recognition receptors². In response to successful recognition of these signals, transmembrane toll-like receptors or inflammasomes activate specific immune signaling pathways that lead to the activation of nuclear factor kappa-light-chain-enhancer of activated B (NF-κB). NF-κBas a result dissociates from IkB and translocates to the nucleus, where transcription occurs³. These events subsequently lead to the secretion of pro-inflammatory cytokines that recruit immune cells such as monocytes and neutrophils at the site of injury. The termination of neutrophils recruitment will lead to wound healing and homeostasis while continuous recruitment of neutrophils to the site of injury will result in the generation of reactive oxygen and nitrogen species that may lead to oxidative stress or damage of macromolecules³.

Robbins S, Cotran R, Kumar V, Abbas A, Aster J, Pathologic basis of disease , 2020; 10. 

Figure 1Overview of Inflammatory Response

Types of Inflammation

Inflammation can be acute or short term inflammation when it lasts only a few days. Signs of an inflammation may include; redness caused by the dilation of small blood vessels at the site of injury, heat that results from the increased blood flow through the affected area, swelling which is caused by fluid accumulated outside the blood vessels due to the release of chemicals by white blood cells that make the capillaries permeable and finally pain that is as a result of tissue distortion caused by chemical mediators of inflammation³. Some factors that can lead to acute inflammation include acute bronchitis, appendicitis, in grown toe nail, a sore throat from cold or flu and physical trauma or wound⁴.

Inflammation can also be chronic and this type of inflammation has a longer duration. Macrophages, lymphocytes and plasma cells are predominating in chronic inflammation compared to the neutrophils that predominate in acute inflammation⁴. Chronic inflammation is harmful and it can lead to various diseases. Chronic inflammation occurs when the body is hypersensitive and this can lead to allergy. Long term, low level exposure to an irritant, such as industrial chemicals can result in chronic inflammation. Also persistent acute inflammation can lead to chronic inflammation. Macrophages, lymphocytes and plasma cells are predominating in chronic inflammation compared to the neutrophils that predominate in acute inflammation⁴. Chronic inflammation is harmful and it can lead to various diseases. A defect in the cells responsible for mediating inflammation leads to persistent inflammation⁴. Chronic inflammation causes a significant amount of diseases that lead to death in the world. Worldwide, 3 of 5 people die due to chronic inflammatory diseases like stroke, chronic respiratory diseases, heart disorders, cancer, obesity and diabetes⁴.  

https://www.pininterest.com/pin/pathwaysofacuteinflammationandchronicinflammation--298574650274900056/

Figure 2 Pathways of Inflammation

Quercetin

Quercetin is categorized as a flavonol, one of the six subclasses of flavonoid compounds. The name has been used since 1857, and is derived from quercetum (oak forest), after Quercus. It is a naturally occurring polar auxin transport inhibitor⁵. The International Union of Pure and Applied Chemistry (IUPAC) nomenclature for quercetin is 3, 31, 41, 5, 7-pentahydroxyflvanone (or its synonym 3, 31, 41, 5, 7-pentahydroxy-2-phenylchromen-4-one). This means that quercetin has an OH group attached at positions 3, 5, 7, 31, and 41. Quercetin is a unique bioflavonoid that is found in abundance in various types of vegetables and fruits⁵. It exhibits numerous beneficial effects on the human health, and acts as a potent antioxidant, anti-carcinogenic, anti-inflammatory, anti-infective, neuroprotective, and psycho stimulant agent⁶.

Quercetin (C15H10O7) is an aglycone, lacking an attached sugar. It is a brilliant citron yellow needle crystal and entirely insoluble in cold water, poorly soluble in hot water, but quite soluble in alcohol and lipids⁷. A quercetin glycoside is formed by attaching a glycosyl group (a sugar such as glucose, rhamnose, or rutinose) as a replacement for one of the OH groups (commonly at position 3) ⁷. The attached glycosyl group can change the solubility, absorption, and in vivo effects. As a general rule of thumb, the presence of a glycosyl group (quercetin glycoside) results in increased water solubility compared to quercetin aglycone⁷. 

Nutritional Quercetin is present mainly as glycosides rather than as aglycones. It shows a relatively higher bioavailability than other phytochemicals, with its main sources being grapes, berries, cherries, apples, citrus fruits, onions, buckwheat, kale, tomatoes, red wine, and black tea⁸.

Bioavailability, Absorption and Metabolism of Quercetin

Bioavailability of quercetin is very low, mostly due to its extensive metabolism. Quercetin is present in plants mainly in its highly hydrophilic glycosylated forms, primarily as β-glycosides of various sugars⁷. The estimated absorption of quercetin glycoside, the naturally occurring form of quercetin, ranges from 3% to 17% in healthy individuals receiving 100 mg⁷. Quercetin glycosides might be differently absorbed based on the type of sugar attached. Due to the different sugar types and sugar group conjugation sites will result in absorption variation. Average daily flavonoid intake is estimated between 50 - 800mg of which quercetin intake is dependent on the consumption of foods rich in quercetin⁹.

When quercetin glycosides are ingested, they are absorbed near the intestinal wall. Quercetin glycosides are first hydrolyzed by lactase-phlorizin hydrolyze enzyme to an aglycone before entering the enterocyte¹⁰. This is the first step because its glycosides form cannot pass through the enterocyte cell membrane due to its high hydrophilic nature. Quercetin aglycone on the other hand undergoes passive diffusion through the phospholipids’ bilayer of enterocytes due to its lipophilic nature¹⁰. After absorption, quercetin becomes metabolized in various organs including the small intestine, colon, liver and kidney. It undergoes biotransformation which involves two phases. The phase I includes oxidation and O-demethylation while the phase II includes methylation, sulfation or glucuronidation¹¹. Resulting conjugates of quercetin are absorbed into the bloodstream via passive diffusion or bisolateral ATP binding cassette (ABC) transporters⁷. These ABC transporters enable ATP to be hydrolyzed and use the energy harnessed for active efflux transport of molecules¹². When these metabolites of quercetin are absorbed in the bloodstream they may bind to albumin and then they can be transported to the liver via the portal vein¹³.Further biotransformation takes place in the liver and subsequently quercetin metabolites can be transported from the liver to other sites such as the kidney where they are excreted in urine⁷. Consequently, after the intake of food rich in quercetin glycosides and aglycone, methylated, glucuronidated, sulfated and combined derivatives of quercetin, such as isorhamnetin-3-glucuronide, quercetin diglucuronide, quercetin glucuronide sulphate, methyl quercetin diglucuronide, etc., have been found in the human plasma⁷.

Functional Properties of Quercetin

Numerous studies have been carried out in order to ascertain the various effects of quercetin in the body.

Studies have reviewed the effects of quercetin as an antioxidant that scavenges oxygen free radicals responsible for oxidative stress thereby reducing cellular damage¹⁴. Free radicals such as nitric oxide as well as reactive oxygen species act as regulatory mediators in signaling processes¹⁵and they are generated from immune cell activation, inflammation, infection, cancer, stress, air pollution and radiation^16-17. Excess production of these free radicals alters cellular functions and induces chronic diseases¹⁵. 

Cellular damage can result to lipid peroxidation that causes damage to organs. Quercetin shows antioxidant action through the decrease in lipid peroxidation and increase in detoxification enzymes¹⁸. Studies also reported that quercetin reduces lipopolysaccharide-induced nitric oxide production in RAW 264.7 macrophages. Nitric oxide (NO) is produced by endothelial cells for vasodilation. However, when a high amount of NO is produced, it can cause oxidative damage¹⁹.

Oxidative stress plays an important role in the development of behavioral impairment²⁰. Several investigations have revealed that depressive-like behavior associated with brain oxidative stress is as a result of enhanced glutathione transferase activity and lipid peroxidation²¹. Lipid peroxidation causes cytotoxic damage in different organs, especially in the brain, leading to cognitive impairment and neurodegenerative diseases²².

Studies have reported evidence of the action of quercetin-rich fruits and vegetables on improved spatial learning and memory impairment in Moris water maze test associated with decrease in reactive oxygen species production and an increase in antioxidant enzyme activity²³. Another study reported quercetin's ability to pass through blood-brain barrier in certain models, which suggests that quercetin, could be a potential neuroprotective approach to slow down degenerative disease progression¹⁸ leading to an improvement of cognitive and behavioral impairment in Parkinson's disease.

Basophils are blood granulocytes involved in hypersensitivity and anaphylactic reactions. They promote chronic allergy inflammation²⁴. When activated basophils degranulate to release histamine, proteglycans and proteolytic enzymes. They also secrete lipid mediators like leukotrienes as well as several cytokines²⁵. Basophils are motile cells and they migrate from the blood to inflamed tissues and act as allergic inflammatory cells. Studies have reported that basophils play an important role in inflammation related angiogenesis through the expression of several forms of vascular endothelial growth factors and their receptors²⁶. In vitro studies about the action of quercetin aglycone reported its ability to inhibit histamine release in human basophils when they are activated and also inhibit peptide presentation in antigen presenting cells²⁷.Quercetin is also known as a natural inhibitor of mast cells exocytosis. It can induce the down regulation of the degranulatory response in mast cells²⁸.

Over the years most In vivo and In vitro studies have investigated the effect of quercetin on leukocyte and smooth muscle contraction²⁹. A study hypothesized that quercetin blocks airway epithelial cells chemokine expression via phosphatidylinositol (PI) 3 kinase-dependent mechanism. They showed that quercetin (3,3,4,5,7 pentahydroxyflavone) blocks the airway epithelial cell IL-8 and monocyte chemoattractant protein (MCP)-1 expression by attenuating the signaling through a PI-3 kinase/Akt/NF-κB pathway and also inhibits chemokine expression via transcriptional and posttranscriptional ways²⁹.  Another study involved the effect of quercetin on cytokine levels and smooth muscle contraction, in vitro and its therapeutic potential effect on a murine model of asthma³⁰. The study showed the reduction of inflammatory cytokines production, tracheal ring relaxation and also reduction of eosinophil peroxidase in the lungs by treatment with quercetin³⁰. In 2017, the effects of several herbs investigated revealed that quercetin could be used to develop new bronchodilators to treat obstructive lung diseases such as asthma and chronic obstructive pulmonary disease³¹.

Quercetin affects immunity and inflammation by acting mainly on leukocytes and targeting many intracellular signaling kinases, enzymes, phosphatases and membrane proteins. A study involving an in vitro treatment of activated T cells with quercetin revealed the inhibition of IL-12-induced tyrosine phosphorylation of JAK2, STAT3, and STAT4, resulting in a decrease in IL-12-induced T cell proliferation³². Several In vitro studies have also shown that quercetin prevents the development of lipopolysaccharide (LPS)-mediated tumor necrosis factor-α (TNF-α) in macrophages and the development of IL-8 induced by inhibiting the activation of p38³³. In addition, quercetin can inhibit TNF-α and Interleukin (IL)-1α levels of LPS-induced mRNA, which results in reduced apoptotic neuronal cell death caused by microglial activation. The potential of quercetin in modulation of inflammation is one of its critical and considerable features as inflammatory enzymes such as cyclooxygenase (COX) and lipoxygenase can be inhibited by this agent and consequently inflammatory mediators including prostaglandins as well as leukotrienes can reduced³⁴.

Quercetin substantially stimulates the gene expression and the development of interferon-γ (IFN-γ) derived from T helper cell-1 (Th-1) and down-regulates IL-4 derived from Th-2 by normal peripheral blood mononuclear cells (PBMC). Quercetin is also known to have inhibitory activity against nuclear factor-kappa B (NF-κB), activator protein 1 (AP-1), mitogen-activated protein kinase (MAPK), expression that causes inflammation³⁵. Quercetin inhibits the nuclear translocation of NF-κB by suppression of the inhibitor of kappa B-protein degradation³⁶.As noted earlier, upon activation NF-κB dissociates from IkB and translocates into the nucleus where it can act as a transcription factor for pro-inflammatory genes. Activator protein-1 is another transcription factor capable of regulating the expression of pro-inflammatory and adhesion molecules. LPS stimulation induces MAPK cascade that results in the activation of AP-1³⁶. 

Studies also reported that quercetin has the ability to counteract the LPS mediated up regulation of the protein expression of NF-κBp65 subunit, toll-like receptor 4, MyD88 and down regulates of IkB in eat intestinal microvascular endothelial cells³⁵. 

A study was designed to determine the effect of quercetin on the indicators of chronic systemic inflammation in coronary artery disease (CAD) patients³². The study involved 85 CAD patients, stable angina pectoris, functional class II, and heart failure. Thirty patients received quercetin at a daily dose of 120 mg for 2 months, while the remaining 55 patients considered as the control group received β-blockers, statins, and aspirin³². An increase in the levels of IL-1β and tumor necrosis factor-α (TNF-α) and a moderate increase in IL-10 levels were detected in the serum of patients with CAD. Under the influence of quercetin, levels of IL-1β and TNF-α were reduced and IL-10 levels tended to decrease³². 

Yu W, Tao B, Yao W, Yue S, Drug delivery based pharmacological enhancement and current insight of quercetin with therapeutic potential against oral diseases, Biomedicine & Pharmacotherapy, 2020; 128:110372.

Figure 3 Mechanism of Action 

In addition, quercetin may indirectly prevent inflammation by increasing peroxisome proliferator‐activated receptor c (PPARγ) activity, which inhibits cytokine induced expression of vascular cell adhesion molecule-1 in endothelial cells³⁷. This action blocks TNF-α-mediated induction of inflammatory cascades³⁷. Quercetin also has the ability to up-regulate nuclear factor 2 erythroid related factor 2 mediated transcription of anti-inflammatory and antioxidant gene such as for hemeoxygenase-1³⁷ which inhibits AP-1 activity and adhesion molecule expression³⁸. Hence the antagonizing effect NF-κB and Nrf2 have on each other³⁸.

Conclusion 

Inflammation is a defense mechanism of the body that protects against infection and injury. Though it is a part of the body’s immune response, persistent inflammation can cause harm to the human body ranging from allergies to various chronic respiratory diseases. Quercetin is an important flavonoid that needs to be incorporated into our daily diet. Several studies have demonstrated its anti-inflammatory properties by down regulating pro-inflammatory factors and up-regulating anti-inflammatory factors inorder to maintain homeostasis. 

The health benefits of quercetin in the body are vast but limited due to its poor bioavailability. Therefore, several studies have been conducted to modify its structure to increase its water solubility and bioavailability and thereby enhance its antioxidant and anti-inflammatory activity.

Abbreviations: STAT: Signal Transducers and Activators of Transcription, COX-2: Cyclooxygenase-2, MAPK: Mitogen Activated Protein Kinase, JNK: Jun-N-Terminal Kinase, AP-1: Activated Protein-1, ICAM-1: Intracellular Adhesion Molecule-1, PPAR: Peroxisome Proliferator-Activated Receptors, Nrf2: Nuclear Factor 2 Erythroid Related Factor 2, HO-1: Heme Oxygenase-1, Nf-kB: Nuclear Factor Kappa B. 

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