Abstract
Honey and its compounds are drawing attention as an effective natural therapy because of its ability to attenuate acute inflammation through enhancing immune response. Several studies have proved its potential healing capability against numerous chronic diseases/conditions, including pulmonary disorders, cardiac disorders, diabetes, hypertension, autophagy dysfunction, bacterial, and fungal infections. More importantly, honey has proved its virucidal effect on several enveloped viruses such as HIV, influenza virus, herpes simplex, and varicella-zoster virus. Honey may be beneficial for patients with COVID-19 which is caused by an enveloped virus SARS-CoV-2 by boosting the host immune system, improving comorbid conditions, and antiviral activities. Moreover, a clinical trial of honey on COVID-19 patients is currently undergoing. In this review, we have tried to summarize the potential benefits of honey and its ingredients in the context of antimicrobial activities, some chronic diseases, and the host immune system. Thus, we have attempted to establish a relationship with honey for the treatment of COVID-19. This review will be helpful to reconsider the insights into the possible potential therapeutic effects of honey in the context of the COVID-19 pandemic. However, the effects of honey on SARS-CoV-2 replication and/or host immune system need to be further investigated by in vitro and in vivo studies.
Keywords: Honey, COVID-19, SARS-CoV-2, Immune response, Viral infection
Honey, COVID-19, SARS-CoV-2, Immune response, Viral infection.
1. Introduction
Recently encountered world pandemic coronavirus disease 2019 (COVID-19) is a serious concern worldwide [1]. It is anticipated that, during the end of the year 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been identified in Wuhan city of Hubei Province of China [2]. Due to its easily transmissible nature, the disease has spread to almost 210 countries in the world within a short period. That is why it has been declared as a world pandemic by WHO on 11th March 2020 [3]. As of 17th June 2020, 8,322,910 people are suffering from this viral infection and the number of deaths is 447,959 [4]. Before the COVID-19 pandemic, two other viruses were belonging to the same genus caused severe infection in the form of pneumonia [3, 5]. All three of these viruses can cause fatal injury to older and immune-compromised people while younger people with a strong immune system are normally considered out of danger with the exception of comorbid conditions. The SARS-CoV-2 readily triggers infection in several body parts including the lung, cardiovascular system as well as liver [5]. It's a matter of concern that no proper treatment has been introduced yet [6]. Therefore, strategies that boost the immune system could be effective to alleviate the complications associated with COVID-19 [7, 8, 9].
The use of chemo drugs comes with several problems including multidrug resistance and side effects which prompt us to think about other alternatives like natural products for reducing the unavoidable side effects [10, 11]. Human has been using plant and its several derivatives as treatments for various types of diseases [12, 13]. In recent years, honey has got the attraction of researchers for combatting efficiently against these difficulties of chemo drugs [14]. Honey contains several compounds including sugars, organic acids, amino acids, phenolic compounds, vitamins, and minerals [15]. This is the reason why honey has been studied for a long time in animal and human models to observe its antioxidant potency [16, 17]. It has proved its potency in several therapeutic properties including immunostimulatory, antibacterial, anti-inflammatory, wound healing, antiulcer, antidiabetic, anticancer, antiviral, and antifungal [18, 19, 20]. It reduces the level of triglycerides (TGs), very-low-density lipoprotein (VLDL), and systolic blood pressure in experimental animals [21]. Reduced acute respiratory distress symptoms have been noticed when honey is ingested daily [22].
A recent in silico approach showed that honey may inhibit SARS-CoV-2 proteases and some compounds of honey may be able to bind SARS-CoV-2 protease, but this has still to be validated experimentally [23]. Methylglyoxal (MGO) modification might be involved in SARS-CoV-2 replication [24]. MGO is a component of manuka honey that can inhibit enveloped virus growth [25]. However, whether honey might be a therapeutic choice for controlling and/or treating the COVID-19, remained to be investigated. In this review, we summarized all promising beneficial roles of honey and its ingredients in the context of antimicrobial activities, numerous chronic diseases, and host immune signaling pathways and thereby tried to make a correlation of honey for the treatment of COVID-19.
2. Methods
A literature search was performed using PubMed, Scopus, and Google that includes all original research articles written in English on beneficial effects of honey against various pathophysiological conditions. Searching was conducted before April 2020 using various keywords including honey, inflammation, oxidative stress, bacterial infection, viral infection, and so on. Figures were generated using BioRender.com, online software.
3. Pharmacological effects of honey
Several studies have observed honey and its active compound(s) on human physiological systems. Various in vivo or in vitro studies have also been performed to utilize its antimicrobial activities. However, the exact mechanism of protective effects of honey in case of viral infection has not been properly established yet. The recent studies on the protective effects of honey against immune dysfunction, anti-inflammatory effects, diabetes, hyperglycemia, cardiovascular disorders, and bacterial, fungal, and viral infections have been summarized and discussed in Table 1. We also tried to make a correlation of therapeutic effects of honey on COVID-19 as all of these above mentioned physiological disorders/comorbid conditions found to be associated with the high fatality rate of SARS-CoV-2 infected individuals [26].
Table 1.
Models | Source of honey | Effects of honey on mechanisms involved | Ref. |
---|---|---|---|
Bacteria | Manuka Honey |
|
[14, 84, 100] |
Fungus | Commercial honey (Nigeria) |
|
[14, 87] |
Virus | Manuka Honey | Interruption in viral transcription, and translation | [25] |
Rats | Tualang Honey | Decreased glucose level in type-2 diabetes mellitus | [19] |
Rats | Tuscany honey |
|
[69] |
Rats (liver cells) | Tuscany honey | Suppressing PTP1B while encouraging alteration in serum lipid profiles and expression of insulin receptor | [69] |
Rat | MGO |
|
[101] |
Human | Natural honey | Prevention of platelet aggregation, extend APPT, PT, and TT while decreasing amount of fibrinogen in platelet-poor plasma | [78] |
Human (peripheral blood) | European honey bee (Apis mellifera) | Mitogenic effect on both B- and T lymphocyte | [49] |
Rat (breast cancer) | Tualang Honey | Increase IFN-γ and IFNGR1 at serum level | [48] |
Human | Manuka Honey |
|
[102] |
Human | Manuka Honey | Increase the concentration of cytokines | [52] |
Influenza B virus | MGO | Inhibition of influenza B virus replication by MGO | [92] |
Human | MGO | Induction of cell death by autophagy and inhibition of the ROS-derived Akt/mTOR signaling pathway | [103] |
Mouse | MGO | Increase in MCP-1 and TNF-α in RAW264.7 macrophages | [104] |
Interleukin-IL, Monocyte chemoattractant protein-MCP-1, Matrix metalloproteinase 9- MMP-9, Partial prothrombin time (APTT), Prothrombin time (PT), Thrombin time (TT), Interferon-gamma- IFN-γ, Interferon-gamma receptor 1-IFNGR1, TNFα- Tumor Necrosis Factor α, MIC- Minimum Inhibitory Concentration, Methylglyoxal -MGO, Protein tyrosine phosphatase 1B -PTP1B, Neutrophil extracellular trap formation- NETosis.
3.1. Oxidative stress
Oxidative stress is the imbalance between oxidative products and antioxidants that leads to cell damage. Oxidative stress has a role in several diseased conditions including neurological disorder, cancer, aging as well as endocrine illness [27]. It also has a main role in the pathology of virus invasion by inducing inflammatory damage which consequently exaggerated immune response, commonly known as a cytokine storm. A buildup in immune cells infiltration and release of their activating compounds or cytokines occurs during cytokine storm [28]. Influenza viruses harm the lungs in presence of inflammatory signals is an example of this event. This is done by producing reactive oxygen species (ROS) which helps the influenza virus to cause infection [29].
Macrophages and neutrophils are known to produce a significant amount of ROS. The increased oxidative stress level has a role to play in pulmonary injuries including acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) [30]. There are several viruses including coronaviruses, influenza viruses that can cause deadly lung damage and can be fatal from ARDS [31]. Increased oxidative stress in ARDS takes place due to the fast liberation of free radicals and cytokines which results in cellular injury, organ failure, severe hypoxemia, uncontrollable inflammation. All of these are harmful to the alveolar-capillary barrier and can cause death [32]. In a recent study, it has been found that the time to cause infection by SARS-CoV-2 is more than 14 days. In a study, it was found that almost 93 % of patients (27 out of 29) showed elevated hypersensitive C reactive protein (CRP) which is a known marker for inflammation and oxidative stress [33].
Honey has proved its antioxidant activity by preventing several acute and chronic diseases which include diseases related to inflammation, diabetes, cardiovascular, and cancer [14]. Moreover, phenolic acids of honey protect humans from hydrogen peroxide-induced oxidative DNA damage in lymphocytes [16]. Along with phenolic acids and flavonoids, several other compounds (such as sugars, proteins, amino acids, carotenes, organic acids, and other minor components) present in honey have shown antioxidant activity for a longer period [34]. Consumption of 1200 mg/kg honey can increase both levels of antioxidants such as glutathione reductase, β-carotene, vitamin C in healthy human subjects [35]. While possible mechanism that could be involved in flavonoids substrate action for hydroxyl, metallic ion chelation, superoxide radical actions, hydrogen donation, free radical sequestration, is not known yet [36]. Though the antioxidant effects of honey have been established in a structured manner, there are several unknown aspects yet to be found.
3.2. Immune responses and inflammation
Human innate and adaptive immune systems might play protective roles against SARS-CoV-2, as no therapeutic intervention has been introduced. Angiotensin-converting enzyme-2 (ACE-2), a receptor of SARS-CoV-2 has been found on various cell surfaces including lungs, heart, kidney, and arteries [37]. The attempt of seizure of healthy cells by this virus generally stimulates different cells in the human body such as macrophages, natural killer cells, T-cells, B-cells, neutrophils, and dendritic cells. These are the classical antigen-presenting cells (APCs) that conduct the killing process of SARS-CoV-2 [38,39]. Toll-like receptors (TLRs) which are also commonly recognized as pathogen recognition receptors are suspected to be a helper for SARS-CoV-2 entry [38]. Stimulation of immune responsive cells occurs when a virus enters the body. APC for SARS-CoV-2 occupy the virus and provide co-stimulation for specific B and T cell proliferation via human leucocyte antigen (HLA) [39]. This is identified by T cell receptor (TCR) which ultimately turns into helper T cells (CD4+) and cytotoxic T cells (CD8+). CD8+ directly attacks virus-infected cells while CD4+ activates several immune responsive cells such as CD8+ T cells, natural killer (NK) cells, and memory T cells [40, 41]. B cell differentiation is stimulated by cytokines which come from helper T cells. IL-2 produced by T-cell is involved in ERK1/2-prompted plasma cell differentiation [42]. Along with plasma B cell, memory B cell creates a direct link with SARS-CoV-2. With the help of this link, antigen-specific antibodies produced by plasma B cells kill SARS-CoV-2. Some of the B cells may form memory and thereby providing a protection system to fight against future invasion [40].
According to a recent study, the adaptive immune response can target viral structural proteins like spike glycoprotein, envelop protein, and others, indicating that humoral immunity (antibodies) may mediate protection against SRAS-CoV-2 [43]. Innate and adaptive immunity against SARS-CoV-2 is provided by B and T lymphocytes which are activated by dendritic cells [44]. IFNs and granzymes secreted by cytotoxic T cells (CD8+ cells) can activate NK cells to kill SARS-CoV-2 by showing cytotoxicity towards virus-infected epithelial cells thus inducing apoptosis [44, 45]. Cytokines and chemokines produced by neutrophils and macrophages can increase CRP levels which are c3a and c5a that possess antiviral activity [46].
Honey may activate T-lymphocytes, B-lymphocytes, and neutrophils which ultimately produce cytokines such as interleukin-1 (IL-1), and interleukin-6 (IL-6), tumor necrosis factor- α (TNF-α) [47]. Honey also increases the serum levels of IFN-γ and IFN-γ receptor 1 (IFNGR1) in breast cancer in rats [48]. As IFN-γ has an affinity to viral spike glycoprotein, nucleocapsid protein, and membrane protein, it may aid in targeting SARS-CoV-2 [43]. Honey has shown a cell dividing (mitosis) effect on both B- and T cells. This proves that it might have a role in inducing an adaptive immune response against SARS-CoV-2 infection [49]. Nigerose, a sugar derived from honey is reported as immune stimulatory [50]. A variety of honey including Manuka, Royal jelly, Pasture, and Nigerian Jungle honey can increase the mediators of immune responses such as TNF-α, IL-1β, IL-6, and apalbumin 1 production [51, 52, 53]. In humans, honey provides beneficial effects by increasing the levels of ascorbic acid, glutathione reductase, minerals, and immune cells such as eosinophils, monocytes, and lymphocytes. At the same time, it decreases immunoglobulin E, ferritin, and enzymes including creatinine kinase, aspartate transaminase, lactate dehydrogenase, and alanine transaminase. It also decreases levels of different enzymes of liver and muscle and fasting blood sugars [35]. These shreds of evidence suggest that honey may be able to give protection against SARS-CoV-2 but proper validation through in vitro and in vivo experiments is required.
Anti-inflammatory effects of honey have been studied where it has shown its potency in form of cell culture model, animal model as well as in clinical trials [54, 55]. In a recent study, it is proved that MGO, a component of Manuka honey effectively senses bacterial invasion by producing mucosal-associated invariant T cells (MAIT cells). It is known that MAIT cells can effectively regulate a diverse range of immune responses which includes antimicrobial defense as well. In human monolayer cells, MGO has significantly increased MAIT cells in vitro [56].
Commonly known inflammatory markers such as mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) can induce other inflammatory factors such IL-1β, IL-6, IL-10, lipoxygenase 2 (LOX-2), cyclooxygenase-2 (COX-2), CRP, and TNF-α [57]. A study reported that honey may be a perfect suppressor agent for these two markers [58]. Several components of honey act as suppressors of pro-inflammatory enzymes, as well as stimulate the process of repairing damage which may prove honey a potential agent against disease [59].
3.3. Autophagy
Autophagy is known as "self-degradation", is a highly conserved catabolic process that governs a cell to remove long-lived proteins, lipid, unwanted or damaged cells, and impurities, thereby helping to recover healthier cells, the process is aided by autophagosome formation and its merging with lysosomes to destroy the selected molecule [60]. Therefore, if the human body ought to fight against a deadly virus like SARS-CoV-2, a strong immune system is must needed which involves several immune responses including autophagy [38]. Fatal viruses like SARS-CoV-2 can decrease the action of autophagy but several compounds can induce autophagy to fight against these types of viruses, therefore this immune response can be considered as a tool to fight against COVID-19 [9,61].
Natural honey is supplemented with flavonoids (kaempferol, catechin, and quercetin) and polyphenolic acid (caffeic acid and gallic acid) which have been found to show anticancer activity. One of the flavonoids present in honey i.e. quercetin has been found to inhibit proteasomal activity and mTOR signals, and promote substantial autophagy [62].
3.4. Diabetes
Diabetes and unrestricted glycemia are some of the main reasons behind death due to infection by several viruses including influenza A (H1N1), SARS-CoV, and MERS-CoV [63, 64, 65]. In a study with SARS-CoV-2 infection, hyperglycemia was found to be a causative agent for death in more than half of the cases [66]. In 2003, confirmed individuals of SARS-CoV showed transient impairment of pancreatic islet cells through hyperglycemia [67].
In a clinical trial with streptozotocin-induced diabetic rats were subjected to honey for evaluating the antidiabetic effect. In that study decreased glucose level in type-2 diabetes mellitus has been observed [19]. Honey has been shown to participate in reducing glucose, fructosamine, and glycosylated hemoglobin serum concentration [68]. Honey can show glycemic control through suppressing protein tyrosine phosphatase 1B (PTP1B). At the same time, it also can encourage alteration in serum lipid profiles and expression of the insulin receptor in liver cells [69]. Honey and quercetin can raise the level of expression of protein kinase B (PKB) which is also called by Akt while reducing phosphorylation of insulin receptor substrate 1 (IRS-1) at serine, NF-κB, and MAPK [70]. Honey significantly increased high density lipoprotein (HDL) and reduced hyperglycemia, TGs, VLDL, non-HDL cholesterol, coronary risk index (CRI), and cardiovascular risk index (CVRI) in diabetic rats [71]. When a dose of 1000 mg/kg is administrated, it can significantly develop glycemic control and hyperlipidemia [71]. Therefore, it can be predicted that honey can show a hypoglycemic effect.
3.5. Cardiovascular disorder and hypertension
A study with 150 positive individuals of COVID-19 showed 7% of death exhibited due to myocarditis with circulatory collapse, meanwhile, 33% myocarditis contributed towards the final severe outcome [72]. Honey is proved for its long-term cardiovascular benefits as well as short-term antiarrhythmic effects [73]. A decreased rate of cardiovascular disease is often associated with flavonoids for example anthocyanin and vitamins including niacin (B3). Both of these present in honey which makes it a potential therapeutic against cardiovascular disease [68, 74, 75, 76, 77]. Another study showed that honey can prevent platelet aggregation, extend partial prothrombin time (APTT), prothrombin time (PT), thrombin time (TT) while it may decrease the amount of fibrinogen in platelet-poor plasma [78].
3.6. Microbial infections
Honey is considered as an ancient remedy which is used by mankind for a long time. This ancient method of therapy is now under investigation because of modern therapeutic agents are failing. Honey has been pointed out as a drug and ointment dated back to 2100-2000 BC whereas in much later time Aristotle (384-322 BC) described honey as “good as a salve for sore eyes and wounds” [79]. Recent studies reported that COVID-19 patients are prone to develop secondary bacterial coinfections such as bacterial pneumonia and sepsis which is a fetal threat [80]. Viral infection followed by secondary infection's contribution to death is surprisingly equal [72]. Bacterial coinfections in between 12%-19% are common in H1N1 influenza and pneumonia infected individuals with other serious illnesses [81]. A typical marker for inflammation and infection is the neutrophil-lymphocyte ratio (NLR). This indicates that bacterial infection comprises pneumonia. Besides, severe SARS-CoV-2-infected individuals were found with elevated NLR. This is the characteristic of a potentially critical condition [31, 82].
3.6.1. Antibacterial properties
Honey provides a favorable environment that promotes healing quickly. At the same time, the antibacterial properties of honey can speed up the healing process by producing white blood cells (WBC) to increase the pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6 [52,83]. Several shreds of evidence showed that honey may act as an antimicrobial agent through lowering pH, osmotic effect of sugars, and H2O2 levels. All of these works against pathogenic bacteria including Streptococcus typhi, Staphylococcus aureus, coagulase-negative Streptococcus, and E. coli [14, 84]. The bacterial growth might be inhibited through urease regulation by the MGO and its precursor dihydroxyacetone (DHA) [14]. However, Wang et al., 2012 demonstrated that honey showed its antibacterial effect by direct killing of bacterial cells by its bactericidal components and disrupting the bacterial quorum sensing (QS) [85]. In the case of cystic fibrosis (CF), manuka honey might play potential roles against deadly lung infections caused by antimicrobial-resistant respiratory bacteria [86].
3.6.2. Antifungal properties
The fungicidal property of honey has been proved against P. chrysogenum, A. niger, M. gypseum, A. flavus, C. albicans as well as Saccharomyces species. Honey can prevents biofilm formation and makes changes to exopolysaccharide [14, 87]. Honey ensures the decrement of the cell surface in biofilm which takes towards the death of biofilm by manipulating the cell membrane of fungus [88].
3.6.3. Antiviral properties
Infections and the formation of a wound are generally promoted by viral nature [89]. Due to the presence of several compounds such as MGO, copper, ascorbic acid, flavonoids, nitric oxide, H2O2, and its derivatives, honey can suppress viral growth by inhibiting viral replication and/or virucidal activity [25]. In some studies, honey has proved its potency against several RNA and DNA viruses i.e. influenza virus, varicella-zoster virus (VZV), rubella, herpes simplex virus (HSV), and has proved that it can be a potential antiviral agent [18, 25, 90, 91]. Shahzad A et al., 2012 demonstrated that both manuka and clover honey inhibit the VZV growth in human malignant melanoma cells (MeWo) but the exact mechanism has not been clarified [18]. Another study reported that MGO, one of the major compounds of manuka honey, showed sensitivity against both influenza B and influenza A viruses proving its virucidal activity [25, 92]. Moreover, the synergistic effect of manuka honey with the anti-influenza A viral drugs zanamivir and oseltamivir has been reported and MGO is useful for the drug-resistant virus isolates [25, 92]. Therefore, these studies suggested that enveloped viruses might be sensitive to the virucidal ingredients of honey (Figure 1).
4. Possible roles of honey against SARS-CoV-2 infection
SARS-CoV-2 is an enveloped and positive-sense single-stranded RNA virus [93]. As discussed above, several enveloped viruses might be killed by the virucidal ingredients of honey therefore it might also have a potent suppressive effect on SARS-CoV-2. Cell death is triggered by viral infection through draining lymphocytes which can be tackled by antioxidants. This proves that there is a relation between antiviral and antioxidant actions [94]. Honey has a broad spectrum of antioxidant effects as described, it can be said that honey might act as protective agents for patients infected with viruses like influenza or corona. But to prove this, clinical trials and proper experiments are needed. The SARS-CoV-2 infected individual having a cytokine storm might be tackled with honey's antioxidant property along with increased IFN-γ level [2, 48, 95]. Various micronutrients have been found to be essential for immunocompetence especially plant-derived polyphenols are very important to reduce the release of inflammatory cytokines [68]. In a case study, it has been observed that a polyphenol-rich environment effectively stimulated the activation of the local immune system and the mechanisms involved in tissue repair. As honey is rich in these bioactive compounds, it can be concluded that honey might have a possible role in alleviating the pain of SARS-CoV-2 infected patients [96]. Therefore, it is hypothesized that honey might be beneficial for SARS-CoV-2 infected patients through several major mechanisms such as direct virucidal properties, regulating/boosting host immune signaling pathways, and curing and/or improving comorbid conditions (Figures 1 and 2). Besides, based on the previous results of several studies, honey may act as a preventive agent against hyper-inflammation caused by SARS-CoV-2.
5. Current status and future directions
The COVID-19 has been discovered at the end of 2019 and currently, it is a pandemic threat of international concern. Currently, there are no targeted therapies effective against COVID-19. However, many vaccines are undergoing clinical trials and a couple of drugs are going through re-purposing schemes [6]. A phase-3 clinical trial of natural honey for the treatment of COVID-19 has also been started as mentioned by the National Institute of Health [97]. It is already proved that honey plays a potential role against several enveloped viruses. Besides, honey acts as an antagonist of platelet-activating factor (PAF) which is involved in COVID-19 [98,99]. Therefore, we can say that honey may have a protective/beneficial effect on COVID-19. A lot of studies have been done to prove that honey is a potential natural medicine that can fight against several chronic diseases including diabetes, hypertension as well as autophagy. Also, honey can heal wound quickly by repairing damaged tissue, boosting up the immune system, and fight with the virus, bacteria as well as fungus. However, so far without some minor issues, there is no report of the serious harmful effect of honey on the human body. This review will be helpful to rethink the insights of possible potential therapeutic effects of honey in fighting against COVID-19 by strengthening the immune system, autophagy, anti-inflammatory, antioxidative, antimicrobial, antidiabetic, anti-hypertensive as well as cardioprotective effects (Figure 2). However, basic research on the effect of honey on SARS-CoV-2 replication and/or host immune system need to be investigated by in vitro and in vivo studies.
Declarations
Author contribution statement
All authors listed have significantly contributed to the development and the writing of this article.
Funding statement
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Data availability statement
No data was used for the research described in the article.
Declaration of interests statement
The authors declare no conflict of interest.
Additional information
No additional information is available for this paper.
References
- 1.Sheam M.M., Syed S Bin, Barman S.K., Hasan M.R., Paul D.K., Islam R. COVID-19: the catastrophe of our time. J. Adv. Biotechnol. Exp. Ther. 2020;3(4):1–13. [Google Scholar]
- 2.Huang C., Wang Y., Li X., Ren L., Zhao J., Hu Y. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497–506. doi: 10.1016/S0140-6736(20)30183-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.WHO WHO Director-General’s opening remarks at the mission briefing on COVID-19. 2020. https://wwwwhoint/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020 Available from:
- 4.Worldometers. COVID-19 Coronavirus Pandemic. 2020. https://www.worldometers.info/coronavirus/ Available from: [Google Scholar]
- 5.Yang X., Yu Y., Xu J., Shu H., Xia J., Liu H. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir. Med. 2020;8(5):475–481. doi: 10.1016/S2213-2600(20)30079-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Sohag A., Hannan M., Rahman S., Hossain M., Hasan M., Khan M. Revisiting potential druggable targets against SARS-CoV-2 and repurposing therapeutics under preclinical study and Clinical Trials: a Comprehensive Review. Drug Dev. Res. 2020:1–23. doi: 10.1002/ddr.21709. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Hannan M.A., Islam M.N., Uddin M.J. Self-confidence as an immune-modifying psychotherapeutic intervention for COVID-19 patients and understanding of its connection to CNS-endocrine-immune axis. J. Adv. Biotechnol. Exp. Ther. 2020;3(4):14–17. [Google Scholar]
- 8.Islam Mohammad Nazrul, Khandkar Shaharina Hossain. Partha Protim Sarker. Ferdous Jannatul, Abdul Hannan Md., Masudur Rahman Md., Dinh-Toi Chu MJU . 2020. Revisiting Pharmacological Potentials of Nigella Sativa Seed: a Promising Option for COVID-19 Prevention and Cure. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Hannan M.A., Rahman M.A., Rahman M.S., Sohag A.A.M., Dash R., Hossain K.S. 2020. Intermittent Fasting, a Possible Priming Tool for Host Defense against SARS-CoV-2 Infection: Crosstalk Among Calorie Restriction, Autophagy and Immune Response. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Castro J.A., De Mecca M.M., Bartel L.C. Toxic side effects of drugs used to treat Chagas’ disease (American trypanosomiasis) Hum. Exp. Toxicol. 2006;25(8):471–479. doi: 10.1191/0960327106het653oa. [DOI] [PubMed] [Google Scholar]
- 11.Koehn F.E., Carter G.T. The evolving role of natural products in drug discovery. Nat. Rev. Drug Discov. 2005;4(3):206–220. doi: 10.1038/nrd1657. [DOI] [PubMed] [Google Scholar]
- 12.Pandiri I., Moni A. Ocimum herb species: a potential treatment strategy for diabetic kidney disease. J. Adv. Biotechnol. Exp. Ther. 2018;1(3):88–91. [Google Scholar]
- 13.Yao L.H., Jiang Y.M., Shi J., Tomás-Barberán F.A., Datta N., Singanusong R. Flavonoids in food and their health benefits. Plant Foods Hum. Nutr. 2004;59:113–122. doi: 10.1007/s11130-004-0049-7. [DOI] [PubMed] [Google Scholar]
- 14.Ahmed S., Sulaiman S.A., Baig A.A., Ibrahim M., Liaqat S., Fatima S. Honey as a potential natural antioxidant medicine: an insight into its molecular mechanisms of action. Oxid. Med. Cell Longev. 2018;2018:8367846. doi: 10.1155/2018/8367846. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Ball D.W. The chemical composition of honey. J. Chem. Educ. 2007;84(10):1643–1646. [Google Scholar]
- 16.Cheng N., Wang Y., Cao W. The protective effect of whole honey and phenolic extract on oxidative DNA damage in mice lymphocytes using comet assay. Plant Foods Hum. Nutr. 2017;72(4):388–395. doi: 10.1007/s11130-017-0634-1. [DOI] [PubMed] [Google Scholar]
- 17.Dżugan M., Sowa P., Kwaśniewska M., Wesołowska M., Czernicka M. Physicochemical parameters and antioxidant activity of bee honey enriched with herbs. Plant Foods Hum. Nutr. 2017;72(1):74–81. doi: 10.1007/s11130-016-0593-y. [DOI] [PubMed] [Google Scholar]
- 18.Shahzad A., Cohrs R.J. In vitro antiviral activity of honey against varicella zoster virus (VZV): a translational medicine study for potential remedy for shingles. Transl. Biomed. 2012;3(2):2. doi: 10.3823/434. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Omotayo E.O., Gurtu S., Sulaiman S.A., Wahab M.S.A., Sirajudeen K.N.S., Salleh M.S.M. Hypoglycemic and antioxidant effects of honey supplementation in streptozotocin-induced diabetic rats. Int. J. Vitam. Nutr. Res. 2010;80(1):74–82. doi: 10.1024/0300-9831/a000008. [DOI] [PubMed] [Google Scholar]
- 20.Patel S., Cichello S. Manuka honey: an emerging natural food with medicinal use. Nat. Prod. Bioprospect. 2013;3(4):121–128. [Google Scholar]
- 21.Erejuwa O.O., Sulaiman S.A., Wahab M.S.A., Sirajudeen K.N.S., Salleh M.S.M., Gurtu S. Differential responses to blood pressure and oxidative stress in streptozotocin-induced diabetic wistar-kyoto rats and spontaneously hypertensive rats: effects of antioxidant (honey) treatment. J. ApiProduct ApiMed. Sci. 2011;2:1888–1907. doi: 10.3390/ijms12031888. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Sulaiman S.A., Hasan H., Deris Z.Z., Wahad M.S.A., Yusof R.C., Naing N.N. The benefit of Tualang honey in reducing acute respiratory symptoms among malaysian hajj pilgrims: a preliminary study. J. ApiProduct ApiMed. Sci. 2011;3(1):38–44. [Google Scholar]
- 23.Hashem H.E. IN silico approach of some selected honey constituents as SARS-CoV-2 main protease (COVID-19) inhibitors. Eurasian J. Med. Oncol. 2020 [Google Scholar]
- 24.Al-Motawa M., Abbas H., Wijten P., Fuente A de la, Xue M., Rabbani N. SSRN Electron J; 2020. Vulnerabilities of the SARS-CoV-2 virus to proteotoxicity — opportunity for repurposed chemotherapy of COVID-19 infection. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Watanabe K., Rahmasari R., Matsunaga A., Haruyama T., Kobayashi N. Anti-influenza viral effects of honey in vitro: potent high activity of manuka honey. Arch. Med. Res. 2014 doi: 10.1016/j.arcmed.2014.05.006. [DOI] [PubMed] [Google Scholar]
- 26.Yang J., Zheng Y., Gou X., Pu K., Chen Z., Guo Q. Prevalence of comorbidities and its effects in coronavirus disease 2019 patients: a systematic review and meta-analysis. Int. J. Infect. Dis. 2020;94:91–95. doi: 10.1016/j.ijid.2020.03.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Lupoli F., Vannocci T., Longo G., Niccolai N., Pastore A. The role of oxidative stress in Friedreich’s ataxia. FEBS Lett. 2018;592(5):718–727. doi: 10.1002/1873-3468.12928. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Liu D., Zhang X., Hu B., Ander B.P. Src family kinases in brain edema after acute brain injury. Acta Neurochir. Suppl. 2016;121:185–190. doi: 10.1007/978-3-319-18497-5_33. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Jacoby D.B., Choi A.M. Influenza virus induces expression of antioxidant genes in human epithelial cells. Free Radic. Biol. Med. 1994;16(6):821–824. doi: 10.1016/0891-5849(94)90198-8. [DOI] [PubMed] [Google Scholar]
- 30.Hecker L. Mechanisms and consequences of oxidative stress in lung disease: therapeutic implications for an aging populace. Am. J. Physiol. Lung Cell Mol. Physiol. 2018;314:L642–L653. doi: 10.1152/ajplung.00275.2017. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Wang D., Hu B., Hu C., Zhu F., Liu X., Zhang J. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA, J. Am. Med. Assoc. 2020;323(11):1061–1069. doi: 10.1001/jama.2020.1585. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Meng L., Zhao X., Zhang H. HIPK1 interference attenuates inflammation and oxidative stress of acute lung injury via autophagy. Med. Sci. Mon. 2019;25:827–835. doi: 10.12659/MSM.912507. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Chen L., Liu H.G., Liu W., Liu J., Liu K., Shang J. Analysis of clinical features of 29 patients with 2019 novel coronavirus pneumonia. Zhonghua Jiehe He Huxi Zazhi. 2020;43(3):203–208. doi: 10.3760/cma.j.issn.1001-0939.2020.03.013. [DOI] [PubMed] [Google Scholar]
- 34.Nagai T., Sakai M., Inoue R., Inoue H., Suzuki N. Antioxidative activities of some commercially honeys, royal jelly, and propolis. Food Chem. 2001;75(2):237–240. [Google Scholar]
- 35.Al-Waili N.S. Effects of daily consumption of honey solution on hematological indices and blood levels of minerals and enzymes in normal individuals. J. Med. Food. 2003;6(2):135–140. doi: 10.1089/109662003322233549. [DOI] [PubMed] [Google Scholar]
- 36.Al-Mamary M., Al-Meeri A., Al-Habori M. Antioxidant activities and total phenolics of different types of honey. Nutr. Res. 2002;22(9):1041–1047. [Google Scholar]
- 37.Zhou P., Lou Yang X., Wang X.G., Hu B., Zhang L., Zhang W. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270–273. doi: 10.1038/s41586-020-2012-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Li G., Fan Y., Lai Y., Han T., Li Z., Zhou P. Coronavirus infections and immune responses. J. Med. Virol. 2020;94(4):424–432. doi: 10.1002/jmv.25685. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Li X., Geng M., Peng Y., Meng L., Lu S. Molecular immune pathogenesis and diagnosis of COVID-19. J. Pharmaceut. Anal. 2020;10:102–108. doi: 10.1016/j.jpha.2020.03.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Nikolich-Zugich J., Knox K.S., Rios C.T., Natt B., Bhattacharya D., Fain M.J. SARS-CoV-2 and COVID-19 in older adults: what we may expect regarding pathogenesis, immune responses, and outcomes. GeroScience. 2020;1–10 doi: 10.1007/s11357-020-00186-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Yi Y., Lagniton P.N.P., Ye S., Li E., Xu R.H. COVID-19: what has been learned and to be learned about the novel coronavirus disease. Int. J. Biol. Sci. 2020;16(10):1753–1766. doi: 10.7150/ijbs.45134. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Le Gallou S., Caron G., Delaloy C., Rossille D., Tarte K., Fest T. IL-2 requirement for human plasma cell generation: coupling differentiation and proliferation by enhancing MAPK–ERK signaling. J. Immunol. 2012;189(1):161–173. doi: 10.4049/jimmunol.1200301. [DOI] [PubMed] [Google Scholar]
- 43.Poland G.A., Ovsyannikova I.G., Kennedy R.B. SARS-CoV-2 immunity: review and applications to phase 3 vaccine candidates. Lancet. 2020 doi: 10.1016/S0140-6736(20)32137-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Nezhad F.S., Mosaddeghi P., Negahdaripour M., Dehghani Z., Farahmandnejad M., Taghipour M.J. Therapeutic approaches for COVID-19 based on the dynamics of interferon-mediated immune responses. Preprints. 2020;2020030206(March):1–26. [Google Scholar]
- 45.Azkur A.K., Akdis M., Azkur D., Sokolowska M., van de Veen W., Brüggen M.C. Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19. Allergy Eur. J. Allergy Clin. Immunol. 2020;75(7):1564–1581. doi: 10.1111/all.14364. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Stegelmeier A.A., van Vloten J.P., Mould R.C., Klafuric E.M., Minott J.A., Wootton S.K. Myeloid cells during viral infections and inflammation. Viruses. 2019;11(2):168. doi: 10.3390/v11020168. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Manyi-Loh C., Leppington-Clarke A., Ndip R. An overview of honey: therapeutic properties and contribution in nutrition and human health. Afr. J. Microbiol. Res. 2011;5(8):844–852. [Google Scholar]
- 48.Ahmed S., Sulaiman S.A., Othman N.H. Oral administration of Tualang and Manuka honeys modulates breast cancer progression in Sprague-Dawley rats model. Evid. base Compl. Alternative Med. 2017;2017:904361. doi: 10.1155/2017/5904361. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.Abuharfeil N., Al-Oran R., Abo-Shehada M. The effect of bee honey on the proliferative activity of human B- and T-lymphocytes and the activity of phagocytes. Food Agric. Immunol. 1999;11(2):169–177. [Google Scholar]
- 50.Murosaki S., Muroyama K., Yamamoto Y., Liu T., Yoshikai Y. Nigerooligosaccharides augments natural killer activity of hepatic mononuclear cells in mice. Int. Immunopharm. 2002;2(1):151–159. doi: 10.1016/s1567-5769(01)00152-7. [DOI] [PubMed] [Google Scholar]
- 51.Takeuchi M., Fukuda M., Kobayashi K., Hirono Y., Miyagawa M., Ishida T. Jungle honey enhances immune function and antitumor activity. Evid. base Compl. Alternative Med. 2011;2011:908743. doi: 10.1093/ecam/nen086. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52.Tonks A.J., Dudley E., Porter N.G., Parton J., Brazier J., Smith E.L. A 5.8-kDa component of manuka honey stimulates immune cells via TLR4. J. Leukoc. Biol. 2007;82(5):1147–1155. doi: 10.1189/jlb.1106683. [DOI] [PubMed] [Google Scholar]
- 53.Bíliková K., Šimúth J. New criterion for evaluation of honey: quantification of royal jelly protein apalbumin 1 in honey by ELISA. J. Agric. Food Chem. 2010;58(15):8776–8781. doi: 10.1021/jf101583s. [DOI] [PubMed] [Google Scholar]
- 54.Jaganathan S.K. Honey Constituents and their apoptotic effect in colon cancer cells. J. ApiProduct ApiMed. Sci. 2009 Apr 1;1(2):29–36. [Google Scholar]
- 55.Subrahmanyam M. A prospective randomised clinical and histological study of superficial burn wound healing with honey and silver sulfadiazine. Burns. 1998;24(2):157–161. doi: 10.1016/s0305-4179(97)00113-7. [DOI] [PubMed] [Google Scholar]
- 56.Tang J.S., Compton B.J., Marshall A., Anderson R., Li Y., Van Der Woude H. Manuka honey-derived methylglyoxal enhances microbial sensing by mucosal-associated invariant T cells. Food Funct. 2020;11(7):5782–5787. doi: 10.1039/d0fo01153c. [DOI] [PubMed] [Google Scholar]
- 57.Yahfoufi N., Alsadi N., Jambi M., Matar C. The immunomodulatory and anti-inflammatory role of polyphenols. Nutrients. 2018;10(11) doi: 10.3390/nu10111618. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 58.Hussein S.Z., Mohd Yusoff K., Makpol S., Mohd Yusof Y.A. Gelam honey inhibits the production of proinflammatory, mediators NO, PGE 2, TNF-α, and IL-6 in carrageenan-induced acute paw edema in rats. Evid. base Compl. Alternative Med. 2012;2012:109636. doi: 10.1155/2012/109636. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 59.Tomblin V., Ferguson L.R., Han D.Y., Murray P., Schlothauer R. Potential pathway of anti-inflammatory effect by New Zealand honeys. Int. J. Gen. Med. 2014;4(7):149–158. doi: 10.2147/IJGM.S45839. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 60.Yin Z., Pascual C., Klionsky D.J. Autophagy: machinery and regulation. Microb. Cell. 2016;3(12):588–596. doi: 10.15698/mic2016.12.546. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61.Deretic V., Levine B. Autophagy balances inflammation in innate immunity. Autophagy. 2018;14(2):243–251. doi: 10.1080/15548627.2017.1402992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62.Klappan A.K., Hones S., Mylonas I., Brüning A. Proteasome inhibition by quercetin triggers macroautophagy and blocks mTOR activity. Histochem. Cell Biol. 2012;137(1):25–36. doi: 10.1007/s00418-011-0869-0. [DOI] [PubMed] [Google Scholar]
- 63.Schoen K., Horvat N., Guerreiro N.F.C., de Castro I., de Giassi K.S. Spectrum of clinical and radiographic findings in patients with diagnosis of H1N1 and correlation with clinical severity. BMC Infect. Dis. 2019;19(1):964. doi: 10.1186/s12879-019-4592-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 64.Yang J.K., Feng Y., Yuan M.Y., Yuan S.Y., Fu H.J., Wu B.Y. Plasma glucose levels and diabetes are independent predictors for mortality and morbidity in patients with SARS. Diabet. Med. 2006;23(6):623–628. doi: 10.1111/j.1464-5491.2006.01861.x. [DOI] [PubMed] [Google Scholar]
- 65.Banik G.R., Alqahtani A.S., Booy R., Rashid H. Risk factors for severity and mortality in patients with MERS-CoV: analysis of publicly available data from Saudi Arabia. Virol. Sin. 2016 doi: 10.1007/s12250-015-3679-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 66.Chen N., Zhou M., Dong X., Qu J., Gong F., Han Y. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):507–513. doi: 10.1016/S0140-6736(20)30211-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 67.Butler S.O., Btaiche I.F., Alaniz C. Relationship between hyperglycemia and infection in critically ill patients. Pharmacotherapy. 2005;25:963–976. doi: 10.1592/phco.2005.25.7.963. [DOI] [PubMed] [Google Scholar]
- 68.Cianciosi D., Forbes-Hernández T.Y., Afrin S., Gasparrini M., Reboredo-Rodriguez P., Manna P.P. Phenolic compounds in honey and their associated health benefits: a review. Molecules. 2018;23(9):2322. doi: 10.3390/molecules23092322. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 69.Lori G., Cecchi L., Mulinacci N., Melani F., Caselli A., Cirri P. Honey extracts inhibit PTP1B, upregulate insulin receptor expression, and enhance glucose uptake in human HepG2 cells. Biomed. Pharmacother. 2019;113:108752. doi: 10.1016/j.biopha.2019.108752. [DOI] [PubMed] [Google Scholar]
- 70.Batumalaie K., Zaman Safi S., Mohd Yusof K., Shah Ismail I., Devi Sekaran S., Qvist R. Effect of gelam honey on the oxidative stress-induced signaling pathways in pancreatic hamster cells. Internet J. Endocrinol. 2013;2013:67312. doi: 10.1155/2013/367312. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 71.Erejuwa O.O., Nwobodo N.N., Akpan J.L., Okorie U.A., Ezeonu C.T., Ezeokpo B.C. Nigerian honey ameliorates hyperglycemia and dyslipidemia in alloxan-induced diabetic rats. Nutrients. 2016;8(3) doi: 10.3390/nu8030095. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 72.Ruan Q., Yang K., Wang W., Jiang L., Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020 doi: 10.1007/s00134-020-05991-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 73.Shrestha T.M., Nepal G., Shing Y.K., Shrestha L. Cardiovascular, psychiatric, and neurological phenomena seen in mad honey disease: a clinical case report. Clin. Case Rep. 2018;6(12):2355–2357. doi: 10.1002/ccr3.1889. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 74.McCullough M.L., Peterson J.J., Patel R., Jacques P.F., Shah R., Dwyer J.T. Flavonoid intake and cardiovascular disease mortality in a prospective cohort of US adults. Am. J. Clin. Nutr. 2012;95(2):454–464. doi: 10.3945/ajcn.111.016634. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 75.Rababah T.M., Al-Omoush M., Brewer S., Alhamad M., Yang W., Alrababah M. Total phenol, antioxidant activity, flavonoids, anthocyanins and color of honey as affected by floral origin found in the arid and semiarid mediterranean areas. J. Food Process. Preserv. 2014;38(3):1119–1128. [Google Scholar]
- 76.Sunkara A., Raizner A. Supplemental vitamins and minerals for cardiovascular disease prevention and treatment. Methodist Debakey Cardiovasc. J. 2019;15(3):179–184. doi: 10.14797/mdcj-15-3-179. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 77.Ajibola A., Chamunorwa J.P., Erlwanger K.H. Nutraceutical values of natural honey and its contribution to human health and wealth. Nutr. Metab. 2012;9:61. doi: 10.1186/1743-7075-9-61. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 78.Ahmed A., Khan R.A., Azim M.K., Saeed S.A., Mesaik M.A., Ahmed S. Effect of natural honey on human platelets and blood coagulation proteins. Pak. J. Pharm. Sci. 2011;24(3):389–397. [PubMed] [Google Scholar]
- 79.Mandal M.D., Mandal S. Honey: its medicinal property and antibacterial activity. Asian Pac. J. Trop. Biomed. 2011;1(2):154–160. doi: 10.1016/S2221-1691(11)60016-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 80.Cox M.J., Loman N., Bogaert D., O’Grady J. Co-infections: potentially lethal and unexplored in COVID-19. The Lancet Microbe. 2020 May;1(1):e11. doi: 10.1016/S2666-5247(20)30009-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 81.MacIntyre C.R., Chughtai A.A., Barnes M., Ridda I., Seale H., Toms R. The role of pneumonia and secondary bacterial infection in fatal and serious outcomes of pandemic influenza a(H1N1)pdm09 11 Medical and Health Sciences 1103 Clinical Sciences 11 Medical and Health Sciences 1117 Public Health and Health Services. BMC Infect. Dis. 2018;18(1) doi: 10.1186/s12879-018-3548-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 82.Liu X., Shen Y., Wang H., Ge Q., Fei A., Pan S. Prognostic significance of neutrophil-to-lymphocyte ratio in patients with sepsis: a prospective observational study. Mediat. Inflamm. 2016;2016:8191254. doi: 10.1155/2016/8191254. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 83.Lusby P.E., Coombes A.L., Wilkinson J.M. Bactericidal activity of different honeys against pathogenic bacteria. Arch. Med. Res. 2005;36(5):464–467. doi: 10.1016/j.arcmed.2005.03.038. [DOI] [PubMed] [Google Scholar]
- 84.Nasir N.A.M., Halim A.S., Singh K.K.B., Dorai A.A., Haneef M.N.M. Antibacterial properties of tualang honey and its effect in burn wound management: a comparative study. BMC Compl. Alternative Med. 2010;10(31) doi: 10.1186/1472-6882-10-31. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 85.Wang R., Starkey M., Hazan R., Rahme L.G. Honey’s ability to counter bacterial infections arises from both bactericidal compounds and QS inhibition. Front. Microbiol. 2012;3(APR) doi: 10.3389/fmicb.2012.00144. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 86.Roberts A.E.L., Powell L.C., Pritchard M.F., Thomas D.W., Jenkins R.E. Anti-pseudomonad activity of manuka honey and antibiotics in a specialized ex vivo model simulating cystic fibrosis lung infection. Front. Microbiol. 2019;10(APR) doi: 10.3389/fmicb.2019.00869. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 87.Anyanwu C. Investigation of in vitro antifungal activity of honey. J. Med. Plants Res. 2012;6(18) [Google Scholar]
- 88.Arnold J.W., Bailey G.W. Surface finishes on stainless steel reduce bacterial attachment and early biofilm formation: scanning electron and atomic force microscopy study. Poultry Sci. 2000;79(12):1839–1845. doi: 10.1093/ps/79.12.1839. [DOI] [PubMed] [Google Scholar]
- 89.Whitley R.J., Kimberlin D.W., Roizman B. Herpes simplex viruses. Clin. Infect. Dis. 1998;26(3):541–555. doi: 10.1086/514600. [DOI] [PubMed] [Google Scholar]
- 90.Zeina B., Othman O., Al-Assad S. Effect of honey versus thyme on Rubella virus survival in vitro. J. Alternative Compl. Med. 1996;2(3):345–348. doi: 10.1089/acm.1996.2.345. [DOI] [PubMed] [Google Scholar]
- 91.Al-Waili N.S. Topical honey application vs. acyclovir for the treatment of recurrent herpes simplex lesions. Med. Sci. Mon. 2004;10(8):MT94–98. [PubMed] [Google Scholar]
- 92.Charyasriwong S., Haruyama T., Kobayashi N. In vitro evaluation of the antiviral activity of methylglyoxal against influenza B virus infection. Drug Discov. Ther. 2016;10(4):201–210. doi: 10.5582/ddt.2016.01045. [DOI] [PubMed] [Google Scholar]
- 93.Pal M., Berhanu G., Desalegn C., Kandi V. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2): an update. Cureus. 2020;12(3) doi: 10.7759/cureus.7423. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 94.Peterhans E. Oxidants and antioxidants in viral diseases: disease mechanisms and metabolic regulation. J. Nutr. 1997;127(5):962S–965S. doi: 10.1093/jn/127.5.962S. [DOI] [PubMed] [Google Scholar]
- 95.Mehta P., McAuley D.F., Brown M., Sanchez E., Tattersall R.S., Manson J.J. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395:1033–1034. doi: 10.1016/S0140-6736(20)30628-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 96.Corrêa T.A., Rogero M.M. Polyphenols regulating microRNAs and inflammation biomarkers in obesity. Nutrition. 2019;59:150–157. doi: 10.1016/j.nut.2018.08.010. [DOI] [PubMed] [Google Scholar]
- 97.Tantawy M.A. ClinicalTrials.gov [Internet]; 2020. Efficacy of Natural Honey Treatment in Patients with Novel Coronavirus.https://clinicaltrials.gov/ct2/show/NCT04323345 Available from: [Google Scholar]
- 98.Semidalas C.E., Demopoulos C., Antonopoulou S., Koussissis S. PAF antagonists in food Isolation and identification of PAF antagonists in honey and wax. Etude Rech N4. 1994;127–32 [Google Scholar]
- 99.Demopoulos C.A. Is platelet-activating factor (PAF) a missing link for elucidating the mechanism of action of the coronavirus SARS-CoV-2 and explaining the side effects-complications of Covid-19 disease. Preprints. 2020:2020060253. [Google Scholar]
- 100.Kim S.-Y., Kang S.-S. Anti-biofilm activities of manuka honey against Escherichia coli O157:H7. Food Sci. Anim. Resour. 2020;40(4):668–674. doi: 10.5851/kosfa.2020.e42. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 101.Imtara H., Al-Waili N., Bakour M., Al-Waili W., Lyoussi B. Evaluation of antioxidant, diuretic, and wound healing effect of Tulkarm honey and its effect on kidney function in rats. Vet. World. 2018;11(10):1491–1499. doi: 10.14202/vetworld.2018.1491-1499. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 102.Minden-Birkenmaier B.A., Smith R.A., Radic M.Z., van der Merwe M., Bowlin G.L. Manuka honey reduces NETosis on an electrospun template within a therapeutic window. Polymer. 2020;12(6):1430. doi: 10.3390/polym12061430. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 103.Lee J.H., Parveen A., Do M.H., Kang M.C., Yumnam S., Kim S.Y. Molecular mechanisms of methylglyoxal-induced aortic endothelial dysfunction in human vascular endothelial cells. Cell Death Dis. 2020;11(5):403. doi: 10.1038/s41419-020-2602-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 104.Ganbaatar B., Fukuda D., Shinohara M., Yagi S., Kusunose K., Yamada H. Empagliflozin ameliorates endothelial dysfunction and suppresses atherogenesis in diabetic apolipoprotein E-deficient mice. Eur. J. Pharmacol. 2020;875:173040. doi: 10.1016/j.ejphar.2020.173040. [DOI] [PubMed] [Google Scholar]
- 105.Dafre A.L., Schmitz A.E., Maher P. Methylglyoxal-induced AMPK activation leads to autophagic degradation of thioredoxin 1 and glyoxalase 2 in HT22 nerve cells. Free Radic. Biol. Med. 2017;108:270–279. doi: 10.1016/j.freeradbiomed.2017.03.028. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 106.Fang L., Li X., Zhong Y., Yu J., Yu L., Dai H. Autophagy protects human brain microvascular endothelial cells against methylglyoxal-induced injuries, reproducible in a cerebral ischemic model in diabetic rats. J. Neurochem. 2015;135(2):431–440. doi: 10.1111/jnc.13277. [DOI] [PubMed] [Google Scholar]
- 107.Tang S.-W., Ducroux A., Jeang K.-T., Neuveut C. Impact of cellular autophagy on viruses: insights from hepatitis B virus and human retroviruses. J. Biomed. Sci. 2012;19(1):92. doi: 10.1186/1423-0127-19-92. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 108.Kudchodkar S.B., Levine B. Viruses and autophagy. Rev. Med. Virol. 2009;19(6):359–378. doi: 10.1002/rmv.630. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 109.Kim J., Kim O.S., Kim C.-S., Kim N.H., Kim J.S. Cytotoxic role of methylglyoxal in rat retinal pericytes: involvement of a nuclear factor-kappaB and inducible nitric oxide synthase pathway. Chem. Biol. Interact. 2010;188(1):86–93. doi: 10.1016/j.cbi.2010.07.002. [DOI] [PubMed] [Google Scholar]
- 110.Hayden M.S., West A.P., Ghosh S. NF-κB and the immune response. Oncogene. 2006;25(51):6758–6780. doi: 10.1038/sj.onc.1209943. [DOI] [PubMed] [Google Scholar]
- 111.Zhao J., He S., Minassian A., Li J., Feng P. Recent advances on viral manipulation of NF-κB signaling pathway. Curr. Opin. Virol. 2015;15:103–111. doi: 10.1016/j.coviro.2015.08.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 112.Jang J.H., Kim E.-A., Park H.-J., Sung E.-G., Song I.-H., Kim J.-Y. Methylglyoxal-induced apoptosis is dependent on the suppression of c-FLIPL expression via down-regulation of p65 in endothelial cells. J. Cell Mol. Med. 2017;21(11):2720–2731. doi: 10.1111/jcmm.13188. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 113.Nainu F., Shiratsuchi A., Nakanishi Y. Induction of apoptosis and subsequent phagocytosis of virus-infected cells as an antiviral mechanism. Front. Immunol. 2017;8(1220) doi: 10.3389/fimmu.2017.01220. [DOI] [PMC free article] [PubMed] [Google Scholar]
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