v
Search
Advanced

Publications > Journals > Exploratory Research and Hypothesis in Medicine > Article Full Text

  • Hypothesis
  • OPEN ACCESS

Tackling Complications of Coronavirus Infection with Quercetin: Observations and Hypotheses

  • Shital Balasaheb Palghadmal1,
  • Prajakta Shriram Kulkarni1,
  • Vishal Makadia2,
  • Mahesh Jagannath Deshmukh3,
  • Priyanka Satish Gondhale3 and
  • Sriram Padmanabhan1,2,3,* 
 Author information  Cite
Exploratory Research and Hypothesis in Medicine   2021;6(4):193-204

doi: 10.14218/ERHM.2021.00015

Abstract

Coronaviruses are enveloped positive-strand RNA viruses that belong to the Coronaviridae family. According to the World Health Organization, this virus family has led to an international public health emergency. On the basis of existing clinical outcomes of patients suffering from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV, it is hypothesized that quercetin can play a potential role in alleviating various symptoms of coronavirus disease 2019 (COVID-19) infection and serve as a supplement to other prescribed anti-viral drugs currently used for the treatment of COVID-19. Quercetin containing medicinal plants can become attractive agents for alleviating various side effects of COVID-19 infection and may potentially affect COVID-19 replication. In this article, we estimated quercetin content, using a RP-HPLC method, in various medicinal plants and propose the possible use of these extracts as health supplements for alleviating different clinical symptoms reported in COVID-19 patients. Also, this article describes the development of a dry powder inhaler (DPI) of quercetin using lactose as a carrier molecule. Moringa oleifera and Glycyrrhiza glabra extracts contain quercetin and can be potentially useful as health supplements for COVID-19 affected patients. The DPI of pure quercetin was found to supply a fine particle fraction of almost 40%, revealing the efficacy of the formulation in the discharge of quercetin into the lungs. Nevertheless, the suggested idea of using quercetin for alleviating side effects of COVID-19 infection does not have any direct experimental evidence. It is therefore believed that these therapeutic strategies may help clinicians to better treat COVID-19 affected patients.

Keywords

COVID-19, Coronavirus, Quercetin, Blood clot, Thrombocytopenia, Male fertility

Introduction

The very contagious and actively spreading SARS-CoV-2 virus has considerably affected the health of people worldwide. Currently, more than 10,778,206 patients have been reported to be affected by this virus with a fatality rate of 3–4%.1 Almost 81% of COVID-19 infection cases belong to the mild case category. For this category, mild pneumonia is common, and patients recover without any special treatment. A total of 14% of subjects belong to the severe illness category. For this category, in addition to dyspnea, disturbances in blood oxygen saturation levels are observed. The critical illness category includes 5% of cases, whereby patients experience respiratory failure, septic shock, coagulation disorders, and/or multiple organ failure.2

The primary organ that is affected by COVID-19 is the lungs, and the airway epithelium is the primary point of entry for the virus. The virus damages alveoli and causes thickening of the lining, which affects the transfer of oxygen to the red blood cells. Because the air sacs are damaged, there is an influx of liquid, which mostly contains inflamed cells and proteins. It is the build-up of this fluid that causes pneumonia.

Until November 2020, there was no specific treatment for COVID-19, and therapeutic strategies to deal with the infection were merely focused on sustaining a patient’s physiological well-being. Very recently, different vaccines have been rolled out for preventing the spread of COVID-19 and building immunity in subjects all over the globe. The two authorized and recommended mRNA vaccines to prevent COVID-19 are the Pfizer-BioNTech COVID-19 vaccine and Moderna’s COVID-19 vaccine which offers nearly 90% protection in humans (a few more vaccines are in phase III clinical trials). While these vaccines act as a preventive measure for COVID-19, it is essential to establish drugs to treat people who are already affected. Some of the drugs being used to treat COVID-19 patients include Favipiravir and Ribavirin, Lopinavir/Ritonavir, Remdesivir, Arbidol, Ivermectin, Chloroquine and hydroxychloroquine, Cyclosporin A, Interferons, Tocilizumab, and plasma therapy. Notably, each of these drugs has its own limitations and efficacy of success. The antiviral activity of these drugs is based on the inhibition of nucleotide biosynthesis, preventing the binding of virus to host cell receptors, preventing viral replication, and reducing cytokine release.3,4

SARS-COV binds to the host cell membrane through the spike glycoprotein using the angiotensin-converting enzyme 2 (ACE2) as a receptor.5 Hamming et al.6 investigated the localization of the ACE2 protein in various human organs and reported that the tongue had the highest levels of ACE2 compared to buccal and gingival tissues. These results indicate that the oral mucosa is a potentially high risk route for COVID-19 infection.7 Since ACE2 is also abundantly expressed in the endothelial cells of the liver,6 the virus can also affect this vital organ.

The biochemical changes involved during COVID-19 infection include elevated levels of blood interleukin 6 (IL6), high-sensitivity cardiac troponin I, fibrin degradation product (d-dimer), serum ferritin, white blood cell count, neutrophil count, lactate dehydrogenase, alanine aminotransferase, aspartate aminotransferase, total bilirubin, serum creatinine, prothrombin time, procalcitonin, C-reactive protein, tumor necrosis factor α, IL1β, granulocyte-colony stimulating factor, interferon gamma-induced protein-10, monocyte chemoattractant protein-1, and macrophage inflammatory proteins 1-α. By contrast, the lymphocyte count and the level of albumin are decreased in COVID-19 cases.8

Clinical complications of COVID-19 infection: observations

COVID-19 and blood pressure

Among various comorbidities, hypertension associated with COVID-19 patients9 results in the risk of adverse outcomes such as mortality, ICU admission, and heart failure. Zhou et al.8 discuss that the most common comorbidity that aggravates COVID-19 infection is hypertension (30%), followed by diabetes (19%) and coronary heart disease (8%).

COVID-19 and male fertility

The high level of ACE2 expression in testicular Leydig and Sertoli cells enables the entry of the SARS-CoV-2 virus. Possible damage to these cells can affect the spermatogenesis process and therefore male fertility.10,11 Since the testicular expression of ACE2 is age-related with the maximum expression seen in young adults of 30 years, younger males carry a higher risk of COVID-19 infection as far as fertility is concerned.

COVID-19 and blood clots

The spike protein of SARS-CoV-2 virus binds to the ACE2 receptor that is expressed in the endothelial cells of blood vessels, and causes the vasoconstriction and activation of the intrinsic pathway of coagulation, eventually forming blood clots.12 Clot formation is extremely rapid and also resistant to breakdown.13 Vascular inflammation and micro-thrombosis appear to be the causal factors of the multi-systemic clinical manifestations associated with COVID-19.14 It is proposed that anticoagulant therapy such as heparin improves the prognosis of patients with severe COVID-19 symptoms.15

COVID-19 and blood platelets

Thrombocytopenia is detected in 5–41.7% of COVID-19 patients,16 the major causes of which are bone marrow infection, destruction of platelets by the immune system and aggregation of platelets in the lungs. The mortality has been reported to increase as platelet count decreases.17

COVID-19 and loss of smell

Coppee et al.18 examined mutations in COVID-19 in samples from different countries like France, Spain, Italy and India. Of the various symptoms that include headache, loss of smell, cough etc., loss-of-smell was significantly more frequent in Spanish (70.5%) and French-speaking (73.3%) COVID-19 populations compared with the Italian COVID-19 population (50.0%). Loss of smell is not an unique feature of COVID-19 infection, since it is known to be associated with other clinical conditions such as Alzheimer’s disease, Parkinson's disease and tremors.

COVID-19 and kidney and liver function

SARS-CoV-2 RNA has been detected in stool and blood samples, which indicates the possibility of viral exposure in the liver.7 In fact, pathological studies in patients with SARS confirmed the presence of the virus in the liver.19 Elevated levels of liver enzymes, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are indicative of liver damage. This has been observed in patients with COVID-19 and has shown an almost 40% rise in comparison to normal levels of these compounds.20

Nearly 36% of patients with SARS-CoV-2 infection develop an acute kidney injury (AKI). Since animal experiments with quercetin display improved renal function and reduced renal inflammation,21 it is possible to expect improved kidney function in COVID-19 patients.

COVID-19 and ACE2 receptor

ACE2 is an 805 amino-acid long transmembrane protein that is localized in lung alveolar epithelial cells, arterial and venous endothelial cells, the renal tubular epithelium, and the epithelia of the small intestine. It is believed to be the host receptor for SARS-CoV-2, as argued by Liu et al.22

COVID-19 and bacterial infections

In viral pneumonia, especially in critically ill patients, bacterial and fungal infections are common complications, and these patients need an intensive care facility to minimize mortality. Common bacterial and fungal cultures of patients with secondary infections of COVID-19 include Acinotobacter baumannii, Klebsiella pneumoniae, Aspergillus flavus, Candida glabrata, and Candida albicans.23

COVID-19 and diabetes

Patients with diabetes also express significantly elevated concentrations of ACE2.24 Ugwueze and co-workers25 showed that patients with diabetes mellitus exhibit an increased predisposition to viral and bacterial infections that include those affecting the respiratory tract. Type 2 diabetes further significantly increases the risk for hospitalization and death in COVID-19 patients.

Albumin levels in COVID-19 patients

Hypoalbuminemia is reported in COVID-19 patients and therefore, examining serum albumin levels at hospital admission may reflect the severity of systemic inflammation and can serve as a predictive factor for COVID-19 outcomes.26 Huang et al.27 hypothesized the infusion of albumin in COVID-19 patients since lower albumin levels were observed in severe COVID-19 with no link to hepatocellular injury.

Nitric oxide levels in COVID-19 infection

During a host’s response to viral infection, nitric oxide (NO) and the reaction product peroxynitrite (ONOO(−)) are generated in excess and in turn contributes to viral pathogenesis by promoting oxidative stress and tissue injury.28 The high amount of NO during viral and bacterial infections accelerates mutation of viral RNA, inhibiting the production of inflammatory mediators (e.g., NO, PGE2, and inflammatory cytokines) that are essential in COVID-19 infection.29,30

Glutathione and COVID-19

An antioxidant that is ubiquitous in most living organisms is glutathione (GSH), a tripeptide of glutamate, cysteine and glycine.31 Reports suggest that there is higher susceptibility for uncontrolled replication of SARS-CoV-2 virus in individuals suffering from GSH deficiency. In particular, COVID-19 patients with moderate and severe illness have lower levels of GSH, higher ROS levels, and greater redox status (ROS/GSH ratio) than mild COVID-19 patients. Men have lower plasma levels of reduced GSH than women, making men more susceptible to oxidative stress, inflammation and COVID-19 infection.32

D Dimer, C-reactive protein, IL6, IL10 levels during COVID-19 infection

Higher levels of cytokines such as TNFα, IFNγ, IL2, IL4, IL6 and IL10 and CRP have been observed in COVID-19 patients. Interestingly, in COVID-19 patients, serum IL6 and IL10 levels are significantly higher in critical patients in comparison to moderately and severely ill patients.33 D-dimer is the most validated laboratory biomarker to predict hyper-coagulability, and in COVID-19 patients the levels increase beyond 0.5 µg/mL. Such an increase in D-dimer levels could be an indirect manifestation of an inflammatory reaction, as inflammatory cytokines could cause the imbalance of coagulation and fibrinolysis in the alveoli, which may activate the fibrinolysis system and increase the level of D-dimer.34

Hypothesis: Use of herbal extracts with quercetin to alleviate side effects of COVID-19

The clinical symptoms identified based on the data from the present outbreak of COVID-19 suggest that SARS-CoV-2 tends to infect lower parts of the respiratory system such as the lungs, bronchi, bronchioles, and alveoli, that show extensive alveolar and interstitial inflammation. We believe that merely controlling viremia in COVID-19 patients through the use of antiviral agents may not be sufficient. It may be that the use of therapeutic supplements is needed to address inflammation and other side effects of COVID-19 patients without compromising the adaptive immune response.

COVID-19 infection renders patients critically–ill if they have comorbidities such as hypertension, diabetes and coronary heart disease. Blood clots in the small vessels of the lungs, heart, liver, and kidney are often responsible for strokes and heart attacks and have been revealed in autopsies of COVID-19 patients. Abnormalities in coagulation and thrombosis commonly elevated levels of fibrinogen and D-dimer, often with mild thrombocytopenia,8 due to these blood clots, which is a real concern that needs to be addressed.12 The degree of D-dimer elevation positively correlates with mortality in COVID-19 patients and therefore, strategies to reduce D-dimer levels would prove beneficial for quicker recovery of COVID-19 patients.

The safety of quercetin in humans has already been established in healthcare workers attending to COVID-19 patients.35 Therefore, it can be postulated that the inclusion of herbal extracts containing quercetin can potentially improve the management of critically ill COVID-19 patients and reduce the side effects to enable faster recovery and discharge from the hospital. Since many of the prescribed anti-viral drugs do not have the capability of alleviating the side effects of COVID-19 infection, a strategy of using quercetin-containing herbal extracts for COVID-19 patients appears promising.

Evaluation of the hypotheses

Quercetin and its anti-viral activity

Recent studies have also demonstrated antiviral activities of quercetin, a carbohydrate-free flavonoid, against a wide variety of viruses that includes the influenza virus, Chikungunya virus, Epstein-Barr virus, hepatitis C virus, Ebola and the Mayaro virus.36 After the SARS-CoV-1 coronavirus outbreak in 2003, researchers in China found quercetin and other small molecules bound to the spike protein of the virus to interfere with its ability to infect host cells. As of March 2020, no COVID-19 cases were recorded among healthcare workers taking prophylactic quercetin and no deaths were observed among patients with COVID-19 on quercetin treatment.35 This result reflects a strong and positive health impact of quercetin on COVID-19-affected patients. Quercetin has also been suggested to serve as a SARS-CoV-2 inhibitor by binding to the active sites of SARS-CoV-2 proteases and prematurely terminate the SARS-COV-2 life cycle by suppressing the functions of proteins required for viral replication (Gu et al., 2021).37

Multifactorial benefits of quercetin

Quercetin and blood pressure

A decrease in blood pressure after quercetin supplementation has been reported both in animals and humans38 with no effect in normal individuals. This is achieved through a decrease in oxidative stress, which is responsible for higher blood pressure. There is also evidence that quercetin may decrease blood pressure through mechanisms independent of the endothelium by directly acting on the vascular smooth muscle.39

Quercetin and male fertility

Sperm motility, viability and concentration have been found to increase after treatment with quercetin in rats as demonstrated by Taepongsorat et al.40 Quercetin improved sperm motility in a dose- and time-dependent manner.41 Quercetin has been observed to significantly improve sperm motility in leukocytospermic patients due to its intensive antioxidant activity42 at 10 µM concentration.

Quercetin and blood clotting

Studies have shown that quercetin inhibits the enzymatic activity of thrombin and FXa and suppresses fibrin clot formation and blood clotting.43

Quercetin and blood platelets

Quercetin is a promising dual antiplatelet and anti-inflammatory/anti-atherosclerosis agent and it is a dietary inhibitor of platelet cell signaling and thrombus formation.44 Quercetin also inhibits platelet density and alpha granule exocytosis when stimulated by different platelet agonists, and inhibits multiple platelet protein kinase.45

Quercetin and loss of smell

The most common known etiologies for loss-of-smell (anosmia) are nasal/sinus congestion and possible upper respiratory tract infection. Interestingly, vitamin D has been linked to improve anosmia through improving sinus congestion and allowing improved olfaction. Polyphenols promote the neurogenesis of the olfactory bulb and nerve cells in the hippocampus, and therefore prevent further oxidative stress and improve the loss-of-smell.46

Quercetin for liver protection

Quercetin has a hepato-protective effect on liver injury and normalizes the level of hepatic enzymes.47 Therefore, the use of quercetin-containing herbal extracts or pure quercetin itself could benefit COVID-19 patients.

Quercetin and ACE2 receptor

Hackl et al.48 reported a 31% decrease in ACE2 activity after quercetin treatment compared with baseline, suggesting that quercetin acts as an ACE2 inhibitor. Quercetin appears to be the most potent rhACE2 inhibitor among all the polyphenols tested, with an IC50 of 4.48 µM.

Anti-bacterial activities of quercetin

Quercetin inhibits the growth of S. aureus and P. aeruginosa at a concentration of 20 mcg/mL, and at a concentration 300 mcg/mL and 400 mcg/mL inhibits the growth of P. vulgaris and E. coli respectively. It is also known to damage cell walls of Gram-positive and Gram-negative bacteria.49

Quercetin and diabetes

Animal studies have shown that quercetin lowers glucose plasma levels relative to controls with no effect on insulin levels.50

Quercetin and albumin relationship

Albumin is the most abundant plasma protein and is highly soluble and stable with an extraordinarily long circulatory half-life of ∼21 days. Quercetin has been reported to bind to the human serum albumin (HSA) molecule at two distinct sites, with no significant perturbation, to enable the improvement in its half-life and be available longer for action in circulation.51,52

Quercetin and its anti-inflammatory effects

The anti-inflammatory actions of flavonoids such as quercetin to effectively inhibit lipopolysaccharide (LPS)-induced prostaglandin E2 production53 may help control disease progression in COVID-19 patients. Since quercetin reduces NO production in nasal epithelial cells,54 it is hypothesized that quercetin may reduce the progression of viral infection in COVID-19 patients. In fact, 10–25 µM quercetin has been reported to inhibit the level of NO and TNFα.55

The two leading causes of death in patients with severe COVID-19 include acute respiratory distress syndrome and acute lung injury due to cytokine storm and severe inflammation. Quercetin has an inhibitory effect on inflammatory responses and suppresses inflammation through interference in various signaling pathways, especially that of NF-κB.56 This is likely done through the inhibition of cyclooxygenase (COX) and lipoxygenase (LOX) enzymes, and the reduction of TNFα production with chronic inflammation.57 In pre-clinical studies, there have been observations of the suppression of macrophages, dendritic, mast cells and IL6 levels after treatment with quercetin.58

Quercetin and glutathione

One of the major causes of lung damage and inflammation is the imbalance in the level of oxidant/antioxidants. GSH is a ubiquitous tripeptide thiol that is a vital intra- and extra-cellular protective antioxidant against oxidative stress, which also plays a key role in the control of signaling and pro-inflammatory processes in the lungs. Quercetin is known for its anti-inflammatory, antihypertensive and vasodilator effects, as well as its anti-obesity, anti-hyper-cholesterolemic and anti-atherosclerotic activities.59 Thus, it appears to play a role in maintaining reduced glutathione levels60 and hence possesses protective abilities against tissue injury induced by various drug toxicities.

Quercetin and levels of D-dimer, IL6 and IL10

Administration of iso-quercetin has been reported to reduce the D-dimer levels in plasma.61 Quercetin at 1,000 mg/day for two weeks showed a significant decrease for C-reactive protein and plasma IL6 and IL10.62

Quercetin as a dry powder inhaler (DPI)

The fine particle fraction (FPF) of drugs from formulations containing anhydrous lactose has been reported to be two times higher than the FPF of the formulation containing regular lactose.63 Lactose is added for a good flow property and dispersibility during inhalation. The ratios of different grades of lactose are used for achieving maximum depositions, emitted dose, fine particle dose, fine particle fraction and mass median aerodynamic diameter of drugs. In this article, we used a ratio of 60:40 of quercetin dihydrate:lactose.

The micronization of quercetin dehydrate was carried out by feeding 5.5 gm of quercetin dihydrate through the Micronizer (Microtech Engineering Co., Mumbai, India) with 8.0 bar of air pressure at a 1.5 g/min feeding rate. After completion of a cycle, the micronized quercetin was collected from the chamber. Micronized quercetin (1.5 g) was sifted with 1.0 g of Respitose ML006 (Inhalation grade lactose) through a 60 mesh sieve. After sifting, the blend was mixed at 25 rpm for 30 min in the Alphie mixer (Hexagon Product Development Pvt. Ltd., Gujrat, India), and then size 3 HPMC capsules were filled in with 25 mg of the above blend.

In vitro aerodynamic particle size distribution of quercetin in NGI

To characterize the aerosolization performance of quercetin-DPI, a formulation weight of 25 mg was considered. The quercetin-DPI powder capsule was placed in the inhaler for use and the mouthpiece adapter was attached to the induction port. The pump was switched on at a pressure of 4 kPa pressure drop across the device. The discharge sequence was repeated four times to ensure complete discharge of the powder to the NGI port. After aerosolization, the amount of drug retained in the inhaler device, induction port, mouth-piece adaptor, pre-separator and NGI cups was extracted by washing with a suitable volume of 90:10 methanol:water for quantitative HPLC analysis of quercetin. All the samples were filtered through a 0.45µm filter and analyzed for quercetin content by HPLC. The important NGI parameters, such as mass median aerodynamic diameter (MMAD), Geometric standard deviation (GSD), the emitted dose (ED) and fine particle fraction (FPF) were calculated using the CITDAS software (COPLEY Scientific, UK).

Empirical data

Quercetin content in a few selected plant species

Quercetin is present in many fruits, vegetables, and grains. Plant sources such as onions, broccoli, and peppers, fruit sources such as apples, berries, and grapes, herbs and some types of tea and wine contain quercetin, although, in low amounts.64 The quercetin content of plant foods differs depending on the cultivars or cultivation conditions,65 and has also been shown to be dependent on light exposure.66

In an attempt to substantiate this hypothesis, we estimated quercetin content in some of the herbal extracts that are known for their anti-viral properties. The method followed for making herbal extracts, extraction and estimation of quercetin in herbal extracts is disclosed in the subsections below.

Preparation of herbal extracts from various herbal raw materials

Various raw materials, (local vendors, India) (50 g) were weighed separately and soaked in five volumes of the respective extracting solvent (water, 50% ethanol, 70% ethanol and 100% ethanol, as provided in Table 1). The extraction process was carried out for 3 h at 70–80 °C and repeated thrice. The pooled extraction liquids was filtered through a polypropylene cloth and dried on a rotary evaporator (Buchi India Pvt. Ltd, Mumbai, India) until dry.

Table 1

: Estimation of quercetin content in extracts of selected plant species

Sr. No.PlantBatch IDExtraction solvent% quercetin content
1Ocimum sanctumAH/363/50901/SHWaterND
2Tinospora cordifoliaRD/TC/CL/17-001WaterND
3Glycyrrhiza glabraRDP/GG/03350% Ethanol0.031
4Andrographis paniculataRD/AP/CL/17-00150% EthanolND
5Withania somniferaRDP/GB/00870% EthanolND
6Trigonella foenumRDP/GB/00370% EthanolND
7Moringa oleiferaRDP/MO/02370% Ethanol0.024
8Asparagus racemosusRD/AR/CL/17-001WaterND
9Picrorrhiza kurroaRDP/PK/015EthanolND
10Bacopa monnieriRDP/GB/00970% EthanolND
11Gymnema sylvestreRDP/GB/00670% EthanolND
12Salacia reticulataRDP/SR/17350% EthanolND

ND, not detectable.

HPLC chromatographic conditions

A gradient mobile phase was applied on a Hypersil BDS C18 column (4.6 × 250 mm, 5 µm) for separation. The mobile phase consisted of buffer (1mM anhydrous potassium dihydrogen orthophosphate (KH2PO4) with 0.5 ml orthophosphoric acid, A) and acetonitrile (100%, B). The percentage of acetonitrile in the mobile phase was programmed as follows: 5% (0 min) − 45% (18 min) − 80% (25 to 28 min) − 45% (35 min) − 5% (40 to 45 min). The injection volume was 20 µl at a flow rate of 1.5 mL/min. HPLC chromatograms were recorded at 370 nm. The elution was carried out at ambient temperature (27 ± 1°C).

Sample preparation

For making a sample of the extract, nearly 100 mg of all the extracts was placed in a 50 ml of volumetric flask containing 30 ml of methanol (diluent), and sonicated for 20 minutes. The diluent was added up to the mark of 50 ml and mixed well to obtain an evenly homogenized sample. The sample was then cooled to room temperature and filtered through 0.45 µm filter paper and a suitable volume (20 µL) was injected into the HPLC system.

The stock solution of quercetin was prepared by accurately weighing 5 mg of pure quercetin dihydrate (Sigma Aldrich, USA) in 10 ml methanol. After sonication, the volume was prepared up to the 25 ml mark with methanol and then filtered through a 0.45 µm filter. Finally, a suitable volume (20 µL) was directly used for injection into the HPLC system.

Figure 1 shows the chemical structure of quercetin while the HPLC chromatogram for pure quercetin is depicted in Figure 2. Figures 3 and 4 show the HPLC chromatograms of the alcoholic extract of Moringa oleifera leaves and Glycyrrhiza glabra roots, respectively, with a peak matching that of quercetin. Table 1 summarizes the quercetin content in herbal extracts tested.

Chemical structure of quercetin.
Fig. 1  Chemical structure of quercetin.
HPLC chromatogram of pure quercetin at 370 nm. Note the retention time (RT) of quercetin as 30.80 min.
Fig. 2  HPLC chromatogram of pure quercetin at 370 nm. Note the retention time (RT) of quercetin as 30.80 min.

The standard solutions were prepared as described in the empirical data section.

HPLC chromatogram of the 70% ethanolic extract of <italic>Moringa oleifera</italic> at 370 nm.
Fig. 3  HPLC chromatogram of the 70% ethanolic extract of Moringa oleifera at 370 nm.

The chromatogram shows an elution profile of several flavonoids, with quercetin at the expected RT of 30.8 min. RT, retention time.

HPLC chromatogram of the 50% ethanolic extract of <italic>Glycyrrihiza glabra</italic> at 370 nm.
Fig. 4  HPLC chromatogram of the 50% ethanolic extract of Glycyrrihiza glabra at 370 nm.

The chromatogram shows the elution profile of several flavonoids, with quercetin at the expected RT of 30.8 min. RT, retention time.

Anti-TMPRSS2 assay

Human transmembrane serine protease 2 (TMPRSS2) is a protein expressed on the surface of endothelial cells across the respiratory and digestive tracts. TMPRSS2 is a protease that facilitates SARS-CoV-2 particle entry into host cells via the spike protein fusion with the ACE2 receptor. Hence, any molecule that restricts SARS-CoV-2 viral entry through inhibition of the TMPRSS2 protease will have potential as an anti-COVID-19 therapeutic agent. The TMPRSS2 Fluorogenic Assay Kit (BPS Bioscience, ref. 78083, lot 201217-K) was used for the protease assay. The positive inhibitor control used was Camostat. Purified quercetin under these experimental conditions showed 30% inhibition of TMPRSS2 activity at 44 µM (data not shown).

Drug dosage form possibilities

Approximately 80% of the world population uses herbal medicines for their primary health care because herbal drugs are less toxic and have fewer side effects than synthetic drugs.67 Plant materials have poor aqueous solubility, are susceptible to degradation by low gastric pH, tend to oxidize, and contain antibacterial preservatives. This results in the irregular absorption from oral solid forms, owing to degradation within the gastrointestinal tract. Thus, alternate routes of delivery, such as pressurized metered-dose inhalers (pMDIs) and DPIs, appear attractive for these drugs. We hypothesize that the simultaneous use of quercetin and other anti-viral agents may be more effective for treating COVID-19 patients. Because DPI devices are used for direct drug delivery to the lungs to treat respiratory disorders (e.g., asthma and chronic obstructive pulmonary disease), we feel that it is important to create DPIs containing Moringa oleifera and Glycyrrhiza glabra extracts as a source of quercetin to treat COVID-19 in the lungs.

In vitro aerodynamic particle size distribution of quercetin in NGI

From the CITDAS report of the quercetin dehydrate DPI, the mean FPF (≤5 µm) was nearly 40% of the nominal dose (which refers to the content of the capsule) for quercetin while the mass median aerodynamic diameter (MMAD) and the GSD value was 3 µm and 2.236 respectively. The total emitted dose of active ingredient, less device deposition per discharge was 11.081 mg. The pattern of drug distribution per discharge of various stages of NGI is shown in Figure 5.

A high fine particle fraction (FPF), defined as the fraction of particles less than 5 μm in diameter, indicates that a significant proportion of the inhaled dose is likely to reach the pulmonary region since particles larger than five microns tend to affect the oropharynx and be swallowed. The aerosolization process in DPIs is driven by the inhalation capacity of the patient and therefore, it is critical that the emission of the API from the capsule and the device disperses an appreciable emitted dose.

<italic>In vitro</italic> Next Gen Impactor aerosolization performance of a quercetin-DPI.
Fig. 5  In vitro Next Gen Impactor aerosolization performance of a quercetin-DPI.

This data was generated using the CITDAS V.3.10 software at 83 L/min. The X axis denotes various stages of the NGI while the Y axis denotes drug deposition (mg). DPI, Dry powder inhaler; CITDAS, Copley Inhaler Testing Data Analysis Software; NGI, Next Generation Impactor.

The in vitro aerodynamic particle size distribution that simulates the in vivo lung deposition of the dose was evaluated using a Next Generation Impactor (NGI) for the quercetin dehydrate DPI that was formulated. Each capsule contained 15 mg of quercetin dehydrate and characterized using Plastiape device with the device flow rate was set at 83 L/min (≈ 4 KPa). Distribution of the dose of quercetin dihydrate in the different stages of NGI depicted in Figure 5 indicated that the fine particle dose (respirable dose) and fine particle fraction (respirable fraction) was 4.5 mg and 40.6% respectively while the mean delivered dose was 12.4 mg per actuation. These results meet the requirements of Ph. Eur.68 that suggests +/− 25% of the target dose from a DPI be delivered while that of the USP69 to deliver +/− 15% of the target dose.

Table 2 describes ongoing human studies with quercetin and indicates the significance of this compound in reducing COVID-19 infection. Back in 2010, a randomized study with 1,002 adult subjects with viral infections of the upper respiratory tract demonstrated a reduction in days of illness in middle-aged and elderly subjects after quercetin was administered at very high doses (1,000 mg/dose) for 12 weeks.70 Recently, patients treated with herbs with high quercetin content have exhibited no side effects and have also displayed an improvement in the symptoms of patients with COVID-19.71

Table 2

Summary of human clinical trials with pure quercetin in COVID-19 patients

Sr.No.Study TitleStatusLocationReference LinkOutcome MeasuresDosage regimen
1Trial to Study the Adjuvant Benefits of Quercetin Phytosome in Patients With COVID-19OngoingLiaquat University Hospital; Jāmshoro, Sindh, Pakistanhttps://clinicaltrials.gov/ct2/show/NCT04578158?term=quercetin&cond=Covid19&draw=2&rank=1 Primary outcome: Percentage of subjects who need hospitalisation when compared to placebo group400 mg/day quercetin given orally
2Effect of Quercetin on Prophylaxis and Treatment of COVID-19CompletedKanuni Sultan Suleyman Training and Research Hospital; Istanbul, Turkeyhttps://clinicaltrials.gov/ct2/show/NCT04377789?term=quercetin&cond=Covid19&draw=2&rank=2 Primary Outcome Measures: Prevalent of Covid-19 and morbidity rate in comparison to Placebo groupStudy with two groups, one with 500 mg/day quercetin and another with 1,000 mg/day quercetin given orally
3The Study of Quadruple Therapy Zinc, Quercetin, Bromelain and Vitamin C on the Clinical Outcomes of Patients Infected With COVID-19OngoingMinistry of health. First health cluster, Riyadh; Riyadh, Saudi Arabiahttps://clinicaltrials.gov/ct2/show/NCT04468139?term=quercetin&cond=Covid19&draw=2&rank=3 Primary Outcome Measures: Number of days required to be in a hospital after treatmentQuercetin 500 mg/day, bromelain 500 mg/day, Zinc 50 mg/day, Vitamin C 100 mg/day via oral route
4Masitinib Combined with Isoquercetin and Best Supportive Care in Hospitalized Patients with Moderate and Severe COVID-19Ongoing1) Centre Hospitalier du Pays d’Aix; Aix-en-Provence, France; 2) Le Tripode, Groupe hospitalier Pellegrin CHU de Bordeaux; Bordeaux, France; 3) CHU Clermont-Ferrand: Site Gabriel-Montpied; Clermont-Ferrand, France; Besides it is running in 3 more hospitalshttps://clinicaltrials.gov/ct2/show/NCT04622865?term=quercetin&cond=Covid19&draw=2&rank=4 Primary Outcome Measure: 1) Clinical status of patients at day-15 using a 7 different measures - 1. No hospitalization with no change in daily activities; 2. No hospitalization with change in daily activities; 3. Hospitalization required without supplemental oxygen; 4. Hospitalization with supplemental oxygen; 5. Hospitalization with non-invasive ventilation or high flow oxygen devices; 6. Hospitalization with invasive mechanical ventilation or ECMO; 7. DeathMasitinib: 3 mg/kg/day for 4 consecutive days followed by 4.5 mg/kg/day and Quercetin: 1 g/day

ECMO, extracorporeal membrane oxygenation.

Discussion

Studies have reported that many herbal medicines exhibit activity against coronavirus, coxsackievirus, dengue, enterovirus, hepatitis B virus, hepatitis C virus, herpes simplex virus, human immunodeficiency virus, influenza virus, measles virus, echovirus, and respiratory syncytial virus. The influence of active constituents from herbal extracts include the effect on viral replication, viral adsorption, cell-to cell spread, viral polymerase activity, and viral inactivation.72

Plants that are known for their anti-viral activities include Allium sativum, Daucus maritimus, Helichrysum aureonitens, Pterocaulon sphacelatum, Quillaja saponaria, Macaranga barteri, Crinum jagus, Terminalia ivorensis, Ageratum conyzoides, and Mondia whitei, antiwei, ginseng, berries, pomegranate, guava tea, and Bai Shao.73–75 Interestingly, the extracts of Bupleurum spp., Heteromorpha spp., Scrophularia scorodonia, Lycoris radiate, Artemisia annua, Pyrrosia lingua, Lindera aggregata, and Glycyrrhiza roots have also been reported to display anti–SARS-CoV activity.76–78

Humans can absorb quercetin from food or supplements quite efficiently and the elimination thereof is quite slow, with a reported half-life ranging from 11 to 28 h.79 Quercetin is also known to enhance immunity in humans.80 As an antioxidant and anti-allergy medicine, it has been classified as generally recognized as safe (GRAS) by the U.S. Food and Drug Administration.81

The incidence of asthma has been observed to be lower in individuals who ingested higher quantities of total flavonoids, including quercetin.82,83 Quercetin has been present in the human diet for many centuries,84 however, the dietary consumption of quercetin differs across countries and ranges from 5 mg to 80 mg per day55 depending purely on the individual’s consumption of quercetin-containing fruits and vegetables.56

Quercetin and asthma treatment drugs such as β2-agonists and corticosteroids83 do not display any drug-drug interactions. Hence, the use of quercetin to treat COVID-19 patients appears to be an attractive option. Also, there is evidence that co-administration of vitamin C and quercetin exerts a synergistic anti-viral effect with increased efficacy, due to the capacity of ascorbate to recycle quercetin.85 Kamel et al.86 recently demonstrated the safety of the combination of zinc, quercetin, Bromalian and vitamin C in COVID-19 patients. However, since quercetin is a zinc chelator and acts as a zinc ionophore, optimization studies are needed to correctly dose such combinations before applying it to use in humans.87 The role of quercetin for the treatment of COVID-19 has been reviewed very recently by Aucoin et al.88 and Derosa et al.,89 and our present article proposes multiple benefits in the use of quercetin in COVID-19 patients.

Future directions

Considering the high rate of transmission of the COVID-19 virus amongst humans and its pandemic nature, any intervention that reduces its transmission and side effects of infection represents a promising therapeutic strategy. This pandemic will indeed last for an extended period of time unless two-thirds of the world’s population becomes immune. If this threshold is not met, control of infection cannot be ascertained. Thus, therapeutic strategies that offer the population an immunity to this virus represent an important weapon to fight against this deadly infection.

The immune-boosting properties of glycyrrihiza glabra have been previously reported.90 The safety of licorice hydrophobic flavonoids and glabridin has been demonstrated, and these compounds exhibit linear pharmacokinetics when administered above the dose range of 300–1,200 mg/person.91 This treatment strategy is therefore effective in enhancing the overall immunity in COVID-19 patients. A key consideration for therapeutic agents COVID-19 is the ability to deliver an effective concentration of the drug into the lungs, particularly at the epithelial barrier where the virus enters. Therefore, it is tempting to think that a strategy that provides quercetin from Glycyrrhiza glabra or Moringa oleifera extract as a dry powder inhaler directly into lungs of COVID-19 patients would be beneficial. The viral load, which is a measure of infection, is estimated in the brancheo–alveolar lavage fluid and is reflective of viral proliferation and release from epithelial cells. In addition, the ACE2 receptor on airway epithelial cells acts as a viral transporter and is thought to be essential for viral infectivity. Thus, if one observes a reduction in the level of viral load after the inhalation of quercetin, it would indicate a reduction in the progression of COVID-19 infection.

The shape, size, and duration of spray from the DPI device are dictated by the combination of different physicochemical properties of DPIs, such as particle size, shape, surface area, and morphology. Because these aerodynamic properties determine the fluidization, dispersion, and delivery of drugs to the lungs, as well as their deposition in peripheral airways, further optimization of licorice formulation for DPIs is needed. Since quercetin exhibits a protective antioxidant effect on bronchial cells in the lungs,92 we hypothesize that the DPI formulation of quercetin or quercetin-containing herbal extracts will allow the drug to reach the lungs and may help reduce the progression of COVID-19 when used in combination with other standard drugs. To the best of our knowledge, this is the first report of the development of quercetin in a DPI dosage form.

We intend to carry out in vitro COVID-19 viral replication inhibition studies with pure quercetin and with the extracts containing either of these constituents to determine the minimum dose of active constituents required to affect COVID-19 virus replication. In addition, we plan to carry out additional experiments to improve the extraction of quercetin from Moringa oleifera and Glycyrrhiza glabra extracts for inhibition studies on the ACE2 receptor and TMPRS22 to elucidate the quercetin-based mechanism of anti-COVID-19 activity. Finally, the generated in vitro data will be used to perform human studies and identify the exact clinical curative effect, optimal dose, and course of treatment.

Conclusions

The quercetin-containing herbal extracts such as Glycyrrhiza glabra and Moringa oleifera have been established as safe for human consumption. While Glycyrryhiza glabra is approved by the US-FDA as a health supplement,93 the ingredients contained in Moringa oleifera products are GRAS. Therefore, our proposal to use these extracts as health supplements along with appropriate anti-viral drugs by COVID-19 patients may alleviate several of the side effects seen during COVID-19 infection and is of critical importance.

Abbreviations

NO: 

nitric oxide

NGI: 

next generation impactor

CITDAS: 

copley inhaler testing data analysis software

DPI: 

dry powder inhaler

TMPRSS2: 

human transmembrane serine protease 2

ACE2: 

angiotensin-converting enzyme 2

Declarations

Acknowledgement

The authors thank Mr. Vinod Jadhav, Chairman SAVA Limited and Mr. Avinaash Mandale, MD, SAVA Limited for their constant source of support and encouragement; Thanks to the SAVA Manufacturing Team, KIADB Industrial Area, Malur, for providing us a few of the herbal extracts used in this study. Thanks also to Natural Remedies Pvt. Ltd, Bangalore, India for sharing the HPLC method for quercetin estimation in herbal extracts.

Data sharing statement

The CITDAS report on % FPF of quercetin DPI is available from the corresponding author.

Funding

This study was supported by SAVA Healthcare Limited, India and no external funding was received for this study.

Conflict of interest

All authors are employees of SAVA Healthcare Limited. The authors declare no other conflicts of interest related to this publication.

Authors’ contributions

The concept of using quercetin for alleviating COVID-19 symptoms was generated by SP while the method of making plant extracts and adapting the HPLC method for estimation of quercetin was done by SBP and PSK. The DPI formulation for pure quercetin was made by VM while the FPF determination of the DPIs was performed by MJD and PSG using the Next Generation Impactor. The manuscript writing and critical revision of the manuscript were carried out by SP. All authors have made a significant contribution to this study and have approved the final form of the manuscript.

References

  1. Ruan S. Likelihood of survival of coronavirus disease 2019. Lancet Infect Dis 2020;20(6):630-631 View Article
  2. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020;323(11):1061-1069 View Article
  3. Chen C, Zhang XR, Ju ZY, He WF. Advances in the research of cytokine storm mechanism induced by Corona Virus Disease 2019 and the corresponding immunotherapies (in Chinese). Zhonghua Shao Shang Za Zhi 2020;36(06):471-475 View Article
  4. Hoffman E, Rahat MA, Feld J, Elias M, Rosner I, Kaly L, et al. Effects of Tocilizumab, an anti-interleukin-6 receptor antibody, on serum lipid and adipokine levels in patients with rheumatoid arthritis. Int J Mol Sci 2019;20(18):4633 View Article
  5. Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003;426(6965):450-454 View Article
  6. Hamming I, Timens W, Bulthuis ML, Lely AT, Navis GJ, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol 2004;203(2):631-637 View Article
  7. Xu H, Zhong L, Deng J, Peng J, Dan H, Zeng X, et al. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int J Oral Sci 2020;12(1):8 View Article
  8. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020;395(10229):1054-1062 View Article
  9. Ran J, Song Y, Zhuang Z, Han L, Zhao S, Cao P, et al. Blood pressure control and adverse outcomes of COVID-19 infection in patients with concomitant hypertension in Wuhan, China. Hypertens Res 2020;43(11):1267-1276 View Article
  10. Özveri H, Eren MT, Kırışoğlu CE, Sarıgüzel N. Atypical presentation of SARS-CoV-2 infection in male genitalia. Urol Case Rep 2020;33:101349 View Article
  11. Abobaker A, Raba AA. Does COVID-19 affect male fertility?. World J Urol 2021;39(3):975-976 View Article
  12. Biswas S, Thakur V, Kaur P, Khan A, Kulshrestha S, Kumar P, et al. Blood clots in COVID-19 patients: Simplifying the curious mystery. Med Hypotheses 2021;146:110371 View Article
  13. Panigada M, Bottino N, Tagliabue P, Grasselli G, Novembrino C, Chantarangkul V, et al. Hypercoagulability of COVID-19 patients in intensive care unit. A report of thromboelastography findings and other parameters of hemostasis. J Thromb Haemost 2020;18(7):1738-1742 View Article
  14. Renzi S, Landoni G, Zangrillo A, Ciceri F. MicroCLOTS pathophysiology in COVID 19. Korean J Intern Med 2020 View Article
  15. Komiyama M, Hasegawa K. Anticoagulant therapy for patients with coronavirus disease 2019: Urgent need for enhanced awareness. Eur Cardiol 2020;15:e58 View Article
  16. Zhang Y, Zeng X, Jiao Y, Li Z, Liu Q, Ye J, et al. Mechanisms involved in the development of thrombocytopenia in patients with COVID-19. Thromb Res 2020;193:110-115 View Article
  17. Yang X, Yang Q, Wang Y, Wu Y, Xu J, Yu Y, et al. Thrombocytopenia and its association with mortality in patients with COVID-19. J Thromb Haemost 2020;18(6):1469-1472 View Article
  18. Coppée F, Lechien JR, Declèves AE, Tafforeau L, Saussez S. Severe acute respiratory syndrome coronavirus 2: virus mutations in specific European populations. New Microbe and New Infect 2020;36:100696 View Article
  19. Zhang C, Shi L, Wang FS. Liver injury in COVID-19: management and challenges. Lancet Gastroenterol Hepatol 2020;5(5):428-430 View Article
  20. Saini RK, Saini N, Ram S, Soni SL, Suri V, Malhotra P, et al. COVID-19 associated variations in liver function parameters: a retrospective study. Postgrad Med J 2020 View Article
  21. Yang H, Song Y, Liang YN, Li R. Quercetin treatment improves renal function and protects the kidney in a rat model of adenine-induced chronic kidney disease. Med Sci Monit 2018;24:4760-4766 View Article
  22. Liu X, Raghuvanshi R, Ceylan FD, Bolling BW. Quercetin and its metabolites inhibit recombinant human angiotensin-converting enzyme 2 (ACE2) activity. J Agric Food Chem 2020;68(47):13982-13989 View Article
  23. Zhou P, Liu Z, Chen Y, Xiao Y, Huang X, Fan XG. Bacterial and fungal infections in COVID-19 patients: A matter of concern. Infect Control Hosp Epidemiol 2020;41(9):1124-1125 View Article
  24. Li XC, Zhang J, Zhuo JL. The vasoprotective axes of the renin-angiotensin system: physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases. Pharmacol Res 2017;125(Pt A):21-38 View Article
  25. Ugwueze CV, Ezeokpo BC, Nnolim BI, Agim EA, Anikpo NC, Onyekachi KE. COVID-19 and Diabetes Mellitus: The Link and Clinical Implications. Dubai Diabetes Endocrinol J 2020;26(2):69-77 View Article
  26. Aziz M, Fatima R, Lee-Smith W, Assaly R. The association of low serum albumin level with severe COVID-19: a systematic review and meta-analysis. Crit Care 2020;24:255 View Article
  27. Huang J, Cheng A, Kumar R, Fang Y, Chen G, Zhu Y, et al. Hypoalbuminemia predicts the outcome of COVID-19 independent of age and co-morbidity. J Med Virol 2020;92(10):2152-2158 View Article
  28. Akaike T, Fujii S, Kato A, Miyamoto Y, Sawa T, Okamoto S, et al. Viral mutation accelerated by nitric oxide production during infection in vivo. FASEB J 2000;14(10):1447-1454 View Article
  29. Kwon HS, Oh SM, Kim JK. Glabridin, a functional compound of liquorice, attenuates colonic inflammation in mice with dextran sulphate sodium-induced colitis. Clin Exp Immunol 2008;151(1):165-173 View Article
  30. Sander WJ, O’Neill HG, Pohl CH. Prostaglandin E2 as a modulator of viral infections. Front Physiol 2017;8:89 View Article
  31. Silvagno F, Vernone A, Pescarmona GP. The role of glutathione in protecting against the severe inflammatory response triggered by COVID-19. Antioxidants (Basel) 2020;9(7):624 View Article
  32. Polonikov A. Endogenous deficiency of glutathione as the most likely cause of serious manifestations and death in COVID-19 patients. ACS Infect Dis 2020;6(7):1558-1562 View Article
  33. Han H, Ma Q, Li C, Liu R, Zhao L, Wang W, et al. Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors. Emerg Microbes Infect 2020;9(1):1123-1130 View Article
  34. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost 2020;18(5):1094-1099 View Article
  35. Qiu X, Kroeker A, He S, Kozak R, Audet J, Mbikay M, et al. Prophylactic efficacy of Quercetin 3-β-O-d-glucoside against ebola virus infection. Antimicrob Agents Chemother 2016;60(9):5182-5188 View Article
  36. Hlavinka E. Quercetin: New Hype for COVID-19?— Parallels drawn with early data on hydroxychloroquine. MedPage Today 2020. Available from: https://www.medpagetoday.com/infectiousdisease/covid19/87373. Accessed March 05, 2021
  37. Gu YY, Zhang M, Cen H, Wu YF, Lu Z, Lu F, et al. Quercetin as a potential treatment for COVID-19-induced acute kidney injury: Based on network pharmacology and molecular docking study. PLoS One 2021;16(1):e0245209 View Article
  38. Larson AJ, Symons JD, Jalili T. Therapeutic potential of quercetin to decrease blood pressures: review of efficacy and mechanisms. Adv Nutr 2012;3(1):39-46 View Article
  39. Edwards RL, Lyon T, Litwin SE, Rabovsky A, Symons JD, Jalili T. Quercetin reduces blood pressure in hypertensive subjects. J Nutr 2007;137(11):2405-2411 View Article
  40. Taepongsorat L, Tangpraprutgul P, Kitana N, Malaivijitnond S. Stimulating effects of quercetin on sperm quality and reproductive organs in adult male rats. Asian J Androl 2008;10(2):249-258 View Article
  41. Karabulut S, Korkmaz O, Altun CE, Zergeroğlu AD, Keskin I. Quercetin enhances human sperm motility in a dose and time dependent manner. Acta Pharmaceutica Sciencia 2020;58(2):170-178 View Article
  42. Diao R, Gan H, Tian F, Cai X, Zhen W, Song X, et al. In vitro antioxidation effect of Quercetin on sperm function from the infertile patients with leukocytospermia. Am J Reprod Immunol 2019;82(3):e13155 View Article
  43. Choi JH, Kim KJ, Kim S. Comparative effect of quercetin and quercetin-3-O-β-d-glucoside on fibrin polymers, blood clots, and in rodent models. J Biochem Mol Toxicol 2016;30(11):548-558 View Article
  44. Hubbard GP, Wolffram S, Lovegrove JA, Gibbins JM. Ingestion of quercetin inhibits platelet aggregation and essential components of the collagen-stimulated platelet activation pathway in humans. J Thromb Haemost 2004;2(12):2138-2145 View Article
  45. Mosawy S. Effect of the flavonol quercetin on human platelet function: A review. Food Public Health 2015;5(1):1-9
  46. Valente T, Hidalgo J, Bolea I, Ramirez B, Anglés N, Reguant J, et al. A diet enriched in polyphenols and polyunsaturated fatty acids, LMN diet, induces neurogenesis in the subventricular zone and hippocampus of adult mouse brain. J Alzheimers Dis 2009;18(4):849-865 View Article
  47. Li S, Tan HY, Wang N, Cheung F, Hong M, Feng Y. The potential and action mechanism of polyphenols in the treatment of liver diseases. Oxidative Med Cell Longev 2018;2018:8394818 View Article
  48. Häckl LPN, Cuttle G, Sanches SS, Lima-Lindman MT, Nicolau M. Inhibition of angiotesin-converting enzyme by quercetin alters the vascular response to brandykinin and angiotensin I. Pharmacology 2002;65(4):182-186 View Article
  49. Wang S, Yao J, Zhou B, Yang J, Chaudry MT, Wang M, et al. Bacteriostatic effect of Quercetin as an antibiotic alternative in vivo and its antibacterial mechanism in vitro. J Food Prot 2018;81(1):68-78 View Article
  50. Jeong SM, Kang MJ, Choi HN, Kim JH, Kim JI. Quercetin ameliorates hyperglycemia and dyslipidemia and improves antioxidant status in type 2 diabetic db/db mice. Nutr Res Pract 2012;6(3):201-207 View Article
  51. Vaneková Z, Hubčík L, Toca-Herrera JL, Furtműller PG, Mučaji P, Nagy M. Analysis of binding interactions of Ramipril and Quercetin on human serum albumin: A novel method in affinity evaluation. Molecules 2020;25(3):547 View Article
  52. Sengupta B, Sengupta PK. Binding of quercetin with human serum albumin: a critical spectroscopic study. Biopolymers 2003;72(6):427-434 View Article
  53. Hämäläinen M, Nieminen R, Asmawi MZ, Vuorela P, Vapaatalo H, Moilanen E. Effects of flavonoids on prostaglandin E2 production and on COX-2 and mPGES-1 expressions in activated macrophages. Planta Med 2011;77(13):1504-1511 View Article
  54. Ebihara N, Takahashi K, Takemura H, Akanuma Y, Asano K, Sunagawa M. Suppressive effect of Quercetin on nitric oxide production from nasal epithelial cells in vitro. Evid Based Complementary Altern Med 2018;2018:6097625 View Article
  55. Chen S, Jiang H, Wu X, Fang J. Therapeutic effects of Quercetin on inflammation, obesity, and type 2 diabetes. Mediators Inflamm 2016;2016:9340637 View Article
  56. Saeedi-Boroujeni A, Mahmoudian-Sani MR. Anti-inflammatory potential of quercetin in COVID-19 treatment. J Inflamm (Lond) 2021;18(1):3 View Article
  57. Nair MP, Mahajan S, Reynolds JL, Aalinkeel R, Nair H, Schwartz SA, et al. The flavonoid quercetin inhibits proinflammatory cytokine (tumor necrosis factor alpha) gene expression in normal peripheral blood mononuclear cells via modulation of the NF-κβ system. Clin Vaccine Immunol 2006;13(3):319-328 View Article
  58. Xiong G, Ji W, Wang F, Zhang F, Xue P, Cheng M, et al. Quercetin inhibits inflammatory response induced by LPS from Porphyromonas gingivalis in human gingival fibroblasts via suppressing NF-κB signaling pathway. BioMed Res Int 2019;2019:6282635 View Article
  59. David AVA, Arulmoli R, Parasuraman S. Overviews of biological importance of Quercetin: A bioactive flavonoid. Pharmacogn Rev 2016;10(20):84-89 View Article
  60. Nájera MO, Tinajero IS, Páez LIR, Toledo SEM, Sánchez JLM. Quercetin improves antioxidant response in diabetes through maintenance of reduced glutathione levels in blood. Afr J Pharm Pharmacol 2013;7(36):2531-2539 View Article
  61. Zwicker JI, Schlechter BL, Stopa JD, Liebman HA, Aggarwal A, Puligandla M, et al. Targeting protein disulfide isomerase with the flavonoid isoquercetin to improve hypercoagulability in advanced cancer. JCI Insight 2019;4(4):e125851 View Article
  62. Maxwell KR, Nieman DC, Henson DA, Williams A, McAnulty S, Jin F, et al. Influence of supplemental quercetin and epigallocatechin 3-gallate on immunity and inflammation. FASEB J 2009;23(S1):907.6 View Article
  63. Larhrib H, Zeng XM, Martin GP, Marriott C, Pritchard J. The use of different grades of lactose as a carrier for aerosolised salbutamol sulphate. Int J Pharm 1999;191(1):1-14 View Article
  64. Mlcek J, Jurikova T, Skrovankova S, Sochor J. Quercetin and its anti-allergic immune response. Molecules 2016;21(5):623 View Article
  65. Nishimuro H, Ohnishi H, Sato M, Ohnishi-Kameyama M, Matsunaga I, Naito S, et al. Estimated daily intake and seasonal food sources of quercetin in Japan. Nutrients 2015;7(4):2345-2358 View Article
  66. Beslic ZS, Todic SR, Tesevic VV, Jadranin MB, Novakovic MM, Tesic D. Pruning effect on content of quercetin and catechin in berry skins of cv. Blaufränkisch (Vitis vinifera L.). Turk J Agric Forestry 2010;34:461-466 View Article
  67. Yewale S, Farash Z, Kolhe S, Sakkan S, Bhope S, Ambekar P, et al. Benefits of Soleris® over the conventional method for enumeration of microbial load in Salacia herbal extract. Polish J Microbiol 2020;69(4):453-462 View Article
  68. European Pharmacopoeia 5. Preparations for inhalation: aerodynamic assessment of fine particles <2.9.18>. European Pharmacopoeia 2013; pp 244-253. Available from: http://library.njucm.edu.cn/yaodian/ep/EP5.0/02_methods_of_analysis/ 2.9.__pharmaceutical_technical_procedures/ 2.9.18.%20Preparations%20for%20inhalation%20%20aerodynamic%20assessment%20of%20fine%20particles.pdf. Accessed March 10, 2021
  69. United States Pharmacopoeia 39. Inhalation and nasal drug products: aerosols, sprays, and powders – performance quality tests <601>, USP38–NF33. United States Pharmacopoeia 2017. Available from: https://www.uspnf.com. Accessed March 10, 2021
  70. Heinz SA, Henson DA, Austin MD, Jin F, Nieman DC. Quercetin supplementation and upper respiratory tract infection: A randomized community clinical trial. Pharmacol Res 2010;62(3):237-242 View Article
  71. Luo E, Zhang D, Luo H, Liu B, Zhao K, Zhao Y, et al. Treatment efficacy analysis of traditional Chinese medicine for novel coronavirus pneumonia (COVID-19): An empirical study from Wuhan, Hubei Province, China. Chinese Med 2020;15:34 View Article
  72. Lin LT, Hsu WC, Lin CC. Antiviral natural products and herbal medicines. J Tradit Complement Med 2014;4(1):24-35 View Article
  73. Sohail MN, Rasul F, Karim A, Karim A, Kanwal U, Attitalla IH. Plant as a source of natural antiviral agents. Asian J Anim Vet Adv 2011;6(12):1125-1152 View Article
  74. Mousa HA. Prevention and treatment of influenza, influenza-like illness, and common cold by herbal, complementary, and natural therapies. J Evid Based Complementary Altern Med 2017;22(1):166-174 View Article
  75. Ogbole OO, Akinleye TE, Segun PA, Faleye TC, Adeniji AJ. In vitro antiviral activity of twenty-seven medicinal plant extracts from Southwest Nigeria against three serotypes of echoviruses. Virol J 2018;15(1):110 View Article
  76. Cinatl J, Morgenstern B, Bauer G, Chandra P, Rabenau H, Doerr HW. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet 2003;361(9374):2045-2046 View Article
  77. Li SY, Chen C, Zhang HQ, Guo H-Y, Wang H, Wang L, et al. Identification of natural compounds with antiviral activities against SARS-associated coronavirus. Antivir Res 2005;67(1):18-23 View Article
  78. Fiore C, Eisenhut M, Krausse R, Ragazzi E, Pellati D, Armanini D, et al. Antiviral effects of Glycyrrhiza species. Phytother Res 2008;22(2):141-148 View Article
  79. Manach C, Mazur A, Scalbert A. Polyphenols and prevention of cardiovascular diseases. Curr Opin Lipidol 2005;16(1):77-84 View Article
  80. Chirumbolo S. The role of quercetin, flavonols and flavones in modulating inflammatory cell function. Inflamm Allergy Drug Targets 2010;9(4):263-285 View Article
  81. Yi L, Li Z, Yuan K, Qu X, Chen J, Wang G, et al. Small molecules blocking the entry of severe acute respiratory syndrome coronavirus into host cells. J Virol 2004;78(20):11334-11339 View Article
  82. Knekt P, Kumpulainen J, Jarvinen R, Rissanen H, Heliövaara M, Reunanen A, et al. Flavonoid intake and risk of chronic diseases. Am J Clin Nutr 2002;76(3):560-568 View Article
  83. Fortunato LR, de Freitas Alves C, Teixeira MM, Rogerio AP. Quercetin: a flavonoid with the potential to treat asthma. Braz J Pharm Sci 2012;48(4):589-599 View Article
  84. Harwood M, Danielewska-Nikiel B, Borzelleca JF, Flamm GW, Williams GM, Lines TC. A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties. Food Chem Toxicol 2007;45(11):2179-2205 View Article
  85. Colunga Biancatelli RML, Berrill M, Catravas JD, Marik PE. Quercetin and Vitamin C: An experimental, synergistic therapy for the prevention and treatment of SARS-CoV-2 related disease (COVID-19). Front Immunol 2020;11:1451 View Article
  86. Kamel A, Abdelseed H, Albalawi Y, Aslsalameen E, Almutairi Y, Alkattan A. Evaluation of the effect of zinc, quercetin, bromelain and vitamin C on COVID-19 patients. MedRxiv ;2020:20245993 View Article
  87. Dabbagh-Bazarbachi H, Clergeaud G, Quesada IM, Ortiz M, O’Sullivan CK, Fernández-Larrea JB. Zinc ionophore activity of quercetin and epigallocatechin-gallate: from Hepa 1-6 cells to a liposome model. J Agric Food Chem 2014;62(32):8085-8093 View Article
  88. Aucoin M, Cooley K, Saunders PR, Cardozo V, Remy D, Cramer H, et al. The effect of quercetin on the prevention or treatment of COVID-19 and other respiratory tract infections in humans: A rapid review. Adv Integr Med 2020;7(4):247-251 View Article
  89. Derosa G, Maffioli P, D’Angelo A, Di Pierro F. A role for quercetin in coronavirus disease 2019 (COVID-19) Review. Phytother Res 2020;35(3):1230-1236 View Article
  90. Li XL, Zhou AG, Zhang L, Chen WJ. Antioxidant status and immune activity of Glycyrrhizin in allergic rhinitis mice. Int J Mol Sci 2011;12(2):905-916 View Article
  91. Aoki F, Nakagawa K, Kitano M, Ikematsu H, Nakamura K, Yokota S, et al. Clinical safety of licorice flavonoid oil (LFO) and pharmacokinetics of glabridin in healthy humans. J Am Coll Nutr 2007;26(3):209-218 View Article
  92. Park HK, Kim SJ, Kwon DY, Park JH, Kim YC. Protective effect of quercetin against paraquat-induced lung injury in rats. Life Sci 2010;87(5-6):181-186 View Article
  93. Omar HR, Komarova I, El-Ghonemi M, Fathy A, Rashad R, Abdelmalak HD, et al. Licorice abuse: time to send a warning message. Ther Adv Endocrinol Metab 2012;3(4):125-138 View Article
Copyright © 2021 Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 4.0 License (CC BY-NC 4.0), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
  • Exploratory Research and Hypothesis in Medicine
  • pISSN 2993-5113
  • eISSN 2472-0712

Article Options

Metrics

Cite this Article

  • © 2024 Xia & He Publishing Inc.
  • Total visits : 2761535
  • Visits today : 2851
Back to Top

Tackling Complications of Coronavirus Infection with Quercetin: Observations and Hypotheses

Shital Balasaheb Palghadmal, Prajakta Shriram Kulkarni, Vishal Makadia, Mahesh Jagannath Deshmukh, Priyanka Satish Gondhale, Sriram Padmanabhan
  • Reset Zoom
  • Download TIFF