Research Progress on the Pharmacological Effects of Quercetin

Quercetin, a polyhydroxy flavonoid compound extracted from rutin, possesses a wide range of biological activities and extensive pharmacological effects. These include antioxidant and free radical scavenging capabilities, as well as anti-inflammatory, antiviral, antitumor, hypoglycemic, and immunomodulatory properties.

1. Antioxidant Effect

The antioxidant effect of quercetin is primarily achieved through three mechanisms: direct scavenging of reactive oxygen species (ROS), chelating metal ions, and inhibiting oxidative damage to low-density lipoprotein (LDL).

① Direct Scavenging of Reactive Oxygen Species (ROS)

The direct scavenging effect of quercetin on ROS is closely related to its rich phenolic hydroxyl groups in its structure. Phenolic hydroxyl groups can exert antioxidant effects by providing active hydrogen to inactivate free radicals, while themselves being oxidized into more stable free radicals. Reactive oxygen species (ROS) are the primary signaling molecules involved in oxidative stress in the body. Under pathological conditions, excessive accumulation of ROS can lead to cytotoxicity and trigger apoptosis. Glutathione (GSH) possesses detoxifying capabilities and effectively scavenges excess ROS, making it one of the most important antioxidants in the body. Quercetin can also enhance the body's antioxidant capacity by regulating GSH levels. When ROS are generated in the body, superoxide dismutase (SOD) rapidly captures oxygen and converts it into hydrogen peroxide (H2O2). SOD further catalyzes the decomposition of H2O2 into non-toxic water (H2O), with GSH acting as a hydrogen donor in this process. Glutathione peroxidase (GSH-Px) specifically catalyzes the reaction between GSH and H2O2, producing oxidized glutathione disulfide (GSSG) and H2O, thereby reducing the production of peroxides and maintaining normal body functions. Multiple animal and cellular experimental studies have found that quercetin participates in inducing the synthesis of GSH in the body.

Using hydrogen peroxide (H2O2) to induce an oxidative stress model in P1G1 normal human melanocytes, with simultaneous pretreatment of the model cells with quercetin, and finally utilizing DCFH-DA to detect changes in reactive oxygen species (ROS) levels within the quercetin-treated cells, the results revealed that the intracellular ROS levels in the quercetin group were significantly lower compared to the H2O2 group, indicating that quercetin can reduce intracellular ROS and protect cells from oxidative damage. In another study, researchers applied quercetin to ovarian cells of ovariectomized rats and found that the mRNA and protein expression levels of the antioxidant-related factor SOD-1 in ovarian cells of rats in the quercetin treatment group were both elevated. Furthermore, the scholars discovered that quercetin significantly improved cell viability by reversing H2O2-induced oxidative stress, while the expression levels of proteins related to H2O2-induced oxidative stress also decreased.

② Chelation with Metal Ions

Metals such as iron and copper can catalyze the generation of free radicals. Cu2+ and Fe2+ can mediate lipid peroxidation, and Fe2+ can also catalyze the production of hydroxyl radicals. Relevant studies have confirmed that quercetin exerts its antioxidant effect by chelating Cu2+ and Fe2+ through its catechol structure. In a model of alcoholic liver disease induced by feeding adult male C57BL/6J mice with an ethanol-containing diet, treatment with quercetin was found to inhibit Fe2+-induced lipid peroxidation by chelating Fe2+, thereby suppressing iron overload and oxidative damage in alcoholic liver disease. Spectral analysis revealed that during the chelation process between quercetin and Cu2+, quercetin is oxidized into a stable benzoquinone product, and Cu2+ loses its ability to mediate lipid oxidation. The use of EDTA can block the formation of copper-quercetin complexes, further confirming that quercetin exerts an anti-oxidative stress effect by chelating Cu2+. Additionally, studies have demonstrated that quercetin protects DNA from reactive oxygen species (ROS) attack through two mechanisms: firstly, by chelating copper to inhibit the formation of ROS; secondly, by mildly embedding free quercetin into DNA to form a protective barrier against stronger embedders, thereby inhibiting the embedding ability of copper-quercetin complexes.

③ Inhibition of LDL Oxidative Damage

Free radicals in the human body can cause lipid oxidation by attacking unsaturated fatty acids in cellular lipids, leading to the formation of lipid radicals. Quercetin reverses this process by inhibiting LDL oxidation. Through observations of changes in thiobarbituric acid reactive substances, phosphatidylcholine hydroperoxides, and fluorescence intensity of oxidized low-density lipoprotein (LDL), it has been confirmed that quercetin can inhibit the oxidative modification of LDL, thereby exerting an inhibitory effect on LDL oxidative damage. Patients with hyperlipidemia often exhibit downregulated expression of LDL receptor (LDL-R) and upregulated expression of proprotein convertase subtilisin/kexin type 9 (PCSK9), leading to LDL oxidative damage and ultimately liver damage. Studies have demonstrated that quercetin at low concentrations can increase LDL-R expression, reduce PCSK9 secretion, and stimulate LDL uptake, thereby inhibiting LDL oxidative damage.

2.Anti-inflammatory and Immunomodulatory Effects

One of the most core and prominent effects of quercetin is its ability to regulate inflammation. Numerous studies have confirmed that quercetin exerts anti-inflammatory effects by inhibiting inflammatory cytokines and enzymes both in vitro and in vivo, acting on various cell types in animal and human models. Despite its low bioavailability and tendency to convert into different derivatives, these derivatives do not impact quercetin's anti-inflammatory properties. In vitro studies have shown that quercetin treatment of lipopolysaccharide-induced inflammatory mouse macrophage tumor cell line models results in a reduction in the expression of inflammatory factors IL-1, IL-6, and IL-10, thereby achieving an anti-inflammatory effect. In rat models of acute gouty arthritis, quercetin inhibited paw joint swelling, altered joint pathological conditions, and reduced the expression of inflammatory factors IL-1 and tumor necrosis factor. Furthermore, quercetin can regulate the PI3K/AKT/NF-κB signaling pathway to improve the degree of hepatic steatosis and alleviate liver inflammation in rat models of non-alcoholic steatohepatitis. In adipocytes, quercetin exerts an anti-inflammatory effect by modulating the gene expression of inflammatory factors IL-12 and nitric oxide synthase (iNOS) through the AMPK/Sirt1 pathway. For vascular inflammation, quercetin reduces the gene expression of specific inflammatory factors such as IL-1R, Ccl8, IKK, and STAT3 to combat inflammation. Atopic dermatitis, a widespread inflammatory skin disease globally, has recently been found to be treatable by quercetin through the regulation of multiple pathways.

Quercetin exerts immunomodulatory effects by inhibiting lymphocyte activation and proliferation. In studies focusing on leukemia cell lines, researchers have found that quercetin exhibits a higher apoptotic potential towards leukemia cell lines compared to peripheral blood mononuclear cells (PBMCs), while simultaneously inhibiting normal immune functions such as T-cell proliferation and activation. Additionally, quercetin can prevent PBMC proliferation and the upregulation of activation markers induced by Staphylococcal enterotoxin B (SEB), indicating that quercetin exerts immunomodulatory effects by interfering with effector T-cell functions.

3.Antiviral Effects

The glycoprotein hemagglutinin of influenza viruses plays a crucial role in the early stages of infection by influenza A virus and H5N1 avian influenza virus. The key to viral fusion lies in its interaction with the HA2 subunit on the cell membrane, making blocking the association between the virus and the HA2 subunit a potential target for the development of anti-influenza therapies. Studies have found that quercetin can interact with the HA2 subunit, thereby blocking viral fusion. Additionally, quercetin has been shown to inhibit H5N1 virus entry into cells by mimicking a viral drug screening system. Further research has revealed that quercetin can significantly reduce the replication rate of Hepatitis C virus (HCV), and that HCV virus particles treated with quercetin exhibit a 65% reduction in infectivity, indicating that quercetin can affect viral integrity. Molecular-level studies have confirmed that quercetin exerts its antiviral effects by preventing the upregulation of diacylglycerol acyltransferase (DGAT) by HCV and disrupting the typical localization of HCV core protein on lipid droplet surfaces.

4.Antitumor Effects

Research has demonstrated that quercetin possesses the ability to inhibit tumor cell growth and induce apoptosis. The pharmacological effects and dosages of quercetin in combating liver, lung, gastric, nasopharyngeal, breast, colon, ovarian, and bladder cancers have been widely studied and recognized both domestically and internationally, often exhibiting a dose- and time-dependent relationship. Studies on the impact of quercetin on the proliferation of brain glioma C6 cells have revealed that both increasing quercetin concentrations and prolonging exposure times significantly inhibit C6 cell proliferation. In research involving gastric cancer cells SGC-7901, quercetin was found to inhibit the proliferation and invasion of these cells in a dose-dependent manner. Furthermore, quercetin inhibits the growth of various liver cancer cell lines. For example, it induces apoptosis in human liver cancer cells LM3 by interfering with their proliferation and cell cycle distribution, promotes autophagy in LM3 cells by inhibiting their migration and invasion, and inhibits the proliferation of CBRH-7919 liver cancer cells by reducing their mitochondrial membrane potential. In lung cancer cells A549, quercetin nanocrystals were found to inhibit cell proliferation and migration through suppression of the STAT3 signaling pathway. Moreover, small quercetin nanocrystals exhibited stronger cytobiological effects in inhibiting cancer cell proliferation, migration, and invasion compared to larger particles.

5.Cardiovascular Protective Effects

Research has shown that quercetin possesses various cardiovascular protective effects, including hypoglycemic, hypotensive, hypolipidemic, anti-atherosclerotic, anti-thrombotic, and coronary heart disease prevention properties. In studies involving hyperlipidemic rats, quercetin was found to reduce blood glucose and lipid levels and improve renal function damage induced by hyperlipidemia. Additionally, quercetin treatment affects the distribution of cholesterol in various tissues of rats, such as the liver, heart, kidney, and small intestine, resulting in decreased total cholesterol, free fatty acids, and cholesterol esters in these tissues, while blood cholesterol, triglycerides, and high-density lipoprotein levels remained unchanged. For diabetic rats, quercetin effectively treats the condition by reducing blood glucose and cholesterol levels and regulating dyslipidemia. Besides reducing cholesterol levels in rats, quercetin also exhibits a dose-dependent reduction in liver cholesterol content in laying hens and cholesterol content in eggs. In juvenile GIFT tilapia, increasing quercetin concentrations gradually decreased serum total cholesterol and triglycerides. Quercetin exerts anti-atherosclerotic effects by downregulating the protein and gene expression of HMGB1 and TLR4 in a dose- and time-dependent manner. Furthermore, quercetin significantly downregulates the expression of autophagy-related proteins, such as mTOR, p62, and LAMP-2, in high-fat diet-induced atherosclerotic mice, thereby alleviating atherosclerotic damage.

References

[1] Liu Shengwen, Liu Jianying. "Research Progress on the Pharmacological Effects of Quercetin." Chinese Journal of Lung Diseases (Electronic Edition), 2020, 13(01): 104-106.

[2] Yang Ying, Wang Yunyun, Jiang Qichen. "Research Progress on the Pharmacological Effects of Quercetin." Special Economic Animal and Plant Sciences, 2020, 23(05): 24-28.

[3] Xia Yingying, Zou Tiande, Li Shuo, et al. "Nutritional and Physiological Functions of Quercetin and Its Prospects in Animal Feed." Journal of Animal Science and Biotechnology, 2021, 33(02): 729-736.

About the Author

Xiaonisha, a food technology professional holding a Master's degree in Food Science, is currently employed at a prominent domestic pharmaceutical research and development company. Her primary focus lies in the development and research of nutritional foods, where she contributes her expertise and passion to create innovative products.