Phytochemistry, metabolism, and ethnomedical scenario of honey: A concurrent review

ABSTRACT

Honey is a natural domestic sweet food material and a chemically diverse superfluous product of nectar acquired from flowers. Owing to the presence of higher amounts of antioxidant compounds covering phenolic, enzymes, organic acids, and bioactive peptides, it holds a strong ability to prevent various maladies. In addition, honey has also been exploited in certain cardiovascular, gastrointestinal, neoplastic, and inflammatory states along with its role in the treatment of copious infections and surgical wounds. Flavonoids and polyphenols are important bioactive components present in honey and have antioxidant properties. Some bioactive compounds, for example luteolin, galangin, isorhamnetin, quercetin, and kaempferol, are present in honey. Phenolic acids and flavonoids have important pharmacological activities such as anti-allergic, anti-biotic, anti-carcinogenic, and hypoglycaemic. Moreover, curative potential of bioactive components and their utilisation in value added food products are also the limelight of this article.

KEYWORDS:

• Ailments
• Bioactive compounds
• Contemporary remedies
• Conventional medication
• Honey
• Natural food

Introduction

Over the last few eras, higher utilisation of plant derived natural foods has been documented owing to the presence of beneficial constituents like phytochemicals, enzymes, hormones, vitamins, minerals, antioxidants, and other nutritional components. These are not only intended to provide essential nutrients for human consumption, but also prevent nutrition-related disorders and improve the overall health of the consumers in their daily lives.^[1]

Honey, an eminent native food product, has been extensively exploited for its ethno medical properties i.e. healing. It encompasses around 200 beneficial bioactive constituents and principally comprises of glucose and fructose, but also grasps fructo-oligosaccharides^[2] several minerals, vitamins, amino acids, and enzymes.^[3] Its configuration diverges in accordance with plants on which the bee nourishes. Approximately every natural honey type enfolds flavonoids (for instance kaempferol, galangin, quercetin chrysin, apigenin, pinocembrin, and hesperidin), ascorbic acid, superoxide dismutase (SOD), reduced glutathione (GSH), phenolic acids (such as caffeic, p-coumaric, ellagic, and ferulic acids), tocopherols, catalase (CAT), peptides, and Maillard reaction products. To offer a synergistic antioxidant effect, these compounds mostly operate in mishmashes.^[4–8]

Honey has earned an imperative spot in conventional medication for epochs.^[9,10] But, still it is underutilised in modern remedial procedures owing to the dearth of scientific backing. Since historic times, it has been emphasised that honey could be functioned to treat not only liver disorders, but cardiovascular and gastrointestinal problems as well.^[11] Primeval Assyrians, Egyptians, Chinese, Greeks, and Romans applied honey on lesions and also utilised for the illnesses of the large and small intestines.^[12] For the last few decades, honey has been exposed to clinical and laboratory inquiries by numerous research congresses. The most striking finding was the anti-bacterial action of honey that was cited in copious dissertations.^[13,14] Natural honey plays an antiseptic role in counter voluminous organisms comprising Helicobacter pylori, Escherichia coli, Salmonella, Shigella etc. Research work also indicated that it may have anti-inflammatory properties and fuel immune retorts in an injury.^[15,16] Scientific research proved that after being ingestion, honey exhibits anti-inflammatory properties.^[17] It has been revealed to avert Reactive-Oxygen Species (ROS), induced Low Density Lipoprotein (LDL) oxidation in few in vitro studies, hence showing defense against cardiovascular ailments.^[18,19] Apart from this, honey also revealed antineoplastic activity in an experimental bladder cancer.^[20]

Life cycle of a honey bee

Honey bee (Apis mellifera) is one of the spectacular creations of God, which is liable for making honey by imbibing nectar from the flowers of the variant plants. In a bee hive (living place of honey bees), there are three types of bees: Queen bee (sole reproducing female), Drone bees (male ones), and Worker bees (non-reproducing females). Queen bee mates with the drone bees and fertilise to produce eggs. These eggs stay there in the cells of the comb (hive). It takes about 3–4 days for larvae to hatch from eggs. These larvae give rise to pupae and afterwards transform into new female worker bees which are being fed by the existing worker bees.^[21] A typical bee colony consists of tens of thousands of individual bees, mainly comprising of the sterile female worker bees. Drones die after mating with the queen and the normal life span of the queen bee lasts about 3–4 years.^[21,22]

The honey is formed by the bees in their “honey stomach”. There are two types of stomachs in the honey bee, one is the normal stomach which aids in the normal functioning of the honey bee and the other one is specifically meant for the preparation of honey in it. Honey bees (Apis mellifera) used to suck the sugar-rich nectar (transparent liquid containing 80% of water and 20% of the complex sugars in it) from variant flowers with the help of their tube like tongue.^[23] A single worker bee visits around hundreds of flowers to fill their honey stomachs with the nectar. Now, here it’s processing initiates immediately by the action of digestive enzymes (amylase, catalase, glucose oxidase, and acid phosphorylase), which aid in breaking down the sucrose into the mixture of glucose and fructose.^[23]

After reaching the bee hive, the process of regurgitation (spitting the nectar into the mouth of the other bees one after the other) starts by the bees. This process momentously aids in the preparation of the final product (honey) from the raw nectar, as every bee’s digestive enzymes imparts its effect on the nectar. This process continues for about 20 min, followed by spitting the resultant product (raw honey) in the cells of the honey comb. At this stage, the moisture content is about 80%, which makes it quite vulnerable for the attack by the microorganisms. This superfluous moisture is evaporated by the fluttering of wings of honey bees creating a strong draft and diminishing the moisture content to less than 20%. Once dried, honey bee seals the cells by wax, to ensure its storage for future usage. This wax is also prepared from honey, by the action of honey bees (Apis mellifera).^[24]

The honey can be extracted from the bee hive by two methods. First one is a traditional technique, which involves calming down or moving the bees away from the hive by the application of smoke into the hive. As soon as the bees calm down or move away, the hive is squeezed to extract the honey out of it. Another method is to place the combs in the metallic bowl after getting rid of all the bees. Burning coals are placed on the combs, honey and the bee’s wax melt down and drain out from the hole where it is collected. But, these conventional ways are not so efficient, which are being replaced by the contemporary ones.^[25] Another honey extraction method being used is by mechanical extractor, which works on the principle of centrifugal force. It consists of a container having the frame basket, which spins, tossing out the honey from the comb without any damage to it, so it can be reused by honey bees (Apis mellifera).^[25]

Physico-chemical properties of natural honey

Natural pure honey has numerous imperative properties besides its taste and composition. A fresh extracted honey is a viscid fluid, whose gluiness is governed by number of substances and consequently differs in its composition with especial reference to its water content.^[26] Hygroscopicity is a quality of honey which defines its capacity to captivate and engross moisture from surroundings. Generally, honey contains water content of up to 18.8% or less, also have the ability to soak moistness from the surrounding air, with relative humidity of more than 60%. Viscosity gives foaming properties to honey.^[27]

Variation exists in the colour of natural honey which initiates from colourless (like water), crystal clear and to sharp amber or black. Honey’s colour fluctuates with its age, botanic source and storage environment, but its transparency depends on the degree of suspended components like pollens.^[28] Rare honey colours include slightly roseate like chest nut, grayish (identical to eucalyptus), bright yellow resembling sunflower, and greenish like honeydew. Upon crystallisation, its colours turns towards lighter tone as the crystals of glucose (major component of honey) are white. Monohydrate glucose crystals are formed in the honey which differs in their dimension, shape, quality and amount depending on the respective storage conditions and composition of honey. Crystallisation process is inversely proportional to its water content. The lesser the water content in the honey, higher will be the percentage of the glucose proportion and rapid will be the crystallisation process and vice versa.^[29]

Pure honey contains nearly 200 variant worthwhile elements, together with vitamins, minerals, amino acids, and enzymes, but it chiefly covers water and sugar. The latter (sugar) accounts for about 95 to 99% of its total dry matter. Fructose is the foremost carbohydrate component of honey whose percentage varies from 32.5 to 38.2% and glucose ranges from 28.5 to 31.3%, which implies 85 to 95% of the total sugars present, which are promptly captivated in digestive tract of humans in post- ingestion process.^[30]

Other sugars comprise of disaccharides like sucrose, maltose, isomaltose, nigerose, turanose, panose, melezitose, maltotriose, and meli-biose. Apart from them, few oligosaccharides also exist. Honey consists of 4 to 5% fructo-oligosaccharides, serving as probiotic agents.^[11] Followed by the sugars, water is the second most significant element of natural honey. Keep in line with the composition, organic acids form about 0.57% of honey comprising mainly of gluconic acid, product derived from enzymatic digestion of glucose. Organic acids give acidity to honey which plays a crucial role in providing its distinctive taste.^[31] The range of mineral compounds in honey is from 0.1 to 1.0%, among which core position holds by potassium, followed by sulphur, sodium, magnesium, phosphorus, and calcium. Minor ones include manganese, zinc, iron, and copper.^[32–34]

With reference to vitamin’s profiling, it includes B-complex vitamins like vitamin B1 (thiamine), B2 (riboflavin), B3 (niacin), vitamin B6, nicotinic acid, pantothenic acid, vitamin C, and nitrogenous compounds are also found in this valuable natural food material.^[31] The proteins (0.1–0.5%) are present only in minute quantities in it.^[3] In accordance with the topical report, particular protein levels diverge in proportion to the honeybee’s origin.^[35,36]

As far as enzymes are concerned, honey contains enzymes for instance; amylase, glucose oxidase, invertase, oxidase, catalase etc. Though, the core ones in this list are diastase (amylase), glucose oxidase, and invertase (saccharase), contributing a crucial part in the formation of honey.^[27,37] The enzyme glucose oxidase has the ability to crop hydrogen peroxide (offers anti-microbial properties) together with gluconic acid from glucose and helps in calcium captivation. Enzyme invertase hydrolyses sucrose to fructose and glucose. Long starch chains owing to the action of amylase, give maltose and dextrin. Catalase assists in generating water and oxygen from hydrogen peroxide.^[37,38]

Phenolic compounds of honey

These are among the best imperative groups of composites that are present in plants, encompassing no less than 8000 diverse identified structures.^[39,40] These components are stated to display anti-atherogenic, anti-inflammatory, anti-carcinogenic, analgesic activities, immune modulating, and anti-thrombotic activities.^[41] Phenolic compounds of honey are in actual flavonoids and phenolic acids that are regarded as possible indicators of the botanic origin of honey.^[42] For instance, the antioxidant function of phenolics are in relation to a number of dissimilar mechanisms such as free radical scavenging, singlet oxygen quenching, metal ion chelation, hydrogen donation and carrying out as a substrate for radicals such as superoxide and hydroxyl.^[43,44]

Honey in Islamic medicines

Honey is considered as a nutritious drink in Islamic curative system. The Holy Quran vibrantly explains the exceptional restorative importance of honey:

And thy Lord educate the bee to make its cells in hills, on trees and in (men’s) residences; To eat products of their desire, bees emerge a juice from their bodies, which proves to be a medicine for humans: this is a sign for those who think.

Likewise, the Holy Prophet of Muslims, Mohammad (PBUH) commended the usage of honey for remedying diarrhoea.^[45] Almost 1000 years ago Avicenna, a legendary Iranian physician and scientist, had endorsed honey therapy as one of the most effective tool for the treatment of tuberculosis.^[46,47]

Honey in the Indian system of Ayurveda

“Ayurveda” is a complex term i.e., ayur means “life principle or life”, and the word veda denotes to the “system of knowledge”. Therefore, “Ayurveda” generally interprets as the “knowledge of life”.^[48] The early vedic’s civilisation considers honey as one of Mother Nature’s supreme favours to entire human race. It was regarded as a blessing for those having poor digestive system, as depicted in traditional texts of this historic civilisation. It had also been emphasised that the ingestion of honey was quite favourable in the therapy of infuriating cough. In accordance with Ayurvedic experts, it was considered as valued natural gadget in triggering the strength of gums and teeth.^[49,50] For centuries, it had also been utilised for the remedy of insomnia, owing to its hypnotic activity and still in use. Moreover, ancient Ayurvedic specialists endorsed it for cardiac pain, skin problems (e.g. burns and wounds) palpitation and also for whole discrepancies of lungs and anaemia. Its regular application on daily basis restores the eye-vision. In addition, it is considered handy in the deterrence of cataract.^[50]

Honey in primordial Egypt

The leading Egyptian drug being cited in 900 therapies was only honey.^[12,26] Its prescription revealed in the Smith papyrus (an Egyptian text, dating between 2600 and 2200 B.C.) calls for a mixture of byt (honey), mrht (grease), and ftt (lint/fibre) as a typical wound lotion.^[9,51] Early Egyptians offered honey as a sacrifice to their goddesses.^[52] Infected injuries were healed by honey because of its antiseptic assets. Moreover, honey was operated as a contemporary ointment.^[53]

People of Egypt use honey to make sweeter bakery products and other dishes in ancient times. Middle-Eastern and Egypt people also used honey for mummifying the dead.^[54] An experimental trial in Egypt indicated that continuous ingestion of honey could affect type 1diabetes. Honey oral rehydration solution promoted in Egypt for recovery from diarrhoea, vomiting and rehydration.^[55]

Honey in primeval Greece

There is a prehistoric Greek beverage involving unfermented grape juice and honey. Honey utilised occasionally as a conventional remedy for gout and few nervous disorders.^[53,56] A simple diet (honey) proposed by Greek scientist, preferred as hydromel (honey and water) for quenching thirst, oxymel (honey and vinegar) for pain and a combination of medicinal constituents.^[9,51] Honey had also been utilised for sore throat, laxative action, contraception, eye diseases, baldness, wound healing, cure and inhibition of scratches by him.^[38]

Sensitivity of pathogens towards honey

Honey was testified having a preventive effect on almost 60 bacterial species comprising gram-positives and gram negatives, anaerobes and aerobes. There are various number of pathogens reported to be sensitive to honey’s anti-infective properties.^[57] The innumerable results are in line with its activity against Serratia marcescens, Coryne bacterium diptheriae, Pasteurella multicoda, Klebsiella pneumonia, Listeria monocytogenes, Haemophilus influenzae, Yersinia enterocolitica, Salmonella diarrhea, Bacillus anthracis, Streptococcus pyogene, Streptococcus mutans, Pseudomonas aeruginosa, Streptococcus faecalis, Vibrio cholera, Salmonellsa typhi, Staphylococcus aureus, Mycobacterium tuberculosis, Streptococcus pneumonia, and Shigella dysentery.^[38,46]

Formerly, some case studies probing the anti-microbial action of honey to counter methicillin-resistant Staphylococcus aureus (MRSA) organisms.^[58] The minimum inhibitory concentration (MIC) of honey was found between 1.8 and 10.8% (v/v). It means, honey had potency to stop bacteriological growth after diluted to at least 9 times and for S. aureus around 56 times.^[59–61] It was indicated that urinary tract infections as certain bacteria instigating this infection, such as Proteus species, E. coli and S. faecalis were sensitive to the shielding effect of honey.^[62,63]

Gastritis was prevented by 20% solution of honey as indicated by in vitro studies of H. pylori isolates.^[56] It has also been stated that, unlike most conventional antibiotics, honey does not lead to the progression of antibiotic-resistant bacteria, and it might be used constantly. Depending on its used concentration, honey can act as both bactericidal and bacteriostatic. Manuka honey (5–11%) and Pasture honey (4–8%) were said to be bacteriostatic and bactericidal action accomplished at 8–15% and 5–10% (v/v), respectively. Contrary to it, synthetic honey was bacteriostatic only at 20–30% and not bactericidal.^[64]

Anti-microbial activity of honey

The antimicrobial activity of honey is dissimilar from antibiotics, which impede intracellular metabolic pathways and abolish the cell wall of bacteria. The antibacterial action of honey is associated with its four properties. Firstly, it contains high amount of the sugar content, which is enough to deter microorganism’s growth. However; antibacterial properties of honey are not only due to the sugar content.^[65] Secondly, its pH ranging from 3.2 to 4.5 and this is low enough to impede the microbial growth. The third and the most vital antibacterial factor is hydrogen peroxide formed by glucose oxidase, however various researchers consider the non-peroxide activity designated as more significant. There are various phytochemical elements in honey exhibited antibacterial activity.^[14,66]

There are numerous antibacterial factors which are non-peroxide e.g. phytochemical elements, glucose oxidase, catalase, and hydrogen peroxide. Moreover, some essential chemical factors that deliver antibacterial properties to honey are organic acids, volatile compounds, propolis, bees wax, lysozyme, pollen, and nectar.^[39,43] Honey also comprises of oligosaccharides in minor amounts. Studies proposed the correlation of honey sugar composition with altered floral sources and the growth reticence of numerous colonic bacteria.^[67,68] Furthermore, it is specified that antibacterial activity might be accredited to the plant source. These chemical and physical features offer distinctive properties to honey as wound healing; it has the ability to heal infections rapidly, speedy debridement of injuries, instant suppression of inflammation, tissue granulation, epithelium growth as well as stimulation of angiogenesis.^[69,70]

Therapeutic role of honey in wound healing

Among the most investigated and efficient usages of honey, it deals with wound healing.^[14] The Russians utilised honey in First World War, not only to foil the infection body part but also to prompt its restorative process. Usage of honey as wound dressing paved a way to prompt the remedial process by briskly dispelling the infection. The German Army pooled both honey and cod liver oil together to fix the problems of boils, fistulas, ulcers, and burns.^[71] All wound types exhibited great response towards honey therapy including abscess, burns, chill blains, abrasion, decubitus ulcers/bed sores, surgical wounds, septic wound, burst abdominal wound, fistulas, amputation, cracked nipples, diabetic, traumatic, cervical, leprosy, sickle cell ulcers, and wounds of abdominal wall. It not only aids in stimulating the tissue regeneration process, diminishes inflammation but also imparts its cleansing action on abscesses. Impregnated pads of honey serve as non-sticking material for efficient dressing of damaged tissues.^[72,73]

The precise process of wound rectification at molecular level, by the application of this marvellous natural food product is yet to be unfolded. Though, frequent recommendations are being offered regarding efficient dressing of injured body organs with honey. Suitable honey type should be applied in appropriate amount, assuring its persistent coverage on infected part, apart from being thinned by wound exudates. Better results can be obtained if the honey is applied on the dressing, but not directly on bruised part.^[74,75] In laparoscopic oncological surgical procedure, it has also been exhausted as a wound barrier. This product has proved so handy for dressing purposes that even a sole infection issue has not been reported, after its submission to open abrasions. Dental illnesses like gingivitis and periodontal can probably cured by its application.^[76,77] In case of its usage on burns, preliminary soothing effect is received by the subject, which latterly transform into swift healing mode. Honey dressing hustles the healing process, sterilises wound and decreases pain.^[78,79] Reduction in the symptoms of Fournier’s gangrene was detected with reduced oedema and discharge, instant restoration with slight or nil scarring, vigorous wound debridement and a diminution in mortality.^[80]

For carcinoma of breast and varicose veins, honey is used efficaciously for curing ulcerations followed by major surgical procedure.^[73] In post-operative wound infections like after caesarean section or hysterectomies, topical application of natural honey results in speedier extermination of bacterial infections, subsequently diminishing the antibiotics intake and hospital stay, quickens wound healing, resultantly minimal scar development occurs. Similar efficacy is observed in decubitus ulcers and bed sores.^[81]

Medical trials were held to check the efficacy of four types of dressings on blisters and burns, including honey, silver sulfadiazine, amniotic membrane, and boiled potato peel dressings. Among all honey dressing evidenced to be the best, unveiling better progress and presented timely healing with minor degree of contracture followed by minute scarring.^[82] Scientists testified that employment of pure natural honey in controlling radiation induced mucositis is very effective.^[83,84] Honey is also reported to be used for the treatment of measles during its initial stages of occurrence. Honey is scrubbed on the eruptions which become more visible on succeeding day. Insistent application of honey causes the eruptions to fade away.^[63]

Honey as wound dressing

Osmotic outflow and the mishmash of bioactive effect of honey are the reasons of its extraordinarily hasty results in cleaning up wounds. Major organic acid present in the honey, gluconic acid, which upon the action of glucose oxidase enzyme produce hydrogen peroxide, which has the antiseptic ability.^[85] The acidity factor of honey puts a supplementary effect and aids in antibacterial activity.^[37,72] The existence of eclectic array of vitamins, trace elements and amino acids also have undeviating nutrient effect on soft tissue rejuvenation. After the application of honey, osmotic discharge aids in lifting dirt and debris from the wound.^[86]

Consequently, honey dressing empowers aching free change and is proved to be non-adhesive. Though, fewer societies have faced discomfort or agony. This might be due to the fact that unadorned nerve endings come in contact with acidity of honey. When honey is subjected to a wound may reveal antibacterial properties and also cause dismissing of wound infection. Contemporary investigations display the multiplication of T-lymphocytes and B-lymphocytes in cell culture and are stimulated by honey at concentration 0.1%. Phagocytes also triggered at as low as 0.1% concentration by honey.^[27,87]

Natural honey ominously amplified the interleukin (IL)-1β and IL-6 release from MonoMac-6 cells and tumour necrosis factor-α (TNF-α), which stimulate the immune response against infection. Hence, it was proposed that stimulation of inflammatory cytokines from monocytic cells might be related to the wound healing effect of honey. Additionally, honey dressing allows fiscal recompenses to the patient. Prompt healing not only lessens hospital stay duration and dressing material but also surgical costs.^[88,89]

Valuable role of honey in treating gastrointestinal tract ailments

Ingestion of honey could cure and also provide shield against stomach infection such as gastritis, duodenitis, and gastric ulceration.^[26] Association of bacteria to mucosal epithelial cells is regarded as the preliminary step in the advancement of gastrointestinal tract bacterial infection. Hindering attachment of pathogenic microorganisms to the intestinal epithelium is potential tactic for deterrence of disease. Rather than the epithelial cells, researchers confirmed that the preclusion of bacterial bonding initiated by honey was through its impact on bacteria.^[90] There are various potential enlightenments for anticipation of adherence of bacteria verified through honey:^[1] massacre of the bacteria as a consequence of the formerly cited antibacterial factors in honey^[2] non-specific automatic inhibition probably through the cover of the bacteria by the honey;^[3] Within honey, few fractions could alter bacterial hydrophobicity or electrostatic charge.^[90]

Gastroenteritis and Diarrhoea are found to be cured rapidly with honey.^[56,91] Honey reduced the interval of diarrhoea when utilised at 5% (v/v) concentration, in case of bacterial gastroenteritis as compared to the group consuming sugar as a replacement fluid; although no change was observed in viral gastroenteritis. In rehydration fluid, without boosting uptake of sodium, honey increases potassium as well as water uptake. It toils as an anti-inflammatory agent because of overhauled dented intestinal mucosa and also fuels the progression of new tissues. Microvascular permeability, indomethacin-induced gastric lesions and myeloperoxidase activity of the stomach was prevented by oral pretreatment of honey i.e. 2 g/kg.^[92] With antibacterial activity of honey, H. Pylori is found to be sensitive because of the presence of hydrogen peroxide at 20% concentration.^[93,94] Perfusion of isotonic honey on stomach brought about reduction of lesions caused by ethanol. It was done for the assessment of gastric cytoprotective properties of pure honey.^[95] Also, it was being advocated that natural honey contains restorative assets to counteract ulcers and might be utilised in controlling peptic ulcer infection like sucralfate.^[96]

Anti-fungal and anti-viral effects infections

Natural honey limits fungal development and obstruction in toxin production was observed due to diluted honey.^[57] Along with all the common dermatophytes, for certain species of Aspergillus, Penicillium, and yeast, an antifungal action has also been detected.^[97] Candidiasis, triggered by Candida albicans, may respond to honey.^[98] Superficial and cutaneous mycoses like athlete’s foot and ringworm are found to be responsive to honey. This responsiveness is owing to the inhibition of bacterial infection and restriction of mycological growth. Additionally, few studies revealed the treatment of dandruff and seborrheic dermatitis owing to the topical application of honey.^[73,99]

Natural honey has depicted antiviral properties, besides its antibacterial and antifungal effects. Scientists examined the effectiveness of the topical honey application on attacks of herpes lesions. Studies verified that application of topical honey was effective in managing the signs and symptoms of periodic lesions from labial and genital herpes contrary to acyclovir cream.^[13] Honey was being conveyed and having preventive effects upon rubella virus activity.^[100]

Honey with reference to ophthalmology

Sight and vision are vital, as they help humans to connect themselves with their surroundings, keep them safe, and also assist in maintaining the sharpness of minds. Apart from playing a significant role in curing numerous human ailments, honey has also been used in the treatment of innumerable ophthalmological disorders like chemical and thermal burns to eyes, keratitis, blepharitis, conjunctivitis, and corneal injuries.^[62,101]

In a case study, non-responsive eye disorder patients were treated with topical application of honey as an ointment. Resultantly, there was improvement observed in 85% patients and no disease progression was mentioned in remaining 15% patients. In infective conjunctivitis, application of honey reduced inflammation, discharge of pus, time to bacterial eradication and redness.^[13,98]

Honey and diabetes mellitus

Honey has been indicated to reduce hyperglycaemia and scavenge reactive oxygen species.^[102,103] There is dose dependency in hypoglycaemic effect whereas supplemented honey improves oxidative stress with no dependency on dose.^[103] It is indicated that the hypoglycaemic effect of honey might be observed due to oligosaccharides and fructose present in it.^[104,105] Additionally, honey ameliorates some metabolic derangements commonly in diabetes, besides oxidative stress, and hyperglycaemic assets.^[105]

Increased serum levels of insulin and reduced concentration of glucose in diabetic rats was administered by honey.^[104] Administration of metformin or glibenclamide drugs reduced hyperglycaemia in combination with honey and significantly reduced very low-density lipoprotein, glycaemic index, cholesterol, serum fructosamine, triglycerides, bilirubin, and creatinine in the diabetic rats. Moreover, anti-diabetic drugs in combination with honey also reduced oxidative damage in pancreas and kidney of diabetic rats.^[103]

Anti-inflammatory effects

Honey diminishes cyclooxygenase-1 and cyclooxygenase-2 activities and thus demonstrating anti-inflammatory properties. Honey also has the ability to validate immunity boosting activities.^[17,106] Lacerations cured with honey display less oedema, less necrosis, better wound contraction, infiltration of fewer granular and mononuclear cells, epithelisation improvement, low glycosaminoglycan, and concentrations of proteoglycan. Besides, it lessens exudation and inflammation, supports healing, reduce blemishes dimension and stimulates tissue rejuvenation. Honey was testified for the treatment of psoriasis, dandruff and eczema.^[17] Honey was as persuasive as prednisolone treatment in an inflammatory model of colitis. Medications for the treatment of inflammation having severe restrictions: corticosteroids devastate growth of tissues, subdue the immune reaction. Anti-inflammatory and the non-steroidal medicines are quite dangerous to cells or organelles, specifically in the stomach. Honey possesses an anti-inflammatory effect and unveiling no adversarial effects.^[61,107]

Antioxidant potential

In numerous types of organisms, it is quite evident by intensive research that radicals cause transformations in molecules and the DNA modifications. Various diseases are caused by oxidative stress,^[43] and experts from different disciplines turn out to be more engrossed towards natural sources, which possibly will offer active constituents to inhibit or decrease oxidation effects on cells.^[108–110]

Pure honey encloses numerous flavonoids such as (hesperetin, pinocembrin, apigenin, quercetin, kaempferol, galangin, and chrysin), phenolic acids (caffeic, p-coumaric, ellagic and ferulic acids), Maillard reaction products, catalase, tocopherols, ascorbic acid, superoxide dismutase, reduced glutathione, and peptides.^[6,7] Therefore, it was proposed that honey, as a natural antioxidant, can assist as a substitute to specific preservers like sodium tripolyphosphate in food preservation to intrude oxidation of lipids.^[5]

The botanic derivation of honey has a paramount impact on its antioxidant potential, whereas its handling, processing and storage conditions impart minor affect to its antioxidant activity.^{[102,111,112]} The antioxidant property of honey is strongly allied with its total phenolic contents. Apart from it, a robust relationship existed between colour and antioxidant activity of honey. Researchers established the fact that honey with dark colour has greater percentage of the total phenolics and resultantly a higher antioxidant activity.^[113,114] The antioxidant effect was positioned in fractions of ether and water, designating the flavonoids of honey that might be accessible to numerous parts of the human body, wherever they can put forth different biological effects.^[113]

Prevention of cardiovascular diseases

More deaths, disability, and also greater economic costs were experienced than any other ailment in the developed world by ischemic heart disease (IHD).^[115,116] Severe indexes of IHD are arrhythmias and myocardial infarction (MI). Ventricular arrhythmias for example ventricular fibrillation and ventricular tachycardia were proved to be the principal causes of mortality during MI and cardiac surgery.^[115] In managing these above conditions, drug therapy could be a lifesaving source. Contrary to it, the side effects of anti-arrhythmic drugs such as lethal arrhythmias in some patients ensure a constraint on other anti-arrhythmic treatments.^[117]

Henceforth, there is a greater affinity to use medications, having fewer confrontational effects and more efficacies. Pure natural honey applied for therapeutic purpose since primeval epochs,^[118,119] however, with reference to cardiovascular maladies; most of the previous research was accomplished on animals and principally concentrated on effect of honey against cardiac risk factors like free radicals production and hyperlipidaemia.^[120–122] Honey antioxidants include flavonoids, vitamin C, polyphenolics, and monophenolics. Flavonoids consumption on regular basis is allied with a diminished risk of cardiac diseases. A comprehensive array of the total phenolic compounds that is present in honey has auspicious effects in the remedy of heart diseases. In coronary heart disease, the protecting effects of phenolic compounds include vasorelaxant, antioxidant, anti-ischemic, and antithrombotic. There are three key actions: 1) improving coronary vasodilatation, 2) dwindling the capacity of platelets in the blood to clot, and 3) thwarting LDLs from oxidizing through which flavonoids shrink the risk of CHD.^[123] The influence of natural honey on the total cholesterol, high density lipoprotein cholesterol (HDL-C), LDL-C, C-reactive protein, triacylglycerol, fasting blood glucose and body weight were scrutinised in 38 overweight individuals. The results disclosed that ingestion of pure honey triggered the total cholesterol reduction, C-reactive protein, triacylglycerol and low density lipoprotein. Several authors clinched that pure natural honey moderates cardiovascular (CVD) risk factors, predominantly in subjects with eminent risk and did not enhance body weight of obese subjects.^[122,124] A study was conducted on humans for the post effects of taking 75 g of natural honey that was matched with equal amount of artificial honey. Rise in insulin and CRP level was ominously greater after the intake of glucose than after consumption of honey. In subjects with hypertriglyceridemia, artificial honey increased triglycerides (TG) while pure honey decreased triglyceride concentration. Patients suffering from hyperlipidaemia, artificial honey geared LDL-C while LDL-C dwindled by natural honey. Honey paralleled to dextrose produced a considerably lower rise of plasma glucose in diabetic patients. Honey consists of nitric oxide metabolites and elevated levels in honey have a defensive effect against cardiac diseases.^[125] Honey also has the ability to lower intravenous blood pressure that can diminish the heart preload and consequently may reduce the venous system congestion.^[7]

Prophylactic effects of natural honey as a pharmacologic preconditioning agent on ischemia/reperfusion (I/R) induced wounds confirmed in isolated rat heart, the results of in vitro study pointed out that prolonged oral intake of natural honey for 45 days produces strong anti- infarction and anti-arrhythmic effects in rats.^[126] In another research, natural honey (5 g/kg) pretreatment of anesthetised normal or stressed rats for 1 h, before adrenaline dose (100 mcg/kg) possibly will guard them from cardiac disorders and epinephrine-induced vasomotor dysfunction and also conserved the affirmative effects of adrenaline. The authors clinched that pure natural honey may induce its cardio protective and healing effects compared to adrenaline-induced cardiac and vasomotor dysfunction directly or indirectly by the release of nitric oxide through the impact of vitamin C from endothelium.^[7,123]

Oxidative stress which may be somewhat liable due to honey’s neuro-protective action in response to in vitro cell death and in vivo focal cerebral ischemia, can be restrained.^[127,128] Organic compounds having antioxidant and free radical scavenging activity in honey composition shows that it keeps the ability to work in human nutrition as a vital source of antioxidants.^[129] Besides, as far as anti-inflammatory effect of honey is concerned, it causes a drop in necrosis tissues.^[130]

Role of honey as food preservative and prebiotic

Growth of Shigella, Listeria monocytogenes, and Staphylococcus aureus averted due to hydrogen peroxide and non-peroxide constituents such as antioxidants that are supposed to aid in the process of food preservation. However, Clostridium botulinum might be found to lesser extents in honey. Reduced deleterious effects of polyphenol oxidase in the processing of fruits and vegetables were observed after honey application, which endores that it also has upright potential to be utilised as a regular antioxidant source.^[131]

In fermented milk foods, honey is supposed to be a suitable sweetener utilised without deterring the development of common bacteria like Streptococcus thermophilus, Lactobacillus acidophilus, Lactobacillus delbruekii, and Bifidobacterium bifidum. All these bacterial species are pretty much important for keeping the gastrointestinal tract condition. Moreover, growth of bifidobacterium also supported and amplified by honey,^[132,133] which is principally due to the existence of a variety of oligosaccharides.^[2,11]

Diverse beneficial effects of honey

Affirmative effects of honey as an anti-carcinogenic agent are reported in few studies.^[61,134] Honey has displayed antineoplastic activity in bladder cancer. Pure honey can impart crucial role in the therapy of chest pain, vertigo and fatigue. In a study, regular honey consumption disclosed a number of constructive effects on blood levels of minerals, enzymes and endocrine system and also on haematological indices.^[135] In another study, orally ingested honey prompted antibody production, during both primary and secondary immune responses against thymus-dependent and thymus-independent antigens.^[57] Honey of stingless bee serves as a shielding agent in contrast to DNA mutilation and could exemplify fascinating evidence concerning the antioxidant activity.^[62] In another research work, honey administration probed on N-ethylmaleimide (NEM) induced liver injury in rats.^[136,137] Studies indicated that honey had advantageous effects on menopausal rats, through suppression of increased body weight, augmented bone density and stopping uterine atrophy.^[138]

Harmful effects of honey

Natural pure honey is comparatively free from antagonistic actions. Current application of honey on skin may give results in momentary stinging sensation. Besides, it is labelled in altered formulas as pain relieving, non-irritating, painless and soothing dressing change. Allergic reactions from honey are quite rare, but there could be one due to either bee proteins or pollen in honey.^[139] Prodigal application of honey may cause tissues dehydration, which could still be reinstated by saline containers. Theoretic hazard of upsurge in levels of glucose in blood might be considered, once utilised for relatively large exposed wound in diabetic subjects. Risk of wound botulism caused by the presence of Clostridia spores, could be curtailed by gamma radiation. These radiations would eradicate the spores of clostridia without any hindrance to antibacterial activity.^[140]

Conclusion

Till now, researchers put more focus on drugs, originated naturally and rely on natural food products might be more proficient therapy in contrast to synthetic medications. Honey as per novel effective remedy for numerous kinds of ailments utilised for topical application on mucocutaneous injuries, post operation wounds and genital lesions. Antibacterial activity is the most eminent effect of honey. Additionally, it was utilised in some neoplastic, cardiac, inflammatory and intestinal conditions which grabbed the attention of scientists, both in ancient and modern ages. Research work is still in progress, on knowing more about its beneficial effects, which could prove beneficial to serve humanity in future.