I am seriously doing scientific literature survey these days on the medicinal uses of honey-bee products through online research since the past one week or so, starting first with the beneficial medicinal uses of bee-honey by different cultures and ancient civilizations down the ages, including India’s ageless, timeless Ayurvedic system of medicine, which is an important Anga, a part, of the sacred Vedas of India. The outcome of this online research is truly encouraging and very promising. Bee-honey has been been very successfully used as a medicine all around the globe since millennia to treat countless medical conditions.
There are loads of modern published scientific papers too from around the globe on the medicinal uses of varieties of honeys, from varieties of floral sources, for treating varieties of medical conditions. In the last 10-15 years of scientific research, the amount of research conducted in this field by scientists is simply mind-boggling. The one topic in this field that has received maximum coverage in modern scientific and medical journals, and that was clearly noticeable during my online literature survey, is the antimicrobial properties of honey, that includes antibacterial, anti-fungal, anti-viral, anti-cancer, and a host of other similar uses.
Many of the published research findings in any scientific field today may be false, as the paper shared below by one of the senior professors of Stanford Medical School says. But then again he says, if several research findings from around the globe report the same results in published literature, we can’t deny the fact that there must definitely be some truth in it.
Therefore, the well-researched antimicrobial properties of honey in today’s scientific and medical literature must be a scientific truth. The research done in this field and the amount of published papers on these crucial topics are simply huge, and stunningly baffling. To begin with, I have shared some of these published papers here to bring a ray of hope to the Corona-infested world of today. In the days to come, I will share here in this blogpost several medicinal uses of honey, and several published papers from scientific literature on this subject.
To be doubly, triply or multiply sure about these soul-elevating results and the efficacy of honey as a medicine in modern healthcare, we may repeat and conduct the same old researches once again, but this time with accurate mathematical precision, so that our scientists and medical scientists around the globe may show us a way to exterminate the Corona virus and bring the deadly virus to a culmination, so that we humans may start living our normal lives once again. But this time not as ordinary mortals eating, drinking and being merry, but with a meaningful spiritual purpose in life, making the fullest use possible of the human birth.
Here are some of the published scientific papers on bee-honey and its beneficial medicinal uses, including its antimicrobial activities. Papers on other bee products like bee-venom, bee-sting, beeswax, bee-hives etc will gradually be shared one after the other in this post in the days and months to come.
Readers may please stay tuned, if this serious topic of scientific research on bee-honey as a unique and an effective medicine interests them :
Original Article : Role of Honey in Ayurvedic Treatment
What is the use of honey in Ayurvedic medicines? What are its properties?
Honey known as Madhu in Ayurvedic scriptures is one of the most important medicines used in Ayurveda. In Ayurveda, honey is used for both internal and external applications. In this ancient Indian system of medicine, it is mainly used for the treatment of eye diseases, cough, thirst, phlegm, hiccups, blood in vomit, leprosy, diabetes, obesity, worm-infestation, vomiting, asthma, diarrhoea and healing of wounds. It is also used as a natural preservative and sweetener in many Ayurvedic preparations. It is also used as a vehicle along with some medicines to improve its efficacy or to mitigate the side effects of the other medicines it is mixed with. It is also known to mitigate the increased Kapha Dosha. (Kapha Dosha is the Ayurvedic category for body constitutions- those with Kapha Dosha are of larger proportions with robust frame.) It should also be kept in mind that fresh honey helps to increase body mass while old honey produces constipation and decreases body mass. Honey should not be heated or consumed warm as it causes toxic effect. Cold honey should always be preferred.
What are the different Ayurvedic names for honey ?
In Ayurveda, honey is know by many names. The names differ from one region to the other. However, the most common names are Madhu, Makshika, Madwikam, Kshaudram, Saradham, Vantham, Varadi, Bringavantham and Pushparasolbhavam.
What are the different types of honey in Ayurveda?
According to Ayurveda, there are eight different types of honey:
1. Makshikam: Used in the treatment of eye diseases, hepatitis, piles, asthma, cough and tuberculosis
2. Bhraamaram: Used in the treatment when blood is vomited
3. Kshoudram: Used in the treatment of diabetes
4. Pauthikam: Used in the treatment of diabetes and urinary infection
5. Chathram: Used in the treatment of worm infestation, when blood is vomited and diabetes
6. Aardhyam: Effective for eye diseases, cough and anaemia
7. Ouddalakam: Increases taste and swarasudhi.Used in the treatment of leprosy and poisoning cases
8. Daalam: It increases digestion and helps in the treatment of cough, vomiting and diabetes.
Is there any particular brand of Ayurvedic honey that you prescribe?
We prescribe a particular brand called Samskritha Madhu (which means cultured or purified honey) which is made by most of the authentic Ayurvedic manufacturing units as per the Ayurvedic scriptures.
In Ayurveda, what is the bee species that is most preferred- are they are Italian species (that are kept in boxes) or Indian species (that are found in the wild)?
As far as Ayurveda is concerned our Acharyas who made this system of medicine utilized Indian honey and tested the wild honey, hence any Ayurvedic physician will prefer the Indian honey, the wild honey.
Antimicrobial Properties of Honey
Honey: a reservoir for microorganisms and an inhibitory agent for microbes : Original Published Paper
Honey is an ancient remedy for the treatment of infected wounds, which has recently been ‘rediscovered’ by the medical profession. The use to which honey is put in medical care is increasing daily with many authors pointing out its importance and role in wound care. There have been reports that honey contains many microorganisms including bacteria and fungi.
The aim of this paper is to highlight the various uses, organisms commonly found in honey, how the organisms arrived in the honey and their effects on wounds and wound care.
The production of honey as well as the storing process account for the presence of microorganisims. Most of these organisms are said to be in inactive forms as they can hardly survive in honey because of its several properties including hygroscopicity, hyperosmolarity, acidity, peroxide content, antibiotic activities etc.
Honey is the natural sweet substance produced by honey bees from nectar or blossoms or from the secretion of living parts of plants or excretions of plants, which honey bees collect, transform, and combine with specific substances of their own to ripen and mature.
Honey in spite of its usefulness is known to contain certain microbes. It is in fact described as a reservoir for microbes.
This reservoir for microbes status however does not diminish the many important uses that honey is known for. In fact the antimicrobial property of honey is giving it a continued place in the management of wounds and injuries.
Honey is an ancient remedy for the treatment of infected wounds, which has recently been rediscovered by the medical profession, particularly where conventional modern therapeutic agents are failing. There are now many published reports describing the effectiveness of honey in rapidly clearing infection from wounds, with no adverse effects to slow the healing process. There is also some evidence to suggest that honey may actively promote healing. In laboratory studies, honey has been shown to have an antimicrobial action against a broad spectrum of bacteria and fungi. Remarkable among the bacteria is Pseudomonas aeruginosa, a notorious organism known for its resistance to antimicrobial compounds.
Is there therefore a contradiction in the medical significance of honey, which on one hand contains several microbes and on the other is active against many organisms?
Honey primarily contains sugar and water. Sugar accounts for 95–99% of honey dry matter. Majority of these are simple sugars, fructose (38.2%) and glucose (31.3%), which represents 85–95% of total sugars. These are simple sugars, 6-carbon sugars that are readily absorbed by the body. Other sugars include disaccharides such as maltose, sucrose, and isomaltose. A few oligosaccharides are also present.
Minerals are present in honey in very small quantities (0.17%) with potassium as the most abundant. Others are calcium, copper, iron, manganese, and phosphorus. Nitrogenous compounds among which the enzymes originate from salivary secretion of the worker honey bees are also present. They have important role in the formation of honey. The main enzymes in honey are invertase (saccharase), diastase (amylase) and glucose oxidase.
Vitamins C, B (thiamine) and B2 complex like riboflavin, nicotinic acid and B6 panthothenic acid are also found in honey
Microorganisms that survive in honey are those that withstand the concentrated sugar, acidity and other antimicrobial characters of honey.
The primary sources of microbial contamination are likely to include pollen, the digestive tracts of honeybees, dirt, dust, air and flowers.
Microbes found in honeycomb are principally bacteria and yeast and come from the bees, the raw materials (nectar) or from external sources. Larvae may be sterile initially but they are fed nectar and pollen by workers and therefore subject to inoculation by the nectar, pollen and workers flora before pupation.
Microorganisms found in honey include bacteria, yeasts and moulds. Most bacteria and other microbes cannot grow or reproduce in honey i.e. they are dormant and this is due to antibacterial activity of honey.
Microorganisms found in Honey
The antimicrobial properties of honey have been known to humans for centuries. Honey was used to treat infected wounds as long ago as 2000 years before bacteria were discovered to be the cause of infection. In c.50 AD, Dioscorides described honey as being “good for all rotten and hollow ulcers”. Honey has been reported to have an inhibitory effect to around 60 species of bacteria including aerobes and anaerobes, gram-positives and gram-negatives. An antifungal action has also been observed for some yeasts and species of Aspergillus and Penicillium, as well as all the common dermatophytes. The current prevalence of antibiotic-resistant microbial species has led to a re-evaluation of the therapeutic use of ancient remedies, including honey. Aristotle (384–322 BC), when discussing different honeys, referred to pale honey as being “good as a salve for sore eyes and wounds”.
The numerous reports of the antimicrobial activities of honey have been comprehensively reviewed. Honey has been found in some instances by some workers to possess antibacterial activities where antibiotics were ineffective. Pure honey has been shown to be bactericidal to many pathogenic microorganisms including Salmonella spp, Shigella spp; other enteropthogens like Escherichia coli, Vibrio cholerae and other Gram negative and Gram positive organisms. High antimicrobial activity is as a result of osmotic effect, acidity, hydrogen peroxide and phytochemical factors.
The clearing of infection seen when honey is applied to a wound may reflect more than just antibacterial properties. Recent research shows that the proliferation of peripheral blood B-lymphocytes and T-lymphocytes in cell culture is stimulated by honey at concentrations as low as 0.1%; and phagocytes are activated by honey at concentrations as low as 0.1%. Honey (at a concentration of 1%) also stimulates monocytes in cell culture to release cytokines, tumour necrosis factor (TNF)-alpha, interleukin (IL)-1 and IL-6, which activate the immune response to infection. A wide range of MIC values (the minimum concentration of honey necessary for complete inhibition of bacterial growth) have been reported in studies comparing different honeys tested against single species of bacteria: from 25% to 0.25% (v/v) 35; >50% to 1.5% (v/v) 20% to 0.6% (v/v), 50 to 1.5% (v/v).
The osmotic effect of honey has been described. Honey is a supersaturated solution of sugars, 84% being a mixture of fructose and glucose. The strong interaction of these sugar molecules will leave very few of the water molecules available for microorganisms. The free water is measured as the water activity. Mean values for honey have been reported, from 0.562 to 0.62.
Although some yeasts can live in honeys that have high water content, causing spoilage of the honey, the water activity of ripened honey is too low to support the growth of any species and fermentation can occur if the water content is below 17.1%. Many species of bacteria are completely inhibited if water activity is in the range of 0.94 to 0.99. These values correspond to solutions of a typical honey (aw of 0.6 undiluted) of concentrations from 12% down to 2%(v/v). On the other hand, some species have their maximum rate of growth when the (aw) is 0.99, so inhibition by the osmotic (water drawing) effect of dilute solutions of honey obviously depends on the species of bacteria.
Honey is characteristically acidic with a pH of between 3.2 and 4.5, which is low enough to be inhibitory to many animal pathogens. The minimum pH values for growth of some common pathogenic species are: Escherichia coli (4.3), Salmonella spp (4.0), Pseudomonas aeruginosa (4.4), Streptococcus pyogenes (4.5). Thus in undiluted honey the acidity is a significant antibacterial factor.
Hydrogen peroxide is produced enzymically in honey. The glucose oxidase enzyme is secreted from the hypopharyngeal gland of the bee into the nectar to assist in the formation of honey from the nectar. The hydrogen peroxide and acidity produced by the reaction:
Glucose+H2O+O2_________Gluconic acid + H2O2 serve to preserve the honey. On dilution of honey, the activity increases by a factor of 2500 to 50,000, thus giving “slow-release” antiseptics at a level, which is antibacterial but not tissue damage. Other workers have however shown a reduction in antibacterial activity of honey on dilution to four times.
Phytochemical factors have been described as non-peroxide antibacterial factors, which are believed to be many complex phenols and organic acids often, referred to as flavonoids. These complex chemicals do not break down under heat or light or affected by honey’s dilution. The stability of the enzyme varies in different honey. There have been reports of honeys with stability well in excess of this variation showing that there must be an additional antibacterial factor involved (i.e. do not break down under heat or light or affected by dilution). The most direct evidence for the existence of non-peroxide antibacterial factors in honey is seen in the reports of activity persisting in honeys treated with catalase to remove the hydrogen peroxide activity.
Several chemicals with antibacterial activity have been identified in honey by various researchers.
Antibacterial activity of honey varies between different types of honey. It has been observed that there are different types of honey and a method has been used to determine the “inhibine number” of honey as a measure of their antibacterial activity. The “inhibine number” is the degree of dilution to which a honey will retain its antibacterial activity representing sequential dilutions of honey in steps of 5 percent from 25% to 5%. Major variation seen in overall antibacterial activity are due to variation in the level of hydrogen peroxide that arises in honey and in some cases to the level of non peroxide factors. Hydrogen peroxide can be destroyed by components of honey, it can be degraded by reaction with ascorbic acid and metal ions and the action of enzyme catalase which comes from the pollen and nectar of certain plants, more from the nectar.
Although it appears that the honey from certain plants has better antibacterial activity than from others, there is not enough evidence for such definite conclusion to be justified because the data are from small numbers of samples. Thus it is important that when honey is to be used as an antimicrobial agent, it is selected from honeys that have been assayed in the laboratory for antimicrobial activity. It is also important that honeys for use as an antimicrobial agent be stored at low temperature and not exposed to light, so that none of the glucose oxidase activity is lost although all honey will stop the growth of bacteria because of its high sugar content.
Honey’s antibacterial properties on different microorganisms
The empirical application of honey on open wounds, burns or use of honey in syrups does show that it stops the growth of many microorganisms. Many of these microorganisms have been isolated and identified.
Mundoi et al discovered that the antimicrobial activity of honey was more with Pseudomonas and Acinetobacter spp, both with resistance to some antibiotics like gentamicin, Ceftriazone, Amikacin and Tobramicin than other bacteria tested. This was attributed to inhibitory effect of ascorbic acid in honey on aerobic microorganisms. Staphylococcus aureus and Streptococcus spp were also found to be sensitive to honey.
Undiluted honey has been found to stop the growth of Candida spp while Clostridum oedemantiens, Streptococcus pyogenes remained resistant. Some species of Aspergillus did not produce aflatoxin in various dilutions of honey while honey has been found to stop the growth of Salmonella, Escherichia coli, Aspergillus niger and Penicillium chrysogenum.
Wounds infected with Pseudomonas, not responding to other treatment, have been rapidly cleared of infection using honey, allowing successful skin grafting. Obaseki etal found that Candida albicans strains are sensitive to honey while Obi et al reported the inhibitory effect of pure honey against local isolates of bacteria agents of diarrhoea. At concentration of 50% and above, honey excellently inhibited the growth of Escherichia coli, Vibrio cholrae, Yersinia enterocolitica, Plesiomonas shigelloides, Aeromonas hydrophila, Salmonella typhi, Shigella boydi and Clostridium jejuni.
While honey easily gets contaminated during the process of its production by bees and microorganisms also get introduced into honey by activities of man including equipment, containers, wind and dust, the status of the microorganisms found in honey is dormant. It is the spore forming microorganisms that survive in honey by remaining dormant i.e suspended without growth.
Non-spore forming bacteria ie vegetative forms are not normally present in honey because they cannot survive. Ten species of non-spore forming intestinal bacteria inoculated into pure honey survived only a few hours. It is possible therefore to assert that the microorganisms found in honey undergo gradual extinction in honey due to its inhibitory properties as highlighted earlier in this discourse. It is also recognized that spores are dormant forms of certain microorganisms. The fact that spores cannot transit into vegetative forms and still remain alive in honey persistently is supportive of the inhibitory role of honey on microorganisms. The failure to take into account the large variance in antibacterial potency of different honeys may contribute, in part, to the large discrepancy in results reported between hospitals using honey in similar ways. Some have reported rapid clearance of infection in a range of different types of wound, with all wounds becoming sterile in 3–6 days, 7 days, 7–10 days. Others have reported bacteria still present in wounds after 2 weeks, 3 weeks and 5 weeks.
There is however the need for caution. Is it possible for the spores in honey to transform to active microorganisms and therefore become pathogenic after honey has been applied to the wounds especially with dilution of the initial high osmolarity and other properties that inhibit microorganisms?
We suggest that swabs from wounds should be cultured, microorganisms isolated and their sensitivity to honey assessed before commencing treatment with honey. This is important not only because of the varying activities of honey but also because of varying microorganisms they may contain. Any honey should not just be used on just any wound without this preparation. This will ensure judicious use of honey for organisms against which it is likely to be active and diminish the possibility of infecting the wounds rather than destroying the microbes. More works may need to be done to give an answer to the conflict.
The emergence of novel coronavirus (SARS-CoV-2) in 2019 in China marked the third outbreak of a highly pathogenic coronavirus infecting humans. The novel coronavirus disease (COVID-19) spread worldwide, becoming an emergency of major international concern. However, even after a decade of coronavirus research, there are still no licensed vaccines or therapeutic agents to treat the coronavirus infection. In this context, apitherapy presents as a promising source of pharmacological and nutraceutical agents for the treatment and/or prophylaxis of COVID-19. For instance, several honeybee products, such as honey, pollen, propolis, royal jelly, beeswax, and bee venom, have shown potent antiviral activity against pathogens that cause severe respiratory syndromes, including those caused by human coronaviruses. In addition, the benefits of these natural products to the immune system are remarkable, and many of them are involved in the induction of antibody production, maturation of immune cells, and stimulation of the innate and adaptive immune responses. Thus, in the absence of specific antivirals against SARS-CoV-2, apitherapy could offer one hope toward mitigating some of the risks associated with COVID-19.
Antimicrobial resistance is an ever-increasing global issue that has the potential to overtake cancer as the leading cause of death worldwide by 2050. With the passing of the “golden age” of antibiotic discovery, identifying alternative treatments to commonly used antimicrobials is more important than ever. Honey has been used as a topical wound treatment for millennia and more recently has been formulated into a series of medical-grade honeys for use primarily for wound and burn treatment. In this systematic review, we examined the effectiveness of differing honeys as an antimicrobial treatment against a variety of multidrug-resistant (MDR) bacterial species. We analysed 16 original research articles that included a total of 18 different types of honey against 32 different bacterial species, including numerous MDR strains. We identified that Surgihoney was the most effective honey, displaying minimum inhibitory concentrations as low as 0.1% (w/v); however, all honeys reviewed showed a high efficacy against most bacterial species analysed. Importantly, the MDR status of each bacterial strain had no impact on the susceptibility of the organism to honey. Hence, the use of honey as an antimicrobial therapy should be considered as an alternative approach for the treatment of antibiotic-resistant infections.
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
Recently encountered world pandemic coronavirus disease 2019 (COVID-19) is a serious concern worldwide. 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. 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. As of 17th June 2020, 8,322,910 people are suffering from this viral infection and the number of deaths is 447,959. Before the COVID-19 pandemic, two other viruses were belonging to the same genus caused severe infection in the form of pneumonia. 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. It’s a matter of concern that no proper treatment has been introduced yet. Therefore, strategies that boost the immune system could be effective to alleviate the complications associated with COVID-19.
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. Human has been using plant and its several derivatives as treatments for various types of diseases. In recent years, honey has got the attraction of researchers for combatting efficiently against these difficulties of chemo drugs. Honey contains several compounds including sugars, organic acids, amino acids, phenolic compounds, vitamins, and minerals. This is the reason why honey has been studied for a long time in animal and human models to observe its antioxidant potency. It has proved its potency in several therapeutic properties including immunostimulatory, antibacterial, anti-inflammatory, wound healing, antiulcer, antidiabetic, anticancer, antiviral, and antifungal. It reduces the level of triglycerides (TGs), very-low-density lipoprotein (VLDL), and systolic blood pressure in experimental animals. Reduced acute respiratory distress symptoms have been noticed when honey is ingested daily.
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. Methylglyoxal (MGO) modification might be involved in SARS-CoV-2 replication. MGO is a component of manuka honey that can inhibit enveloped virus growth. 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.
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.
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 .
Table 1 :
Effects of honey on various pathophysiological conditions.
|Models||Source of honey||Effects of honey on mechanisms involved||Ref.|
|Bacteria||Manuka Honey||-Lowering pH, osmotic effect of sugars, and H2O2-Inhibition of biofilm activity against Escherichia coli O 157:H7||[14, 84, 100]|
|Fungus||Commercial honey (Nigeria)||-Prevention of biofilm formation and making changes to exo-polysaccharide-Synthesis of hydrogen peroxide in water-diluted honey could be the possible reason||[14, 87]|
|Virus||Manuka Honey||Interruption in viral transcription, and translation|||
|Rats||Tualang Honey||Decreased glucose level in type-2 diabetes mellitus|||
|Rats||Tuscany honey||-Reduced formation of fats and proteins in diabetic rat-Inhibition of alpha-glucosidase activities|||
|Rats (liver cells)||Tuscany honey||Suppressing PTP1B while encouraging alteration in serum lipid profiles and expression of insulin receptor|||
|Rat||MGO||-Reduced wound size-Increase urine osmolarity, osmolar clearance, creatinine clearance, and free water clearance|||
|Human||Natural honey||Prevention of platelet aggregation, extend APPT, PT, and TT while decreasing amount of fibrinogen in platelet-poor plasma|||
|Human (peripheral blood)||European honey bee (Apis mellifera)||Mitogenic effect on both B- and T lymphocyte|||
|Rat (breast cancer)||Tualang Honey||Increase IFN-γ and IFNGR1 at serum level|||
|Human||Manuka Honey||-Reduction of IL-8/CXCL8, IL-1β, MMP-9, and TNF-α release while increasing IL-10 and IL-1ra release from the neutrophils-Reduction in neutrophil extracellular trap formation (NETosis)|||
|Human||Manuka Honey||Increase the concentration of cytokines|||
|Influenza B virus||MGO||Inhibition of influenza B virus replication by MGO|||
|Human||MGO||Induction of cell death by autophagy and inhibition of the ROS-derived Akt/mTOR signaling pathway|||
|Mouse||MGO||Increase in MCP-1 and TNF-α in RAW264.7 macrophages|||
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.
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 . 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. 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.
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). There are several viruses including coronaviruses, influenza viruses that can cause deadly lung damage and can be fatal from ARDS . 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. 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.
Honey has proved its antioxidant activity by preventing several acute and chronic diseases which include diseases related to inflammation, diabetes, cardiovascular, and cancer. Moreover, phenolic acids of honey protect humans from hydrogen peroxide-induced oxidative DNA damage in lymphocytes. 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. Consumption of 1200 mg/kg honey can increase both levels of antioxidants such as glutathione reductase, β-carotene, vitamin C in healthy human subjects. 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. Though the antioxidant effects of honey have been established in a structured manner, there are several unknown aspects yet to be found.
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. 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. Toll-like receptors (TLRs) which are also commonly recognized as pathogen recognition receptors are suspected to be a helper for SARS-CoV-2 entry. 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). 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. 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. 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.
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. Innate and adaptive immunity against SARS-CoV-2 is provided by B and T lymphocytes which are activated by dendritic cells. 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. Cytokines and chemokines produced by neutrophils and macrophages can increase CRP levels which are c3a and c5a that possess antiviral activity.
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). Honey also increases the serum levels of IFN-γ and IFN-γ receptor 1 (IFNGR1) in breast cancer in rats. As IFN-γ has an affinity to viral spike glycoprotein, nucleocapsid protein, and membrane protein, it may aid in targeting SARS-CoV-2. 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. Nigerose, a sugar derived from honey is reported as immune stimulatory. 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. 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. 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. 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.
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. A study reported that honey may be a perfect suppressor agent for these two markers. 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.
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. 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. 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.
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.
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. 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. In 2003, confirmed individuals of SARS-CoV showed transient impairment of pancreatic islet cells through hyperglycemia.
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. Honey has been shown to participate in reducing glucose, fructosamine, and glycosylated hemoglobin serum concentration. 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. 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. 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. When a dose of 1000 mg/kg is administrated, it can significantly develop glycemic control and hyperlipidemia. Therefore, it can be predicted that honey can show a hypoglycemic effect.
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. Honey is proved for its long-term cardiovascular benefits as well as short-term antiarrhythmic effects. 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. 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.
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”. 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. Viral infection followed by secondary infection’s contribution to death is surprisingly equal. Bacterial coinfections in between 12%-19% are common in H1N1 influenza and pneumonia infected individuals with other serious illnesses. 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.
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. 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. The bacterial growth might be inhibited through urease regulation by the MGO and its precursor dihydroxyacetone (DHA). 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). In the case of cystic fibrosis (CF), manuka honey might play potential roles against deadly lung infections caused by antimicrobial-resistant respiratory bacteria.
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. Honey ensures the decrement of the cell surface in biofilm which takes towards the death of biofilm by manipulating the cell membrane of fungus.
Antiviral properties :
Infections and the formation of a wound are generally promoted by viral nature. 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. 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. 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. 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. 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. Therefore, these studies suggested that enveloped viruses might be sensitive to the virucidal ingredients of honey (Figure 1).
Possible roles of honey against SARS-CoV-2 infection :
SARS-CoV-2 is an enveloped and positive-sense single-stranded RNA virus. 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. 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. Various micronutrients have been found to be essential for immunocompetence especially plant-derived polyphenols are very important to reduce the release of inflammatory cytokines. 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. 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 and2).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.
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. 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. 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. 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.
The new coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has recently put the world under stress, resulting in a global pandemic. Currently, there are no approved treatments or vaccines, and this severe respiratory illness has cost many lives. Despite the established antimicrobial and immune-boosting potency described for honey, to date there is still a lack of evidence about its potential role amid COVID-19 outbreak. Based on the previously explored antiviral effects and phytochemical components of honey, we review here evidence for its role as a potentially effective natural product against COVID-19. Although some bioactive compounds in honey have shown potential antiviral effects (i.e., methylglyoxal, chrysin, caffeic acid, galangin and hesperidinin) or enhancing antiviral immune responses (i.e., levan and ascorbic acid), the mechanisms of action for these compounds are still ambiguous. To the best of our knowledge, this is the first work exclusively summarizing all these bioactive compounds with their probable mechanisms of action as antiviral agents, specifically against SARS-CoV-2.
Despite the developments in controlling infectious disease around the world, they are still the second biggest cause of morbidity and mortality due in part to the increase in drug resistance among large numbers of the bacterial strains. This means that new strategies are needed to prevent and treat infectious disease. As a result, several ancient methods have been re-evaluated and the substances/procedures employed historically to cure diseases are now attracting renewed scientific attention. Honey is one such product that used to be widely used to combat bacteria. This review covers the antibacterial activity of honey, its use in the treatment of infection and diseases, and the features that are relevant to its activity.
The use of natural products is becoming an ever more popular approach in both medical treatments and the preservation of foods. The increase in their popularity is due to their potent activities and generally very low toxicity. According to the World Health Organization (WHO) statistics, up to 80% of the population in some developed countries have used natural products in their primary health care. Moreover, 80% of people depend on these types of treatment in Asian countries such as China and India. Natural products can be utilised in the discovery of new antimicrobial drugs and in the treatment of infectious diseases. Scientists have found that natural materials are generally more acceptable to consumers, and if these alternative approaches are effective, this may reduce the reliance on more synthetic substances. Furthermore, the study of such natural compounds may lead to the discovery of an active component that could be used to prevent some environmental hazards or perhaps have an ameliorative effect on a disease process in mammalian cells. The increase in the resistance of pathogenic bacteria to antibiotics is also an increasingly important factor behind the growing interest in the use of these natural compounds.
Herbs, plants extracts, essential oils, and honey are the most common sources for these new active compounds, and these products have been found to be effective against a range of bacterial infections and inflammatory cases. Some novel agents have been approved as therapeutic alternatives for treatment against antibiotic-resistant bacteria on the basis of their in vitro and in vivo efficacy. Moreover, in some cases, these products/compounds can be used in combination with antibiotics to enhance their activity. Many of these substances have been discovered to have similar inhibitory effect and mechanisms of action to antibiotics, causing damage to bacterial cell walls as well as affecting protein synthesis in bacterial cells.
Honey is an example of a naturally available product and is the only concentrated sweetener that can be found in nature. It has been used for several centuries in many countries as a treatment of disease, even before knowledge existed on the causes of infection. It has been known to be very effective in almost all cases of infection and for the promotion of healing especially in burn injury and wounds. As a result, many studies have analysed the composition of honey and have studied the physical and chemical properties that may give rise to its ability to work against various microorganisms.
It is evident that many different kinds of honey can be found around the world and as different regions will have different flora, this will influence the production and activity of different sorts of honey. Furthermore, it is possible to differentiate honey into two main types: floral honey that is made from the nectar of blossoms (blossom honey) and honeydew honey is prepared from the secretions of living parts of plants or the excretions of plant-sucking insects. This review will focus on floral honey.
Honey Composition :
Honey is a supersaturated sugar solution. Its composition is complex and variable, and it contains at least 181 different substances. These substances can mainly be divided into two groups: the major compounds such as the monosaccharaides (glucose and fructose) and the minor compounds including amino acids, enzymes, vitamins and minerals, and polyphenols. Some of the differences in the composition of honey are due to the differences between regions (floral sources) but seasonal differences can also be important. Bees collect many materials to produce honey, including nectar, volatiles essential oils, pollen, and propolis, and these various botanical origins will also affect the composition of honey. Some components of these raw materials possess important antibacterial properties that can contribute to the total antibacterial activity of honey. These variations in the constituents of honey, however, do not generally affect the main components, fructose and glucose, which are always the major sugars present. For example, a compositional analysis of 26 samples of honey showed some important differences between different honey varieties but these did not include the sugar composition. Nevertheless, the content of individual carbohydrates did vary and ranged between 329.2 to 426.3 mg/g for fructose and glucose (as the dominant components).
Another analysis of different types of honey demonstrated that the average of the main components in honey are 17% water, 82.5% sugars (38.5% fructose, 31% glucose, 7% maltose, 4% trisaccharides, and 1.5% sucrose), and 0.5% protein as well as some mineral components. This is similar to the findings of other studies and demonstrates the consistency amongst different varieties in terms of the key components. However, according to the International Honey Commission, the acceptable range of moisture content is 16.4–20.0% and reducing sugar content is 31.2–42.4% for fructose and 23–32% for glucose.
Interestingly, honeydew honey contains a higher concentration of oligosaccharides and amino acids and also has a higher water content than blossom honey. Several physicochemical parameters can be easily used in the routine classification of honeydew and blossom honey, including the sum of glucose and fructose (G + F) and the electrical conductivity which can be influenced by the water content. Blossom honey should have a G + F of 60 g/100 g or higher, whereas in honeydew honey, the G + F content is much lower at 45 g/100 g with a F/G average ratio of between 1.2 and 1.3.
The colour of honey reflects various components present such as polyphenols, minerals, and pollen, with dark honey having a higher amount of pigments such as flavonoids. The colour of honey ranges from light yellow, through to amber and dark reddish amber to a nearly black colour. According to the results of Estevinho et al., dark honey has a high level of phenolic compounds and this has been shown to have a good correlation with its higher antibacterial activity. Molan also highlights that dark-coloured honey obtained from the mountains of central Europe has a particularly high antibacterial activity compared to the light variant from the same region. Other dark-coloured honeys have also demonstrated high antibacterial activity such as sweet chestnut honey (Castanea sativa), Manuka honey (Leptospermum scoparium), and Heather honey (Calluna vulgaris).
The moisture content of honey can also vary between different honey varieties and can be affected by climate, season, and moisture content of the original plant nectar. Nanda et al. observed that in northern India, honey moisture content ranged between 14.63 and 21.8%.
Protein content in honey is very low and ranges between 0.1 and 0.5%. Different proteins have been detected in different honey varieties, predominantly related to different types of honeybees or different types of plants/flowers; however, a group of major royal jelly proteins are shared by all honeybees. Other important components of honey are the enzymes present which contribute to its antioxidant and antibacterial activities. These include glucose oxidase, invertase (α-glucosidase), catalase, diastase (α-and β-amylase), and peroxidase. Although it is believed that some of these enzymes come from nectar, it is known that the α-amylase and α-glucosidase in honey comes from bee salivary secretions.
Methods of Measurements of Antibacterial Activity :
The antibacterial effects of honey have been known in practical terms for over a hundred years in the absence of a proper understanding of their specific mechanisms of action. The first explanation of the antibacterial activity of honey was reported in 1892 by Van Ketel. Inhibine is a term that has been used to define the antibacterial agent in honey, with the “inhibine number” being used to describe the degree of dilution to which a particular type of honey keeps its antibacterial activity. These terms were coined by Dold and Witzenhausen in 1955 and involve the formation of a scale of 1 to 5 equal to honey dilutions in 5% steps, from 25% to 5% (w/v) (Table 1). The inhibine was identified as hydrogen peroxide, a main antibacterial compound in honeys.
There are several other methods that have been used to measure the antibacterial activity of honey. Bacterial susceptibility to honey can be measured quantitatively by several methods, broth (micro) dilution assay, well/disk diffusion assay, agar dilution methods, and time-kill assay. These methods are commonly used in microbiological laboratories according to CLSI guidelines (Clinical & Laboratory Standards Institute). The agar diffusion assay technique, for example, is a method in which a small quantity of honey or solution of honey is applied to the centre of a well (about 6 mm in diameter) cut into nutrient agar plate previously inoculated with a microbial culture. During the time in which the plate is incubating, the honey diffuses out into the agar from its point of application. The size of the clear zone around the honey application site, zone of inhibition (ZOI), is a measure of the potency of the honey being tested. It is important to note, however, that in this assay the effective antibacterial concentration can be lower than the concentration applied to the agar due to honey’s dilution during diffusion.
In other methods, honey is incorporated into the nutrient agar or into the nutrient broth in which the bacterial culture is grown. The most commonly used bacterial susceptibility assay is a broth micro- or macrodilution assay. The method involves preparing two-fold dilutions of honey in a broth and dispensing them to tubes (macrodilution version) or to 96-well microtiter plates (microdilution version). Each tube or well is inoculated with the standardized test microorganisms and incubated. The bacterial growth (change in turbidity) is assessed spectrophotometrically. By using a series of different concentrations of honey within the broth or agar, it is possible to determine the minimum inhibitory concentration (MIC) for each type of honey studied. MIC is used to determine the in vitro activity of an antibacterial substance and can be defined as the lowest concentration of an antibacterial agent that will inhibit the visible growth of microorganisms after an overnight incubation.
Measurement of absorbance using fluorimetry or the spectrophotometric determination of growth has a greater sensitivity especially when used with low honey concentrations. Due to its sensitivity, the broth microdilution assay, where inhibition of bacterial growth is determined spectrophotometrically, is the most appropriate method. This method is usually used to establish the MIC and also MBC values in conjunction with the standard plate count. Further methods that focus on the assessment of a growth indicator (e.g., a specific metabolite such as lactic acid), or direct microscopic counts can also be used. In general, it is important to appreciate that the results will depend largely on the technique and scientific judgment, and this needs to be considered when comparing results using different methods.
Features of Honey Relevant to Its Antimicrobial Activity :
Many factors have been shown to contribute to the antibacterial activity of honey, such as its high viscosity, mostly due to a high sugar concentration and low water content, which helps to provide a protective barrier to prevent infection. In addition, the mild acidity and hydrogen peroxide content have obvious antimicrobial effects.
Low Water Activity :
Water activity is a measure of the unbound water molecules in food; the less the unbound water, the harder it is for bacteria to grow in foods. The water activity (aw) of honey ranges from 0.562 and 0.62, which means it provides a very low water availability to support the growth of any microorganisms, lower than the range where the growth of bacteria is completely inhibited (aw 0.94–0.99). In other words, the process of osmosis is an important feature in the antibacterial activity of honey and the extent of inhibition will depend on the concentration of the honey as well as the species of bacteria being studied. Osmosis occurs because of the high sugar content. It is evident that undiluted honey has the ability to stop the growth of bacteria completely because of the high content of sugar; high sugar concentration of honey exerts osmotic pressure on bacterial cells which causes transport of water out of bacterial cells through osmosis. Cells become dehydrated and unable to grow and proliferate in hypertonic sugar solution. This antibacterial action will be reduced when honey is diluted by body fluids at the site of infection.
Although a high concentration of sugar and a low water activity will stop the growth of many microorganisms such as Staphylococcus aureus, studies have shown that often no effective bacterial inhibition occurs in the presence of “artificial” honey which can be prepared using a mixture of mono-and disaccharides at the same concentrations as those present in honey. In addition, studying the effect of honey on the growth of bacteria such as S. aureus, which has a high tolerance of low water activity, gives clear evidence that the antibacterial activity of honey must also be attributed to other factors. S. aureus needs an aw of lower than 0.86 for complete inhibition which is equivalent to a concentration of honey of 29% (v/v). In contrast, S. aureus has been found to be completely inhibited by one honey variety at 17% when impregnated in nutrient agar.
Moreover, a 1.8% (v/v) concentration of Manuka honey has been shown to completely inhibit the growth of S. aureus during an 8 h incubation. Manuka honey, originated from nectars of Leptospermum spp., differs from other types of honey by containing a high concentration of methylglyoxal. This compound, and not hydrogen peroxide, is considered the main antibacterial agent in Manuka honey. In a similar study using Manuka and Pasture honey from the same region in New Zealand, all 58 strains of S. aureus were inhibited by 2-3% (v/v) of Manuka honey and between 3 and 4% for Pasture honey. This indicates that obviously much lower than the 29% honey that would be required if the effect was based solely on water activity. This suggests that honey contains other important components with antibacterial properties.
Nevertheless, some bacterial strains are more sensitive to the osmotic effects of carbohydrate monomers and dimers than others, and it has been shown that a concentration of 15% (w/v) carbohydrate (fructose, glucose, and glucose and fructose combinations) was sufficient to have a similar inhibitory effect as honey on all 28 tested isolates of Helicobacter pylori.
The acidity of honey, with a pH between 3.2 and 4.5, is another important active factor in its antibacterial activity since most bacteria grow in a pH range between 6.5 and 7.5. This acidity is due to the presence of organic acids, particularly gluconic acid which is present at ∼0.5% (w/v). White et al., reported that gluconic acid is an effective antibacterial factor produced as a result of glucose oxidation by endogenous glucose oxidase. This low pH can be an effective antibacterial factor in undiluted honey, but the pH will not be enough in itself to inhibit the growth of many bacterial species when diluted in a food or by body fluids.
Hydrogen Peroxide (H2O2) :
Hydrogen peroxide (H2O2) is an important oxidizing and sanitizing agent. It is produced enzymatically in honey and can be an important feature in its antibacterial activity. Although the enzyme, glucose oxidase, is naturally present in honey, it is inactive in undiluted honey because of the low pH conditions. Glucose oxidase is activated when honey is diluted, however, which allows it to act on the endogenous glucose to produce hydrogen peroxide. Indeed, the maximum level of hydrogen peroxide produced can be obtained from a 30–50% honey dilution, potentially ranging between 5 and 100 µg H2O2/g honey (which is equivalent to ∼0.146–2.93 mM). According to Bang et al., the production of hydrogen peroxide in some honey samples can increase continuously over time to a point depending on the dilution used. Indeed, H2O2 levels in honey can reach 2.5 mmol in 30-minute, and this can double on prolonged incubation. Scholars have determined the level of hydrogen peroxide in a large number of honey samples as summarised in Table 2 . The average level of H2O2 in these studies was 1 mM. A similar range of hydrogen peroxide concentrations (1 mM to 2.5 mM) was enough to kill E. coli in 15 minutes. A linear correlation between the honey content of hydrogen peroxide and the antibacterial activity of honeys has also been reported.
It is important to note that the level of hydrogen peroxide in honey is also determined by the presence and action of catalase. Indeed, Weston showed that an important relationship exists between the levels of this enzyme and glucose oxidase and the resultant antibacterial effectiveness. Weston assumed that a high level of glucose oxidase would relate to a high level of hydrogen peroxide. Furthermore, a low level of catalase would also mean a high level of hydrogen peroxide.
It was originally believed that hydrogen peroxide is the only factor responsible for the antibacterial effect of diluted honey, and this antibacterial activity of honey could be completely removed by the addition of catalase. However, the sensitivity of bacteria to hydrogen peroxide produced in honey can be influenced by the presence of phytochemical compounds in honey. To investigate the fact that the antibacterial activity of honey is not only due to the activity of glucose oxidase, some studies have shown that adding catalase to honey is insufficient to remove all the antibacterial activity. This highlights the role of other important factors that can contribute to the effect of hydrogen peroxide and the acidity in the antibacterial activity of honey.
Nonperoxide Antibacterial Compounds :
Studies have shown the antibacterial activity of catalase-treated honey, the nonperoxide antibacterial activity (NPABA), has been identified. This discovery has provoked an increase in the number of studies that have investigated the effect of substances other than peroxide activity.
According to some studies, honey has been shown to possess a high level of phenolic compounds which might contribute to its antibacterial activity. As early as the 1990s, phenolic acids and flavonoids were recognised as important components of the antibacterial substances in honey. The phenolic acid level in honey can be affected by its botanical and geographical origin as it depends upon the source of the nectar. Moreover, it is evident that the season also has a noticeable effect on the total phenolic (TP) acid content of honey. To illustrate this, Lachman et al., evaluated the total polyphenol content of honey varieties harvested in the period from May to August 2006 and found the highest TP acid content occurred in the honey collected at the beginning of June (on average 170.21 mg/Kg) and July (on average 163.32 mg/Kg), whereas it was much lower in samples (83.60 mg/Kg) collected during the other months. Honey type also has an effect on its phenolic content. In Lachman et al.’s study, the content was very low and ranged between 82.5 and 242.5 mg/kg honey with the main phenols being flavonoids and phenolic acids. Manuka honey, meanwhile, has a phenolic acid content that ranges between 430–2706 mg/kg compared with Kanuka honey (424–1575 mg/kg) collected at the same time and from the same site. Viper’s bugloss and Heather honey have also been studied and shown to have a much lower phenolic acid content, ranging between 132.17 ± 0.05 and 727.77 ± 0.23 mg/Kg. In terms of composition, Biesaga and Pyrzynska have reported that all the honey samples that they assessed contained traces of similar phenolic compounds but in different amounts such as chlorogenic acid, vanillic acid, caffeic acid, syringic acid, myricetin, and apigenin. Yaoa et al., meanwhile, found gallic acid and coumaric acid to be the main phenolic acids in Australian tea tree, crow ash, brush box, and heath honey. The TP contents ranged between 21.3 and 184.3 mg/kg and the main phenolic acid in all honey samples was gallic acid with 4.52, 4.11, 1.39, and 3.63 mg/100 g, respectively, for the different honey types mentioned above.
High-performance liquid chromatography (HPLC) analysis has been used to identify the phenolic compounds in two honey extracts from north east Portugal. The results showed the presence of 14 phenolic compounds which were mainly phenolic acids and flavonoids. These phenolic acids included protocatechuic acid, p-hydroxybenzoic acid, caffeic acid, chlorogenic acid, vanillic acid, p-coumaric acid, and benzoic acid. The flavonoids were naringenin, kaempferol, apigenin, pinocembrin, and chrysin. The effects of flavonoids such as pinocembrin and rutin were shown to correlate with antibacterial activity of honey. Other phenolic compounds were present in similar quantities, but these were not specifically identified due to a lack of analytical standards. Furthermore, Weston et al., found two unidentified polar components with elution times of 44 and 47 min.
Methyl syringate (MSYR) was the major product in phenolic extracts of active Manuka honey isolated by Weston et al., comprising more than 45% of the TP.
Methylglyoxal (MGO; CH3-CO-CH=O or C3H4O2) is also an important constituent of honey that has recently been shown to contribute to its antibacterial activity with a minimum inhibition concentration (MIC) of 1.1 mM when tested against E. coli and S. aureus. An equivalent activity could be made by using a 15–30% honey dilution which contains similar amounts of MGO. A good linear correlation has been shown to exist between MGO content and the antibacterial activity of Manuka honey. Manuka honey is considered to have a unique factor (unique Manuka factor (UMF)) responsible for its antibacterial activity, and this is considered to be MGO. High amounts of MGO are found in Manuka honey, up to around 800 mg/kg (up to 100-fold) higher compared to conventional honey. This clearly demonstrates that the pronounced antibacterial activity of New Zealand Manuka honey may be linked to it being rich in MGO. Furthermore, the concentration of MGO increases as Manuka honey matures and after storage (up to 120 days) at 37°C, which has been attributed to the nonenzymatic conversion of dihydroxyacetone to MGO during long-term storage. Dihydroxyacetone is a substance that occurs at high levels in the nectar from which Manuka honey is made.
The nature of nonperoxide antibacterial activity in Manuka honey was reported by Snow and Manley-Harris using S. aureus in alkaline honey solution. The effect of a 10-fold excess catalase upon the antibacterial assay was examined but no statistical difference was evident in the outcome between the normal amount of catalase and the 10-fold excess, thus indicating that nonperoxide antibacterial activity was not due to residual hydrogen peroxide.
Moreover, Brudzynski and Miotto reported a good correlation between honey colour, total phenolic content, levels of Maillard reaction-like products (MRLPs), antioxidant activity, and the antibacterial activity of unheated honey . This demonstrates the wide range of compounds that could contribute to the antibacterial properties of honey.
In general, honeys might be classified to two groups: honeys whose activity is hydrogen-peroxide dependent (honeys of American, European, and some Asian origin) and honeys whose activity depends on the presence of methylglyoxal, like New Zealand Manuka honey.
Studies on the Antibacterial Activity of Honey :
Several research studies have investigated honey and its effect on various species of bacteria (Table 3). It is evident that the antibacterial activity of honey can vary quite considerably and different microorganisms have different susceptibilities to different types and concentrations of honey.
Many aspects of the antibacterial properties of honey have been reviewed and the growth of different bacteria has been tested in the presence of different concentrations of honey.
Honey of different botanical origin and geographical area showed wide range of variation in their antibacterial potency. The most potent honeys, such as Manuka, dark buckwheat, Heather, or chestnut honeys, have their MIC values, ranging from 1% to 12.5% (w/v). On the other hand, light-colour honeys such as clover honey (pasture honey) and acacia or rapeseed honey showed to be less potent as antibacterial agent with MIC higher than 25–50% (w/v).
In one early study, Jeddar et al. evaluated the antibacterial effect of pure honey in vitro. They tested the growth of bacteria in media which contained different concentrations of honey, namely, 10%, 20%, 30%, 40%, and 50% (w/v). Most pathogenic bacteria failed to grow at the 40% concentration of honey and above, and the mechanism was explained through the following reasons:
- The osmotic effect of the honey caused shrinkage and disruption among the bacterial cells
- The low pH
- The presence of other unidentified antibacterial substances in honey
Jeddar et al.’s study has been followed up by a number of other studies seeking to measure and justify the antibacterial action of honey. Bogdanov studied the antibacterial activity of eleven types of honey, including the common varieties such as acacia, blossom, chestnut, lavender, and orange against Staphylococcus aureus and Micrococcus luteus and found that the inhibition of the different honey varieties ranged from 37 to 74%. The pH of the honey was considered to be the most important and effective factor in inhibiting microorganism growth which ranged between pH 3 and 5.4.
Basson and Grobler tested the antibacterial potency of different honey varieties produced from indigenous wild flowers grown in South Africa against S. aureus. The result showed that the South African honey varieties did not have strong bactericidal activity, and honey concentration above 25% was necessary for antibacterial activity, due to the osmolality and carbohydrate concentration.
Another aspect of the studies was susceptibility of different bacteria to honey. Honey exhibits a broad-spectrum of antibacterial activity against both Gram-positive bacteria and Gram-negative bacteria, including antibiotic-resistant (MRSA) ones.
Honey has been shown to have a strong activity against many bacteria in both media and in culture. Six types of honey varieties were studied by Lusby et al., to investigate the antibacterial activity against 13 species of bacteria and one yeast species. Three types of honey (lavender, red stringy bark, and Paterson’s curse) were γ-irradiated with 15 KGY, whereas the other three (Manuka, Rewa rewa, and Medihoney) were marketed as therapeutic honeys with antibacterial activity. All samples were tested at different concentrations (0.1%, 1%, 5%, 10%, and 20% (w/v)). No inhibition was observed at 0.1% but the 1% concentration showed some inhibition with C. freundii, E. coli, M. phlei, and three species of Salmonella. A progressive increase in the inhibition was reported for most honey samples at the highest concentration in this study (at 20% at least 75% inhibition) except for K. pneumoniae which interestingly showed no inhibition at all.
A study of the biological activity of chestnut, Herero floral, and Rhododendron honeys obtained from Anatolia in Turkey revealed activity against all the test microorganisms but the extracts gave rise to moderate inhibition against only a few microorganisms, e.g., H. pylori and S. aureus.
Al-Jabri et al. studied the antibacterial activity of 24 samples of honey (16 from Oman and eight from Africa) against three bacteria, namely, S. aureus, E. coli, and P. aeruginosa. They found that 81% of the Omani honey samples and 88% of the African honey samples assessed in the study had antistaphylococcal activity, but only 63% of Omani honeys and 62% of African honeys showed any activity against E. coli. Activity against P. aeruginosa was less common in Omani honey (38%) but more common in African honey (75%).
Some researchers have studied the action of enzymes in the antibacterial activity of honey. Allen et al., tested 345 samples of honey against S. aureus in the agar well diffusion assay with phenol as the reference standard. The samples included Kanuka, Manuka, Heather, and Kamah honey. The antibacterial activity ranged between 2% to 58% (w/v) with a median of 13.6%. Interestingly, most honey samples showed no antibacterial activity in the presence of catalase except Manuka honey. This was supported by another study in which solutions of pasture honey 25% (w/v) showed no detectable antibacterial activity in the presence of catalase but an activity equivalent to 14.8% phenol without catalase, whereas the same solution of Manuka honey had activity equivalent to 13.2% with and without catalase.
The susceptibility of Campylobacter jejuni to the antibacterial activity of Manuka honey was also tested, and the results showed that 1% (v/v) of Manuka honey was sufficient to give the minimum inhibitory effect.
In a comparative study of the activities of Manuka honey and Malaysian Tualang honey (Koompassia excelsa) against an extensive spectrum of microorganisms, Tan et al., found that MICs of Tualang honey ranged between 8.75% and 25% which means that Tualang honey has a similar antibacterial activity to Manuka honey with therefore potential for use used for the same medical purposes.
A study by Alnaqdy et al. in 2005 which characterised the effect of honey on the adherence of Salmonella to intestinal epithelial cells showed that a honey dilution of 1 : 8 reduced the adherence from 25.6 ± 6.5 to 6.7 ± 3.3 bacteria per epithelial cell.
Infected mice have been used to study the effect of honey on wound infection. Al-Waili used a wide range of concentrations (10–100% (w/v)) of new honey (origin and type unspecified in the paper), stored honey, heated honey, ultraviolet-exposed honey, and heated-stored honey in acidic, neutral, and alkaline media to determinate their activities against common human pathogens in comparison with a glucose solution. Samples with concentrations between 30% and 100% gave rise to complete inhibition while the 100% glucose sample did not for some microorganisms. Interestingly, heating honey at 80°C and storing honey were reported as important factors which could cause a decrease in the antibacterial activity of honey.
In another in vivo experiment, a significant decrease in the count of E. coli cells in faecal samples was observed in rats that had previously been inoculated orally with E. coli and fed 2 g honey daily for three days in comparison with glucose-, fructose-, and sucrose-fed controls.
Wilkinson and Cavanagh investigated the antibacterial activity of 13 honey varieties against E. coli and P. aeruginosa. All honey samples as well as artificial honey were tested at a number of concentrations (1%, 2.5%, 5%, and 10% (w/v)). None of the samples was active at 1%, whereas all samples had inhibitory effects on the growth of E. coli and P. aeruginosa at 2.5% (w/v). In this study, E. coli showed more susceptibility to inhibition by the honey than P. aeruginosa.
Moreover, another study demonstrated that a 10% concentration of Manuka honey was able to inhibit the formation of a biofilm of oral bacteria such as Streptococcus mutans, suggesting that honey might be able to reduce oral pathogens within dental plaque. Also, honey was active against biofilms formed by methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), and Pseudomonas aeruginosa with bactericidal rates ranging from 63–82%, 73–63%, and 91–91%, respectively, that was higher than the effect of commonly used single antibiotics commonly used.
Comparison of the Antibacterial Activity of Honey with Antibiotics :
As the antibacterial effects of honey have been shown to be quite potent, a number of studies have sought to draw comparisons with the activities of conventional antibiotics. This is especially important since the current rise in the number of antibiotic-resistant microbial species highlights the need to source other antibacterial substances. One study compared the activity against P. aeruginosa and E. coli. of gentamicin and three kinds of pure honey obtained from Ibadan and Abeokuta in south west Nigeria, using undiluted and fresh aqueous dilutions of 1 : 2, 1 : 4, and 1 : 6 in an agar diffusion method. Undiluted honey and its 1 : 2 to 1 : 6 aqueous dilutions showed activity of 100% and 96.4%, respectively, against P. aeruginosa and E. coli. However, gentamicin showed generally lower antibacterial activity when used in concentrations of 8.0 and 4.0 μg/ml.
In another study, thirty samples of honey from different parts of Oman were investigated for their activity against S. aureus. Of these, 43% of honey samples showed excellent anti S. aureus activity. Thirty-eight percent of S. aureus strains were killed by 50% honey in 30 minutes and 45% after one hour. Gentamicin at the concentration of 4 µg/ml killed 70% of S. aureus after 30 min and 88% after one hour, whereas the percentage increased when a combination of honey and gentamicin was used (92% and 93% at 30 minutes and one hour, respectively). In contrast, Agbaje et al., reported that 100% honey might not proffer a total solution to the current problems facing bacterial chemotherapy when compared to 0.2% ciprofloxacin and 2.5% tetracycline.
Overall, the antibacterial activity of honey has been proven although there are contrasting results between researchers as to what concentration is effective and what is not. It is clear that this feature is due to more than one factor. More research is needed in this area. Moreover, the world today needs further assessments of natural substances that can be used to combat microorganisms with minimal side effects or consequences of overdose or high consumption.
Coronavirus Disease (COVID-19) has infected people in 210 nations and has been declared a pandemic on March 12, 2020 by the World Health Organization (WHO). In the absence of effective treatment and/or vaccines for COVID-19, natural products of known therapeutic and antiviral activity could offer an inexpensive, effective option for managing the disease. Benefits of products of honey bees such as honey, propolis, and bee venom, against various types of diseases have been observed. Honey bees products are well known for their nutritional and medicinal values, they have been employed for ages for various therapeutic purposes. In this review, promising effects of various bee products against the emerging pandemic COVID-19 are discussed. Products of honey bees that contain mixtures of potentially active chemicals, possess unique properties that might help to protect, fight, and alleviate symptoms of COVID-19 infection.
In addition to being used as food, honey has been used as an alternative medicine for thousands of years. Honey has a great potential to be used as a medicine because it is not suitable for micro-organisms, it is very acidic and has a very high sugar content, which causes an osmotic effect that prevents the growth of some micro-organisms, moreover, in some honey, hydrogen peroxide is found, which has a strong antibacterial effect. However, properties and appearances of honey vary greatly according to the floral source in which the bee collects the nectar, so some honey also have a strong antioxidant and anti-inflammatory activity. Recently, there are several studies, mainly in vitro, that prove the effectiveness of honey for various medical purposes due to its components and its antibacterial, anti-inflammatory, antioxidant, antiviral, antifungal, and anticancer properties.
Honey is a compound widely used as a medicine and food source for thousands of years. Several natural products that have been used as medicine have been replaced by modern pharmaceuticals, but recently they have returned to the world stage due to the growing public interest. In ancient Egypt, beekeeping has been practiced for more than 4000 years, and honey has been used as a medicine in the treatment of wounds, ulcers, burns, abscesses, gastrointestinal diseases, inflammations, rigid joints, and even as a contraceptive method. In Asia, honey is recognized for its medicinal value since 2000 BC. There are also references to different uses of honey in the bible and in the Qur’an. The ancient Greek Hippocrates, known as the father of modern medicine, used honey to clean wounds, gastrointestinal diseases, and ulcers. In Ancient Rome, honey was also prescribed alone or in combinations, often used to treat throat problems, pneumonia, and even snake bites.
The main components of honey are sugars, among which are predominantly fructose and glucose. However, there are other compounds in smaller quantities and very variable depending on the type of each honey, from the floral source where the bee collects the nectar, such as water and free amino acids. Among them, the most found is proline. Some specific enzymes are also found, the main enzymes of honey are invertase, amylase, and glucose oxidase, but other enzymes such as catalase and phosphatase. Honey is also composed of organic acids that contribute to its characteristic flavor and are responsible for the excellent stability of honey against micro-organisms, for example, formic, acetic, butyric, oxalic, lactic, succinic, folic, malic, citric, and glycolic. Gluconic acid is considered one of the most important organic acids in honey; it is the product of catalytic oxidation of glucose oxidase, in this oxidation, hydrogen peroxide is also formed, which has a strong antibacterial effect.
Honey may still have some mineral substances, such as potassium, magnesium, sodium, calcium, phosphorus, iron, manganese, cobalt, and copper; studies show that honey can contain several types of minerals, but potassium is the most abundant in various types of honey. Carotenoids, flavones, and anthocyanins can still be found, which contribute to the antioxidant action of honey. About 80 aromatic compounds have been detected in honey, including carboxylic acids, aldehydes, ketones, alcohols, hydrocarbons, and phenols. These compounds also contribute to the organoleptic properties of honey. The appearance of honey varies from almost colorless to dark brown; it can be liquid, viscous, or solid. Its flavor, aroma, and composition vary enormously, depending on the floral source in which the honeybee collects the nectar. However, some environmental factors can strongly influence honey composition, such as temperature and humidity.
Honey is a food that contains high energy carbohydrates, being that 95–99% of the total solids are composed by sugars, which are easily digestible, since they are similar to many fruits. Proteins and enzymes in honey often have no significant nutritional value, as they are usually not present in sufficient amounts. Several of the essential vitamins are present in honey, such as vitamin K, B1, B2, B6, and C, but generally at insignificant levels. The mineral content of honey is variable, usually darker honeys have significant amounts of minerals, but honey can be considered a nutritive sweetener, mainly due to its high fructose content.
In addition to its food value, honey has great potential in medicine; it has been used for thousands of years, and has now been widely studied as an alternative medicine. Honey is not a suitable medium for bacteria, since it is very acidic and has a very high sugar content. This causes an osmotic effect that prevents the growth of bacteria, this effect works literally drying the bacteria. Another type of antibacterial property of honey was called inhibition in 1940 by Dold. And in 1963, Jonathan White proposed that this inhibitory effect described in 1940 was due to the hydrogen peroxide produced and accumulated in the diluted honey, which we know today, is a by-product of the formation of gluconic acid by the enzyme glucose oxidase.
Historically, honey has been used for various medical purposes; and recent research has confirmed the effectiveness in the treatment of several diseases due to its components and its properties antibacterial, anti-inflammatory, antioxidants, antiviral, and others that will be addressed in this chapter.
Properties of honey:
Inflammation is nothing more than a defense response of the body to a tissue that has suffered a certain damage, which consists of the recruitment of leucocytes and plasma proteins of the blood. This damage can be caused by physical, chemical, or even microbial agents; inflammation is characterized by edema, erythema, pain, and increased temperature.
It is well known that propolis, another product from honeybee colony, has potential anti-inflammatory properties, including in vivo. But studies on the anti-inflammatory power of honey also are promising, such as the study that evaluated the anti-inflammatory and antioxidant effects of Tualang honey against conventional treatment in alkaline lesions in the eyes of rabbits and the results showed that there was no difference in the clinical inflammatory characteristics between the group treated with honey and the group with conventional treatment, so it is possible to infer that Tualang may be an alternative treatment. Other studies have also been depending on the use of honey, such as chronic ocular surface diseases and infectious conjunctivitis.
Gastric ulcers are among the most common diseases affecting humans, a study demonstrated that the use of honey in conjunction with other compounds may promote gastroprotection. Later, a recent study investigated the effect of gastric protection using only honey against gastric ulcers induced by ethanol in rats and also suggested this effect as gastroprotection. Manuka honey significantly decreased the ulcer, completely protected the mucus of the lesions and preserved the gastric mucus glycoprotein, significantly increased the mucus levels of gastric nitric oxide, reduced glutathione, glutathione peroxidase, and superoxide dismutase, and also decreased lipid peroxidation of the mucus and tumor necrosis factor-α, interleukins-1β, and concentrations of interleukins-6. Honey has been shown to be efficient in other types of ulcers, and this Manuka honey exerted an antiulcer effect, keeping enzymes and antioxidants, non-enzymatic and inflammatory cytokines reduced.
In addition to the Manuka honey and the Tualang honey, the anti-inflammatory effect of Malaysia’s Gelam honey was also studied, which is associated with anti-inflammatory effects on tissues. Malaysia Gelam honey was tested in rats induced by inflammation. Paw edema was induced by a subplantar injection and the rats were treated with either the anti-inflammatory drug Indomethacin or Gelam honey. Results showed that Gelam honey can reduce dose-dependent edema in inflamed rat paws, decrease the production of nitric oxide, prostaglandin, tumor necrosis factor-α, and interleukin-6 in plasma, and suppress expression of synthase inducible nitric oxide, cyclooxygenase-2, tumor necrosis factor-α, and interleucine-6 in paw tissue. The oral pre-treatment of Gelam honey at 2 g/kg body weight at two times (1 and 7 days) showed a decreased production of proinflammatory cytokines, which was similar to the effect of the anti-inflammatory indomethacin, both in plasma and in the tissue, and Gelam honey has anti-inflammatory effects and is potentially useful for the treatment of inflammatory conditions. Another study demonstrated that different types of honey promoted increased release of TNF-α, IL-1β, and IL-6 from monocytes, which are cells that assist in healing.
We can also compare the anti-inflammatory activity of honey with another herbal remedy in a study carried out in 2012 to test the activity of honey and brown sugar, surgically treated guinea pigs that were treated with honey, brown sugar, and a control group treated with saline solution, it is already known that sugar can help healing. The honey group showed a decrease in the area of the wound and the formation of granulation tissue before the brown sugar group and control; the honey group was still the only one that presented no crust in any wound and promoted a faster healing by stimulating the faster formation of granulation tissue and re-epithelization. In addition, honey showed a higher antibacterial effect in relation to brown sugar and control group. Another study had the same result, honey was effective in reducing bacterial contamination and wound healing.
Recent studies proved the anti-inflammatory activity of honey; different types of honey, different regions and different floral sources, were studied and both showed anti-inflammatory responses. Treatment with Tualang honey and Gelam honey showed similar responses to conventional anti-inflammatories used for specific treatments. Honey still has a better anti-inflammatory activity than brown sugar, promoting faster healing. Also, honey is a relatively cheap and easily accessible anti-inflammatory compound that needs to be further studied and later applied in modern medicine.
One of the advances of modern medicine has been the development of antibiotics; these antibiotics can be bactericidal, which kill the micro-organisms directly, or bacteriostatic, which prevent the growth of micro-organisms. However, micro-organisms are increasingly developing resistance to these antibiotics, which is a major concern. In addition to antibiotics, the prevention of bacterial diseases can be carried out with the use of vaccines and with basic sanitary methods.
Many different micro-organisms can cause disease and be transmitted even by contaminated water, and among the major aquatic pathogens are Escherichia coli and Pseudomonas aeruginosa. Some studies have already shown that honey can combat these pathogens. A study in 2011 tested the bacterial activity of honey, for which the Revamil® and Manuka honey were used, and it was found that both honeys had activity against Escherichia coli, Pseudomonas aeruginosa, and also against Bacillus subtilis. Manuka honey still had a greater efficacy than Revamil® against Staphylococcus aureus-methicillin resistant bacteria after 24-h incubation. Despite the efficiency of honey, propolis has higher antibacterial activity against Staphylococcus aureus. Overall, Revamil® honey clearly had more potent bactericidal activity than Manuka after 2 h of incubation, while Manuka honey was more potent after 24 h.
The bacteria Streptococcus pyogenes and Streptococcus pneumoniae are important human respiratory pathogens; Streptococcus pneumoniae can cause invasive lung infections that can develop in secondary infections and other respiratory disorders.. The antibacterial activity of honey was tested using dressings soaked with two types of honey, including Aquacel-Tualang honey and Aquacel-Manuka honey, the conventional dressing for burn treatment, Aquacel-Ag and only the curative Aquacel (control), against bacteria isolated from patients with burns (in vitro). Seven organisms were isolated from burns, four types of Gram-negative bacteria, Enterobacter cloacae, Klebsiella pneumoniae, Pseudomonas spp., and Acinetobacter spp., and three Gram-positive bacteria, Staphylococcus aureus, Coagulase-negative Staphylococcus aureus, and Streptococcus spp. Aquacel-Ag and Aquacel-Manuka dressings provided a better zone of inhibition for Gram-positive bacteria. However, similar results between Aquacel-Manuka and Aquacel-Tualang were obtained against Gram-negative bacteria.
Salmonellosis is a gastrointestinal disease caused by eating food contaminated with Salmonella, such as eggs, chicken, meat, and raw vegetables, or by handling animal or animal products contaminated by the bacterium. It is the most common bacterial food infection in the United States. However, most Escherichia coli strains are not pathogenic to humans, but the few pathogenic strains of Escherichia coli are transmitted by food and produce potent enterotoxins. In the literature, there are several studies that demonstrate the efficiency of honey against bacteria important to human health, one of them demonstrated the antibacterial potential of honey against clinical isolates of Escherichia coli, Pseudomonas aeruginosa, and Salmonella enterica Typhi by in vitro methods. Honey showed excellent antibacterial activity against all bacteria studied, which are related, respectively, to urinary tract infection, skin lesion, and enteric fever in human patients; and thus, honey can be considered an alternative treatment against such infection. In addition to honey being effective against bacterial infections, it can be used as a treatment for one of the most common bacterial contamination symptoms, when honey is administered as oral rehydration fluid, it can decrease the duration of bacterial diarrhea.
Another form of food poisoning is caused by enterotoxins produced by Gram-positive bacteria, such as Staphylococcus aureus; these toxins cause nausea, vomiting, diarrhea, and dehydration, and is a major public health problem. The antibacterial action of Tualang, Gelam, and Durian honeys was tested against Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecium, Enterococcus faecalis, Escherichia coli, Salmonella enterica Typhi, and Klebsiella pneumoniae. Durian honey did not produce substantial antibacterial activity, while Tualang and Gelam honey showed a spectrum of antibacterial activity with its growth inhibitory effects against all bacterial species tested, including vancomycin-resistant Enterococci (VRE), the results still suggest the Gelam honey has the highest antibacterial effect among the honey samples from Malaysia tested.
Clostridiums are anaerobic bacteria that are capable of growing up in canned food. In addition to the antibacterial activity of honey against the bacteria dating to the top, Manuka honey still has antibacterial effect on Clostridium difficile, which is a Gram-positive anaerobic bacillus, which was associated with approximately 29,000 deaths in 2001 in the United States. A recent study has shown that Manuka honey exhibited a bactericidal action against Clostridium difficile; this is yet another feature that makes Manuka honey highly attractive in the treatment of bacterial infections. However, Manuka honey was considered ineffective against other bacteria Helicobacter pylori when tested in vivo, despite having been found effective in vitro.
Honey has an excellent antibacterial effect against different types of bacteria, as previously mentioned; honey is very acidic and has a very high sugar content, which does not serve as a suitable medium for bacteria. Moreover, in some honeys, the peroxide of hydrogen is found, which has a strong antibacterial effect. Remavil® honeys, Manuka honey, Tualang honey, and Gelam honey were tested with different types of bacteria and had positive results. The bacteria tested and susceptible to some of these honeys were Escherichia coli, Pseudomonas aeruginosa, Pseudomonas spp., Bacillus subtilis, Staphylococcus aureus, Staphylococcus aureus-resistant methicillin, coagulase-negative Staphylococcus aureus, Staphylococcus epidermidis, Enterobacter cloacae, Klebsiella pneumoniae, Acinetobacter spp., Streptococcus spp., Enterococcus faecium, Enterococcus faecalis, Salmonella enterica serovar Typhimurium, vancomycin-resistant Enterococci, and Clostridium difficile.
Of all human infectious diseases, the most prevalent and difficult to treat are those that are caused by viruses, because viruses usually remain infectious in dry mucus for a long time. Also, viruses need a host cells to occur its replication; so killing the virus means killing your host cell as well. Hence, vaccination is the most efficient way to prevent these diseases.
Chickenpox is caused by the varicella-zoster virus and it is a very common childhood disease that usually does not cause many problems; but when it affects the elderly, it can be easily fatal. Varicella-zoster is highly contagious and is transmitted by infectious droplets, which results in a systemic rash on the skin. As honey can be conveniently applied to the skin, it is easily found and relatively inexpensive, it can be considered an excellent remedy against Zoster rash, especially in developing countries, or in countries where antiviral drugs are relatively expensive and difficult to access. Therefore, a study determined in vitro antiviral effect of honey against the varicella-zoster virus; two types of honey were used, Manuka honey and clover honey, and both types showed antiviral activity against the varicella-zoster virus, showing that honey has significant antiviral activity against varicella-zoster. A study on the relationship of honey to another virus, analyzed in vivo, showed that the use of topical honey is safe and effective in the treatment of recurrent herpes and genital herpes lesions.
Respiratory syncytial virus is the most common cause of viral respiratory infections in infants and young children, also seriously affects adults, the elderly and immunocompromised, causing deaths mainly in the elderly. The antiviral activity of honey was tested for its action against the respiratory syncytial virus. A variety of tests using cell culture was developed to assess the susceptibility of respiratory syncytial virus to honey. The results confirmed that treatment with honey promoted inhibition of viral replication. Attempts to isolate the antiviral component in honey demonstrated that sugar was not responsible for the inhibition of respiratory syncytial virus, but could be methylglyoxal; this component of honey may play a role in the increased potency of Manuka honey against respiratory syncytial virus. Thus, honey may be an alternative and effective antiviral treatment for the therapy of respiratory viral infections, such as respiratory syncytial virus; however, other measures, such as an effective vaccine, are still necessary for the control of this disease.
Influenza is a highly infectious respiratory disease of viral origin that causes even more deaths than the respiratory syncytial virus at all ages, except in children less than a year old. Influenza viruses are transmitted from person to person through the air, especially from droplets expelled during coughing and sneezing and are a serious threat to human health, and there is an urgent need for the development of new drugs against these viruses. Therefore, the anti-influenza virus activity of honey from several sources was studied. The results showed that honey, in general, and particularly Manuka honey, has potent inhibitory activity against the influenza virus, demonstrating a potential medicinal value. In addition to honey, propolis has also been studied against the influenza virus and appears to decrease the activity of the influenza virus.
Honey, especially Manuka honey, has strong antiviral properties. Studies show that honey has action against the varicella-zoster virus, the respiratory syncytial virus, and also has anti-influenza activity. New studies on this property of honey are necessary, mainly with other types of honey.
Most people associate fungi with organic matter decomposition or superficial fungal infections, but fungi can cause various human diseases, from mild to firmly established systemic diseases; the most serious infections can even be fatal. The incidence of Candida infections is increasing worldwide. Candida albicans is present in the normal human microbiota; however, this fungus can cause a variety of diseases, such as vaginal, oral, and systemic infections, especially in immunosuppressed patients, as carriers of the HIV virus, these infections can be further aggravated by the increase in resistance levels of this fungus to the medicines. Clinical isolates of Candida albicans, Candida glabrata, and Candida dubliniensis were tested against four different honeys. The antifungal activities of floral honeys were significantly higher than artificial honey against Candida albicans and Candida glabrata; but for Candida dubliniensis, only Jarrah honey was significantly active. Candida glabrata, which is innate less susceptible to many conventional antifungals, was also the least susceptible to the honey tested.
As previously stated, honey has antifungal properties and may act against Candida. A study in 2012 evaluated the clinical and mycological cure rates of a mixture of honey and vaginal mucus compared to local antifungal agents for the treatment of patients with vulvovaginal candidiasis during pregnancy, recurrent asymptomatic candidiasis in early pregnancy is associated with preterm birth. The clinical cure rate was significantly higher in the honey and mucus group than in the conventional antifungal group, while the mycological cure rate was higher in the conventional antifungal group than in the mucus and honey group; therefore, the mixture of honey and mucus can be used with a complement or an alternative to antifungal agents, especially in patients with vulvovaginal candidiasis during pregnancy.
In addition to the antifungal activity of honey against Candida albicans, the antifungal activity against Rhodotorula sp. was studied; this fungus can also affect humans, cases of meningitis caused by Rhodotorula species in immunosuppressed people have been reported. Four honeys from Algeria from different botanical origins were analyzed to test the antifungal effect against Candida albicans and Rhodotorula sp., different concentrations of honey were studied in vitro for antifungal activity, and the study demonstrated that, in vitro, these natural products clearly show antifungal activity against Rhodotorula sp. and Candida albicans.
Aspergillus spp. is a saprophyte commonly found in nature as a mold of leaves, produces potent allergens, and often causes asthma and other hypersensitivity reactions. The antifungal activities of some samples of honey obtained from different geographic locations in Nigeria were tested against some fungal isolates. Honey samples were examined for antifungal activity against Aspergillus niger, Aspergillus flavus, Penicillium chrysogenum, Microsporum gypseum, Candida albicans, and Saccharomyces sp., and results show that honey samples had different levels of inhibitory activity at various concentrations against the fungi tested, with zones of inhibition increasing with increasing honey concentration; Microsporum gypseum, which can infect immunosuppressed patients, was the most sensitive of all fungal isolates studied, while Candida albicans was the least sensitive, other studies have shown efficient inhibitory activity of honey against the growth of Candida albicans. Honey samples used in the study showed spectrum and promising antifungal activity, the honey from Nigeria may serve as a source of antifungal for possible development of antifungal drugs for the treatment of fungal infections.
Besides the antibacterial and antiviral properties, some honeys also have antifungal properties. Recent studies showed some honey have properties against Candida albicans, Candida glabrata, Candida dubliniensis, Rhodotorula sp., Aspergillus niger, Aspergillus flavus, Penicillium chrysogenum, Microsporum gypseum, and Saccharomyces sp., which make these honey as possible alternative medicines, especially against candidiasis, a disease that is growing worldwide.
In 2016, the cancer mortality rate has dropped 23% since 1991. Despite this progress, mortality rates are increasing for liver, pancreatic, and uterine cancers; and cancer is now the leading cause of death in 21 states from United States, lung cancer is still the most lethal, followed by breast cancer. The advance for cancer treatment needs more clinical and basic research.
Many scientists have focused on the antioxidant property of honey. Studies indicate that ingestion of honeybee products, such as honey, can prevent cancer. Through the use of human renal cancer cells, the antiproliferative activities, apoptosis, and the antitumor activity of honey were investigated. Honey decreased cell viability in malignant cells regardless of concentration and time. Honey induced apoptosis of human renal cancer cells according to honey concentration, and apoptosis plays an important role, most of the drugs used in the treatment of cancer are apoptotic inducers, so the apoptotic nature of honey is considered vital.
The anticancer activity of honey samples was extracted from three different Egyptian floral sources and was tested against colon, breast, and liver tumor lineage. Cassia honey showed moderate cytotoxic activity against colon cancer and breast cancer, with the weakest cytotoxic activity against liver cancer; Citrus honey exhibited the highest cytotoxic activity against breast cancer; and Ziziphus honey showed potent efficiency against colon, liver, and breast cancer. Breast cancer, which is the type of cancer that most affects and kills women, was also tested for another type of honey, the Manuka honey, and the results showed that it is cytotoxic to MCF-7 breast cancer cells in vitro and the effects are mainly correlated with the total content of phenols and their antioxidant power.
The phytochemical content and antioxidant activity of melon honey and Manuka honey and their cytotoxic properties were tested against human and metastatic colon adenocarcinoma. The ability to induce apoptosis in colon cancer cells depends on the concentration of honey and type of cell line, in addition to having a great relation with the phenolic content and residues of tryptophan. Honey was analyzed for phenolic, flavonoid, amino acid, and protein contents, as well as their free radical scavenging activities. Melon honey presented the highest amount of phenolics, flavonoids, amino acids, and proteins, as well as antioxidant capacity in relation to Manuka honey. Both melon honey and Manuka honey induced cytotoxicity and cell death independently of dose and time in human and metastatic colon adenocarcinoma cells. Melon honey showed to be more efficient in concentrations. The results indicate that melon honey and Manuka honey can induce inhibition of cell growth and the generation of reactive oxygen species in colon adenocarcinoma and metastatic cells, which may be due to the presence of phytochemicals with antioxidant properties. These results suggest a potential chemo-preventive agent against colon cancer; in addition, honey can improve the functioning of other substances already used in cancer treatment.
Research on cancer control has shown the importance of adjuvant therapies. Aloe vera may reduce tumor mass and rates of metastasis, and its association with conventional therapy can produce benefits for the treatment, while honey may inhibit tumor growth. The influence of Aloe vera and honey on tumor growth and the apoptosis process was evaluated by evaluating tumor size, the rate of cell proliferation for Walker 256 carcinoma. Tumor-bearing mice received a daily dose of Aloe vera and honey, and the control group received only sodium chloride solution. The effect of Aloe vera and honey against tumor growth was observed through a decrease in relative weight (%). The results suggested that Aloe vera and honey can modulate tumor growth, reduce cell proliferation, and increase susceptibility to apoptosis. Studies have shown that honey has antiproliferative activity because of its ability to induce apoptosis, so this combination is a possible adjuvant therapy.
Several types of honey have been studied because of their anticancer properties. Currently, cancer is one of the world’s leading diseases, requiring further studies. Some honey have already been tested against colon, breast, and liver tumor, as well as human kidney cancer and Ehrlich ascites carcinoma cell lines, where most have weak to strong cytotoxic activity depending on the type of honey tested and depending on the dose of honey. The effect of Aloe vera on honey has also been studied, and the whole has the capacity to modulate tumor growth, reducing cell proliferation, and also increasing susceptibility to apoptosis. The antitumor effects of honey were highly correlated with their ability to induce apoptosis of cells and with their antioxidant power. The effect of Aloe vera along with honey has also been studied, and the set has the capacity to modulate tumor growth, reducing cell proliferation, and also increasing susceptibility to apoptosis. The antitumor effects of honey were highly correlated with its ability to induce cell apoptosis and with its antioxidant activity.
Antioxidants, which are present in large amounts of honey, making it a food with great antioxidative potential, are free radical scavengers that reduce the formation or neutralize free radicals. A comparative analysis of total phenolic content and antioxidant potential of commercially available common honey was performed along with Malaysia’s Tualang honey. Biochemical analyzes revealed a significantly high phenolic content in Tualang honey. In addition, the antioxidant capacity of Tualang honey was higher than that of common honey; these data suggested that the high activity of elimination of free radicals and antioxidant activity observed in Tualang honey were due to the increase in the level of phenolic compounds, it was also observed that the antioxidant activity of honey depends on its botanical origin. Therefore, the favorable antioxidant properties of Tualang honey can be important for nutrition and human health.
Type 2 diabetes consists of progressive hyperglycemia, insulin resistance, and β-pancreatic cell failure, which may result from glucose toxicity, inflammatory cytokines, and oxidative stress, and is responsible for 90–95% of all cases of diabetes. A study investigated the effect of pre-treatment with Gelam honey, and the individual flavonoid components chrysin, luteolin, and quercetin on the production of reactive oxygen species, cell viability, lipid peroxidation, and insulin in hamster pancreatic cells, cultured under normal conditions and hyperglycemic, the pre-treatment of cells with Gelam honey extract or flavonoid components showed a significant decrease in the production of reactive oxygen species, glucose-induced lipid peroxidation, and a significant increase in insulin content and viability of cultured cells under hyperglycemic conditions. The results indicated the in vitro antioxidant property of Gelam honey and flavonoids on hamster β cells, creating a protective effect against hyperglycemia. Another study demonstrated the effect of honey on diabetics, the study with rats concluded that the pancreatic tissues of rats with diabetes were exposed to great oxidative stress and that supplementation with other honey, Tualang honey, had protective effects in the pancreas.
Honey contains antioxidants, such as phenolic compounds that prevent cellular oxidative damage that leads to aging, disease such as cancer, metabolic disturbances, cardiovascular dysfunction and even death. The antioxidant effect of honey in young and middle-aged rats was compared, the rats were fed with pure water (control), those supplemented with 2.5 and 5.0 g/kg of Gelam honey for 30 days. Results showed that Gelam honey supplementation reduced DNA damage, plasma malondialdehyde level, and glutathione peroxidase. Liver activity superoxide dismutase also decreased in young rats supplemented with 5 g/kg of Gelam honey. Gelam honey reduces the oxidative damage of young and middle-aged rats by modulating the activities of the antioxidant enzymes that were more prominent in higher concentration compared to the lower concentration. Another study indicates that honey has these antioxidant and free radical sequestering properties, mainly due to its phenolic compounds.
Honey has antioxidant properties that can be further explored and studied, because antioxidants reduce free radicals and oxidative stress, which can help to promote and maintain health. Besides the previously described, the antioxidant effect of honey can be an important property to help in the anticancer effect.
Several studies have proven the effectiveness of honey as an alternative medicine; some have even shown that honey is as good a medicine as conventional medicine. Use of different types of honeys showed anti-inflammatory effect very similar to the conventional drug and that can be used as an alternative medicine in the treatment of diseases or inflammations. Honey can also be used as an antimicrobial agent anti-inflammatory, antibacterial, antivirals, antifungal, anticancer, and antioxidants. However, there is still a need to increase research on honey, especially in its potential as a medicine and also a dissemination of this knowledge to the population and the medical community, so an increase in the use of this powerful compound will be possible.
Honey has been applied for medicinal purposes since ancient times. Its antibacterial effects have been established during the past few decades. Still, modern medical practitioners hesitate to apply honey for local treatment of wounds. This may be explained by the expected messiness of such local application. Moreover, secondary infectious disease may be caused by contamination of honey with microorganisms. Hence, if honey is to be applied for medicinal purposes, it has to meet certain criteria. The authors evaluated the use and safety of a honey-medicated dressing that was developed to meet these criteria in a feasibility (phase II) study featuring 60 patients with chronic (n = 21), complicated surgical (n = 23), or acute traumatic (n = 16) wounds. In all but 1 patient, it was found easy to apply, helpful in cleaning the wounds, and without side effects. Based on these results, the authors advise to subject this dressing to a randomized, double blind, phase III study.
Honey and other bee products were subjected to laboratory and clinical investigations during the past few decades and the most remarkable discovery was their antibacterial activity. Honey has been used since ancient times for the treatment of some diseases and for the healing of wounds but its use as an anti-infective agent was superseded by modern dressings and antibiotic therapy. However, the emergence of antibiotic resistant strains of bacteria has confounded the current use of antibiotic therapy leading to the re-examination of former remedies. Honey, propolis, royal jelly and bee venom have a strong antibacterial activity. Even antibiotic-resistant strains such as epidemic strains of methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycine resistant Enterococcus (VRE) have been found to be as sensitive to honey as the antibiotic-sensitive strains of the same species. Sensitivity of bacteria to bee products varies considerably within the product and the varieties of the same product. Botanical origin plays a major role in its antibacterial activity. Propolis has been found to have the strongest action against bacteria. This is probably due to its richness in flavonoids. The most challenging problems of using hive products for medical purposes are dosage and safety. Honey and royal jelly produced as a food often are not well filtered, and may contain various particles. Processed for use in wound care, they are passed through fine filters which remove most of the pollen and other impurities to prevent allergies. Also, although honey does not allow vegetative bacteria to survive, it does contain viable spores, including clostridia. With the increased availability of licensed medical stuffs containing bee products, clinical use is expected to increase and further evidence will become available. Their use in professional care centres should be limited to those which are safe and with certified antibacterial activities. The present article is a short review of recent patents on antibiotics of hives.
Honey is one of the most appreciated and valued natural products introduced to humankind since ancient times. Honey is used not only as a nutritional product but also in health described in traditional medicine and as an alternative treatment for clinical conditions ranging from wound healing to cancer treatment. The aim of this review is to emphasize the ability of honey and its multitude in medicinal aspects. Traditionally, honey is used in the treatment of eye diseases, bronchial asthma, throat infections, tuberculosis, thirst, hiccups, fatigue, dizziness, hepatitis, constipation, worm infestation, piles, eczema, healing of ulcers, and wounds and used as a nutritious supplement. The ingredients of honey have been reported to exert antioxidant, antimicrobial, anti-inflammatory, antiproliferative, anticancer, and antimetastatic effects. Many evidences suggest the use of honey in the control and treatment of wounds, diabetes mellitus, cancer, asthma, and also cardiovascular, neurological, and gastrointestinal diseases. Honey has a potential therapeutic role in the treatment of disease by phytochemical, anti-inflammatory, antimicrobial, and antioxidant properties. Flavonoids and polyphenols, which act as antioxidants, are two main bioactive molecules present in honey. According to modern scientific literature, honey may be useful and has protective effects for the treatment of various disease conditions such as diabetes mellitus, respiratory, gastrointestinal, cardiovascular, and nervous systems, even it is useful in cancer treatment because many types of antioxidant are present in honey. In conclusion, honey could be considered as a natural therapeutic agent for various medicinal purposes. Sufficient evidence exists recommending the use of honey in the management of disease conditions. Based on these facts, the use of honey in clinical wards is highly recommended.
Summary: There are several evidence that suggesting the usage of honey in the management of disease. Therefore, honey in clinical wards is highly recommended. Abbreviations Used: WA: Water activity, RDI: Recommended daily intake, Si: Silicon, RB: Rubidium, V: Vanadium, Zr: Zirconium, Li: Lithium, Sr: Strontium, Pb: Lead, Cd: Cadmium, As: Arsenic, MIC: Minimum inhibitory concentration, PARP: Poly (ADP-ribose) polymerase, ROS: Reactive oxygen species, iNOS: Inducible nitric oxide synthase, NKcells: Natural killer cells, SCFA: Short-chain fatty acid, CRP: C-reactive protein.
Indeed, medicinal importance of honey has been documented in the world’s oldest medical literatures, and since the ancient times, it has been known to possess antimicrobial property as well as wound-healing activity. The healing property of honey is due to the fact that it offers antibacterial activity, maintains a moist wound condition, and its high viscosity helps to provide a protective barrier to prevent infection. Its immunomodulatory property is relevant to wound repair too. The antimicrobial activity in most honeys is due to the enzymatic production of hydrogen peroxide. However, another kind of honey, called non-peroxide honey (viz., manuka honey), displays significant antibacterial effects even when the hydrogen peroxide activity is blocked. Its mechanism may be related to the low pH level of honey and its high sugar content (high osmolarity) that is enough to hinder the growth of microbes. The medical grade honeys have potent in vitro bactericidal activity against antibiotic-resistant bacteria causing several life-threatening infections to humans. But, there is a large variation in the antimicrobial activity of some natural honeys, which is due to spatial and temporal variation in sources of nectar. Thus, identification and characterization of the active principle(s) may provide valuable information on the quality and possible therapeutic potential of honeys (against several health disorders of humans), and hence we discussed the medicinal property of honeys with emphasis on their antibacterial activities.
Antimicrobial agents are essentially important in reducing the global burden of infectious diseases. However, as resistant pathogens develop and spread, the effectiveness of the antibiotics is diminished. This type of bacterial resistance to the antimicrobial agents poses a very serious threat to public health, and for all kinds of antibiotics, including the major last-resort drugs, the frequencies of resistance are increasing worldwide. Therefore, alternative antimicrobial strategies are urgently needed, and thus this situation has led to a re-evaluation of the therapeutic use of ancient remedies, such as plants and plant-based products, including honey.
The use of traditional medicine to treat infection has been practiced since the origin of mankind, and honey produced by Apis mellifera (A. mellifera) is one of the oldest traditional medicines considered to be important in the treatment of several human ailments. Currently, many researchers have reported the antibacterial activity of honey and found that natural unheated honey has some broad-spectrum antibacterial activity when tested against pathogenic bacteria, oral bacteria as well as food spoilage bacteria. In most ancient cultures honey has been used for both nutritional and medical purposes. The belief that honey is a nutrient, a drug and an ointment has been carried into our days, and thus, an alternative medicine branch, called apitherapy, has been developed in recent years, offering treatments based on honey and other bee products against many diseases including bacterial infections. At present a number of honeys are sold with standardized levels of antibacterial activity. The Leptospermum scoparium (L. scoparium) honey,the best known of the honeys, has been reported to have an inhibitory effect on around 60 species of bacteria, including aerobes and anaerobes, gram-positives and gram-negatives. Tan et al reported that Tualang honey has variable but broad-spectrum activities against many different kinds of wound and enteric bacteria. Unlike glucose oxidase, the antibacterial properties from Leptospermum spp. honeys are light- and heat-stable. Natural honey of other sources can vary as much as 100-fold in the potency of their antibacterial activities, which is due to hydrogen peroxide. In addition, honey is hygroscopic, which means that it can draw moisture out of the environment and dehydrate bacteria, and its high sugar content and low level pH can also prevent the microbes from growth.
Based upon the extensive searches in several biomedical science journals and web-based reports, we discussed the updated facts and phenomena related to the medicinal property of honeys with emphasis on their antibacterial activities in this review.
Medicinal Property :
Honey is an ancient remedy for the treatment of infected wounds, which has recently been ‘rediscovered’ by the medical profession, particularly where conventional modern therapeutic agents fail. The first written reference to honey, a Sumerian tablet writing, dating back to 2100-2000 BC, mentions honey’s use as a drug and an ointment. Aristotle (384-322 BC), when discussing different honeys, referred to pale honey as being “good as a salve for sore eyes and wounds”. Manuka honey has been reported to exhibit antimicrobial activity against pathogenic bacteria such as Staphylococcus aureus (S. aureus) and Helicobacter pylori (H. pylori) making this honey a promising functional food for the treatment of wounds or stomach ulcers.
The honey has been used from ancient times as a method of accelerating wound healing, and the potential of honey to assist with wound healing has been demonstrated repeatedly. Honey is gaining acceptance as an agent for the treatment of ulcers, bed sores and other skin infections resulting from burns and wounds. The healing properties of honey can be ascribed to the fact that it offers antibacterial activity, maintains a moist wound environment that promotes healing, and has a high viscosity which helps to provide a protective barrier to prevent infection. There are many reports of honey being very effective as dressing of wounds, burns, skin ulcers and inflammations; the antibacterial properties of honey speed up the growth of new tissue to heal the wound. The medihoney and manuka honey have been shown to have in vivo activity and are suitable for the treatment of ulcers, infected wounds and burns.
The honey, when applied topically, rapidly clears wound infection to facilitate healing of deep surgical wounds with infection. The application of honey can promote the healing in infected wounds that do not respond to the conventional therapy, i.e., antibiotics and antiseptics, including wounds infected with methicillin-resistant S. aureus,. Moreover, it can be used on skin grafts and infected skin graft donor sites successfully.
The manuka, jelly bush and pasture honeys are capable of stimulating the monocytes, the precursors of macrophages, to secrete TNF-α. On the other hand, glycosylated proteins can induce TNF-α secretion by macrophages, and this cytokine is known to induce the mechanism of wound repairing.Furthermore, the ability of honey to reduce ‘reactive intermediates release’ may well limit tissue damage by activated macrophages during wound healing. Thus, the immunomodulatory property of honey is relevant to wound repair.
The support for using honey as a treatment regimen for peptic ulcers and gastritis comes from traditional folklore as well as from reports in modern times. Honey may promote the repair of damaged intestinal mucosa, stimulate the growth of new tissues and work as an anti-inflammatory agent. Raw honey contains copious amounts of compounds such as flavonoids and other polyphenols which may function as antioxidants. Clinical observations have been reported of reduced symptoms of inflammation when honey is applied to wounds. The removal of exudate in wounds dressed with honey is of help in managing inflamed wounds.
Antibacterial Activity and Potential Antibacterial Agent :
The use of honey as a traditional remedy for microbial infections dates back to ancient times. Research has been conducted on manuka (L. scoparium) honey, which has been demonstrated to be effective against several human pathogens, including Escherichia coli (E. coli), Enterobacter aerogenes, Salmonella typhimurium, S. aureus. Laboratory studies have revealed that the honey is effective against methicillin-resistant S. aureus (MRSA), β-haemolytic streptococci and vancomycin-resistant Enterococci (VRE). However, the newly identified honeys may have advantages over or similarities with manuka honey due to enhanced antimicrobial activity, local production (thus availability), and greater selectivity against medically important organisms. The coagulase-negative staphylococci are very similar to S. aureus in their susceptibility to honey of similar antibacterial potency and more susceptible than Pseudomonas aeruginosa (P. aeruginosa) and Enterococcus species.
The disc diffusion method is mainly a qualitative test for detecting the susceptibility of bacteria to antimicrobial substances; however, the minimum inhibitory concentration (MIC) reflects the quantity needed for bacterial inhibition. Following the in vitro methods, several bacteria (mostly multidrug resistant; MDR) causing human infections that were found susceptible to honeys are presented in Table 1.
Table 1 :
Antibacterial activity of honey against bacteria causing life-threatening infection to humans.
|Bacterial strain||Clinical importance||Authors|
|Proteus spps.||Septicemia, urinary infections, woundinfections||Molan|
|Agbagwa and Frank-Peterside|
|Serratia marcescens||Septicemia, wound infections||Molan|
|S. aureus||Community acquired and nosocomial infection||Taormina et al|
|Chauhan et al|
|Sherlock et al|
|E. coli||Urinary tract infection, diarrhea, septicemia, wound infections||Chauhan et al|
|Sherlock et al|
|P. aeruginosa||Wound infection, diabetic foot ulcer, Urinary infections||Chauhan et al|
|Sherlock et al|
|Mullai and Menon|
|S. maltophilia||Pneumonia, urinary tract infection, blood stream infection, nosocomial infection||Tan et al|
|A. baumannii||Opportunistic pathogen infects immunocompromised individuals through open wounds, catheters and breathing tubes||Tan et al|
|A. schubertii||Burn- wound infection||Hassanein et al|
|H. pylori||Chronic gastritis, peptic ulcer, gastric malignancies||Ndip et al|
|Salmonella enterica serovar Typhi||Enteric fever||Mulu et al|
|Chauhan et al|
|Mycobacterium tuberculosis||Tuberculosis||Asadi-Pooya et al|
The MICs of various types of honeys for various pathogenic bacterial strains have been determined by many authors; in this article for oral bacterial strains and bacterial strains causing wound infections, honey MICs are depicted in Figure 2 and and33.
Mechanism and factors affecting antibacterial activity : Mechanism of antibacterial activity :
The beneficial role of honey is attributed to its antibacterial property with regards to its high osmolarity, acidity (low pH) and content of hydrogen peroxide (H2O2) and non-peroxide components, i.e., the presence of phytochemical components like methylglyoxal (MGO). The antimicrobial agents in honey are predominantly hydrogen peroxide, of which the concentration is determined by relative levels of glucose oxidase, synthesized by the bee and catalase originating from flower pollen. Most types of honey generate H2O2 when diluted, because of the activation of the enzyme glucose oxidase that oxidizes glucose to gluconic acid and H2O2, which thus attributes the antimicrobial activity. But, in some cases, the peroxide activity in honey can be destroyed easily by heat or the presence of catalase.
Besides H2O2, which is produced in most conventional honeys by the endogenous enzyme glucose oxidase, several other non-peroxide factors have been found to be responsible for the unique antibacterial activity of honey. Honey may retain its antimicrobial activity even in the presence of catalase (absence of glucose oxidase), and thus this type of honey is regarded as “non-peroxide honey”. Several components are known to contribute the non-peroxide activity, such as the presence of methyl syringate and methylglyoxal, which have been extensively studied in manuka honey that is derived from the manuka tree (L. scoparium). Unlike manuka honey, the activity of ulmo honey is largely due to H2O2 production: 25 % (v/v) solution of ulmo honey had no detectable antibacterial activity when tested in presence of catalase, while, at the same concentration the manuka honey retained its antibacterial activity in the presence of catalase (absence of H2O2). Neither type of activity is influenced by the sterilizing procedure of gamma-irradiation.
Honey is characteristically acidic with pH between 3.2 and 4.5, which is low enough to be inhibitory to several bacterial pathogens. Figure 4 depicts the pH values of different honeys. The minimum pH values for growth of some common pathogenic bacteria are: E. coli (4.3), Salmonella spp. (4.0), P. aeruginosa (4.4), S. pyogenes (4.5), and thus in undiluted honey the acidity is a significant antibacterial factor. The antibacterial property of honey is also derived from the osmotic effect of its high sugar content and low moisture content, along with its acidic properties of gluconic acid and the antiseptic properties of its H2O2. A recent study examining the antimicrobial properties of honey in vitro found that H2O2, MGO and an antimicrobial peptide, bee defensin-1, are distinct mechanisms involved in the bactericidal activity of honey.
Factors affecting antibacterial nature of honey :
Molan and Cooper reported that the difference in antimicrobial potency among the different honeys can be more than 100-fold, depending on its geographical, seasonal and botanical source as well as harvesting, processing and storage conditions. The antibacterial nature of honey is dependent on various factors working either singularly or synergistically, the most salient of which are H2O2, phenolic compounds, wound pH, pH of honey and osmotic pressure exerted by the honey. Hydrogen peroxide is the major contributor to the antimicrobial activity of honey, and the different concentrations of this compound in different honeys result in their varying antimicrobial effects. It has further been reported that physical property along with geographical distribution and different floral sources may play important role in the antimicrobial activity of honey. Several authors reported that different honeys vary substantially in the potency of their antibacterial activity, which varies with the plant source. Thus, it has been shown that the antimicrobial activity of honey may range from concentrations < 3 % to 50 % and higher. The bactericidal effect of honey is reported to be dependent on concentration of honey used and the nature of the bacteria. The concentration of honey has an impact on antibacterial activity; the higher the concentration of honey the greater its usefulness as an antibacterial agent. Taormina et al reported that the concentration of honey needed for complete inhibition of S. typhimurium growth is <25%.
Microbial resistance to honey has never been reported, which makes it a very promising topical antimicrobial agent against the infection of antibiotic-resistant bacteria (e.g., MDR S. maltophilia) and in the treatment of chronic wound infections that do not respond to antibiotic therapy. Hence honey has been used as a last-resort medication. Manuka honey has been widely researched and its antibacterial potential is renowned worldwide. The potency of honeys, such as Tualang honey, against microorganisms suggests its potential to be used as an alternative therapeutic agent in certain medical conditions, particularly wound infection.
Lusby et al reported that honeys other than the commercially available antibacterial honeys (e.g., manuka honey) can have equivalent antibacterial activity against bacterial pathogens. The growth of bacterial species that cause gastric infections, such as S. typhi, S. flexneri and E. coli, are inhibited by Tualang honey at the low concentrations. The Tualang honey has been reported to be effective against E. coli, S. typhi and S. pyogenes, and thus, when taken orally in its pure undiluted form, this honey may help speed up recovery from such infections. Honey is effective when used as a substitute for glucose in oral rehydration and its antibacterial activity shortened the duration of bacterial diarrhoea.
Currently, the emerging antimicrobial resistance trends in burn wound bacterial pathogens are a serious challenge. Thus, honey with effective antimicrobial properties against antibiotic-resistant organisms such as MRSA and MDR P. aeruginosa, Acinetobacter spp.. and members of the family Enterobacteriaceae, which have been associated with infections of burn wounds and in nosocomial infections, is much anticipated.
Overall, the unpredictable antibacterial activity of non-standardized honey may hamper its introduction as an antimicrobial agent due to variation in the in vitro antibacterial activity of various honeys. At present a number of honeys are sold with standardized levels of antibacterial activity, of which the best known is manuka (Leptospermum) honey as well as Tualang (Koompassia excelsa) honey. The medical-grade honey (Revamil, medihoney), which has the potential to be a topical antibacterial prophylaxis because of its broad-spectrum bactericidal activity, or to be a treatment for topical infections caused by antibiotic-resistant as well as antibiotic-sensitive bacteria, should be considered for therapeutic use. Moreover, mountain, manuka, capillano and eco-honeys have exhibited inhibitory activity against H. pylori isolates at concentration 10% (v/v), demonstrating that locally produced honeys possess excellent antibacterial activity comparable to the commercial honeys. Therefore it is necessary to study other locally produced but yet untested honeys for their antimicrobial activities.
Honey is a common household product with many medicinal uses described in traditional medicine. Modern system of medicine is also finding the honey efficacious in various medical and surgical conditions. Antimicrobial, antioxidant and wound healing properties of honey are being evaluated with successful outcome. Prevention and treatment of various infections due to a wide variety of organisms and promoting surgical wound healing are some of the areas where honey is making its mark.
Indian Honey: A Natural Product with Antibacterial Activity Against Antibiotic Resistant Pathogens, an in vitro Study
The present study designed to investigate the antibacterial activity of honey obtained from different state of India. A total of 10 honey samples (five from Uttaranchal state and five from Uttar Pradesh state) were investigated for their antibacterial activity against antibiotic resistant bacterial isolates of S. epidermidis and E. coli using the disc diffusion method. Marked variations were observed in the antibacterial activity of different sample of honey. Three (60%) of the five Uttaranchal samples and two (40%) of the five Uttar Pradesh samples showed excellent antibacterial activity against gram-positive and gram-negative bacteria. Both Uttaranchal state and Uttar Pradesh state honey samples possess in vitro antibacterial activity against antibiotic resistant isolates of S. epidermidis and E. coli bacteria at 400 uL/disc quantity of 60% concentration (v/v).
Resistance to antibiotics continues to rise and few new therapies are on the horizon. Honey has good antibacterial activity against numerous microorganisms of many different genera and no honey-resistant phenotypes have yet emerged. The mechanisms of antimicrobial activity are just beginning to be understood; however, it is apparent that these are diverse and often specific for certain groups or even species of bacteria. Manuka honey has been most thoroughly characterized and is commercially available as a topical medical treatment for wound infections. Furthermore, since most data are available for this honey, there is a considerable focus on it in this review. It is becoming evident that honeys are more than just bactericidal, as they impact on biofilm formation, quorum sensing and the expression of virulence factors. With this in mind, honey represents an attractive antimicrobial treatment that might have the potential to be used alongside current therapies as a prophylactic or to treat wound infection with multidrug-resistant bacteria in future.
Background: Renewed interest in honey for various therapeutic purposes including treatment of infected wounds has led to the search for new antibacterial honeys. In this study we have assessed the antibacterial activity of three locally produced honeys and compared them to three commercial therapeutic honeys (including Medihoney and manuka honey).
Methods: An agar dilution method was used to assess the activity of honeys against 13 bacteria and one yeast. The honeys were tested at five concentrations ranging from 0.1 to 20%.
Results: Twelve of the 13 bacteria were inhibited by all honeys used in this study with only Serratia marcescens and the yeast Candida albicans not inhibited by the honeys. Little or no antibacterial activity was seen at honey concentrations <1%, with minimal inhibition at 5%. No honey was able to produce complete inhibition of bacterial growth. Although Medihoney and manuka had the overall best activity, the locally produced honeys had equivalent inhibitory activity for some, but not all, bacteria.
Conclusions: Honeys other than those commercially available as antibacterial honeys can have equivalent antibacterial activity. These newly identified antibacterial honeys may prove to be a valuable source of future therapeutic honeys.
Honey has been widely accepted as food and medicine by all generations, traditions, and civilizations, both ancient and modern. For at least 2700 years, honey has been used by humans to treat a variety of ailments through topical application, but only recently have the antiseptic and antimicrobial properties of honey been discovered. Honey has been reported to be effective in a number of human pathologies. Clinical studies have demonstrated that application of honey to severely infected cutaneous wounds rapidly clears infection from the wound and improves tissue healing. A large number of in vitro and limited clinical studies have confirmed the broad-spectrum antimicrobial (antibacterial, antifungal, antiviral, and antimycobacterial) properties of honey, which may be attributed to the acidity (low pH), osmotic effect, high sugar concentration, presence of bacteriostatic and bactericidal factors (hydrogen peroxide, antioxidants, lysozyme, polyphenols, phenolic acids, flavonoids, methylglyoxal, and bee peptides), and increase in cytokine release, and to immune modulating and anti-inflammatory properties of honey; the antimicrobial action involves several mechanisms. Despite a large amount of data confirming the antimicrobial activity of honey, there are no studies that support the systemic use of honey as an antibacterial agent.
Honey: a potential therapeutic agent for managing diabetic wounds