Introduction

In late 2019, a cluster of viruses identified as the severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) surfaced in Wuhan, China, resulting in cases of pneumonia [1, 2]. SARS-CoV-2, a highly transmissible virus with an initially unknown identity, has sparked a global pandemic, affecting more than 500 million individuals and leading to the tragic loss of over 6 million lives by April 2022 [3]. Patients infected with COVID-19 exhibit a diverse array of non-specific symptoms, such as high body temperature, aching throat, queasiness, throwing up, muscle pain, and a feeling of lightheadedness [4]. While the majority of individuals typically recover from their illnesses within a short period, approximately five percent of patients may endure severe and life-threatening conditions, such as acute respiratory distress syndrome (ARDS) and multiple organ dysfunctions [5]. The elderly and individuals with chronic diseases are at a higher risk of severe COVID-19 [6]. Despite the development of vaccines for COVID-19, new viral variants, such as Delta, Lambda, and Omicron, continue to emerge [7]. The increased spread of COVID-19 is attributed to the rapid genetic recombination of the S protein in the receptor-binding domain (RBD) [8]. The virus manifests itself in different organs such as the brain, kidneys, lungs, and gastrointestinal tract, with angiotensin-converting enzyme-2 (ACE2) being a key player in the development of the disease [9,10,11].

COVID-19 follows three stages, including primary viral infection, the pulmonary stage, and the inflammatory stage [12, 13]. Cytokine storms of upregulated interleukins tumor necrosis factor and excessive coagulation contribute to further disease severity and mortality [14]. Critically ill COVID-19 patients show higher levels of neutrophils, proinflammatory cytokines, and reactive oxygen species (ROS) [15]. Endothelial cell dysfunction and platelet aggregation can also worsen the severity of COVID-19 [15]. Polyphenols, which are abundant antioxidants found in the diet, can have anti-inflammatory and antiviral effects [16]. Polyphenols have one or more phenolic rings containing hydroxyl groups and are classified into several active types, such as flavonoids, isoflavones, and phenols [17,18,19,20]. The immune system, inflammatory cytokine storm, and oxidative stress play significant roles in the pathogenesis of COVID-19 [21]. Therefore, therapeutic agents with anti-viral, anti-inflammatory, antioxidant, and immunomodulatory activities may be beneficial in preventing and treating COVID-19 [22]. This review article aims to discuss the potential beneficial effects of various polyphenols in treating COVID-19.

Methods

For this research, we conducted a thorough search across various online databases like Web of Science, MEDLINE (PubMed), Scopus, and Embase, utilizing specific keywords such as "Polyphenols," "viral diseases," "virus-related diseases," "COVID-19," "SARS-CoV-2," and "coronaviruses." Our focus was on selecting peer-reviewed studies written in English that were pertinent to our study. Any articles lacking sufficient data on polyphenols and COVID-19 were eliminated from consideration. The features of the studies that met our criteria are summarized in Table 1.

Table 1 Summary of studies on the effect of polyphenols on COVID-19 and related pathways
Full size table

Clinical manifestations of COVID-19

COVID-19 presents a range of symptoms in the general population. This infectious disease is primarily spread through air droplets, with pulmonary symptoms being the most common. Clinically, COVID-19 can appear as either a symptomless infection or a severe illness with complications such as severe pneumonia, acute respiratory distress syndrome, respiratory failure, or organ failure [39, 40]. The available data suggests that COVID-19 can impact organs beyond the lungs, including the neurological, olfactory, cardiovascular, digestive, liver, kidney, endocrine, and skin systems. A significant number of patients experience a range of neurological symptoms related to COVID-19. Gastrointestinal symptoms are often linked to a longer duration of illness. Liver function impairment is associated with the severity of the disease. Critically ill COVID-19 patients are more prone to experiencing acute kidney injury. Additionally, diabetes ketoacidosis and high blood sugar levels are among the endocrine issues observed in COVID-19 cases. The most common skin symptoms seen were skin bumps that looked like frostbite or cold sores, then red spots with bumps, blister-like sores, purple or dead skin patches, widespread rashes, and tiny bruises [41]. Additionally, a thorough examination revealed that six symptoms were prevalent in over 25% of cases, which included fever, cough, shortness of breath, fatigue, malaise, and sputum/secretions. Alongside these common symptoms were neurological manifestations, skin issues, loss of appetite, muscle pain, sneezing, sore throat, runny nose, goosebumps, headaches, chest discomfort, and diarrhea. Hemoptysis was the least commonly reported sign/symptom. In studies that involved over 100 patients, fevers, coughs, and shortness of breath were the most frequently encountered symptoms [42].

SARS-CoV-2 entry and reproduction

The infection process of SARS-CoV-2 involves several important steps for the spike protein to attach and penetrate the host cell. The spike protein interacts with ACE2 receptors on the cell surface, facilitating the entry of the virus [43, 44]. The spike protein is then split by the activation of the S1 subunit in its receptor-binding domain, which releases the S1 and enables the S2 to merge with the cell membrane [45, 46]. The spike protein needs cellular proteases like Transmembrane serine protease 2 (TMPRSS2) to prepare for fusion with the host cell. The S protein also triggers the entry of SARS-CoV into the cell by endocytosis, which can be dependent or independent of the virus [47, 48]. Endocytosis is the process of cells taking in substances from the outside. SARS-CoV can use different ways of endocytosis to get into cells, such as clathrin, caveolae, macropinocytosis, or other new methods that do not involve clathrin or caveolae. Endocytic pathways that rely on the virus are called SARS-CoV-dependent endocytosis, while those that do not are called SARS-CoV-independent endocytosis [49, 50].

The membranes of the virus and the host cell join together, forming a fusion pore that lets the viral genome enter the cell cytoplasm [51]. This is how the virus gets to the host cell’s DNA and makes copies of itself. The viral RNA genome that gets into the cytoplasm is replicated, and the new genome is turned into two structural proteins and polyproteins [52]. The enveloped glycoproteins then go to the Golgi or the endoplasmic reticulum [52]. The nucleocapsid, which is made of nucleocapsid proteins and genomic RNA, is also created [53]. The virus particles are then found in the endoplasmic reticulum-Golgi intermediate compartment (ERGIC), and the virus-filled vesicles fuse with the plasma membrane to let the virus out [53, 54].

The role of coronavirus infection in the presentation of antigens

When the virus infiltrates the host cells, its antigens are transferred to the antigen-presenting cells (APCs), which play a crucial role in the body's immune response against the virus [55]. The identification of antigenic peptides occurs through the interaction with the major histocompatibility complex (MHC) of the human leukocyte antigen (HLA), ultimately resulting in the activation of specific cytotoxic T lymphocytes (CTLs) targeting viral infections [55, 56]. By focusing on the STAT1-IRF1-NLRC5 axis, SARS-CoV-2 has been able to lower the levels of MHC-I expression by hindering the activation of the MHC class I pathway responsible for introducing antigens to T cells. This decrease in MHC-I activation is a result of the virus's spike glycoprotein interfering with peptide binding to MHC molecules [57, 58]. Furthermore, variations in the mannose-binding lectin (MBL) gene, which influences antigen presentation, have been correlated with susceptibility to SARS-CoV infection [59].

Humoral and cellular immunity

The humoral and cellular immune antigen response is induced by both B and T cells [60]. As with other acute viral infections, IgM and IgG antibody profiles are produced against the SARS-CoV virus [60, 61]. IgM antibodies are significantly reduced by the end of week 12, while IgG antibodies can persist for a long time, suggesting that IgG antibodies may primarily play a protective role [62, 63]. Patients with SARS-CoV-2 have been observed to have significantly fewer CD8+ and CD4+ T cells in their peripheral blood, although they are still active [64].

Immune response

COVID-19 pneumonia is characterized by hypoxemia, which can progress to acute respiratory distress syndrome and alveolar edema in severe cases [65]. The over-expression of inflammatory cytokines is a hallmark of critical COVID-19, which can be detected in both the bloodstream and the lungs [65, 66]. Various immune system responses, such as from neutrophils and macrophages, sense damaged structures and pathogens and trigger inflammatory reactions, which are supported by endothelial and epithelial cells that are susceptible to infection and inflammation-induced cell death [67, 68].

Cytokines are induced downstream of pattern recognition receptors (PRRs) that sense danger-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs) related to the disorder of homeostasis or viral molecules, respectively [69, 70]. This leads to the production of specific cytokines and increases the likelihood of developing "viral sepsis" [61]. SARS-CoV-2-induced viral sepsis is characterized by high levels of pro-inflammatory cytokines, including TNFα, IL-8, IL-6, interferon-γ (IFNγ), and IL-17, which are closely associated with disease severity [62, 71]. In contrast, the essential antiviral response, dominated by type III IFN (IFNγ) and type I IFN (IFNα/β) responses, is delayed and reduced in COVID-19 patients [71, 72].

Coronavirus immune evasion

There have been sophisticated mechanisms developed by SARS-CoV-2 to evade the host immune response [73, 74]. Antagonizing dsRNA sensors [75], inhibiting IFN synthesis, and targeting viral sensing processes [76] are some strategies for evasion. Furthermore, the virus utilizes several evasion mechanisms, including spike protein camouflage, MHC-I inhibition, and interferon inhibition [77]. There are several ways in which the spike protein of SARS-CoV-2 contributes to immune evasion, including mutations that alter neutralizing antibodies and immunity to antibody-mediated immunity [78]. RBMs of RBDs are primary targets for neutralizing antibodies, and most vaccine developments for COVID-19 target the spike protein [79]. Antiviral responses are slowed by viral proteins that act on viral sensing processes so that the virus can block the immune response [76]. Additionally, SARS-CoV can create double-membrane vesicles that lack PRRs, allowing the virus to replicate within them undetected by the host cells [74, 80].

Food sources, bioavailability, and pharmacological characteristics of polyphenols

Several molecules with polyphenol structures (many hydroxyl groups on aromatic rings) have been recognized in plants and fungi [81]. These compounds are classified into diverse groups based on the structural elements that connect the rings or the number of phenolic rings they have in their structure. The flavonoids have two aromatic rings in their structure, which are connected by 3 carbon atoms, forming an oxygen heterocycle (ring C) that includes anthocyanidin flavones, flavonols, flavanones, and isoflavones [82]. Polyphenols can also be associated with various organic acids and carbohydrates, as well as with each other. Drinks and fruits such as red wine and tea are essential sources of polyphenols. Some polyphenols, such as quercetin, are found in the vast majority of plant products (cereals, vegetables, fruits, juices, legumes, tea, wine, etc.), while others are found in certain foods (isoflavones in soy, flavonoids in citrus, fluoride in apple) [83, 84].

Although polyphenols are prevalent in human food, they may not initially be effective in the body because they may be poorly absorbed in the intestine, metabolized or substrates for transporters, and are often rapidly eliminated [84]. Many polyphenols are metabolized similarly with the aglycone (without sugar) form absorbed from the small intestine [85]. The vast majority of polyphenols exist in food in the form of polymers, esters, or glycosides that cannot be readily absorbed in their native form [85]. The small intestine and the liver are the two main sites where polyphenols are conjugated during the absorption process [86]. This proceeding phase-II metabolism chiefly involves glucuronidation, methylation, and sulfation. In this process, many xenobiotics undergo metabolic detoxification that serves to limit any potential toxic effects and enhances their hydrophilicity, thus enabling the polar metabolites to be effectively eliminated through bile and urine [86].

The conjugation mechanisms are very efficient, so aglycones are commonly present in low concentrations in blood after the use of nutritional doses. Circulating polyphenols are extensively bound to albumin. Lactase-phlorizin hydrolase (LPH), which is particularly abundant in small intestinal epithelial cells, is substrate-specific for flavonoid-O-beta glycosides, and the released aglycone may enter epithelial cells as a result of inactive release [87]. On the other hand, there is also another digestive enzyme called cytosolic beta-glucosidase (CBG) in epithelial cells, which intermittently hydrolyzes many phenolic glycosides after transfer through the epithelium [88]. For CBG glycosylation to occur, (polar) glycosides must first be transferred to epithelial cells [87, 89].

Numerous polyphenols, such as luteolin, curcumin, quercetin, and resveratrol, play an important role in various physiological conditions of the body, such as regulating the body's metabolism, including pain, digestion, depression, and detoxification [90,91,92,93,94,95]. Polyphenols are also effective in biochemical pathways such as inhibiting NF-κB, TLR-4, and MAPK pathways, reducing the expression of lipid peroxidation, increasing the expression of Nrf-2, and modulating the activity of the immune system [96]. Furthermore, polyphenols have been shown to play a significant role in the prevention and management of various diseases, including cancer, infectious diseases, cardiometabolic disorders, and weight loss [84, 97,98,99,100,101,102,103,104,105,106,107,108,109], though controversial reports also exist [110,111,112,113]. Ongoing research is focused on determining the exact mechanisms by which these compounds exert their effects on disease processes. As such, incorporating polyphenol-rich foods into our diets may have potential therapeutic benefits in the prevention and treatment of various diseases. Figure 1 shows the structure of some selected flavonoids.

Fig. 1
figure 1

Chemical structure of selected flavonoids

Full size image

Anti-inflammatory and antioxidant effects of polyphenols

Polyphenols have been shown to possess anti-inflammatory properties by inhibiting the production of pro-inflammatory cytokines and enzymes [114]. These substances can disrupt the communication pathways associated with inflammation, ultimately decreasing the release of substances that cause inflammation. By inhibiting the creation of signaling molecules like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), polyphenols have the potential to alleviate the extreme inflammatory reaction observed in severe cases of COVID-19 [115]. Curcumin and resveratrol exert antioxidant effects by activating Nrf2 and inhibiting the NFκB pathway [93, 94, 116,117,118]. The synergistic blend of curcumin, vitamin C, and glycyrrhizinic acid enhances interferon production and modulates the inflammatory response, thereby bolstering the immune defense against SARS-CoV-2 infection. Additionally, curcumin and quercetin are pivotal in regulating iron levels through their iron-chelating properties. Essentially, they function as iron chelators, resulting in hepatocyte degradation, a reduction in the iron storage protein ferritin, an elevation in TfR1, and stimulation of iron regulatory proteins [119, 120]. Research has shown that hydroxytyrosol possesses strong antioxidant and anti-inflammatory properties, making it a potential treatment for pulmonary fibrosis in rats. Additionally, it has been found to reduce oxidative stress caused by respiratory neutrophil bursts. Another polyphenol, Epigallocatechin gallate (EGCG), commonly found in teas, has been proven to inhibit pro-inflammatory agents including TNF, IL-1, COX-2, iNOS, IL-1β, and IL-6 signaling pathways [121] and suppress the gene or protein expression of inflammatory cytokines and inflammation-related enzymes in green tea [28]. EGCG can also play a role in suppressing inflammation by reducing the expression of nuclear factor-kB and other inflammatory factors such as MAPKs and AKT/PI3K/mTOR [29, 121]. Kaempferol has been recognized as a promising candidate for treating both COVID-19 and pulmonary fibrosis (PF) conditions. It works by targeting key proteins such as epidermal growth factor receptor (EGFR), proto-oncogene tyrosine-protein kinase SRC (SRC), mitogen-activated protein kinase 3 (MAPK3), MAPK1, MAPK8, RAC-alpha serine/threonine-protein kinase (AKT1), transcription factor p65 (RELA), and phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA) [122]. Furthermore, studies have revealed that EGFR, interleukin 17 (IL-17), tumor necrosis factor (TNF), hypoxia-inducible factor 1 (HIF-1), phosphoinositide 3-kinase/AKT serine/threonine kinase (PI3K/AKT), and Toll-like receptor signaling pathways play a critical role in combatting the co-occurrence of COVID-19 and pulmonary fibrosis [122]. In a study conducted by Tang et al. [123], it was found that administering quercetin to rats with sepsis led to a notable decrease in the expression of TNF-α and HMGB 1, while also resulting in an increase in AMPK expression. Additionally, quercetin was observed to hinder the production of inflammatory mediators like leukotrienes and prostaglandins in septic mice by suppressing inflammatory enzymes such as COX-2.

Moreover, quercetin was found to be effective in promoting the M2 polarization of macrophages through the activation of AMPK-activating transcription factor 3 (ATF3) pathways, which are calcium-dependent. This natural compound also prevents the excessive production of inflammatory factors [124]. Not only do polyphenols in green tea possess antioxidant qualities, but they have also been found to exhibit pro-oxidant properties, though this impact is not necessarily detrimental. Research has indicated that the consumption of green tea can help lower oxidative stress and protect cells from damage. In certain illnesses, the polyphenols found in green tea may contribute to maintaining redox balance [125]. Due to their properties, polyphenols have been discovered to have anti-inflammatory and health-promoting effects that play a key role in preventing disease. Moreover, polyphenols help in reducing the production of inflammatory cytokines and genes related to inflammation by modulating the immune system and employing anti-inflammatory mechanisms [126]. Studies have indicated that Resveratrol can offset the negative impacts of the angiotensin II (Ang II)/angiotensin II type 1 receptor (AT1R) pathway, as well as boost the AT2R/Angiotensin 1–7 (Ang 1–7)/Mas receptor pathway. This helps protect the aging kidney from damage [127]. This particular impact of resveratrol on the two opposing pathways within the renin-angiotensin system (RAS) may also prove advantageous for individuals with SARS-CoV-2 infection [128]. Angiotensin-converting enzyme 2 (ACE-2) governs the classical RAS, which regulates blood pressure and fluid balance, but unfortunately, this enzyme is exploited by SARS-CoV-2 to infiltrate cells [129]. Resveratrol has a significant impact on the essential pathways related to the development of SARS-CoV-2. These pathways include the regulation of the RAS system, the expression of ACE-2 receptors, the activation of the immune system, and the inhibition of the release of inflammatory cytokines [130]. Significantly, resveratrol supplementation has been observed to decrease ACE-2 levels along with leptin, a pro-inflammatory adipokine, in adipose tissue where ACE-2 is abundantly present. This positive impact could potentially influence the course of COVID-19 [131]. More research is needed to fully grasp and explain the exact process by which resveratrol hinders the entry of the SARS-CoV-2 virus or reduces the severity of COVID-19. Current studies are looking into different combinations and preparations containing resveratrol. It has been observed that resveratrol effectively inhibits the replication of the SARS-CoV-2 virus without causing significant damage to cells [132, 133]. Another study conducted on human primary bronchial epithelial cell cultures infected with SARS-CoV-2 yielded similar results [134]. Xu, Li [135] showed in a study that resveratrol and polydatin, compounds extracted from the Chinese herb Polygonum cuspidatum, have a targeted inhibition on certain proteases of SARS-CoV-2 when tested in a lab setting. Furthermore, Marinella proposed that resveratrol (combined with indomethacin) may serve as a potential supplements in managing or preventing SARS-CoV-2 infection, as evidenced by promising results in a canine coronavirus model [136]. In a recent study that was randomized, double-blind, and placebo-controlled, it was demonstrated that resveratrol had a significant impact on reducing the number of hospitalizations, emergency room visits related to COVID, and cases of pneumonia in outpatients with mild COVID-19 when compared to those in the placebo group [137]. The research emphasizes the potential healing benefits of resveratrol and its ability to combat respiratory tract infections. This was explored in a review article by Filardo and colleagues in a review article [138]. Resveratrol's potential to suppress hypoxia-inducible factors indicates promise in mitigating severe symptoms of COVID-19, especially in individuals who are obese [139, 140]. In addition, resveratrol has been shown to have anti-thrombotic and anti-inflammatory effects that may help lessen the severity and mortality of COVID-19. There is potential for further research to investigate its ability to alleviate blood clotting complications linked to DNA Adenovirus vector vaccines [141]. Additional research is needed to investigate the role of resveratrol specifically in pediatric patients and elderly COVID-19 patients experiencing excessive oxidative stress [141]. To evaluate the positive impact of curcumin on patients with COVID-19, Hassaniazad et al. [142] conducted a randomized, triple-blind clinical trial. Their study focused on examining the effects of nano micelles containing curcumin on various types of immune responses at a cellular level and the overall clinical outcomes. The researchers found that curcumin was able to significantly reduce the activity of the T-Box Transcription Factor (TBX1) gene, which is associated with Th1 responses. At the same time, curcumin was shown to increase the expression of the forkhead box P3 (FOXP3) gene, which is linked to the regulatory T-cell population in COVID-19 patients. Th1 responses are known to promote inflammatory reactions by activating CD8 T lymphocytes and macrophages through the release of cytokines such as IFN-γ and IL-12 [143]. In individuals infected with COVID-19, the heightened cellular immune reactions targeting virus-infected lung cells frequently result in a cytokine storm, which plays a role in the damage to lung tissue [144]. One way to potentially reduce the impact of COVID-19 is by adjusting how the body's immune system responds. Curcumin has been shown to effectively adjust the body's immune response by decreasing the activity of the TBX1 gene, which is linked to a type of immune response known as Th1. Furthermore, curcumin also affects the activity of the RORC gene associated with Th17 responses and the GATA3 gene related to Th2 response. This suggests that curcumin not only helps regulate inflammatory immune responses through Th1 and regulatory T cells but also through Th17 and Th2 responses [145]. Curcumin has shown promise in regulating T cell-mediated immune responses in individuals with COVID-19. Research indicates that curcumin can reduce the expression of the RORC gene, which is linked to the Th17 response seen in COVID-19 patients. This suggests that curcumin may have an immunomodulatory effect on inflammatory responses driven by neutrophils, as well as the inflammation that occurs following Th17-related responses [145]. Multiple proposed mechanisms of how polyphenols can act on COVID-19 are illustrated in Fig. 2.

Fig. 2
figure 2

Proposed multiple mechanisms of action of polyphenols on COVID-19. AMPK, AMP-activated protein kinase; ERK, extracellular signal-regulated kinase; IKKα, inhibitory κB kinase α; IL-1β, interleukin-1β; iNOS, inducible nitric oxide synthase; IκBα, an inhibitor of κBα; JNK/SAPK, c-jun N-terminal or stress-activated protein kinases; LPSs, lipopolysaccharides; NF-κB, nuclear factor kappa B; NO, nitric oxide; NK, natural killer; Nrf-2, nuclear factor erythroid 2-related factor 2; p-IκBα, phosphorylated-IκBα; RNS, reactive nitrogen species; ROS, reactive oxygen species; TNF-α, tumor necrosis factor-α

Full size image

Immunomodulatory effects of polyphenols

Effects of polyphenols on polymorphonuclear macrophages and monocytes

Monocytes, myeloid cells, and macrophages are crucial players in the progression of severe COVID-19. This includes various types such as monocytes, monocyte-derived macrophages (MDMs), resident alveolar macrophages (AMs), and transmissible MDMs. Their significant role cannot be understated in the severity of critical COVID-19 outcomes [146]. Research indicates that in cases of severe disease, Anti-inflammatory Macrophages (AMs) are depleted from bronchoalveolar lavage (BAL) fluids, whereas proinflammatory Monocyte-Derived Macrophages (MDMs) are plentiful in the BAL fluids of critically ill COVID-19 patients. This imbalance leads to an overproduction of inflammatory cytokines by macrophages in critically ill patients, exacerbating the severity of COVID-19 [147, 148]. Medical treatments that influence the body's immune system can be key in managing diseases. These treatments include non-steroidal anti-inflammatory drugs (NSAIDs) and small non-peptide molecules like polyphenols. Research on animals with conditions like sepsis, SARS-COVID, dynamic simulation, and molecular docking has shown that polyphenols found in plants, such as resveratrol, quercetin, epigallocatechin gallate, and curcumin, may have the ability to inhibit the impact of SARS-CoV-2 infection by regulating the immune response [149,150,151,152,153].

Research conducted on animals and in controlled laboratory environments has shown that quercetin can enhance the immune system by promoting various immune functions. These include increasing the movement of neutrophils toward infection sites, enhancing the ability of macrophages to engulf pathogens, boosting the cytotoxic activity of natural killer cells, and stimulating the proliferation of lymphocytes when exposed to certain compounds. Furthermore, data is suggesting that quercetin plays a role in regulating specific genes involved in the production of cytokines [154]. Moreover, studies have shown that curcumin can boost the differentiation of T-reg cells and promote the polarization of M2 macrophages in laboratory settings. This increase in M2 macrophages and T-reg cells could potentially aid in the reduction of pulmonary inflammation and facilitate tissue repair following curcumin administration [149, 155]. Patients suffering from COVID-19 may experience myelosuppression, a condition marked by a reduction in the amount of neutrophils and monocytes, thereby heightening their susceptibility to secondary infections. Studies in mice have shown that curcumin enhances myelopoiesis, although the exact mechanisms behind this effect remain unknown [149]. Curcumin, quercetin, and epigallocatechin gallate can influence the function of cells in bronchoalveolar lavage (BAL) fluid, which consists of five distinct subpopulations of monocytes/macrophages in the lungs. These cells play a crucial role in producing cytokines like TNF-α, IL-8, IL-6, IL-1β, and C-X-C motif chemokine 10 (CXCL10) [149,150,151,152, 156, 157]. These compounds can control a specific group of macrophages known as Macro C2-CCL3L1 and monocytes known as Mono C1-CD14-CCL3. These cells are known to produce inflammatory molecules like CCL8, CXCL10/11, CCL20, CX3CL2, CX3, and IL-6 [158,159,160]. Furthermore, substances like curcumin and quercetin have been found to suppress the generation of IL-8, a type of inflammatory protein produced by macrophages. Additionally, these compounds can decrease the production of IL-12, MIP-1α (MCP-1), by interfering with the activation of the NF-κB signaling pathway in monocytes and macrophages. Research trials have indicated that curcumin and quercetin have the potential to elevate IL-12 levels in the nearby lymph nodes by enhancing the population of antigen-presenting cells (APC) [161,162,163]. IL-12 plays a crucial role in enhancing the activity of T cells, particularly T helper 1 (Th1) cells, by boosting the production of IFN-γ. Various research studies have suggested that polyphenols such as quercetin and curcumin can inhibit the secretion of MIP-1α, IL-1β, MCP-1, IL-8, and TNF-α by alveolar macrophages and monocytes that have been stimulated by LPS [161, 164, 165]. Resveratrol has been identified as a safe immunomodulatory substance in SARS-CoV-2 viral infection. Previous research has shown that it can block various mediators, leading to the irreversible inhibition of IFNγ and IL-2 production in splenic lymphocytes. In addition, it can also suppress the release of GM-CSF and CXCL8 chemokines, decrease IL-6 and TNFα secretion, and downregulate NF-κB in lung inflammatory cells. Furthermore, resveratrol has been found to reduce the levels of cytokines such as IL-1β, IL-8, and IL-12. In summary, resveratrol has a calming effect on the cytokine storm and helps alleviate hyper-inflammatory responses in the body [166]. Moreover, Chen et al. [167] conducted a study to examine the impact of resveratrol at a concentration of 100 mg/mL on stimulating macrophages during cases of acute kidney injury. Their findings indicated that resveratrol reduced the negative impacts of LPS on macrophages by significantly inhibiting the release of cytokines and preventing TLR-4 activation. Furthermore, Lovelace et al. [168] noted a significant reduction in pro-inflammatory cytokines and immune response in HIV patients due to the inhibitory effects of silymarin, a polyphenol, on T-cell stimulation.

Effect of polyphenols on polymorphonuclear neutrophil cells

In the human body, polymorphonuclear neutrophils (PMNs) are the most abundant type of white blood cells found in circulation. These cells play a crucial role in the body's natural immune defenses [169]. Chemokines released from virus-infected lungs attract neutrophils, causing them to infiltrate the lungs and release inflammatory cytokines like IL-8 [170]. Curcumin, luteolin, resveratrol, and quercetin have been found to diminish the migration of neutrophils into inflamed tissues by interacting with receptors on the neutrophils. These polyphenols also hinder the movement of neutrophils by suppressing the production of superoxide, AKT phosphorylation, PI3K activity, and IL-8, which acts as a mediator for neutrophil movement. Moreover, quercetin, luteolin, and curcumin influence the chemotactic behavior of neutrophils to decrease the formation of neutrophil extracellular traps (NETs), a major complication in viral sepsis that can lead to organ failure [161].

Kaneider et al. [171] demonstrated that resveratrol and quercetin interfere with the proinflammatory signaling of thrombin, leading to the prevention of decreased neutrophil function and adenosine nucleotide discharge from activated platelets. In another study, Tsai and Chen [172] indicated that resveratrol reduces integrin expression, degranulation, respiratory burst, and cell adhesion in activated neutrophils in a dose-dependent manner. Furthermore, Kaneider et al. [173] indicated that EGCG blocked neutrophil infiltration via direct action on neutrophils.

Immunomodulatory effect of polyphenols on polymorphonuclear adaptive and innate lymphocytes

Extensive research has been conducted regarding the involvement of both adaptive and innate lymphocytes in the progression of COVID-19. Specifically, Natural killer (NK) cells play a crucial role in combating the SARS-CoV-2 virus through their antiviral activity [173]. In individuals suffering from COVID-19, there is a heightened activity of blood NK cells, leading to the increased presence of CD56 bright cells. These CD56 bright cells are characterized by the expression of the cytotoxic molecules granzyme B and perforin [174]. Polyphenolic plant compounds like quercetin, curcumin, and resveratrol can decrease the release of inflammatory substances such as IL-15 and IFN/α&β by regulating the function of natural killer (NK) cells [175,176,177]. The decrease in the production of inflammatory substances leads to a decrease in the production of antigens and IFN/gamma by NK cells, ultimately decreasing the Th1 activity [177, 178].

Meroni et al. [179] investigated how different amounts of silybin (0.5, 10, and 25 mg/mL) affected the activation of human T lymphocytes. They found that silybin had a significant dose-dependent effect on decreasing the proliferation response to the monoclonal anti-CD3 antibody. Additionally, they noted that silybin led to an increase in the proliferation of alloantigen or mitogen-stimulated lymphocytes in a dose-dependent manner, as well as an enhancement in the secretion of IL-4, IFN-γ, and IL-10 [179, 180]. The immune system of COVID-19 patients responds by activating more lymphocytes, which are white blood cells that include CD8+ and CD4+ T cells. These T cells also multiply and diversify their receptors to fight the virus. CD4+ Th lymphocytes are divided into several subunits, including T regulatory cells, Th17, Th1, and Th2 [181, 182].

Multiple research studies have demonstrated that certain polyphenols like luteolin, resveratrol, quercetin, green tea, and curcumin can hinder the growth and specialization of Th17 cells. This is achieved by inhibiting the production of related orphan receptor gamma t (RORγt) IL‐17, IL‐21, and IL‐6, as well as the phosphorylation of signal transducers and activators of signal transducer and activator of transcription 3 (STAT3) [183,184,185]. Polyphenols such as curcumin, resveratrol, quercetin, and luteolin also help reduce the expression of CD8+ T cells by reducing macrophage-derived inflammatory factors such as IL-1β, CXCL10, and IL-6 [124, 186,187,188]. Furthermore, research has demonstrated that EGCG is capable of hindering the replication of HIV-1 at multiple points in the process. Specifically, the compound found in tea disrupts the interaction between gp120 and CD4 by interfering with the activity of reverse transcriptase [189]. A study suggested that EGCG prevents the expression of p24 antigen on macrophages, isolated CD4+ T cells, and CD4 receptor cells, relative to its dose [190].

Innate and adaptive immunity responses can be regulated by CD4+ CD25+ Tregs. Tregs produce cytokines such as IL-4 and IL-10, which can significantly impact the immune response to COVID-19 [191]. The activity and development of CD25+ CD4+ Tregs are dependent on FOXP3, a transcription factor protein expressed mostly by these cells. Studies have shown that resveratrol and curcumin can increase the expression of CD25+ CD4+ Foxp3+ Tregs, leading to upregulation of IL‐10 and TGF‐β production, which can reduce the proliferation activity of CD25− CD4+ T cells in the spleen of septic mice [192,193,194].

DCs play a crucial role in initiating both adaptive and innate immune responses and are part of the proprietary antigenic prescribing cells [195]. Curcumin has been found to prevent the maturation of DCs and block the up-regulation of CD 80, MHC II, CD86, and CD40 on the surfaces of DCs, while also inhibiting LPS-induced TNF-α, IL-1β, IL-12, and IL-6 production, as well as MAPK phosphorylation and NF-κB nuclear translocation [195]. Additionally, treatment with quercetin has been shown to reduce IL-12 production and increase the expression of ILT4, ILT5, immunoglobulin-like transcript (ILT)-3, CD39, and CD73 in septic rats [194].

Effects of polyphenols on reduced mucin hypersecretion

Early symptoms of COVID-19 mediated by SARS-CoV-2-induced cytokine storm include excessive mucin secretion, which activates various inflammatory pathways and contributes to the pathogenesis of the disease [196]. Mucins play a crucial role in defending the respiratory tract's front line against invading microbes and viruses in response to physiological stimuli [197, 198]. A high viral load can cause overproduction of mucins, leading to obstruction of the respiratory tract lumen and limited airflow [197]. Additionally, hypersecretion of mucins leads to ciliary dysfunction, which further exacerbates COVID-19 symptoms by compromising respiratory clearance [198]. The initial signs are connected to the excessive production of mucins caused by SARS-CoV-2, leading to an inflammatory storm that has the potential to trigger various inflammatory pathways [197, 199].

Several studies have shown that natural compounds can alleviate COVID-19 symptoms related to excessive mucin production. Liang et al. [200] demonstrated that epigallocatechin-3-gallate (50 mg/kg) reduced inflammation, neutrophils, airway mucus production, and collagen deposition in rats. In other studies, Li et al. showed that quercetin can prevent the induction of MUC5AC by human neutrophil elastase in a dose-dependent manner, by utilizing the PKC/MAPK/EGFR/ERK1/2 signal transduction pathways [201]. Additionally, a further study demonstrated that curcumin at a dose of 10 mg in NCI-H292 cells inhibits LPS-induced inflammation and airway mucus hypersecretion via the upregulation of Nrf2 gene expression [202]. Curcumin also attenuated mucus hypersecretion and inflammation in mice, blocked IL-4-induced expression of MCP-1 and MUC5AC both in vivo and in vitro through a peroxisome proliferator-activated receptor gamma (PPARγ) dependent NF-κB signaling pathway [203].

Polyphenols preventing SARS-CoV-2 entry/fusion

Polyphenols attaching to S protein

Protein S is one of the major membrane glycoproteins, which is part of the class I viral fusion glycoproteins [204]. The circumferential amino subunit (S1) attaches independently to cellular receptors, while the carboxy terminus (S2) is located in the viral coat and is critical to aid in the integration of cell membranes and viruses [38, 205, 206]. Coronaviruses are only capable of entering cells via their S protein [206]. Luteolin, quercetin, emodin, and curcumin in different doses prevented SARS-CoV infection by hindering the virus from entering Vero-E6 cells [207, 208]. Luteolin's strong affinity for the SARS-CoV S protein suggests a potent antiviral mechanism that disrupts the protein's function [207, 209]. In addition, one study discovered that emodin, an anthraquinone polyphenol found in rhubarb roots (Rheum officinale), interfered with the S-ACE2 protein [210]. Research using computer simulation techniques has revealed that fifteen specific plant compounds found in A. paniculata can bind and engage with the S-protein, as well as the C-terminal and N-terminal cleavage sites on the viral polyprotein of SARS-CoV-2 [211]. According to dynamic simulation and molecular docking analyses, it is predicted that various plant polyphenols like neohesperidin, apigenin 6,8-diC-glucoside, hesperidin from C. medical, curcumin, and citrus can interact with the protein S RBD. As a result, these polyphenols can potentially inhibit the effects of SARS-CoV-2 [212,213,214]. Hesperidin is believed to interact with the binding site between ACE2 and the S protein by binding to the central shallow pit on the surface of the S protein RBD [215]. A temporary treatment for COVID-19 approved by the FDA involves naringenin, a polyphenol present in various fruits and herbs such as grapefruit. This compound has shown strong binding energy with the spike glycoprotein associated with the virus [215, 216]. Epigallocatechin gallate, a compound plentiful in tea and Rhodiola spp. (Golden Root), has been shown to interact with the S RBD protein [217].

Polyphenols that target ACE2

ACE2 is a metalloproteinase enzyme found on the cell membrane in various tissues including the kidneys, heart, lungs, epithelial cells, blood vessels, and liver [218]. ACE2 plays a crucial role as an enzyme within the physiological renin-angiotensin system. It has been hypothesized that ACE2 could serve as a key gateway for SARS-CoV-2 to infect host cells, making it a potential target for therapeutic interventions against foreign substances [219, 220]. Research suggests that eriodictyol, a compound present in Yerba santa (Eriodictyon californicum), shows a strong attraction towards human ACE2 receptors. Through a molecular analysis utilizing a computational model of the SARS-CoV-2 protein binding to the human ACE2 receptor, it was established that eriodictyol exhibits the greatest affinity for this receptor [37, 219]. Several other research studies have shown that compounds like catechin and curcumin, which are flavonoids, may have the ability to interact with ACE2 through the formation of hydrogen bonds, carbon-hydrogen bonds, and π-σ interactions [221]. It is becoming increasingly clear that regulatory ACE2 expression may contribute to modulating COVID-19 symptoms. SARS-CoV infection decreased ACE2 receptor expression, which may exacerbate the severity of the disease [36, 222]. New research indicates that polyphenols like curcumin and resveratrol, which are present in red wine grapes, have the potential to influence the impact of SARS-CoV-2 by controlling the function and expression of ACE2 [222, 223]. Therefore, polyphenols have the potential to reduce SARS-CoV-2 viral infection by attaching to the ACE2 receptor, preventing the virus from entering cells, and regulating the severity of lung damage associated with COVID-19 by altering ACE2 expression [223, 224].

Relationship between polyphenols and SARS-CoV-2 proliferation

Polyphenols preventing SARS-CoV-2 viral proteases

Coronaviruses rely on replicase polyproteins that undergo processing by viral proteases [225, 226]. Out of all the proteases identified, 3CLpro stands out for its crucial function in facilitating the replication and transcription processes of SARS-CoV-2, establishing it as a primary target for drug development against coronavirus infections [226,227,228]. Natural compounds that have been found to inhibit SARS-CoV proteases include terpenoids [229, 230], flavonoids [231,232,233], cinnamic amides [234], diarylheptanoids [235, 236], and coumarins [237]. In vitro, inhibition of 3CLpro has been demonstrated with gallocatechin gallate, epigallocatechin gallate, isoquercetin, and quercetin [233, 238, 239]. Flavonoids lacking the OH group at the 5'B-ring position have been shown to reduce the hindering activity of 3CLpro [233]. Flavonoids such as isoliquiritigenin, kaempferol, naringenin, margarine, and curcumin have been found to interfere severely with the SARS-CoV-2 3CLpro and PLpro substrate binding domains [232, 236]. Quercetin not only inhibits the H+-ATPase of lysosomal membranes and prevents virus coat removal [240], but also inhibits the ATPase of proteins related to drug resistance, which increases the bioavailability of some antiviral drugs [34, 241]. Hence, quercetin shows great potential as a candidate for antiviral treatments [32, 242].

The role of polyphenols in inhibiting SARS-CoV-2 RdRp

Focusing on inhibiting the SARS-CoV-2 RdRp enzyme has emerged as a key approach in developing treatments for COVID-19 [243]. Resveratrol has been found to notably inhibit MERS-CoV proliferation in vitro by preventing nucleocapsid protein and RNA expression [243]. Other studies have reported that myricetin, epigallocatechin gallate, baicalin from Scutellaria baicalensis, (2S)-eriodictyol 7-O-(6″-O-galloyl)-β-d-glucopyranoside (EBDGp) from P. emblica, a β2-adrenoceptor polyphenolic receptor agonist, and quercetin showed high affinity for RdRp in both SARS-CoV and SARS-CoV-2 [33, 215, 244, 245]. Furthermore, a research study investigating the efficacy of P. amarus against SARS-CoV-2 infection revealed that computer-generated docking models of polyphenol flavonoid compounds (such as astragalin, kaempferol, quercetin, quercetin-3-O-glucoside, and quercetin) along with tannins (such as corilagin and geraniin) exhibited a strong attraction towards binding to RdRp (RNA-dependent RNA polymerase) and papain-like protease on SARS-CoV-2 in comparison to remdesivir [211].

Side effects and toxicity associated with polyphenols

Finding compounds with minimal cytotoxicity is one of the biggest challenges in the development of new therapeutic agents [31, 32, 246]. Polyphenols have an advantage in this regard, as they have a high safety profile without major side effects [224]. Studies have shown that when polyphenols are consumed in the form of fruits and vegetables, their toxic effects are highly unlikely [35, 247]. Additionally, most polyphenols do not exhibit cytotoxicity at high concentrations [25,26,27, 30, 246]. However, some polyphenols may have toxic effects in high doses. For instance, quercetin, despite being generally safe, may induce side effects such as headache and paresthesias in the hands and legs at doses of up to 1 g daily. High doses of quercetin may also pose a potential risk of renal toxicity, and it could interact with antibiotics such as quinolones and other drugs such as diclofenac, celecoxib, and immunosuppressants, leading to an increased side effect profile [24, 241, 248]. Similarly, under high-dose conditions, some studies have shown that EGCG may have a significant prooxidant effect, which can be both beneficial and potentially harmful. High doses of EGCG have been reported to cause cytotoxicity in vitro and may result in liver damage, kidney damage, and gastrointestinal disturbances (vomiting and diarrhea) [23, 249, 250]. Furthermore, emodin may have irreversible pathological effects on organs and disrupt glutathione and fatty acid metabolism in very high doses (4000 mg/kg). Emodin is also genotoxic and reproductively toxic [208]. To mitigate drug toxicity, it is crucial to avoid the long-term administration of high doses. Enhancing bioavailability is fundamental to reducing the administered dose.

Conclusion

The present review discussed the efficacy of various polyphenols in suppressing COVID-19. It has been shown that polyphenols can significantly reduce COVID-19 severity and the damage induced by viral infection by acting as immunomodulators, anti-inflammatory, and antioxidants. There are multiple molecular and cellular pathways involved in their mechanism of action against COVID-19, including disrupting viruses' life cycle by binding to their essential proteins, inhibiting viral enzymes, and disrupting viral structural proteins from interacting with host cells which ultimately leads to inhibition of cytokine storm, reduction of oxidative damage, and increase in virus resistance. To confirm such findings, further studies on patients are required to demonstrate the efficacy and safety of the specific polyphenols. Moreover, polyphenols tend to be poorly bioavailable, which requires additional research into pharmaceutical technology leading to the right formulation.