Article

Zinc Ionophore Activity of Quercetin and Epigallocatechin-gallate: From Hepa 1-6 Cells to a Liposome Model

Authors:
  • Vascular Biology Lab, Institute of Medicine and Experimental Biology of Cuyo (IMBECU) CONICET, School of Medical Sciences, National University of Cuyo, Mendoza, Argentina,
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Abstract

Labile zinc - a tiny fraction of total intracellular zinc that is loosely bound to proteins and easily interchangeable - modulates the activity of numerous signalling and metabolic pathways. Dietary plant polyphenols such as the flavonoids quercetin and epigallocatechin-gallate act as antioxidants and as signalling molecules. Remarkably, the activities of numerous enzymes that are targeted by polyphenols are dependent on zinc. We have previously shown that these polyphenols chelate zinc cations and hypothesized that these flavonoids might be also acting as zinc ionophores, transporting zinc cations through the plasma membrane. To prove this hypothesis, herein we have demonstrated the capacity of quercetin and epigallocatechin-gallate to rapidly increase labile zinc in mouse hepatocarcinoma Hepa 1-6 cells as well as, for the first time, in liposomes. In order to confirm that the polyphenols transport of zinc cations across the plasma membrane independently of plasma membrane zinc transporters, quercetin, epigallocatechin-gallate or clioquinol, alone and combined with zinc, were added to unilamellar dipalmitoylphosphocholine/cholesterol liposomes loaded with membrane-impermeant FluoZin™-3. Only the combinations of the chelators with zinc triggered a rapid increase of FluoZin™-3 fluorescence within liposomes, thus demonstrating, the ionophore action of quercetin, epigallocatechin-gallate and clioquinol on lipid membrane systems. The ionophore activity of dietary polyphenols may underlay the raising of labile zinc levels triggered in cells by polyphenols and, thus, many of their biological actions.

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... This analysis helped identify a range of compounds containing nitrogen, oxygen or sulphur functionalities ( Figure 2). In the literature, many of these compounds have hypothesised synergy with zinc, such as levamisole [30], quercetin [31], hydroxychloroquine [17] and clioquinol [32], or are currently formulated with zinc for therapeutic purposes, such as erythromycin (Zyneryt ® ), carnosine (Polaprezinc ® ), pyrithione (Head & Shoulders ® shampoo) and ascorbic acid (e.g., Beeline ® Vitamin C + Zinc). This analysis helped identify a range of compounds containing nitrogen, oxygen or sulphur functionalities ( Figure 2). ...
... This analysis helped identify a range of compounds containing nitrogen, oxygen or sulphur functionalities ( Figure 2). In the literature, many of these compounds have hypothesised synergy with zinc, such as levamisole [30], quercetin [31], hydroxychloroquine [17] and clioquinol [32], or are currently formulated with zinc for therapeutic purposes, such as erythromycin (Zyneryt ® ), carnosine (Polaprezinc ® ), pyrithione (Head & Shoulders ® shampoo) and ascorbic acid (e.g., Beeline ® Vitamin C + Zinc). ...
... The potency of CQL with respect to 8-HQ may be explained by the greater partition coefficient of CQL or indeed by the presence of the chlorine electron withdrawing groups on CQL. Figure 4 suggests that quercetin is a more potent zinc ionophore than naringenin, requiring concentrations of 0.1 and 1 mM respectively to produce the responses shown. This has been confirmed previously in liposomal assays prepared via a different methodology where quercetin again demonstrated significantly greater ionophoric activity than naringenin [21,31]. The lack of a hydroxyl group on naringenin may confer weaker affinity for zinc and may explain this difference in effect. ...
Article
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The importance of zinc in biology has gained greater recognition in recent years due to its essential contributions to the function of many endogenous enzymes. Disruption of zinc homeostasis may be useful in treating pathological conditions, such as Alzheimer’s, and for antiviral purposes. Despite the growth of knowledge and increased interest in zinc, little is known about the structure and function of zinc ionophores. In this study we analyse the Cambridge Structural Database and solution complexation studies found in the literature to identify key functional groups which may confer zinc ionophorism. Pharmaceuticals, nutraceuticals and amino acids with these functionalities were selected to enable us to explore the translatability of ionophoric activity from in vitro assays to cellular systems. We find that although certain species may complex to zinc in the solid and solution states, and may carry ions across simple membrane systems, this does not necessarily translate into ionophoric activity. We propose that the CSD can help refine key functionalities but that ionophoric activity must be confirmed in cellular systems.
... Quercetin contains four phenolic groups, which make it a strong scavenger of the reactive oxygen species (ROS), antioxidant, immune booster, and anti-inflammatory substance [18]. Quercetin is also an excellent metal ionophore (antioxidative, anti-inflammatory, and immunomodulatory zinc ionophore) [19], and also increases the glutathione (antioxidant) level in the body [20]. These properties make quercetin an important therapeutic agent to prevent/treat many diseases caused by oxidative stress and the release of pro-inflammatory substances in the body ( Figure 1) [18,21,22]. ...
... Accordingly, the authors trust that the physicochemical and metabolic drug interactions of quercetin must be understood before making a combination of quercetin with other drugs/compounds. Further, quercetin is also an established metal ionophore [19]. It binds with beneficial metals like zinc, which provides a synergistic effect. ...
... The literature has highlighted interactions of quercetin Table 2. metabolic drug interactions of quercetin must be understood before making a combination of quercetin with other drugs/compounds. Further, quercetin is also an established metal ionophore [19]. It binds with beneficial metals like zinc, which provides a synergistic effect. ...
Article
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Quercetin is a phenolic flavonol compound with established antioxidant, anti-inflammatory, and immuno-stimulant properties. Recent studies demonstrate the potential of quercetin against COVID-19. This article highlighted the prophylactic/therapeutic potential of quercetin against COVID-19 in view of its clinical studies, inventions, and patents. The literature for the subject matter was collected utilizing different databases, including PubMed, Sci-Finder, Espacenet, Patentscope, and USPTO. Clinical studies expose the potential of quercetin monotherapy, and also its combination therapy with other compounds, including zinc, vitamin C, curcumin, vitamin D3, masitinib, hydroxy- chloroquine, azithromycin, and ivermectin. The patent literature also examines claims that quercetin containing nutraceuticals, pharmaceuticals, and dietary supplements, alone or in combination with other drugs/compounds, including favipiravir, remdesivir, molnupiravir, navitoclax, dasatinib, disulfiram, rucaparib, tamarixin, iota-carrageenan, and various herbal extracts (aloe, poria, rosemary, and sphagnum) has potential for use against COVID-19. The literature reveals that quercetin exhibits anti-COVID-19 activity because of its inhibitory effect on the expression of the human ACE2 receptors and the enzymes of SARS-CoV-2 (MPro, PLPro, and RdRp). The USFDA designated quercetin as a “Generally Recognized as Safe” substance for use in the food and beverage industries. It is also an inexpensive and readily available compound. These facts increase the possibility and foreseeability of making novel and economical drug combinations containing quercetin to prevent/treat COVID-19. Quercetin is an acidic compound and shows metabolic interaction with some antivirals, antibiotics, and anti-inflammatory agents. Therefore, the physicochemical and metabolic drug interactions between quercetin and the combined drugs/compounds must be better understood before developing new compositions.
... Although these changes are known to be associated with both tumor suppressive and oncogenic responses, the cumulative effect was increased PCa cell death [107]. In addition, quercetin has been found to enhance the uptake of Zn in human intestinal Caco-2 cells [77,88]. A study found that quercetin is able to quickly increase the labile Zn in mouse hepatocarcinoma Hepa 1-6 cells [88]. ...
... In addition, quercetin has been found to enhance the uptake of Zn in human intestinal Caco-2 cells [77,88]. A study found that quercetin is able to quickly increase the labile Zn in mouse hepatocarcinoma Hepa 1-6 cells [88]. Quercetin enhances the mobility of Zn via its ability to form a Znpolyphenol chelation complex, which can move across the bilayer of liposomes [88]. ...
... A study found that quercetin is able to quickly increase the labile Zn in mouse hepatocarcinoma Hepa 1-6 cells [88]. Quercetin enhances the mobility of Zn via its ability to form a Znpolyphenol chelation complex, which can move across the bilayer of liposomes [88]. In a very recent study from our lab, we evaluated the effect of quercetin and resveratrol combination in the diet in transgenic adenocarcinoma of the mouse prostate (TRAMP) and have found significant inhibition in PCa development and progression. ...
Article
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Studies have suggested an important role of the trace element zinc (Zn) in prostate biology and functions. Zn has been shown to exist in very high concentrations in the healthy prostate and is important for several prostatic functions. In prostate cancer (PCa), Zn levels are significantly decreased and inversely correlated with disease progression. Ideally, restoration of adequate Zn levels in premalignant/malignant prostate cells could abort prostate malignancy. However, studies have shown that Zn supplementation is not an efficient way to significantly increase Zn concentrations in PCa. Based on a limited number of investigations, the reason for the lower levels of Zn in PCa is believed to be the dysregulation of Zn transporters (especially ZIP and ZnT family of proteins), metallothioneins (for storing and releasing Zn), and their regulators (e.g., Zn finger transcription factor RREB1). Interestingly, the level of Zn in cells has been shown to be modulated by naturally occurring dietary phytochemicals. In this review, we discussed the effect of selected phytochemicals (quercetin, resveratrol, epigallocatechin-3-gallate and curcumin) on Zn functioning and proposes that Zn in combination with specific dietary phytochemicals may lead to enhanced Zn bioaccumulation in the prostate, and therefore, may inhibit PCa.
... Consequently, there is a mechanism of action that can explain why we should anticipate the combination of zinc with a zinc ionophore (i.e. hydroxychloroquine, or quercetin [66], or EGCG [67]) to inhibit the replication of the influenza viruses. Other RNA viruses, including the respiratory syncytial virus (RSV) [68] and the highly pathogenic Marburg and Ebola viruses [69,70], are also using the RDRP protein to replicate, raising the question of whether the zinc/zinc ionophore concept could also play a useful role against them. ...
... McCullough's therapeutic recommendations for handling the cytokine injury phase and the thrombosis phase of the COVID-19 illness are, for the most part, standard on-label treatments for treating hyper-inflammation and preventing blood clots. The most noteworthy innovations to the antiviral part of the protocol are the addition of ivermectin [72][73][74][75][76][77], which has 20 known mechanisms of action against COVID-19 [78], to be used as an alternative or in conjunction with hydroxychloroquine, the addition of a nutraceutical bundle [79][80][81] combined with a zinc ionophore (quercetin [66] or EGCG [67]) for both lowrisk and high-risk patients, and lowering the age threshold for high-risk patients to 50 years. The MATH+ protocol [6,7], developed for hospitalized patients by Marik's group, follows the same principles of a sequenced multi-drug treatment. ...
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When confronted with a public health emergency where the pre-existing standard of care is inadequate, significant innovative treatment protocols can sometimes be discovered by medical doctors at the front lines based on repurposed medications. We propose a statistical framework for analyzing the case series of patients treated with such new protocols, that enables a comparison with our prior knowledge of expected outcomes, in the absence of treatment. The goal of the proposed methodology is not to provide a precise measurement of treatment efficacy, but to establish the existence of treatment efficacy, in order to facilitate the binary decision of whether the treatment protocol should be adopted on an emergency basis. The methodology consists of a frequentist component that compares a treatment group against the probability of an adverse outcome in the absence of treatment, and calculates an efficacy threshold that has to be exceeded by this probability, in order to control the corresponding $p$-value, and reject the null hypothesis. The efficacy threshold is further adjusted with a Bayesian technique, in order to also control the false positive rate. A random selection bias threshold is then calculated from the efficacy threshold to control for random selection bias. Exceeding the efficacy threshold establishes the existence of efficacy by the preponderance of evidence, and exceeding the more demanding random selection bias threshold establishes the existence of efficacy by the clear and convincing evidentiary standard. The combined techniques are applied to case series of high-risk COVID-19 outpatients, that were treated using the early Zelenko protocol and the more enhanced McCullough protocol.
... Mx proteins are the "gatekeepers" of the host cells in overcoming RNA viruses and other virus families that replicate in the host nucleus [116]. Polyphenols also help transport Zn cations into across the plasma membrane independently of plasma membrane zinc transport proteins [117]. Zn cations have been shown to inhibit the activity of viral RNA-dependent RNA polymerase [118]. ...
... Inhibition and reversal of the parvovirus-induced expression of pro-apoptotic genes Bid, Bad, Bim, and Bak. [114] Quercetin and epigallocatechin gallate Not determined Zinc ionophore [117] ...
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Propolis is a complex phytocompound made from resinous and balsamic material harvested by bees from flowers, branches, pollen, and tree exudates.Humans have used propolis therapeutically for centuries. The aim of this article is to provide comprehensive review of the antiviral, antibacterial, antifungal, and antiparasitic properties of propolis. The mechanisms of action of propolis are discussed. There are two distinct impacts with regards to antimicrobial and anti-parasitic properties of propolis, on the pathogens and on the host. With regards to the pathogens, propolis acts by disrupting the ability of the pathogens to invade the host cells by forming a physical barrier and inhibiting enzymes and proteins needed for invasion into the host cells. Propolis also inhibits the replication process of the pathogens. Moreover, propolis inhibits the metabolic processes of the pathogens by disrupting cellular organelles and components responsible for energy production. With regard to the host, propolis functions as an immunomodulator. It upregulates the innate immunity and modulates the inflammatory signaling pathways. Propolis also helps maintain the host’s cellular antioxidant status. More importantly, a small number of human clinical trials have demonstrated the efficacy and the safety of propolis as an adjuvant therapy for pathogenic infections.
... One of the interesting features of cyanorona-20 structure is its explicit ability to act as a multizincophore (zinc ionophores or zinc ion carriers, e.g., chloroquine [21], hydroxychloroquine [21], quercetin [22], epigallocatechin gallate [22], CoViTris2020 [23], and Taroxaz-104 [24], transport extracellular Zn 2+ ions across the hydrophobic cell membranes to enter the living cell, and have been studied mainly for their antiviral activities, as they have been shown to effectively inhibit the replication of various viruses in vitro [25]). Zn 2+ inhibits coronavirus RdRp activity (i.e., inhibits coronaviral replication and transcription) in vitro (Zn 2+ ion is the only known elemental cofactor and ligand present in the crystal structure of SARS-CoV-2 RdRp and, thus, it has an extremely important role in controlling the activity of this COVID-19 RNA-synthesizing enzymatic machine) and, therefore, zinc ionophores have been shown to successfully block the replication process of coronaviruses intracellularly in cell cultures [26][27][28]. ...
... One of the interesting features of cyanorona-20 structure is its explicit ability to act as a multizincophore (zinc ionophores or zinc ion carriers, e.g., chloroquine [21], hydroxychloroquine [21], quercetin [22], epigallocatechin gallate [22], CoViTris2020 [23], and Taroxaz-104 [24], transport extracellular Zn 2+ ions across the hydrophobic cell membranes to enter the living cell, and have been studied mainly for their antiviral activities, as they have been shown to effectively inhibit the replication of various viruses in vitro [25]). Zn 2+ inhibits coronavirus RdRp activity (i.e., inhibits coronaviral replication and transcription) in vitro (Zn 2+ ion is the only known elemental cofactor and ligand present in the crystal structure of SARS-CoV-2 RdRp and, thus, it has an extremely important role in controlling the activity of this COVID-19 RNA-synthesizing enzymatic machine) and, therefore, zinc ionophores have been shown to successfully block the replication process of coronaviruses intracellularly in cell cultures [26][27][28]. ...
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Explicit hindrance and blockade of the viral RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 is considered one of the most promising and efficient approaches for developing highly potent remedies for COVID-19. However, almost all of the reported viral RdRp inhibitors (either repurposed or new antiviral drugs) lack specific selectivity against the novel coronaviral RdRp and still at a beginning phase of advancement. Herein, I discovered and introduce a new pyrazine derivative, (E)-N-(4-cyanobenzylidene)-6-fluoro-3-hydroxypyrazine-2-carboxamide (cyanorona-20), as the first potent SARS-CoV-2 RdRp inhibitor with very high selectivity (209- and 45-fold more potent than favipiravir and remdesivir, respectively). This promising selective specific anti-COVID-19 compound is also deemed to be the first distinctive derivative of favipiravir. Cyanorona-20, the unprecedented nucleoside/nucleotide analog, was designed, synthesized, characterized, computationally studied, and biologically evaluated for its anti-COVID-19 actions (through a precise in vitro anti-COVID-19 assays). The results of the biological assay displayed that cyanorona-20 surprisingly exhibited very high and largely significant anti-COVID-19 activities (anti-SARS-CoV-2 EC50 = 0.45 μM), and, in addition, it could be also a very promising guide and lead compound for the design and synthesis of new anti-SARS-CoV-2 and anti-COVID-19 agents through structural modifications and further computational studies. Further appraisal for the improvement of cyanorona-20 medication is a prerequisite requirement in the coming days. In a word, the ascent of the second member (cyanorona-20 “Corona Antidote”) of the novel and promising class of anti-COVID-19 pyrazine derivatives would drastically make a medical uprising in the pharmacotherapeutic treatment regimens and protocols of the recently-emerged SARS-CoV-2 infection and its accompanying COVID-19.
... 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. ...
... Unfortunately, pyrithione is not recommended for use internally, whereas it is IL-x interleukin x IL-1RN IL-1 receptor antagonist protein IP-10 interferon-g-inducible protein M1,2 macrophage type 1, (or 2) MMP-2,9 matrix metallopeptidase 2, (or 9) NF-kB nuclear factor k-light-chain-enhancer of activated B efficacious and safe when used topically. Other proven zinc ionophores include chloroquine and hydroxychloroquine (HCQ) [12,32,33], disulfiram [33], quercetin and epigallocatechin-gallate [34], and zincophorin [35]. In addition, Rizzo [36] presented a sound rationale for ivermectin being an ionophore for zinc. ...
Article
Despite the development of a number of vaccines for COVID-19, there remains a need for prevention and treatment of the virus SARS-CoV-2 and the ensuing disease COVID-19. This report discusses the key elements of SARS-CoV-2 and COVID-19 that can be readily treated: viral entry, the immune system and inflammation, and the cytokine storm. It is shown that the essential nutrients zinc, ω-3 polyunsaturated fatty acids (PUFAs), vitamin D and magnesium provide the ideal combination for prevention and treatment of COVID-19: prevention of SARS-CoV-2 entry to host cells, prevention of proliferation of SARS-CoV-2, inhibition of excessive inflammation, improved control of the regulation of the immune system, inhibition of the cytokine storm, and reduction in the effects of acute respiratory distress syndrome (ARDS) and associated non-communicable diseases. It is emphasized that the non-communicable diseases associated with COVID-19 are inherently more prevalent in the elderly than the young, and that the maintenance of sufficiency of zinc, ω-3 PUFAs, vitamin D and magnesium is essential for the elderly to prevent the occurrence of non-communicable diseases such as diabetes, cardiovascular diseases, lung diseases and cancer. Annual checking of levels of these essential nutrients is recommended for those over 65 years of age, together with appropriate adjustments in their intake, with these services and supplies being at government cost. The cost:benefit ratio would be huge as the cost of the nutrients and the testing of their levels would be very small compared with the cost savings of specialists and hospitalization.
... Similar positive effects may be expected when zinc supplementation without chloroquine is used (Guastalegname & Vallone, 2020). Supposedly, a similar effect can be predicted when applying other zinc ionophores (Dabbagh-Bazarbachi et al., 2014) with lower toxicity. This required further studies to support the prediction. ...
Article
In 2019, a novel type of coronavirus emerged in China called SARS-COV-2, known COVID-19, threatens global health and possesses negative impact on people's quality of life, leading to an urgent need for its diagnosis and remedy. On the other hand, the presence of hazardous infectious waste led to the increase of the risk of transmitting the virus by individuals and by hospitals during the COVID-19 pandemic. Hence, in this review, we survey previous researches on nanomaterials that can be effective for guiding strategies to deal with the current COVID-19 pandemic and also decrease the hazardous infectious waste in the environment. We highlight the contribution of nanomaterials that possess potential to therapy, prevention, detect targeted virus proteins and also can be useful for large population screening, for the development of environmental sensors and filters. Besides, we investigate the possibilities of employing the nanomaterials in antiviral research and treatment development, examining the role of nanomaterials in antiviral- drug design, including the importance of nanomaterials in drug delivery and vaccination, and for the production of medical equipment. Nanomaterials-based technologies not only contribute to the ongoing SARS- CoV-2 research efforts but can also provide platforms and tools for the understanding, protection, detection and treatment of future viral diseases.
... [24,29,34,34,[321][322][323][324][325][326][327][328] In addition, quercetin acts as a zinc ionophore. [329] c. Vitamin C improves the potency of Quercetin and has antiviral and anti-inflammatory activity. ...
Article
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This brief note introduces the reproduction of medical content, authored by Doctor Paul E. Marik. Dr. Marik is Professor of Medicine and Chief of Pulmonary Medicine and Critical Care at Eastern Virginia Medical School in Norfolk, Virginia (USA). Dr. Marik is an extremely qualified and experienced professional. The reprinting of the material was authorized by Dr. Marik himself on 12/02/2020. This material is relevant in the Brazilian scenario due to standardized procedures for patients infected with the coronavirus. Only 1 of the 5 files kindly provided by the author, in PDF format, was selected and reproduced as received, without any editing. Due to the pandemic's long duration, the Journal editors (who are not medical doctors) have already had the opportunity to monitor the development of the disease in more than one infected person. The type of treatment offered to patients seems to influence the course, duration, and severity of the disease. The treatments described in the materials below appear to be effective and have good results. The editors will refrain from making additional comments on the proposed methods not to influence anyone, restricting themselves to suggesting that they be discussed with the reader's trusted doctor in case of need or doubts. Complete, updated information and also translated into Portuguese are available at . We are grateful to Dr. Marik for his kindness in giving us his time in this troubled period.
... Unfortunately, HCQ inhibits the proliferation of T cells which is not good for severe COVID-19 cases who suffer from acute respiratory problems [106]. Flavonoids such as quercetin and epigallocatechin 3-gallate (EGCG) demonstrate antioxidant activity [110]. According to a hypothesis, flavonoids can ameliorate SARS-CoV-2 infection by reducing both the transmembrane peptidase serine 2 (TMPRSS2) and Furin [111]. ...
Article
The novel SARS-CoV-2 which was first reported in China is the cause of infection known as COVID-19. In comparison with other coronaviruses such as SARS-CoV and MERS, the mortality rate of SARS-CoV-2 is lower but the transmissibility is higher. Immune dysregulation is the most common feature of the immunopathogenesis of COVID-19 that leads to hyperinflammation. Micronutrients such as zinc are essential for normal immune function. According to the assessment of WHO, approximately one-third of the world’s society suffer from zinc deficiency. Low plasma levels of zinc are associated with abnormal immune system functions such as impaired chemotaxis of polymorphonuclear cells (PMNs) and phagocytosis, dysregulated intracellular killing, overexpression of the inflammatory cytokines, lymphopenia, decreased antibody production, and sensitivity to microbes especially viral respiratory infections. Zinc exerts numerous direct and indirect effects against a wide variety of viral species particularly RNA viruses. The use of zinc and a combination of zinc-pyrithione at low concentrations impede SARS-CoV replication in vitro. Accordingly, zinc can inhibit the elongation step of RNA transcription. Furthermore, zinc might improve antiviral immunity by up-regulation of IFNα through JAK/STAT1 signaling pathway in leukocytes. On the other hand, zinc supplementation might ameliorate tissue damage caused by mechanical ventilation in critical COVID-19 patients. Finally, zinc might be used in combination with antiviral medications for the management of COVID-19 patients. In the current review article, we review and discuss the immunobiological roles and antiviral properties as well as the therapeutic application of zinc in SARS-CoV-2 and related coronaviruses infections.
... It can inhibit the Fenton reaction by interfering with ferrous iron (207). It can also bind to zinc and facilitate zinc trafficking into cells (208), which in turn functions as an antioxidant (209). Lipid peroxidation is the process by which unsaturated fatty acids are converted to lipid peroxyl radicals by hydrogen oxidation, which, in turn, extract hydrogen from other fatty acid molecules to create more free radicals (210). ...
Article
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The vascular endothelium occupies a catalog of functions that contribute to the homeostasis of the cardiovascular system. It is a physically active barrier between circulating blood and tissue, a regulator of the vascular tone, a biochemical processor and a modulator of coagulation, inflammation, and immunity. Given these essential roles, it comes to no surprise that endothelial dysfunction is prodromal to chronic age-related diseases of the heart and arteries, globally termed cardiovascular diseases (CVD). An example would be ischemic heart disease (IHD), which is the main cause of death from CVD. We have made phenomenal advances in treating CVD, but the aging endothelium, as it senesces, always seems to out-run the benefits of medical and surgical therapies. Remarkably, many epidemiological studies have detected a correlation between a flavonoid-rich diet and a lower incidence of mortality from CVD. Quercetin, a member of the flavonoid class, is a natural compound ubiquitously found in various food sources such as fruits, vegetables, seeds, nuts, and wine. It has been reported to have a wide range of health promoting effects and has gained significant attention over the years. A growing body of evidence suggests quercetin could lower the risk of IHD by mitigating endothelial dysfunction and its risk factors, such as hypertension, atherosclerosis, accumulation of senescent endothelial cells, and endothelial-mesenchymal transition (EndoMT). In this review, we will explore these pathophysiological cascades and their interrelation with endothelial dysfunction. We will then present the scientific evidence to quercetin's anti-atherosclerotic, anti-hypertensive, senolytic, and anti-EndoMT effects. Finally, we will discuss the prospect for its clinical use in alleviating myocardial ischemic injuries in IHD.
... [4] Amino acids, such as L-histidine and methionine, have positive effects on Zn absorption and have been used for Zn supplementation. [5] Furthermore, Zn ionophores can be used to increase labile Zn within cells, and quercetin can act as a Zn ionophore, transporting Zn cations through the plasma membrane, hence improving the biological functions of Zn. [6] In conclusion, further randomized controlled blinded clinical trials are required to substantiate the efficacy of high-dose ...
... In another investigation, both in vitro and in vivo experiments had shown that zinc ions can block hepatitis E virus replication by inhibiting the activity of viral RdRp [53]. The charged zinc ions require a transporter for the influx into the cell, and quercetin acts as an ionophore that mediates zinc influx into the cells through plasma membrane [54]. While correlating these results, it is evident that the combination of quercetin and zinc is a potential strategy against SARS-CoV-2, imparting greater antiviral efficacy at a lower cytotoxicity. ...
Article
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Background The world pandemic COVID-19 caused by SARS-CoV-2 is currently claiming thousands of lives. Flavonoids abundantly present in the fruits and vegetables, especially quercetin, are shown to have antiviral activities. Main text This paper reviews the capability of the plant flavonoid quercetin to fight the novel coronavirus and the possibility for drug development based on this. The mode of action explaining the known pathways through which this molecule succeeds in the antiviral activity, action of quercetin on SARS-CoV-2 main protease 3CL pro , antiviral activities of its derivatives on human viruses, effect of combination of zinc co-factor along with quercetin in the COVID-19 treatment, and the regulation of miRNA genes involved in the viral pathogenesis are discussed. Proof for this concept is provided following the virtual screening using ten key enzymes of SARS-CoV-2 and assessing their interactions. Active residues in the 3D structures have been predicted using CASTp and were docked against quercetin. Key proteins 3CL pro , spike glycoprotein/ human ACE2-BOAT1 complex, RNA-dependent RNA polymerase, main peptidase, spike glycoprotein, RNA replicase, RNA binding protein, papain-like protease, SARS papain-like protease/ deubiquitinase, and complex of main peptidase with an additional Ala at the N-terminus of each protomer, have shown the binding energies ranging between − 6.71 and − 3.37 kcal/ Mol, showing that quercetin is a potential drug candidate inhibiting multiple SARS-CoV-2 enzymes. Conclusion The antiviral properties of flavonoid and the molecular mechanisms involved are reviewed. Further, proof for this concept is given by docking of key proteins from SARS-CoV-2 with quercetin. Graphical abstract
... Thereby, it facilitates Zn's entry across a cell's lipid membrane and considerably increases Zn's intracellular levels, particularly in the endosomallysosomal section. 142,[188][189][190][191] Raised concentration intracellular Zn 2+ demonstrates antiviral activity, including COVID-19 involving three distinct antiviral mechanisms of action [ Figure 3]. 142,190,192 The exact mode of action of hydroxychloroquine remains elusive to date. ...
... Thereby, it facilitates Zn's entry across a cell's lipid membrane and considerably increases Zn's intracellular levels, particularly in the endosomallysosomal section. 142,[188][189][190][191] Raised concentration intracellular Zn 2+ demonstrates antiviral activity, including COVID-19 involving three distinct antiviral mechanisms of action [ Figure 3]. 142,190,192 The exact mode of action of hydroxychloroquine remains elusive to date. ...
Article
Full-text available
Abstract: The global pandemic from COVID-19 infection has generated significant public health concerns, both health-wise and economically. There is no specific pharmacological antiviral therapeutic option to date available for COVID-19 management. Also, there is an urgent need to discover effective medicines, prevention, and control methods because of the harsh death toll from this novel coronavirus infection. Acute respiratory tract infections, significantly lower respiratory tract infections, and pneumonia are the primary cause of millions of deaths worldwide. The role of micronutrients, including trace elements, boosted the human immune system and was well established. Several vitamins such as vitamin A, B6, B12, C, D, E, and folate; microelement including zinc, iron, selenium, magnesium, and copper; omega-3 fatty acids as eicosapentaenoic acid and docosahexaenoic acid plays essential physiological roles in promoting the immune system. Furthermore, zinc is an indispensable microelement essential for a thorough enzymatic physiological process. It also helps regulate gene-transcription such as DNA replication, RNA transcription, cell division, and cell activation in the human biological system. Subsequently, zinc, together with natural scavenger cells and neutrophils, are also involved in developing cells responsible for regulating nonspecific immunity. The modern food habit often promotes zinc deficiency; as such, quite a few COVID-19 patients presented to hospitals were frequently diagnosed as zinc deficient. Earlier studies documented that zinc deficiency predisposes patients to a viral infection such as herpes simplex, common cold, hepatitis C, severe acute respiratory syndrome coronavirus (SARS-CoV-1), the human immunodeficiency virus (HIV) because of reducing antiviral immunity. This manuscript aimed to discuss the various roles played by zinc in the management of COVID-19 infection.
... Thereby, it facilitates Zn's entry across a cell's lipid membrane and considerably increases Zn's intracellular levels, particularly in the endosomallysosomal section. 142,[188][189][190][191] Raised concentration intracellular Zn 2+ demonstrates antiviral activity, including COVID-19 involving three distinct antiviral mechanisms of action [ Figure 3]. 142,190,192 The exact mode of action of hydroxychloroquine remains elusive to date. ...
Article
Full-text available
Abstract: The global pandemic from COVID-19 infection has generated significant public health concerns, both health-wise and economically. There is no specific pharmacological antiviral therapeutic option to date available for COVID-19 management. Also, there is an urgent need to discover effective medicines, prevention, and control methods because of the harsh death toll from this novel coronavirus infection. Acute respiratory tract infections, significantly lower respiratory tract infections, and pneumonia are the primary cause of millions of deaths worldwide. The role of micronutrients, including trace elements, boosted the human immune system and was well established. Several vitamins such as vitamin A, B6, B12, C, D, E, and folate; microelement including zinc, iron, selenium, magnesium, and copper; omega-3 fatty acids as eicosapentaenoic acid and docosahexaenoic acid plays essential physiological roles in promoting the immune system. Furthermore, zinc is an indispensable microelement essential for a thorough enzymatic physiological process. It also helps regulate gene-transcription such as DNA replication, RNA transcription, cell division, and cell activation in the human biological system. Subsequently, zinc, together with natural scavenger cells and neutrophils, are also involved in developing cells responsible for regulating nonspecific immunity. The modern food habit often promotes zinc deficiency; as such, quite a few COVID-19 patients presented to hospitals were frequently diagnosed as zinc deficient. Earlier studies documented that zinc deficiency predisposes patients to a viral infection such as herpes simplex, common cold, hepatitis C, severe acute respiratory syndrome coronavirus (SARS-CoV-1), the human immunodeficiency virus (HIV) because of reducing antiviral immunity. This manuscript aimed to discuss the various roles played by zinc in the management of COVID-19 infection.
... Thereby, it facilitates Zn's entry across a cell's lipid membrane and considerably increases Zn's intracellular levels, particularly in the endosomallysosomal section. 142,[188][189][190][191] Raised concentration intracellular Zn 2+ demonstrates antiviral activity, including COVID-19 involving three distinct antiviral mechanisms of action [ Figure 3]. 142,190,192 The exact mode of action of hydroxychloroquine remains elusive to date. ...
Article
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Nandeeta Samad,1 Temitayo Eniola Sodunke,2 Abdullahi Rabiu Abubakar,3 Iffat Jahan,4 Paras Sharma,5 Salequl Islam,6 Siddhartha Dutta,7 Mainul Haque8 1Department of Public Health, North South University, Dhaka, 1229, Bangladesh; 2Department of Anatomy, University of Ilorin, Ilorin, Kwara State, Nigeria; 3Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Bayero University, Kano, 700233, Nigeria; 4Department of Physiology, Eastern Medical College, Cumilla, Bangladesh; 5Department of Pharmacognosy, BVM College of Pharmacy, Gwalior, India; 6Department of Microbiology, Jahangirnagar University, Dhaka, 1342, Bangladesh; 7Department of Pharmacology, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India; 8The Unit of Pharmacology, Faculty of Medicine and Defence Health, Universiti Pertahanan Nasional Malaysia (National Defence University of Malaysia), Kuala Lumpur, MalaysiaCorrespondence: Mainul HaqueUnit of Pharmacology, Faculty of Medicine and Defence Health, Universiti Pertahanan Nasional Malaysia (National Defence University of Malaysia), Kem Perdana Sungai Besi, Kuala Lumpur, 57000, MalaysiaTel +60 10 926 5543Email runurono@gmail.comAbstract: The global pandemic from COVID-19 infection has generated significant public health concerns, both health-wise and economically. There is no specific pharmacological antiviral therapeutic option to date available for COVID-19 management. Also, there is an urgent need to discover effective medicines, prevention, and control methods because of the harsh death toll from this novel coronavirus infection. Acute respiratory tract infections, significantly lower respiratory tract infections, and pneumonia are the primary cause of millions of deaths worldwide. The role of micronutrients, including trace elements, boosted the human immune system and was well established. Several vitamins such as vitamin A, B6, B12, C, D, E, and folate; microelement including zinc, iron, selenium, magnesium, and copper; omega-3 fatty acids as eicosapentaenoic acid and docosahexaenoic acid plays essential physiological roles in promoting the immune system. Furthermore, zinc is an indispensable microelement essential for a thorough enzymatic physiological process. It also helps regulate gene-transcription such as DNA replication, RNA transcription, cell division, and cell activation in the human biological system. Subsequently, zinc, together with natural scavenger cells and neutrophils, are also involved in developing cells responsible for regulating nonspecific immunity. The modern food habit often promotes zinc deficiency; as such, quite a few COVID-19 patients presented to hospitals were frequently diagnosed as zinc deficient. Earlier studies documented that zinc deficiency predisposes patients to a viral infection such as herpes simplex, common cold, hepatitis C, severe acute respiratory syndrome coronavirus (SARS-CoV-1), the human immunodeficiency virus (HIV) because of reducing antiviral immunity. This manuscript aimed to discuss the various roles played by zinc in the management of COVID-19 infection.Keywords: zinc therapy, microelement, immune-boosting, efficacy, COVID-19, viral infections, pneumonia, pandemic
... Quercetin-3-beta-galactoside was identified as a natural inhibitor of the protease by molecular docking [43,44]. The benefits of quercetin might be also modulated by zinc actions; the ionophore actions of quercetin increase the levels of zinc [45]. The administration of quercetin and vitamin C might have synergic antiviral properties, as ascorbate might recycle quercetin increasing its efficacy [46]. ...
Article
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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) was declared a pandemic in March 2020, triggering important changes for the entire society and healthcare systems, as well as significant lockdown measures aimed to limit the disease spread. We herein intended to catch the dynamic of Romanian physicians’ perceptions of COVID-19 impact. For this purpose, after a literature review, a 30-item questionnaire was designed. The questionnaire was twice distributed online, about 1 month apart, during which partial relaxation measures were decreed in Romania. The questionnaire was voluntarily filled in by Romanian physicians who were willing to participate in the study. A total of 214 physicians answered the questionnaire upon its first release, and 199 respondents were registered upon its second release, most of whom (94.9%) were involved in clinical work, with one-third working in units dedicated to COVID-19 patients. In parallel with the relaxation of lockdown measures, along with increased confidence in the efficiency of protective measures (46.7% vs. 31.3%), separation from household members decreased from 36.9% to 22.1%. Nevertheless, the feeling of rejection felt by doctors remained similar (22.4% vs. 24.6%). Furthermore, answers regarding the clinical picture, diagnostic approach, and treatment options are discussed. Most of therapeutic options considered for SARS-CoV-2 treatment (e.g., lopinavir/ritonavir, oseltamivir, hydroxychloroquine, azithromycin, tocilizumab, and convalescent plasma) failed to confirm significant efficiency. On the contrary, vaccines for widescale use are already available despite the initial skepticism. In the beginning of the pandemic, 25.2% (18.2% vs. 32.2%) considered that there will not be an effective COVID-19 vaccine, while 41.6% (43.0% vs. 40.2%) thought that a vaccine would be available after at least 12 months. In conclusion, initially, following only a 1 month period, Romanian physicians’ intention to consider treatments such as hydroxychloroquine or lopinavir/ritonavir for COVID-19 decreased significantly. Moreover, confidence in the efficiency of available protective measures increased, and the rates of separation from household members decreased.
... Quercetin is a polyphenol that has a theoretical mechanism of action that could reduce the activity of a SARS-CoV-2 entry through the ACE2 receptor, inhibit viral proteases via conveyance of zinc, and attenuate inflammatory responses mediated through interleukin-6 (Bastaminejad and Bakhtiyari, 2020; Cione et al., 2019;Dabbagh-Bazarbachi et al., 2014;Derosa et al., 2020). The mechanisms of action favorably affect viral replication and immune response, so it is conceivable that this agent taken in combination with others discussed could play an assistive role in reducing early viral amplification and tissue damage (Colunga Biancatelli et al., 2020). ...
... Hypothetically, such an effect may be also observed using other zinc ionophores like quercetin and epigallocatechin-gallate (83) with substantially lower toxicity, although clinical trials supported by experimental in vitro studies are required to support this hypothesis (84). Another Zn-related approach to modulation of COVID-19 may include targeting Zn ions in the structure of viral proteins. ...
... Based on recent studies, zinc in absence of chloroquine might indicate similar advantages without harmful side effects of chloroquine [158]. These results have been reported regarding the effects of zinc ionophores (quercetin and epigallocatechin-gallate) [159] with lower toxicity. However, there is an essential need to conduct clinical trials and evaluate this hypothesis [160]. ...
Article
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The escalating prevalence of coronavirus disease 2019 (COVID-19) worldwide, with an increased rate of morbidity and mortality, highlights an urgent need to develop more effective therapeutic interventions. Despite the authorized treatment against COVID-19 by the European Union (EU), the safety and effectiveness of this therapeutic strategy for a wide variety of patients have remained a significant challenge. In this respect, micronutrients such as vitamins and minerals, as essential factors, can be considered for improving the function of the immune system and accelerating the treatment procedure. Dietary supplements can attenuate vascular and inflammatory manifestations related to infectious diseases in large part due to their anti-inflammatory and antioxidant properties. Recently, it has been revealed that poor nutritional status may be one of the notable risk factors in severe COVID-19 infections. In the current review, we focus on the micronutrient therapy of COVID-19 patients and provide a comprehensive insight into the essential vitamins/minerals and their role in controlling the severity of the COVID-19 infection. We also discuss the recent advancements, challenges, negative and positive outcomes in relevance to this approach.
... Quercetin is a polyphenol that has a theoretical mechanism of action that could reduce the activity of a SARS-CoV-2 entry through the ACE2 receptor, inhibit viral proteases via conveyance of zinc, and attenuate inflammatory responses mediated through interleukin-6 (Bastaminejad and Bakhtiyari, 2020; Cione et al., 2019;Dabbagh-Bazarbachi et al., 2014;Derosa et al., 2020). The mechanisms of action favorably affect viral replication and immune response, so it is conceivable that this agent taken in combination with others discussed could play an assistive role in reducing early viral amplification and tissue damage (Colunga Biancatelli et al., 2020). ...
Article
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The SARS-CoV-2 virus spreading across the world has led to surges of COVID-19 illness, hospitalizations, and death. The complex and multifaceted pathophysiology of life-threatening COVID-19 illness including viral mediated organ damage, cytokine storm, and thrombosis warrants early interventions to address all components of the devastating illness. In countries where therapeutic nihilism is prevalent, patients endure escalating symptoms and without early treatment can succumb to delayed in-hospital care and death. Prompt early initiation of sequenced multidrug therapy (SMDT) is a widely and currently available solution to stem the tide of hospitalizations and death. A multipronged therapeutic approach includes 1) adjuvant nutraceuticals, 2) combination intracellular anti-infective therapy, 3) inhaled/oral corticosteroids, 4) antiplatelet agents/anticoagulants, 5) supportive care including supplemental oxygen, monitoring, and telemedicine. Randomized trials of individual, novel oral therapies have not delivered tools for physicians to combat the pandemic in practice. No single therapeutic option thus far has been entirely effective and therefore a combination is required at this time. An urgent immediate pivot from single drug to SMDT regimens should be employed as a critical strategy to deal with the large numbers of acute COVID-19 patients with the aim of reducing the intensity and duration of symptoms and avoiding hospitalization and death.
... On the other hand, Refaat et al. showed that liposomes containing the Egyptian propolis extract displayed an effect similar to that of Remdesivir for inhibition of SARS-CoV-2 replication in vitro. Polyphenols from propolis were shown to inhibit viral replication and to have ability to transport Zn ions, which inhibit the viral enzymes necessary for replication in the host cells [49,[54][55][56]. ...
Article
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Current studies suggest that cariogenic bacteria in dental plaque influence the severity of COVID-19 complications since the oral cavity is a reservoir for respiratory pathogens potentially responsible for the development of hospital-acquired pneumonia. This article focuses on the association between dental plaque and COVID-19 concerning the influence of altered oral biofilm on the risk of increased severity of SARS-CoV-2 infection. Moreover, it concentrates on the usefulness of propolis, with its apitherapeutic antibacterial properties, for treating oral bacterial infections co-occurring with SARS-CoV-2 infection. A review of the literature on PubMed, Cochrane Library and Medline between 2000 and 2021 revealed 56 published articles indicating that a link between dental plaque and COVID-19 complications was probable. Furthermore, they indicated that propolis may minimize COVID-19 severity by reducing dental plaque accumulation. The possibility that improved oral health could reduce the risk of COVID-19 complications should be of interest to scientists.
... Besides these actions, quercetin supplementation will also help to circumvent the zinc deficiency problem in COVID-19 infected/elderly subjects as it acts as a zinc ionophore (Dabbagh-Bazarbachi et al., 2014), thereby helping in increasing the labile intracellular zinc concentration ( Figure 1). It is noteworthy to mention that zinc has been shown to inhibit RNA-dependent RNA polymerase (RdRp) activity of the SARS virus under in vitro conditions in a dose-dependent manner (reviewed in Read, Obeid, Ahlenstiel, & Ahlenstiel, 2019). ...
Article
The interim results of the large, multinational trials on coronavirus disease 2019 (COVID‐19) using a combination of antiviral drugs appear to have little to no effect on the 28‐day mortality or the in‐hospital course. Therefore, there is a still vivid interest in finding alternate re‐purposed drugs and nutrition supplements, which can halt or slow the disease severity. We review here the multiple preclinical studies, partially supported by clinical evidence showing the quercetin's possible therapeutic/prophylaxis efficacy against severe acute respiratory syndrome coronavirus (SARS‐CoV) as well as comorbidities like chronic obstructive pulmonary disease (COPD), diabetes mellitus, obesity, coagulopathy, and hypertension. Currently, 14 interventional clinical trials are underway assessing the efficacy of quercetin along with other antiviral drugs/nutritional supplements as prophylaxis/treatment option against COVID‐19. The present review is tempting to suggest that, based on circumstantial scientific evidence and preliminary clinical data, the flavonoid quercetin can ameliorate COVID‐19 infection and symptoms acting in concert on two parallel and independent paths: inhibiting key factors responsible for SARS‐CoV‐2 infections and mitigating the clinical manifestations of the disease in patients with comorbid conditions. Despite the broad therapeutic properties of quercetin, further high power randomized clinical trials are needed to firmly establish its clinical efficacy against COVID‐19.
... Since chloroquine treatment has shown adverse side effects in the past, the use of zinc without chloroquine might have an equally positive effect [145]. Theoretically, zinc ionophores like epigallocatechin-gallate and quercetin, with substantially lower toxicity levels, can also be used as an alternative, though clinical trials supported by in vitro studies must be performed to support this theory [146]. In the case of COVID-19, Zn 2+ ions can be specifically targeted in the configuration of the viral proteins. ...
Article
Background On 31st December 2019 in Wuhan, China, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), was acknowledged. This virus spread quickly throughout the world causing a global pandemic. The World Health Organization declared COVID-19 a pandemic disease on 11th March 2020. Since then, the whole world has come together and have developed several vaccines against this deadly virus. Similarly, several alternative searches for pandemic disease therapeutics are still ongoing. One of them has been identified as nanotechnology. It has demonstrated significant promise for detecting and inhibiting a variety of viruses, including coronaviruses. Several nanoparticles, including gold nanoparticles, silver nanoparticles, quantum dots, carbon dots, graphene oxide nanoparticles, and zinc oxide nanoparticles, have previously demonstrated remarkable antiviral activity against a diverse array of viruses. Objective This review aims to provide a basic and comprehensive overview of COVID-19's initial global outbreak and its mechanism of infiltration into human host cells, as well as the detailed mechanism and inhibitory effects of various nanoparticles against this virus. In addition to nanoparticles, this review focuses on the role of several antiviral drugs used against COVID-19 to date. Conclusion COVID-19 has severely disrupted the social and economic lives of people all over the world. Due to a lack of adequate medical facilities, countries have struggled to maintain control of the situation. Neither a drug nor a vaccine has a 100% efficacy rate. As a result, nanotechnology may be a better therapeutic alternative for this pandemic disease.
... Te Velthuis and colleagues demonstrated that zinc together with the zinc ionophore pyrithione inhibited the activity of the SARS-CoV RNA-dependent RNA polymerase blocking viral replication in a cell culture [162]. It should be noted that both hydroxychloroquine and the plant phytochemical quercetin are zinc ionophores [163,164]. However, the role of zinc with or without the addition of zinc ionophores in the treatment of COVID-19 remains speculative [165]. ...
Article
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In December 2019, coronavirus disease 2019 (COVID-19), a severe respiratory illness caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China. The greatest impact that COVID-19 had was on intensive care units (ICUs), given that approximately 20% of hospitalized cases developed acute respiratory failure (ARF) requiring ICU admission. Based on the assumption that COVID-19 represented a viral pneumonia and no anti-coronaviral therapy existed, nearly all national and international health care societies recommended "supportive care only" avoiding other therapies outside of randomized controlled trials, with a specific prohibition against the use of corticosteroids in treatment. However, early studies of COVID-19-associated ARF reported inexplicably high mortality rates, with frequent prolonged durations of mechanical ventilation (MV), even from centers expert in such supportive care strategies. These reports led the authors to form a clinical expert panel called the Front-Line COVID-19 Critical Care Alliance (www.flccc.net). The panel collaboratively reviewed the emerging clinical, radiographic, and pathological reports of COVID-19 while initiating multiple discussions among a wide clinical network of front-line clinical ICU experts from initial outbreak areas in China, Italy, and New York. Based on the shared early impressions of "what was working and what wasn't working", the increasing medical journal publications and the rapidly accumulating personal clinical experiences with COVID-19 patients, a treatment protocol was created for the hospitalized patients based on the core therapies of methylprednisolone, ascorbic acid, thiamine, heparin and non-antiviral co-interventions (MATH+). This manuscript reviews the scientific and clinical rationale behind MATH+ based on published in-vitro, pre-clinical, and clinical data in support of each medicine, with a special emphasis of studies supporting their use in the treatment of patients with viral syndromes and COVID-19 specifically.
... Quercetin has many beneficial effects on the human body, including antithrombotic, anti-inflammatory, and antitumor properties [1]. It has been regarded as a good antioxidant that removes reactive oxygen species produced naturally in the body, such as O 2 -and ONOO-, and promotes the transfer of zinc into cells as an intracellular antioxidant [2,3], enhancing antioxidation ability of cells. e incidence of cardiovascular disease has increased dramatically year by year, becoming a serious health challenges not only in developed countries but also in developing countries, with the improvement and changes of food. ...
Article
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Objective: The patency and quality of transplanted great saphenous vein (GSV) can seriously influence the physical state and life quality of patients who accepted the coronary artery bypass grafting (CABG). Quercetin is known for antioxidant, antithrombotic, anti-inflammatory, and antitumor properties. In this study, we examined the protection of quercetin to the great saphenous vein from oxidative and inflammatory damage. Methods: The GSVs were collected from 15 patients undergoing CABG and cultured. Treated the veins by H2O2 and detected the NO, SOD, and MDA content by the relevant kits to explore the quercetin protection against oxidative damage. Then, for another group of GSVs, sheared them and detected the inflammatory cytokines, such as IL-6, TNFα, CCL20, PCNA, and VEGF. Collect the veins for H&E staining and PCNA and VEGF immunofluorescent staining. Results: Pretreatment by quercetin reduced the production of NO and MDA induced by H2O2, and increased SOD activity. Quercetin also supressed the mRNA expressions of IL-6, TNFα after mechanical damage and had no influence on CCL20 and VEGF. Consistent with the lower expression of PCNA treated by quercetin, the vein intima was thinner. Conclusion: These results demonstrated that quercetin protects GSVs by reducing the oxidative damage and inflammatory response and also suppresses the abnormal thickening of venous endothelium by inhibiting cell proliferation. It reminded that, to some extent, quercetin has the potential to release the great saphenous vein graft damage.
... Some natural ionophores, such as dietary plant polyphenols quercetin (red raspberry, black grapes, broccoli, and red onion) and epigallocatechin-gallate (tea), rapidly increased cell concentrations of zinc [28]. ...
... Among natural compounds, polyphenols like EGCC (Fig. 6), quercetin, and resveratrol can act as Zn ionophores [122,123]. In particular, resveratrol at 5 and 10 μM caused a dramatic increase of cellular total Zn concentration, especially in the presence of a large amount of Zn ions, inhibiting the cell growth of normal human prostate epithelial (NHPrE). ...
Article
Zinc can play a pathophysiological role in several diseases and can interfere in key processes of microbial growth. This evidence justifies the efforts in applying Zinc ionophores to restore Zinc homeostasis and treat bacterial/viral infections such as coronavirus diseases. Zinc ionophores increase the intracellular concentration of Zinc ions causing significant biological effects. This review provides, for the first time, an overview of the applications of the main Zinc ionophores in Zinc deficiency, infectious diseases, and in cancer, discussing the pharmacological and coordination properties of the Zinc ionophores.
... In addition to antimicrobial properties, studies have demonstrated that zinc ionophores such as EGCG [694] and Quercetin [103] have immunomodulatory effects that are associated with beneficial health outcomes including the prevention of cardiovascular diseases and cancers [695][696][697][698][699][700], anti-angiogenic [701,702], anti-arthritic [703,704], anti-oxidative [705,706], cholesterol lowering [707,708], neuroprotective [709,710] and other anti-inflammatory [271,711] properties. Although many mechanisms of action have been proposed for how these compounds achieve the aforementioned effects [271,712] (Table 7), there is limited information on how, or to what extent, ionophore activity plays a role. ...
Article
Ionophores are a diverse class of synthetic and naturally occurring ion transporter compounds which demonstrate both direct and in-direct antimicrobial properties against a broad panel of bacterial, fungal, viral and parasitic pathogens. In addition, ionophores can regulate the host-immune response during communicable and non-communicable disease states. Although the clinical use of ionophores such as Amphotericin B, Bedaquiline and Ivermectin highlight the utility of ionophores in modern medicine, for many other ionophore compounds issues surrounding toxicity, bioavailability or lack of in vivo efficacy studies have hindered clinical development. The antimicrobial and immunomodulating properties of a range of compounds with characteristics of ionophores remain largely unexplored. As such, ionophores remain a latent therapeutic avenue to address both the global burden of antimicrobial resistance, and the unmet clinical need for new antimicrobial therapies. This review will provide an overview of the broad-spectrum antimicrobial and immunomodulatory properties of ionophores, and their potential uses in clinical medicine for combatting infection.
... It should be stressed that both quercetin and epigallocatechin gallate act as antioxidants and signaling molecules, and the functions of many enzymes activated by polyphenolic compounds depend on zinc. Flavonoids have also been shown to act as zinc ionophores, transporting zinc cations through the plasma membrane [104]. In theory, this could enhance the antiviral effects of zinc. ...
Article
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The virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the disease coronavirus disease 2019 (COVID-19). The cumulative number of cases reported globally is now nearly 197 million and the number of cumulative deaths is 4.2 million (26 July to 1 August 2021). Currently we are focusing primarily on keeping a safe distance from others, washing our hands, and wearing masks, and the question of the effects of diet and diet-dependent risk factors remains outside the center of attention. Nevertheless, numerous studies indicate that diet can play an important role in the course of COVID-19. In this paper, based on select scientific reports, we discuss the structure and replication cycle of SARS-CoV-2, risk factors, dietary standards for sick patients, and the roles of the microbiome and dietary components supporting the immune system in preventing COVID-19.
Article
The study aimed to isolate and characterize zinc ionophores from Terminalia bellirica fruit using a liposome assay and test its utility in H9c2 rat cardiomyoblasts cells subjected to hypoxia/reoxygenation. Ethyl acetate extract that exhibited zinc ionophore activity was resolved to yield three polyphenols that were characterized as epicatechin-3-gallate (ECG), epigallocatechin-3-gallate (EGCG) and epigallocatechin (EGC) by nuclear magnetic resonance and electrospray ionization-mass spectra. The polyphenols enhanced the uptake of zinc into the liposomes and increased FluoZin-3 fluorescence. These polyphenols in the presence of 10 μM ZnCl2 enhanced the zinc import into H9c2 cells, whose intracellular zinc levels were otherwise lowered upon hypoxia/reoxygenation. EGCG proved to be more potent than ECG, which indeed was more effective than EGC in improving cellular zinc levels and in attenuating the apoptosis of H9c2 cells after hypoxia/reoxygenation injury. The polyphenols required zinc for anti-apoptotic effect. The cardioprotective effect is indeed due to enhanced zinc uptake mediated by these polyphenols.
Chapter
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Zinc is a trace metal ion that has a role in both physiological and pathological processes, making it one of the most common and necessary components involved in brain function. Besides, zinc is required for cell proliferation control in a variety of mechanisms, including hormonal regulation of cell division. Also, zinc serves as a biochemical signal to immune cells and transcription factors involved in the synthesis of inflammatory cytokines. On the other hand, zinc has a variety of crucial roles in neurogenesis and also acts as a neuromodulator on a wide range of membrane receptors, ion channels, and transporters. Zinc is produced by neurons under several conditions to activate microglia. The link between zinc dysregulation and psychiatric disorder was that zinc acts as an inhibitory modulator at the N-methyl-D aspartic acid (NMDA) glutamate receptor. Ionophores are ion carrier molecules that reversibly bind and transport ions through biological membranes. Ionophores can be natural or synthetic products. Zinc ionophores such as quercetin, epigallocatechin gallate (EGCG), hinokitol, and proanthocyanidins have been shown to protect brain health, particularly in depression clinically significant depression and depressive symptoms in post-COVID-19 syndrome may have severe implications as it relates to life outcomes quality, herein according to previous research studies, we showed zinc deficiency as a possible risk factor for depression symptoms, which were commonly observed following severe infection of COVID-19.
Article
Metal ion dysregulation has been implicated in a number of diseases from neurodegeneration to cancer. While defective metal ion transport mechanisms are known to cause specific diseases of genetic origin, the role of metal dysregulation in many diseases has yet to be elucidated due to the complicated function (both good and bad!) of metal ions in the body. A breakdown in metal ion speciation can manifest in several ways from increased reactive oxygen species (ROS) generation to an increase in protein misfolding and aggregation. In this review, we will discuss the role of Zn in the proper function of the p53 protein in cancer. The p53 protein plays a critical role in the prevention of genome mutations via initiation of apoptosis, DNA repair, cell cycle arrest, anti-angiogenesis, and senescence pathways to avoid propagation of damaged cells. p53 is the most frequently mutated protein in cancer and almost all cancers exhibit malfunction along the p53 pathway. Thus, there has been considerable effort dedicated to restoring normal p53 expression and activity to mutant p53. This includes understanding the relative populations of the Zn-bound and Zn-free p53 in wild-type and mutant forms, and the development of metallochaperones to re-populate the Zn binding site to restore mutant p53 activity. Parallels will be made to the development of multifunctional metal binding agents for modulating the aggregation of the amyloid-beta peptide in Alzheimer's Disease (AD).
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Quercetin is a flavonoid present in fruits, vegetables and plants with beneficial effects in several human disorders, including liver cancer. The antioxidant and anti-inflammatory properties make quercetin an interesting drug to be evaluated in hepatocarcinoma (HCC), the major primary liver tumor with a high mortality rate. Moreover, increasing number of studies reported a high variety of antitumor actions which places quercetin as a promising antitumor agent, not only as single treatment but also improving current therapeutic options against advanced HCC.
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Background Propolis is a resinous product that is collected from plants by bees to cover holes and crevices in their hives. Propolis has potent antibacterial, antiviral, anti-inflammatory, wound healing, and anticancer properties. Propolis has been used therapeutically by humans for centuries, including the treatment of dental caries and mouth infections. Highlight This review article attempts to analyze the potential use of propolis in general dentistry and oral health management. Conclusion Propolis is potentially useful in dentistry and oral health management based on available in vitro, in vivo, and ex vivo studies, as well as human clinical trials.
Article
Ninjin-yoei-to (NYT), a Kampo medicine, has ameliorative effects on cognitive dysfunction via enhancing cholinergic neuron activity. To explore an efficacy of NYT administration for prevention and cure of Alzheimer’s disease, here we examined the effect of NYT on amyloid β1-42 (Aβ1-42)-induced neurodegeneration in the dentate gyrus. A diet containing 3% NYT was administered to mice for 2 weeks and human Aβ1-42 was intracerebroventricularly injected. Neurodegeneration in the dentate granule cell layer of the hippocampus, which was determined 2 weeks after the injection, was rescued by administration of the diet for 4 weeks. Aβ staining (uptake) was not modified in the dentate granule cell layer by pre-administration of the diet for 2 weeks, while Aβ1-42-induced increase in intracellular Zn²⁺ was reduced, suggesting that pre-administration of NYT prior to Aβ injection is effective for reducing Aβ1-42-induced Zn²⁺ toxicity in the dentate gyrus. As a matter of fact, Aβ1-42-induced neurodegeneration in the dentate gyrus was rescued by pre-administration of NYT. Interestingly, the level of metallothioneins, intracellular Zn²⁺-binding proteins, which can capture Zn²⁺ from Zn-Aβ1-42 complexes, was elevated in the dentate granule cell layer by pre-administration of NYT. The present study suggests that pre-administration of NYT prevents Aβ1-42-mediated neurodegeneration in the dentate gyurs by induced synthesis of metallothioneins, which reduces intracellular Zn²⁺ toxicity induced by Aβ1-42.
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Zinc deficiency is linked to poor prognosis in COVID-19 patients while clinical trials with Zinc demonstrate better clinical outcome. The molecular target and mechanistic details of anti-coronaviral (SARS-CoV2) activity of Zinc remain obscure. We show that ionic Zinc not only inhibits SARS-CoV-2 main protease (Mpro) with nanomolar affinity, but also viral replication. We present the first crystal structure of Mpro-Zinc ²⁺ complex at 1.9 Å and provide the structural basis of viral replication inhibition.
Article
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Zinc plays an important role in the regulation of many cellular functions; it is a signaling molecule involved in the transduction of several cascades in response to intra and extracellular stimuli. Labile zinc is a small fraction of total intracellular zinc, that is loosely bound to proteins and is easily interchangeable. At the cellular level, several molecules can bind labile zinc and promote its passage across lipophilic membranes. Such molecules are known as ionophores. Several of these compounds are known in the scientific literature, but most of them can be harmful to human health and are therefore not allowed for medical use. We here performed a theoretical three-dimensional study of known zinc ionophores, together with a computational energetic study and propose that some dietary flavonoids, glutathione and amino acids could form zinc complexes and facilitate the transport of zinc, with the possible biological implications and potential health benefits of these natural compounds. The study is based on obtaining a molecular conformational structure of the zinc complexes with the lowest possible energy content. The discovery of novel substances that act as zinc ionophores is an attractive research topic that offers exciting opportunities in medicinal chemistry. We propose that these novel complexes could be promising candidates for drug design to provide new solutions for conditions and diseases related to zinc deficiency or impairment derived from the dysregulation of this important metal.
Research Proposal
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Research Proposal DOI:10.6084/m9.figshare.15153186 License CC BY 4.0 Authors and Affiliation: Amr Kamel Khalil Ahmed - Director of the tuberculosis program Ghubera, public health department, First health cluster, Ministry of Health, Riyadh, Saudi Arabia ORCiD: https://orcid.org/0000-0003-3477-236X Mahmoud Elkazzaz - Department of chemistry and biochemistry, Faculty of Science, Damietta University, Egypt ORCiD: https://orcid.org/0000-0003-3703-520X Michelle Carole Orzechowski - CEO of Coronavirus Corporation Epidemiology, Research, and Development, - Vaccines/Medications/Lab Testing, Lutz, United States of America ORCiD: https://orcid.org/0000-0002-8541-8726 Project Title: The Combination of Quercetin and Bromelain with Zinc, EGCG, Retinoic Acid, Vitamin C and Vitamin D for the potential Symptom Reducer, Prevention, and Treatment for Coronavirus Disease 2019 (COVID-19) These products are unapproved new drugs not being sold in violation of section 505(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 2pt1 U.S.C. § 355(a). Furthermore, these products are not misbranded drugs under section 502 of the FD&C Act, 21 U.S.C. § 352. The introduction or delivery for introduction of these products into interstate commerce is prohibited under sections 301(a) and (d) of the FD&C Act, 21 U.S.C. § 331(a) and (d). [1] Hypotheses: The Combination of Quercetin and Bromelain with Zinc, EGCG, Retinoic Acid, Vitamin C, and Vitamin D when taken together may Inhibit the Viral Replication of Anti-Cytokine Storm and an Antiviral against RNA Viruses like Coronavirus Disease 2019 (COVID-19) by using the formulations including Zinc; Zinc Ionophores (Quercetin); Bromelain, EGCG, Retinoic Acid, Vitamin C and Vitamin D. Zinc Ionophores possibly enhance transport of Zinc into the Cells to effect Intra-Cellular Zinc levels and potentially impair intracellular replication of Coronavirus Disease 2019 (COVID-19). [12] Zinc regulates Adaptive Immune Cell Functions with High levels of Intracellular pH as RNA-dependent and RNA polymerase decreases the replication of RNA viruses like COVID-19. Quercetin has chelate Zinc Ions and acts as a Zinc Ionophore. Bromelain activates Natural Killer Cells and the production of Granulocyte-Macrophage Colony Stimulating Factor, Interleukin-2, and Interleukin-6 decreases the activation of T-helper cells. EGCG can suppress ACE2 (a cellular receptor for SARS-CoV-2) and TMPRSS2, which mediate cell entry of the virus. Retinoic Acid has a characteristic of antiviral, Immunity induction, ACE2 upregulation or downregulation, and anti-clotting. Vitamin C has Enzymatic Co-Factor for Hormone Production, Collagen Synthesis, and Immune Potentiation. Vitamin D regulates the Inflammatory Cytokine Response. Vitamin D deficiency has been associated with increased COVID-19 mortality and is commonly confounded by increasing age, obesity, diabetes, darker skin tones, and lack of fitness. Introduction: Zinc alone is a potent inhibitor of viral replication. Zinc in the combination with Quercetin potentially synergistic in reducing viral replication since Quercetin is potentially a Zinc Ionophore facilitating intracellular entry and inhibition of intracellular viral replication. Zinc in the combination with Quercetin can access the DNA cellular layer and stop SARS-CoV-2 from replicating RNA cells, potentially resetting replicated cells, Treating the Coronavirus disease 2019 (COVID-19). Quercetin 800 mg, bromelain 165 mg, zinc acetate 50 mg and ascorbic acid 1 g once daily as supplements for 3 to 5 days were safe for patients infected with SARS-CoV-2 and may prevent poor prognosis through restraining from hyper-inflammation and cytokine storm. Randomized clinical trials are needed in the future to ensure the efficacy of quercetin, bromelain, zinc, and ascorbic acid combination. [11.2] In addition to proper PPE and the COVID-19 vaccination, The Combination of Quercetin and Bromelain with Zinc, EGCG, Retinoic Acid, Vitamin C, and Vitamin D may be an effective Symptom Reducer for Coronavirus Disease 2019 (COVID-19) [14] On 09/30/2021 The Center for Biologics Evaluation and Research Vaccines and Related Biological Products Advisory Committee will meet. [15] The pathogen, a novel coronavirus (SARS-CoV-2), was identified by local hospitals using a surveillance mechanism for "pneumonia of unknown etiology" that was established in the wake of the 2003 SARS outbreak to allow timely identification of novel pathogens. The immune system plays a critical role in protecting the human body from infectious diseases. T-cell counts are reduced significantly in COVID-19 patients, and the surviving T-cells appear functionally exhausted. Non-ICU patients with total T cell counts lower than 800/μ L may still require urgent intervention, even in the immediate absence of more severe symptoms due to a high risk for further deterioration in condition. Further research on the severity of comorbidities and all medication received by the patients is mandatory to shed light on these associations. [11] The Role of Zinc Since the discovery of the first reported case with zinc - deficiency in Iran by Prasad et al. in 1961 we have learned a lot about Zinc, and we have much more left to learn. Zinc is the second most abundant common trace mineral in the human body, with vital biological functions from cell growth and development to cell homeostasis and immune response. Mechanical ventilation is a necessary intervention to support patients with lung injury and acute respiratory distress syndrome (ARDS) but can also exacerbate injury through mechanical stress-activated signaling pathways. It is shown that stretch applied to cultured human lung cells, and mouse lungs in vivo induce robust expression of metallothionein, a potent antioxidant and cytoprotective molecule critical for cellular zinc homeostasis. Furthermore, genetic deficiency of murine metallothionein genes exacerbated lung injury caused by injurious mechanical ventilation, identifying an adaptive role for these genes in limiting lung injury. Stretch induction of metallothionein required zinc and the zinc-binding transcription factor MTF- We further show that dietary zinc- deficiency in mice potentiates ventilator-induced lung injury, and that plasma zinc levels were significantly reduced in human patients with ARDS compared to healthy and non-ARDS ICU controls. [11] Zinc sulfate 220 mg (50 mg elemental zinc) can be taken orally per day. [3] Zinc: It May have some anti-viral properties. Doses of 15-30 mg of zinc per day are presumed to be safe, short-term, for one to two weeks. Zinc can interact with other medications (antibiotics and antivirals), and long-term use of high doses of zinc can cause copper deficiency. [13] The Role of Quercetin A natural flavonoid molecule that is distributed broadly in many fruits and vegetables including red onion, cranberry, kale, tomatoes, Hungarian wax, and watercress. It was revealed in previous studies that quercetin has an anti-inflammatory and anti-hypersensitivity effect by preventing pro-inflammatory prostaglandins and leukotrienes through inhibiting cyclooxygenase (COX) and lipoxygenase (LOX) enzymes, therefore; quercetin was used as an extract in various trials to treat different infectious and non-infectious diseases. In addition, quercetin showed to reduce tumor necrosis factor-alpha (TNF-α) production with chronic inflammation. Reduction in the ratio of CD4 + CD8 + T cells and suppression of macrophages, dendritic, mast cells, and interleukin-6 (IL-6) levels were revealed after a specific tissue was treated with quercetin in pre-clinical studies. Besides, quercetin is expected to have antiviral activity by acting as a zinc chelator and as a zinc ionophore as well. However, because most of these studies were done by using quercetin in-vitro with high concentration and in-vivo studies cannot use the same doses; it's showed minimum effect during clinical trials. The available data clarifies that quercetin is a very safe molecule and used as a nutritional supplement with a dose reached 1500 mg divided per day. [11.2] Quercetin (also known as 3,5,7,3',4' pentahydroxyflavone, is a widely distributed plant flavonoid, found in several vegetables, leaves, seeds, and grains, where it is conjugated with residual sugars to form Que glycosides. Studies suggest that Quercetin supplementation may promote antioxidant, anti-inflammatory, antiviral, and immune protective effects. Quercetin has been studied in various types and models of viral infection due to its promising antiviral effects in inhibiting polymerases, proteases, reverse transcriptase, suppressing DNA gyrase, and binding viral capsid proteins. Recently, Quercetin has been shown to inhibit in vitro production of cyclooxygenase (COX) and lipoxygenase (LOX) which are typically induced by inflammation. The anti-inflammatory effect has been supported by in vivo experiments as well. Examples of Quercetins inhibitory qualities include the significant blocking of pro-inflammatory cytokines in cultured fibroblasts. 10 𝜇M Quercetin downregulated the production of COX-2, the Nuclear Factor kappa B (NF-𝜅B), and NO. 10–25 𝜇M Quercetin inhibited the level of NO and TNF-𝛼. Other properties of 50 and 100 𝜇M Quercetin include reducing the secretion of IL6 and TNF-𝛼 in LPS-stimulated RAW 264.7 microphages, while at 25 and 50 𝜇M it proved to be the most efficient blocker of TNF-𝛼 secretion in macrophages. Finally, at low concentrations, Quercetin (less than 50 𝜇M) also stimulated anti-inflammatory cytokine IL-10. Similarly, 25𝜇M Quercetin blocked IL-1𝛽, IL-6, IFN-𝛾, and TNF-𝛼 secretion in human whole blood induced by LPS. Quercetin can also inhibit pro-inflammatory cytokines. A six-week regiment of 150 milligrams of Quercetin taken daily by human subjects significantly lowered cytokine TNF-𝛼 serum concentrations. Quercetin effectively inhibited LPS-induced DC activation by reducing the production of pro-inflammatory cytokines/chemokines and the expression levels of MHC class II and costimulatory molecules. In addition, Quercetin uniquely blocked endocytosis by Dendritic Cells DCs, and the LPS-induced DC migration was diminished by Quercetin treatment. Quercetin has been shown clinically to block human mast cell cytokine release, possibly inhibiting the clinical manifestation of a cytokine storm. Severe COVID-19 disease progression is associated with increased levels of C-Reactive protein, D-Dimer, Ferritin, IL-2, and IL-6. Quercetin has been shown in studies to reduce all these markers. Balancing systemic iron levels within narrow limits is critical for maintaining human health. There are no known pathways to eliminate the excess iron from the body and therefore iron homeostasis is maintained by modifying dietary absorption so that it matches daily obligatory losses. Several dietary factors can modify iron absorption. Polyphenols are plentiful in the human diet and many compounds, including Quercetin's most abundant dietary polyphenol, are potent iron chelates. Quercetin is a zinc ionophore and could have a similar antiviral activity to chloroquine but is described as a safe choice in the treatment of viral infections. [11.3] Quercetin is a polyphenol that has a theoretical mechanism of action that could reduce the activity of a SARS-CoV-2 entry through the ACE2 receptor, inhibit viral proteases via conveyance of Zinc, and attenuate inflammatory responses mediated through interleukin-6. The mechanisms of action favorably affect viral replication and immune response, so it is conceivable that this agent taken in combination with others discussed could play an assistive role in reducing early viral amplification and tissue damage. The suggested dose of quercetin is 500 mg BID. [10] Quercetin: A naturally occurring antioxidant/flavonoid that may have benefits for allergic rhinitis and possibly in exercise-induced respiratory infections. Quercetin may interact with some antibiotics known as fluoroquinolones (ciprofloxacin, levofloxacin) and could also interact with other medications that are metabolized through your liver system known as the cytochrome p450 enzyme system (3A4 and 2C9). These drugs may include warfarin, midazolam, cyclosporine, drugs known as the "statins" (atorvastatin, pravastatin, rosuvastatin, simvastatin), medications known as non-steroidal anti-inflammatory drugs (ibuprofen, diclofenac, naproxen), tamoxifen, and possibly losartan. There is also a possibility it may interact in those individuals with hypothyroidism. Use caution in these patients. Doses of 500 mg twice daily have been studied and shown to be possibly safe for up to twelve weeks. [13] The Role of Bromelain Protein enzyme is found mainly in the stem of the pineapple plant. The bioavailability of bromelain was high through the oral route and was safe even when consumed more than 11 grams per day. In vitro studies showed that bromelain exerts anti-inflammatory effects through reducing bradykinin serum and modulating the expression of some genes related to inflammation. Three genes related to inflammation including TLR4, TNF-α, and IL-8 were found to be less expressed after bromelain treatment. On the other hand, PPARγ gene expression was elevated after treatment with bromelain. Therefore, bromelain may have a role in reducing inflammations during various disorders and may be used in combination with other analgesics and anti-inflammatory drugs. Since the inflammatory status of patients during COVID-19 may lead to severe consequences and even death if not prevented or treated adequately; it is important to ensure high-quality care to patients and provide evidence-based prophylaxis and treatment. [11.2] Bromelain activates the inflammatory mediators, including interleukin (IL)-1β, IL-6, interferon (INF)-γ, and tumor necrosis factor (TNF)-α in mouse macrophage and human peripheral blood mononuclear cells (PBMC) (Barth). These results indicated that bromelain potentially activates the healthy immune system in association with the rapid response to cellular stress. Conversely, bromelain reduces IL-1β, IL-6, and TNF-α secretion when immune cells are already stimulated in the condition of inflammation-induced overproduction of cytokines. It was also found that bromelain upregulated p53 and Bax with consequent activation of Caspase 3 and Caspase 9 with a concomitant decrease in BCL2. Marked inhibition of cyclooxygenase 2 (COX2) expression with inactivation of NF Kappa B by blocking phosphorylation and degradation of IK B α were blocked by bromelain. Furthermore, bromelain ameliorated extracellular signal of regulated protein kinase ERK1/2, P38 mitogen-activated protein kinase MAPK and Akt activity. So, it modulated defective cellular signaling cascades. Bromelain prevents or minimizes the severity of angina pectoris and transient ischemic attack (TIA). It is useful in the prevention and treatment of thrombophlebitis. It may also break down cholesterol plaques and exert a potent fibrinolytic activity. A combination of bromelain and other nutrients protects against ischemia/reperfusion injury in skeletal muscle. Bromelain influences blood coagulation by increasing the serum fibrinolytic ability and by inhibiting the synthesis of fibrin, a protein involved in blood clotting. [11.3] Bromelain: An enzyme that comes from the stalk of the pineapple. It has been shown to have some activity in reducing symptoms for acute sinusitis2. It can, however, interact with blood thinners such as warfarin, and also certain antibiotics such as tetracyclines. Use with caution for these agents [13] The Role of EGCG Via activating Nrf2, can suppress ACE2 (a cellular receptor for SARS-CoV-2) and TMPRSS2, which mediate cell entry of the virus. Through inhibition of SARS-CoV-2 main protease, EGCG may inhibit viral reproduction. EGCG via its broad antioxidant activity may protect against SARS-CoV-2 evoked mitochondrial ROS (which promote SARS-CoV-2 replication) and against ROS burst inflicted by neutrophil extracellular traps. By suppressing ER-resident GRP78 activity and expression, EGCG can potentially inhibit the SARS-CoV-2 life cycle. EGCG also shows protective effects against 1) cytokine storm-associated acute lung injury/acute respiratory distress syndrome, 2) thrombosis via suppressing tissue factors and activating platelets, 3) sepsis by inactivating redox-sensitive HMGB1, and 4) lung fibrosis through augmenting Nrf2 and suppressing NF-κB. These activities remain to be further substantiated in animals and humans. The possible concerted actions of EGCG suggest the importance of further studies on the prevention and treatment of COVID-19 in humans. These results also call for epidemiological studies on the potential preventive effects of green tea drinking on COVID-19. [12] The Role of Retinoic Acid Angiotensin-converting enzyme (ACE2) protein found on the cell membranes is the target of SARS-CoV-2 for entering into the host cells. Viral spike protein-binding with ACE2 down-regulates it. As ACE2 is known to protect the lung from injuries, SARS-CoV-2-induced ACE2 deficiency may expose patients to lung damage. In this Review, we use established and emerging evidence based on the findings of previous studies and researches to propose a testable hypothesis that a Combination of chemopreventive agents (All-Trans Retinoic acid and Tamoxifen) can be tested to prevent inflammatory complications in severe acute respiratory syndrome coronavirus 2 infections via two mechanisms by inhibiting bradykinin B1, B2 receptors expression and upregulating the depleted ACE2 in COVID-19. Bradykinin B1 receptors are not expressed under physiological conditions but are induced under inflammatory conditions. Here we hypothesize that permanent attack and invasion of COVID-19 to lung epithelial cells via binding to ACE2 leads to tissue injury and inflammation and that increases BK levels and BK-B2-receptor (B2R) stimulation A study reported that tissue injury and inflammation increases BK levels and BK-B2-receptor (B2R) stimulation. We suggest that Bradykinin mediates and induces lung injury, pro-inflammatory cytokines, and inflammation likely precipitates life-threatening respiratory complications in COVID-19. Further experiments showed that BK treatment stimulated IL-6 production On the other hand a study reported that cells treated with Retinoic acid and Tamoxifen for 48 h significantly decreased the BK-B2 receptor protein levels (70.3 ± 0.6% vs. 100% of control, P < 0.05). Retinoids inhibit bradykinin B1 receptor-sensitized responses and this action could participate in their anti-inflammatory and immunomodulatory effects. In addition, retinoic acid is known to possess in vivo anti-inflammatory, antiplatelet and fibrinolytic activities. A study investigated the in vitro thrombin and platelet aggregation inhibitory activities of retinoic acid and retinaldehyde. Retinoic acid, retinaldehyde, and retinol exhibited potent inhibition of thrombin, with IC50 values of 67μg/ml, 74μg/ml and 152μg/ml, respectively for the inhibition of thrombin (Sigma); and 49μg/ml, 74μg/ml and 178μg/ml, respectively for the inhibition of thrombin (plasma). Amongst vitamin A and its derivatives, retinoic acid showed the highest inhibition of both forms of thrombin. Besides the effectiveness of TAM on cancer cells, it also has other effects on numerous microbes including parasites, fungi, bacteria, and some viruses such as the Ebola virus and human immunodeficiency virus (HIV). Furthermore, Tamoxifen can block the action of interleukin 6 and inhibit neutrophils. A study demonstrated that tamoxifen has side effects associated with neutropenia. Since tamoxifen can cause neutropenia and subsequently influence the neutrophil-to-lymphocyte ratio (NLR) value In addition it has an anti-malarial effect similar to chloroquine In conclusion. [16] The Role of Vitamin C Exerts its antiviral properties by supporting lymphocyte activity, increasing interferon-α production, modulating cytokines, reducing inflammation, improving endothelial dysfunction, and restoring mitochondrial function. There are also suggestions that Vitamin C may be directly viricidal. The in vitro effects constitute a reflection of both the supra-physiological concentrations of ascorbate and the interaction between Vitamin C and metal-containing culture media - both of which are pro-oxidant, generating reactive oxygen species. [11] Vitamin C has been used in a variety of viral infections and could be useful in combination with other supplements in COVID19 [10] Vitamin C: may help reduce the severity and duration of a cold, especially if you start taking Vitamin C before feeling ill. 500 mg- 1000 mg of Vitamin C twice a day is a typical starting dose to try to help boost immunity. People with kidney issues should use it with caution as Vitamin C is eliminated by the kidneys. [13] The Role of Vitamin D Coronavirus disease 2019 (COVID-19) has caused global disruption and a significant loss of life. Existing treatments that can be repurposed as prophylactic and therapeutic agents could reduce the pandemic's devastation. Emerging evidence of potential applications in other therapeutic contexts has led to the investigation of dietary supplements and nutraceuticals for COVID-19. Such products include Quercetin, Bromelain, Zinc, EGCG, Vitamin C, and Vitamin D; all of which are currently under clinical investigation. In this review, we critically appraise the evidence surrounding dietary supplements and nutraceuticals for the prophylaxis and treatment of COVID-19. Overall, further study is required before evidence-based recommendations can be formulated, but nutritional status plays a significant role in patient outcomes, and these products could help alleviate deficiencies. For example, evidence indicates that vitamin D deficiency may be associated with a greater incidence of infection and severity of COVID-19, suggesting that vitamin D supplementation may hold prophylactic or therapeutic value. A growing number of scientific organizations are now considering recommending vitamin D supplementation to those at high risk of COVID-19. Because research in vitamin D and other nutraceuticals and supplements is preliminary, here we evaluate the extent to which these nutraceutical and dietary supplements hold potential in the COVID-19 crisis. [12.23] Vitamin D: May help reduces the number of respiratory illnesses, especially for those who are deficient. Supplementing with 1,000-2,000 international units per day may be beneficial. Vitamin D levels can be monitored, it is recommended to not exceed blood levels of 50 nanograms/ milliliter of Vitamin D. [13] Background: Milan, Italy had the first specimen detect SARS-CoV-2 from the specimen source: Oropharyngeal Swab, collected on 2019-12-05 but was submission received was reported on 2020-11-30. Wuhan, China, however, had the first specimen identified SARS-CoV-2 from the specimen source: Bronchoalveolar lavage, collected on 2019-12-24 and submission received was reported first on 2020-01-11. Reported submissions of SARS-CoV-2 globally in Humans, Animals, and the Environment. Currently, 9 different Variants are emerging from SARS-CoV-2 including Alpha, Beta, Gamma, Delta, Eta, Iota, Kappa, Lambda, and Mu that have been reported as of 01-Sep-2021. There have been over 1,200 reported cases of SARS-CoV-2 in the following submitted specimens for 14 different Animals including Dog, Cat, Hamster, Mouse, Otter, Monkey, Gorilla, Anteater, Mink, Lion, Tiger, Leopard, Snow Leopard, and Bat. There have been over 1,200 reported cases of SARS-CoV-2 in the Environment from the following samples: Sewer and Wastewater. [0] There is currently a global outbreak of respiratory disease caused by a novel coronavirus that has been named "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2). The disease caused by the virus has been named "Coronavirus Disease 2019" (COVID-19). On January 31, 2020, the Department of Health and Human Services (HHS) issued a declaration of a public health emergency related to COVID-19 and mobilized the Operating Divisions of HHS. In addition, on March 13, 2020, there was a Presidential declaration of a national emergency in response to COVID-19. Therefore, FDA is taking urgent measures to protect consumers from certain products that, without approval or authorization by FDA, claim to mitigate, prevent, treat, diagnose, or cure COVID-19 in people. [1] At the Pharmacy Compounding Advisory Committee on September 12, 2018, the FDA was proposing that quercetin dihydrate NOT be included on the 503A Bulks List. The Vote Result proposing if quercetin dihydrate should be placed on the list was: YES: 0 NO: 11 ABSTAIN: 0. The Meeting Committee Discussion for the Vote was that: The committee unanimously agreed that quercetin dihydrate NOT be included on the 503A Bulks List. Many committee members expressed concerns with the lack of reasonable data supporting the use of quercetin dehydrate in its proposed indications, the number of known drug interactions with this product, and the number of products that are currently available for these conditions are already proven to be safe and efficacious. Several committee members also noted that the product is widely available over-the-counter as an oral dietary supplement, and in the future, more substantial data would be needed to consider an IV formulation. Please note that one committee member was not present for the vote. Please see the transcript for details of the committee discussion. [2] Discussion: There are an overwhelming amount of Abstracts currently for Coronavirus Disease 2019 (COVID-19) using either Quercetin, Bromelain, Zinc, EGCG, Vitamin C, or Vitamin D as a Symptom Reducer, Prevention and/or treatment. [12] There is only ONE study currently on https://clinicaltrials.gov for Quercetin and Bromelain with Zinc and Vitamin C for Coronavirus Disease 2019 (COVID-19) [11] There are ZERO studies on https://clinicaltrials.gov for Quercetin and Bromelain with Zinc, EGCG, Vitamin C, and Vitamin D for Coronavirus Disease 2019 (COVID-19) [12] Limitations: There is a lack of research conducted for Quercetin and the FDA voted not to during Evaluation and Research on 09/2018 [2], The FDA decreased the daily dose of Zinc, Vitamin C, and Vitamin D on 03/2020 [3], A 02/2021 FDA warning letter issued regarding Zinc, Vitamin C and Vitamin D stating without approval or authorization by FDA to claim to mitigate, prevent, treat, diagnose, or cure COVID-19 in people. [1] On 11-FEB-2021 the COVID-19 Treatment Guidelines Panel Voted as followed and was published for the 25-AUG-2021 COVID-19 Treatment Guidelines: [15] Vitamin C - There is insufficient evidence for the COVID-19 Treatment Guidelines Panel (the Panel) to recommend either for or against the use of vitamin C for the treatment of COVID-19. Vitamin D - There is insufficient evidence for the Panel to recommend either for or against the use of vitamin D for the treatment of COVID-19. Zinc - There is insufficient evidence for the Panel to recommend either for or against the use of zinc for the treatment of COVID-19. • The Panel recommends against using zinc supplementation above the recommended dietary allowance for the prevention of COVID-19, except in a clinical trial (BIII). In addition to the antiviral medications and the immune-based therapies that are discussed elsewhere in the COVID-19 Treatment Guidelines, adjunctive therapies are frequently used in the prevention and/or treatment of COVID-19 or its complications. Some of these agents are being studied in clinical trials. Some clinicians advocate for the use of vitamin and mineral supplements to treat respiratory viral infections. Ongoing studies are evaluating the use of vitamin and mineral supplements for both the treatment and prevention of SARS-CoV-2 infection. [15] The Food and Drug Administration, Center for Drug Evaluation and Research on 12-Sep-2018 unanimously voted not to research quercetin dihydrate for the indications: Asthma, allergy, cancer prevention and treatment, and hypertension. Many committee members expressed concerns with the lack of reasonable data supporting the use of quercetin dehydrate in its proposed indications, the number of known drug interactions with this product, and the number of products that are currently available for these conditions Also, that are already proven to be safe and efficacious. the product is widely available over-the-counter as an oral dietary supplement [2] On 18-Feb-2021 the FDA took urgent measures to protect consumers from certain products that, without approval or authorization by FDA, claim to mitigate, prevent, treat, diagnose, or cure COVID-19 in people. [1] With changes on March 2020 for the Daily Value and Percent Daily Value: Changes on the New Nutrition and Supplement Facts Labels. FDA suggested doses as of 03/2020 are as followed: [3] Zinc - 11 mg QD - FDA suggested dose Before 03/2020 Zinc 15 mg QD [1] Vitamin A – 900 mcg QD - FDA suggested dose Before 03/2020 5,000 IU QD [1] Vitamin C - 90 mg QD - FDA suggested dose Before 03/2020 60 mg QD [1] Vitamin D - 20 mcg QD - FDA suggested dose Before 03/2020 400 IU QD [1] Significance: The Counter use of Quercetin and Bromelain is available for ages Two Years Old and older at a Maximum Suggested Dose of Quercetin 800 mg, and Bromelain 200 mg. [6.3] [7.5] Conclusion: Over the Counter Quercetin 800 mg QD, Bromelain 200 mg QD, Zinc 11mg QD, Vitamin A 900 mcg QD, Vitamin C 90 mg QD, and Vitamin D 20 mcg QD taken in combination together with Green Tea is potentially safe together for reducing the severity of symptoms in COVID-19 infection from ages Two Years Old and Older. The Combination of Quercetin and Bromelain with Zinc, EGCG, Retinoic Acid, Vitamin C, and Vitamin D might help reduce the COVID-19 vaccine symptoms and would potentially be a promising addition to proper PPE with COVID-19 Vaccinations to help combat the fight on Coronavirus Disease 2019 (COVID-19). This combination is available online and in stores around the world. [17] Conflict of Interest: The Authors have no Conflict of Interest. Funding: N/A Authors: Dr. Amr Ahmed - Ministry of Health - Saudi Arabia Dr. Abdullah Al.Kattan - King Faisal University - Saudi Arabia Mahmoud Elkazzaz - Biochemistry Master Degree – Kafr Elksheikh University, Egypt Michelle C. Orzechowski - Certified Clinical Research Coordinator – United States of America Correspondence to: Author/Abstract Writer: Michelle C. Orzechowski, CCRC Email: Morzechowski4122014@Gmail.com Keywords: Quercetin Intake, Bromelain Treatment, Zinc Chelating Strategies, EGCG, Retinoic Acid, Vitamin C Effect, Vitamin D Acts References: [0] Evidence of SARS-CoV-2 RNA in an Oropharyngeal Swab Specimen, Milan, Italy, Early December 2019 https://wwwnc.cdc.gov/eid/article/27/2/20-4632_article GISAID [1] Secretary of Health and Human Services, Determination that a Public Health Emergency Exists (originally issued Jan. 31, 2020, and subsequently renewed), available at https://www.phe.gov/emergency/news/healthactions/phe/Pages/default.aspx. Proclamation on Declaring a National Emergency Concerning the Novel Coronavirus Disease (COVID-19) Outbreak (Mar. 13, 2020), available at https://trumpwhitehouse.archives.gov/presidential-actions/proclamationdeclaring-national-emergency-concerning-novel-coronavirus-disease-covid-19-outbreak/. As explained in the next paragraph, there is currently an outbreak of a respiratory disease named "Coronavirus Disease 2019" (COVID-19) https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/mercolacom-llc-607133-02182021 [2] Food and Drug Administration Center for Drug Evaluation and Research Summary Minutes of the Pharmacy Compounding Advisory Committee Meeting September 12, 2018, https://www.fda.gov/media/121380/download https://www.fda.gov/drugs/human-drug-compounding/bulk-drug-substances-used-compounding-under-section-503a-fdc-act [3] Daily Value and Percent Daily Value: Changes on the New Nutrition and Supplement Facts Labels https://www.fda.gov/media/135301/download [4] Zinc https://www.drugs.com/npp/zinc.html https://www.drbvitamins.com/shop/zinc-90-veggiecap Zinc and SARS‑CoV‑2: A molecular modeling study of Zn interactions with RNA‑dependent RNA‑polymerase and 3C‑like proteinase enzymes Link: https://www.spandidos-publications.com/10.3892/ijmm.2020.4790 [5] EGCG https://www.drugs.com/npp/green-tea.html https://www.nowfoods.com/supplements/egcg-green-tea-extract-400-mg-veg-capsules [6] Quercetin https://www.drugs.com/npp/quercetin.html https://www.drbvitamins.com/shop/quercetin-bromelain-veggiecap https://reddremedies.com/products/childrens-sinus-support https://www.nowfoods.com/supplements/quercetin-bromelain-veg-capsules [7] Bromelain https://www.drugs.com/npp/pineapple.html https://www.drbvitamins.com/shop/quercetin-bromelain-veggiecap https://www.fda.gov/food/generally-recognized-safe-gras/enzyme-preparations-used-food-partial-list https://rd.springer.com/content/pdf/10.1007/PL00000936.pdf https://creeksidenaturals.com/product/snifflex/ https://www.nowfoods.com/supplements/quercetin-bromelain-veg-capsules [8] Vitamin C https://www.drugs.com/mtm/vitamin-c.html https://www.drbvitamins.com/shop/vitamin-c-1000mg-360-veggiecaps https://www.nowfoods.com/supplements/c-1000-zinc-immune-veg-capsules [9] Vitamin D https://www.drugs.com/pro/vitamin-d-ergocalciferol.html https://www.drbvitamins.com/shop/vitamin-d-5000iu-360-softgel https://www.nowfoods.com/supplements/vitamin-d-3-5000-iu-softgels [10] Sabine Hazan, M.D A Study of Hydroxychloroquine, Vitamin C, Vitamin D, and Zinc for the Prevention of COVID-19 Infection (HELPCOVID-19) https://clinicaltrials.gov/ct2/show/NCT04335084 Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19) Link: https://dx.doi.org/10.31083/j.rcm.2020.04.264 Detection of SARS‑CoV‑2 from patient fecal samples by whole genome sequencing Link: https://dx.doi.org/10.1186/s13099-021-00398-5 [11] Dr. Abdullah Al.Kattan & Dr. Amr Ahmed The Study of Quadruple Therapy Zinc, Quercetin, Bromelain and Vitamin C on the Clinical Outcomes of Patients Infected With COVID-19 Link: https://clinicaltrials.gov/ct2/show/NCT04468139 Ahmed, Amr & Abdelseed, Heba & Albalawi, Yousef & Aslsalameen, Eman & Almutairi, Yousef & Alkattan, Abdullah & Arabia, Saudi. (2020). Evaluation of the Effect of Zinc, Quercetin, Bromelain, and Vitamin C on COVID-19 Patients. 10.1101/2020.12.22.20245993. Coronavirus disease 2019 (COVID-19) is an infectious disease caused by a new strain of coronavirus. There are three phases of COVID-19: early infection stage, pulmonary stage, and hyper-inflammation stage respectively. It is important to prevent lung or other organs injuries by preventing phase-II and phase-III via pharmacological or non-pharmacological treatments. This was a case series study done on twenty-two patients confirmed to be infected with SARS-CoV-2 and diagnosed with COVID-19. Patients in this study have been using quercetin 800 mg, bromelain 165 mg, zinc acetate 50 mg, and ascorbic acid 1 g once daily as supplements for 3 to 5 days during SARS-CoV-2 infection. This study aims to evaluate the safety and efficacy of quercetin, bromelain, zinc, and ascorbic acid combination supplements on patients with COVID-19. The mean levels of WBC, ANC, ALC, AMC, and AST were normal among all included patients before and after taking quercetin, bromelain, zinc, and ascorbic acid supplements (P-value > 0.05). Quercetin 800 mg, bromelain 165 mg, zinc acetate 50 mg, and ascorbic acid 1 g once daily supplements were safe for patients infected with SARS-CoV-2 and may prevent poor prognosis. Randomized clinical trials are needed in the future to ensure the efficacy of quercetin, bromelain, zinc, and vitamin c combination. Research References: Evaluation of the Effect of Zinc, Quercetin, Bromelain and Vitamin C on COVID-19 Patients December 2020 https://dx.doi.org/10.1101/2020.12.22.20245993 Sadeghi Dousari, Amin et al. "COVID-19 (Coronavirus Disease 2019): A New Coronavirus Disease." Infection and drug resistance vol. 13 2819-2828. 12 Aug. 2020, Link: https://dx.doi.org/10.2147/IDR.S259279 Kaur, Supreet et al. "The looming storm: Blood and cytokines in COVID-19." 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Clinical and vaccine immunology: CVI vol. 13,3 (2006): 319-28. Link: https://dx.doi.org/10.1128/CVI.13.3.319-328.2006 Kobori, Masuko et al. "Quercetin suppresses immune cell accumulation and improves mitochondrial gene expression in adipose tissue of diet-induced obese mice." Molecular nutrition & food research vol. 60,2 (2016): 300-12. Link: https://doi:10.1002/mnfr.201500595 Gang Xiong, Wansheng Ji, Fei Wang, Fengxiang Zhang, Peng Xue, Min Cheng, Yanshun Sun, Xia Wang, Tianliang Zhang, "Quercetin Inhibits Inflammatory Response Induced by LPS from Porphyromonas gingivalis in Human Gingival Fibroblasts via Suppressing NF-κB Signaling Pathway", BioMed Research International, vol. 2019, Article ID 6282635, 10 pages, 2019 Link: https://dx.doi.org/10.1155/2019/6282635 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. 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Link: https://dx.doi.org/10.1007/s12250-017-4057-9doi:10.3892/br.2016.720 Verma N, Meena NK, Majumdar I, Paul J (2017) Role of Bromelain as Herbal AntiInflammatory Compound Using In Vitro and In Vivo Model of Colitis. J Autoimmune Disord Vol 3:52. 15 Wong G, He S, Siragam V, Bi Y, Mbikay M, Chretien M, Qiu X. Antiviral activity of quercetin-3-β-O-D-glucoside against Zika virus infection. Virol Sin. 2017 Dec;32(6):545-547. PMID: 28884445; PMCID: PMC6598929 Link: https://dx.doi.org/10.1007/s12250-017-4057-9 Qiu, Xiangguo, et al. "Prophylactic Efficacy of Quercetin 3-β-O-d-Glucoside against Ebola Virus Infection." Antimicrobial agents and chemotherapy vol. 60,9 5182-8. 22 Aug. 2016, Link: https://dx.doi.org/10.1128/AAC.00307-16 Chiow, K H et al. "Evaluation of antiviral activities of Houttuynia cordata Thunb. extract, quercetin, quercetrin and cinanserin on murine coronavirus and dengue virus infection." Asian Pacific journal of tropical medicine vol. 9,1 (2016): 1-7. Link: https://dx.doi.org/10.1016/j.apjtm.2015.12.002 Jasso-Miranda, Carolina, et al. "Antiviral and immunomodulatory effects of polyphenols on macrophages infected with dengue virus serotypes 2 and 3 enhanced or not with antibodies." Infection and drug resistance vol. 12 1833-1852. 1 Jul. 2019, Link: https://dx.doi.org/10.2147/IDR.S210890 Aucoin, Monique et al. "The effect of quercetin on the prevention or treatment of COVID-19 and other respiratory tract infections in humans: A rapid review." Advances in integrative medicine, 10.1016/j.aimed.2020.07.007. 30 Jul. 2020, Link: https://dx.doi.org/10.1016/j.aimed.2020.07.007 Wu, Wenjiao et al. "Quercetin as an Antiviral Agent Inhibits Influenza A Virus (IAV) Entry." Viruses vol. 8,1 6. 25 Dec. 2015, Link: https://dx.doi.org/10.3390/v8010006 Ahmed, Amr & Albalawi, Yousef & Shora, Hassan & Abdelseed, Hiba & Al-Kattan, Abdulla. (2020). Effects of Quadruple Therapy: Zinc, Quercetin, Bromelain, and Vitamin C on the Clinical Outcomes of Patients Infected with COVID-19. 10.37179/rijed.000005. ABSTRACT COVID-19 emerged in Wuhan, China in December 2019, reached epidemic proportions, and spread globally as a serious life-threatening pandemic. SARS- Cov-2 is the causative virus that causes severe acute respiratory distress, pneumonia, respiratory failure, and septic shock leading to increased mortality. High-risk patients include those with chronic non-communicable diseases such as diabetes, hypertension, coronary heart disease, and cancers. No specific treatment is available and supportive care is all that could be done to rescue patients. Quadruple therapy consisting of Zinc, Quercetin, Bromelain, and Vitamin C showed promising results in improving clinical outcomes among COVID-19 patients. Keywords: COVID-19, Cytokines, zinc, Quercetin, Bromelain, Vitamin C. 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Link: https://bit.ly/2Qx0hLx Carr AC, Maggini S (2017) Vitamin C, and Immune Function. Nutrients.9: 1211. Link: https://bit.ly/31CvDGM Furuya A, Uzaki M, Yamasaki H, Arakawa T, Arita Koyama MAH (2008) Antiviral effects of ascorbic and dehydroascorbic acids in vitro. Int J Mol Med. 22: 541–545. Link: https://bit.ly/31yX98d Colunga BRML, Berrill M, Catravas JD, Marik PE (2020) Quercetin and Vitamin C: An Experimental, Synergistic Therapy for the Prevention and Treatment of SARS-CoV-2 Related Disease (COVID-19). Frontiers in Immunology 11: 1451. Link: https://bit.ly/2QxVppr Chen S, Jiang H, Wu X, Fang J (2016) Therapeutic Effects of Quercetin on Inflammation, Obesity, and Type 2 Diabetes. Mediators Inflamm 2016: 9340637. Link: https://bit.ly/2EzcZaf Huang RY, Yu YL, Cheng WC, OuYang CN, Fu E, et al. (2010) Immunosuppressive effect of quercetin on dendritic cell activation and function. J Immunol. 184: 6815-6821. Link: https://bit.ly/3jzRh51 Zuyi W, Bodi Z, Shahrzad A, Nikolaos S, Alan Butcher, et al. (2012) Quercetin Is More Effective than Cromolyn in Blocking Human Figure 2: Quercetin and bromelain for blocking the interleukin. Mast Cell Cytokine Release and Inhibits Contact Dermatitis and Citation: Ahmed AK, Albalawi YS, Shora HA, Abdelseed HK, Al-Kattan AN (2020) Effects of Quadruple Therapy: Zinc, Quercetin, Bromelain and Vitamin C on the Clinical Outcomes of Patients Infected with COVID-19. Rea Int J of End and Diabe.1(1): 018-021. DOI: 10.37179/rijed.000005 Re Int Jou of end and dia 021 Volume 1 Issue 1 – 1005 Photosensitivity in Humans. PLoS One 7: e33805. Link: https://bit.ly/32wunUZ Lesjak M, Rukshana H, Sara B, Vernon S, Edward S, et al. (2014) Quercetin Inhibits Intestinal Iron Absorption and Ferroportin Transporter ExpressionIn Vivo and In Vitro. PLoS ONE 9: e102900. Link: https://bit.ly/2YI9SUu Dabbagh-Bazarbachi H, Gael C, Isabel MQ, Mayreli O, Ciara KOH, et al. (2014) "Zinc ionophore activity of quercetin and e-epigallocatechin gallate: from Hepa 1-6 cells to a liposome model." J Agric Food Chem. 62: 8085-8093. Link: https://bit.ly/2EzfuJF Onken JE, Greer PK, Calingaert B, Hale LP (2008) Bromelain treatment decreases secretion of pro-inflammatory cytokines and chemokines by colon biopsies in vitro. Clin Immunol 126: 345-352. Link: https://bit.ly/3gCCrsz Pavan R, Jain S, Shraddha, Kumar A (2012) Properties and therapeutic application of bromelain: a review. Biotechnol Res Int. 2012: 976203. Link: https://bit.ly/3b4COdY Rathnavelu V, Alitheen NB, Sohila S, Kanagesan S, Ramesh R (2016) Potential role of bromelain in clinical and therapeutic applications (Review) Biomed. Reports 5: 283-288. Link: https://bit.ly/3hDc0UO Hu PA, Chen CH, Guo BC, Kou YR, Lee TS (2020) Bromelain Confers Protection against the Non-Alcoholic Fatty Liver Disease in Male C57BL/6 Mice. Nutrients. 12: 1458. Link: https://bit.ly/3gCeGRh [12] Abstract References: The combination of Quercetin and Bromelain with Zinc, Vitamin C, and Vitamin D, when taken together, may inhibit the viral replication of antiviral and Anti-Cytokine Storm by restraining Hyper-Inflammation and Cytokine Storm An Antiviral against RNA viruses like COVID-19 using the combination of Zinc with a Zinc Ionophore Acidifies parts of Cellular Milieu and increase Metallothioneins. Link: https://dx.doi.org/10.6084/m9.figshare.15153186 Dietary Supplements for COVID-19 Chapter May 2021Advances in Experimental Medicine and Biology Gerard E. 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Susan Wieland https://dx.doi.org/10.1016/j.explore.2021.06.004 Vitamin D Supplementation in Influenza and COVID-19 Infections Article Full-text availableMay 2020Nutrients Kow Chia SiangMuhammad Abdul HadiSyed Shahzad Hasan 11 Citations Link: https://dx.doi.org/10.3390/nu12061626 COVID-19 and nutriceutical therapies, especially using zinc to supplement antimicrobials Article Publisher preview available Jan 2021 Inflammo pharmacology Desley ButtersMichael Whitehouse 3 Citations Link: https://dx.doi.org/10.1007/s10787-020-00774-8 Vitamin D and COVID-19: A Physiological Perspective Article Full-text availableMay 2021Biomedical Research and Therapy Pendhamma Sindhusen Link: https://dx.doi.org/10.15419/bmrat.v8i5.674 Safety of COVID-19 Vaccination in Immune-Deficient Patients Receiving Supplemental Immunoglobulin Therapies ArticleJun 2021 Journal of Clinical Immunology Jacqueline D. SquireAvni Y. Joshi Link: https://dx.doi.org/10.1007/s10875-021-01101-8 Vitamin D supplementation, COVID-19 & Disease Severity: A meta-analysis Article Jan 2021QJM: monthly journal of the Association of Physicians Komal ShahDeepak SaxenaDileep Mavalankar 13 Citations Link: https://dx.doi.org/10.1093/qjmed/hcab009 Potential health benefits of zinc supplementation for the management of COVID‐19 pandemic Article Full-text availableJan 2021Journal of Food Biochemistry Ademola OyagbemiTemitayo AjibadeYapo Guillaume Aboua[...]Momoh A Yakubu 3 Citations Link: https://dx.doi.org/10.1111/jfbc.13604 Vitamin D supplementation and clinical outcomes in COVID-19: a systematic review and meta-analysis Article Full-text availableJun 2021Journal of Endocrinological Investigation Rimesh PalMainak BanerjeeSanjay Bhadada[...]Abhinav Vyas 2 Citations Link: https://dx.doi.org/10.1007/s40618-021-01614-4 Clinical Significance of Micronutrient Supplementation in Critically Ill COVID-19 Patients with Severe ARDS Article Full-text availableJun 2021Nutrients Quirin NotzJohannes HerrmannTobias Schlesinger[...]Christian Stoppe 1 Citation Link: https://dx.doi.org/10.3390/nu13062113 Dietary Intake and Supplement Use Among Saudi Residents during COVID-19 Lockdown Article Full-text availableJun 2021International Journal of Environmental Research and Public Health Hanan A AlfawazNasiruddin KhanGhadah A. Aljumah[...]Nasser M Al-Daghri Link: https://dx.doi.org/10.1016/j.cmi.2021.01.013DOI:10.3390/ijerph18126435 Prophylaxis for COVID-19: a systematic review January 2021Clinical Microbiology and Infection 27(4) Link: https://dx.doi.org/10.1016/j.cmi.2021.01.013 The suggested role of Vitamin D supplementation in COVID-19 severity Article Aug 2020 Journal of Contemporary Medical Sciences Parviz AfsharMohammad GhaffaripourHamid Sajjadi Link: https://dx.doi.org/10.22317/jcms.v6i4.822 Adjunctive Nutraceutical Therapies for COVID-19 Article Full-text availableFeb 2021International Journal of Molecular Sciences Lalita SubediStephanie TchenBhakta Prasad Gaire[...]Kurt Hu 3 Citations Link: https://dx.doi.org/10.3390/ijms22041963 Dietary supplements and herbal medicine for COVID-19: A systematic review of randomized control trials Article Full-text availableMay 2021Clinical Nutrition ESPEN Zitong FengJuan YangMingzhu Xu[...]Shaoyang Cui Link: https://dx.doi.org/10.1016/j.clnesp.2021.05.018 Role of Vitamin D Supplementation in Prevention and Treatment of COVID-19 Article Full-text availableJul 2020Indian Journal of Clinical Biochemistry Aakriti KhemkaArpita SuriNaveen Kumar SinghSanjiv Kumar Bansal 3 Citations Link: https://dx.doi.org/:10.1007/s12291-020-00908-3 For people with moderate to severe COVID-19, what are the benefits and harms of vitamin D supplementation? Article May 2021 Sera TortJane Burch Link: https://dx.doi.org/10.1002/cca.3689 Patients' Behavior Regarding Dietary or Herbal Supplements Before and During COVID-19 in Saudi Arabia Article Full-text availableMay 2021 International Journal of Environmental Research and Public Health Leen A AldwihiShahd I. KhanFaisal Fahad Alamri[...]Omar A. Almohammed 1 Citation Link: https://dx.doi.org/10.3390/ijerph18105086 Prophylaxis for COVID-19: a systematic review Article Full-text availableJan 2021Clinical Microbiology and Infection Mikaela SmitAnnalisa MarinosciThomas Agoritsas[...]Alexandra Calmy 3 Citations Link: https://dx.doi.org/10.1016/j.cmi.2021.01.013 Use Of Vitamin C, Vitamin D, and Zinc Supplements To Avoid COVID-19 In Article Full-text available Mar 2021 Ebru Kuyumcu Savan Link: https://dx.doi.org/10.19070/2379-1586-2100038 Role of adjunctive vitamin C supplement therapy in combating COVID-19 Article Full-text availableNov 2020International Journal of Basic & Clinical Pharmacology Gnaneswari Regati Link: https://dx.doi.org/10.18203/2319-2003.ijbcp20205135 Vitamin D supplementation as a rational pharmacological approach in the COVID-19 pandemic Article Full-text availableNov 2020AJP Lung Cellular and Molecular Physiology Leon FerderVirna Margarita Martín GiménezFelipe Inserra[...]Walter Manucha 10 Citations Link: https://dx.doi.org/10.1152/ajplung.00186.2020 Vitamin C and D to decrease the risk and severity of COVID 19 symptoms. 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Article Full-text availableJul 2021Food and Nutrition Adrian Isaza Link: https://dx.doi.org/10.33425/2641-4295.1043 The Covid-19 infection: An opportunity to develop systematic vitamin D supplementation in psychiatry Article Feb 2021 L Encéphale Guillaume FondMarc MassonRaphaelle Richieri[...]Laurent Boyer Link: https://dx.doi.org/10.1016/j.encep.2021.02.002 Modest effects of dietary supplements during the COVID-19 pandemic: insights from 445,850 users of the COVID Symptom Study app Article Full-text availableMar 2021BMJ Nutrition Prevention & Health Panayiotis LoucaBenjamin MurrayKerstin Klaser[...]Cristina Menni 5 Citations Link: https://dx.doi.org/10.1136/bmjnph-2021-000250 Vitamin C and D supplementation and the severity of COVID-19: A protocol for systematic review and meta-analysis Article Full-text availableJul 2021Medicine Gislani Acásia da Silva ToscanoIvani Iasmin de AraújoTalita Araujo de Souza[...]Gilson De Vasconcelos Torres COVID-19 and Dentistry Article Full-text availableJun 2021 Hugh DevlinParisa SoltaniStephen Bustin Link: https://dx.doi.org/10.1097/MD.0000000000026427 Clinical Effects of Zinc Supplementation in Patients Hospitalized with COVID-19: A Systematic Review and Meta-analysis Article Jun 2021Korean Journal of Clinical Pharmacy Hye Won ParkSo Yeon LeeSook Hee An Link: https://dx.doi.org/10.24304/kjcp.2021.31.2.136 Vitamin D supplementation to mitigate COVID-19 morbidity in the vulnerable Article Full-text availableJun 2020 Koenraad Van den AbbeelePeter A.M. de Beer Link: https://nutrition.bmj.com/content/3/1/67.responses Potential role of Zinc supplement in CVD and COVID-19 co- morbidity Preprint Full-text availableNov 2020 Muhammad Manjurul KarimShahnaz SultanaRokaia SultanaMohammad Tariqur Rahman Link: https://dx.doi.org/10.14293/S2199-1006.1.SOR-.PP3ZKDJ.v1 Effect of COVID‑19 on Awareness and Consumption of Dietary Supplements in Saudi Arabia JNatSciMed42190-5118721 141307 Article Full-text availableJun 2021 Sulaiman A Alshammari Link: https://dx.doi.org/10.4103/jnsm.jnsm_156_20 The fight against COVID-19 the role of drugs and food supplements Article Full-text availableJun 2020 Dario RuscianoRoberta GaleazziPaola Bagnoli 7 Citations Link: file:///C:/Users/ne113669/Downloads/ThefightagainstCOVID19theroleofdrugsandfoodsupplements.pdf Vitamin D supplementation and Covid-19 outcomes: A systematic review, meta-analysis, and meta-regression Article Full-text availableJun 2021 Reviews in Medical Virology Timotius Ivan HariyantoDenny IntanJoshua Edward Hananto[...]Andree Kurniawan 1 Citation Link: https://dx.doi.org/10.1002/rmv.2269 COVID-19 and vitamin D supplementation: Is there any evidence-based to reduce the risk? Article Full-text available Jan 2021 Amina Chentouf Link: https://dx.doi.org/10.51745/najfnr.4.10.S19-S24 A TGF - beta2 enriched formula as an oral nutritional supplement for hospitalized COVID-19 patients Article Apr 2021 I. GrandoneMassimiliano CavalloLuisa Barana[...]Gaetano Vaudo Link: https://dx.doi.org/10.23736/S2724-5985.21.02820-8 Potential Role of Zinc Supplementation in Prophylaxis and Treatment of COVID-19 Article Apr 2020Medical Hypotheses Amit KumarYuichi KubotaMikhail ChernovHidetoshi Kasuya 83 Citations Link: https://dx.doi.org/10.1016/j.mehy.2020.109848 Vitamin D supplementation: a potential approach for COVID-19 therapeutics? Preprint Apr 2020 John ArboledaSilvio Urcuqui-Inchima 7 Citations Link: https://dx.doi.org/10.31219/osf.io/cgd4t Adjuvant therapy with Serratiopeptidase and Vitamin D for COVID-19 patients: A new perspective Article Full-text available May 2021 Kuldeep Kumar GuptaAdil RahmanAjai Kumar[...]Priyanka Asia Link: https://www.ijmscr.com Bromelain: A Review on its Potential as a Therapy for the Management of Covid-19 June 2020Nigerian journal of physiological sciences: official publication of the Physiological Society of Nigeria 35(1):10-19 Link: https://www.bioline.org.br/np Bromelain and its potential therapeutic effects in COVID-19-induced respiratory complications December 2020 Link: https://dx.doi.org/10.31254/jmr.2020.6614 Bromelain: A potential therapeutic application in SARS- CoV-2 infected patients June 2021 Link: https://dx.doi.org/10.17352/aaa.000011 Bromelain Inhibits SARS-CoV-2 Infection in VeroE6 Cells September 2020 Link: https://dx.doi.org/10.1101/2020.09.16.297366 The combination of bromelain and curcumin as an immune-boosting nutraceutical in the prevention of severe COVID-19 November 2020Metabolism Open Link: https://dx.doi.org/10.1016/j.metop.2020.100066 Potential protective mechanisms of green tea polyphenol EGCG against COVID-19 Author Zhichao Zhang, Xiangchun Zhang, Keyi Bi, Yufeng He, Wangjun Yan Chung S.Yang, Jinsong Zhang Link: https://dx.doi.org/10.1016/j.tifs.2021.05.023 [13] Northwell Health COVID-19 Supplements Sheet https://www.northwell.edu/sites/northwell.edu/files/2020-10/covidsupplementonesheet.pdf https://naturalmeds@vivohealthpharmacy.com [14] https://www.nbcnews.com/nightly-news/video/inside-tampa-icu-seeing-spike-in-covid-cases-119375941724 [15] https://www.covid19treatmentguidelines.nih.gov/ https://www.fda.gov/advisory-committees/advisory-committee-calendar [16] Mahmoud Elkazzaz, Biochemistry Master Degree – Kafr Elksheikh University, Egypt Assessment of the Activity Value of Isotretinoin (13- Cis-Retinoic Acid ) in the Treatment of COVID-19 ( Isotretinoin in Treatment of COVID-19) (Randomized) (Isotretinoin) Link: https://clinicaltrials.gov/ct2/show/NCT04353180 Combination of Chemopreventive Agents (All-Trans Retinoic Acid and Tamoxifen) as Potential Treatment for the Lung Complication of COVID-19 Link: https://clinicaltrials.gov/ct2/show/NCT04568096 In silico identification of Tretinoin as a SARS-CoV-2 envelope (E) Protein ion channel inhibitor Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574788/ All-Trans Retinoic Acid Exhibits Antiviral Effect against SARS-CoV-2 by Inhibiting 3CLpro Activity Link: https://doi.org/10.3390/v13081669 [17] Online Store Reviews https://www.amazon.com/gp/aw/reviews/B08CBBHPTF/ref=cm_cr_dp_mb_top?ie=UTF8 https://www.amazon.com/gp/aw/reviews/B089XTSC1K/ref=cm_cr_dp_mb_top?ie=UTF8 https://www.amazon.com/gp/aw/reviews/B08MV751Y5/ref=cm_cr_dp_mb_top?ie=UTF8 https://www.amazon.com/gp/aw/reviews/B08DG8LQ19/ref=cm_cr_dp_mb_top?ie=UTF8 https://www.amazon.com/gp/aw/reviews/B08FGVQRV2/ref=cm_cr_dp_mb_top?ie=UTF8 https://www.amazon.com/gp/aw/reviews/B08WM4D4RG/ref=cm_cr_dp_mb_top?ie=UTF8 https://www.amazon.com/gp/aw/reviews/B089NKZT59/ref=cm_cr_dp_mb_top?ie=UTF8 https://www.amazon.com/gp/aw/reviews/B08J9X5H1N/ref=cm_cr_dp_mb_top?ie=UTF8
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