Penelitian

Introduction

Honey is a natural product that has been widely used for its therapeutic effects. It has been reported to contain about 200 substances. Honey is composed primarily of fructose and glucose but also contains fructo-oligosaccharides (1) and many amino acids, vitamins, minerals and enzymes (2). The composition of honey varies depending on the plants on which the bee feeds. However, almost all natural honey contains flavonoides (such as apigenin, pinocembrin, kaempferol, quercetin, galangin, chrysin and hesperetin), phenolic acids (such as ellagic, caffeic, p-coumaric and ferulic acids), ascorbic acid, tocopherols, catalase (CAT), superoxide dismutase (SOD), reduced glutathione (GSH), Millard reaction products and peptides. Most of those compound works together to provide a synergistic antioxidant effect (3-7).

Honey has had a valued place in traditional medicine for centuries (8, 9). However, it has a limited use in modern medicine due to lack of scientific support (10). For a long time, it has been observed that honey can be used to overcome liver, cardiovascular and gastrointestinal problems (11). Ancient Egyptians, Assyrians, Chinese, Greeks and Romans employed honey for wounds and diseases of the intestine (12). Since a few decades ago, honey was subjected to laboratory and clinical investigations by several research groups. The most remarkable discovery was antibacterial activity of honey that has been mentioned in numerous studies (13, 14). Natural honey exhibits bactericidal activity against many organisms including Salmonella, Shigella, Escherichia coli (3, 15), Helicobacter pylori (9), etc. In an inflammatory model of colitis, honey was as effective as prednisolone treatment (16]. Research has also indicated that honey may possess anti-inflammatory activity and stimulate immune responses within a wound (17, 18). Al-Waili and Boni (2003) demonstrated anti-inflammatory effects of honey in human after ingestion of honey (19). Honey, interestingly, has been shown to prevent reactive oxygen species (ROS)-induced low density lipoprotein (LDL) oxidation in some in vitro studies, thus exhibiting beneficial cardiovascular protection (20, 21). Honey also had antineoplastic activity in an experimental bladder cancer (22). This article has reviewed important traditional and modern uses of natural honey in human diseases.

CHEMICAL COMPOSITION OF NATURAL HONEY

Natural honey contains about 200 substances, including amino acids, vitamins, minerals and enzymes, but it primarily contains sugar and water. Sugar accounts for 95–99% of honey dry matter. The principal carbohydrate constituents of honey are fructose (32.56 to 38.2%) and glucose (28.54 to 31.3 %), which represents 85–95% of total sugars that are readily absorbed in the gastrointestinal tract (23, 11).

Other sugars include disaccharides such as maltose, sucrose, isomaltose turanose, nigerose, meli-biose, panose, maltotriose, melezitose. A few oligosaccharides are also present. Honey contains 4 to 5% fructooligosaccharides, which serve as probiotic agents (1, 11). Water is the second most important component of honey. Organic acids constitute 0.57% of honey and include gluconic acid which is a by product of enzymatic digestion of glucose. The organic acids are responsible for the acidity of honey and contribute largely to its characteristic taste (24). The concentration of mineral compounds ranges from 0.1% to 1.0 %. Potassium is the major metal, followed by calcium, magnesium, sodium, sulphur and phosphorus. Trace elements include iron, copper, zinc and manganese (25-27).

Nitrogenous compounds, vitamins C, B1 (thiamine) and B2 complex vitamins like riboflavin, nicotinic acid, B6 and panthothenic acid are also found (24). Honey contains proteins only in minute, 0.1–0.5 percent quantities (28, 29). According to a recent report, specific protein quantities differ according to the honeybee origin (30).

PHYSICAL PROPERTIES OF NATURAL HONEY

Honey has several important qualities in addition to composition and taste. Freshly extracted honey is a viscous liquid. Its viscosity depends on large variety of substances and therefore varies with its composition and particularly with its water content. Hygroscopicity is another property of honey and describes the ability of honey to absorb and hold moisture from environment. Normal honey with water content of 18.8% or less will absorb moisture from air of a relative humidity of above 60%. The surface tension of honey varies with the origin of the honey and is probably due to colloidal substances. Together with high viscosity, it is responsible for the foaming characteristics of honey (24).

The color in liquid honey varies from clear and colorless (like water) to dark amber or black. The various honey colors are basically all shades of yellow and amber. Color varies with botanical origin, age, and storage conditions, but transparency or clarity depends on the amount of suspended particles such as pollen (24). Less common honey colors are bright yellow (sunflower), reddish undertones (chest nut), grayish (eucalyptus) and greenish (honeydew). Once crystallized, honey turns lighter in color because the glucose crystals are white. Honey crystallization results from the formation of monohydrate glucose crystals, which vary in number, shape, dimension, and quality with the honey composition and storage conditions. The lower the water and the higher the glucose content of honey, the faster the crystallization (24).

PHYSICAL PROPERTIES OF NATURAL HONEY

Honey has several important qualities in addition to composition and taste. Freshly extracted honey is a viscous liquid. Its viscosity depends on large variety of substances and therefore varies with its composition and particularly with its water content. Hygroscopicity is another property of honey and describes the ability of honey to absorb and hold moisture from environment. Normal honey with water content of 18.8% or less will absorb moisture from air of a relative humidity of above 60%. The surface tension of honey varies with the origin of the honey and is probably due to colloidal substances. Together with high viscosity, it is responsible for the foaming characteristics of honey (24).

The color in liquid honey varies from clear and colorless (like water) to dark amber or black. The various honey colors are basically all shades of yellow and amber. Color varies with botanical origin, age, and storage conditions, but transparency or clarity depends on the amount of suspended particles such as pollen (24). Less common honey colors are bright yellow (sunflower), reddish undertones (chest nut), grayish (eucalyptus) and greenish (honeydew). Once crystallized, honey turns lighter in color because the glucose crystals are white. Honey crystallization results from the formation of monohydrate glucose crystals, which vary in number, shape, dimension, and quality with the honey composition and storage conditions. The lower the water and the higher the glucose content of honey, the faster the crystallization (24).

TRADITIONAL USES OF NATURAL HONEY

Human use of honey is traced to some 8000 years ago as depicted by Stone Age paintings (32). The ancient Egyptians, Assyrians, Chinese, Greeks and Romans employed honey for wounds and diseases of the gut (12). Here, some of the beneficial effects of honey which have been utilized by ancient races are summarized.

Place of honey in modern medicine

ANTIMICROBIAL PROPERTIES OF HONEY

In addition to important role of natural honey in the traditional medicine, during the past few decades, it was subjected to laboratory and clinical investigations. Antibacterial activity of honey is one of the most important findings that was first recognized in 1892; by van Ketel (39).

PATHOGENS FOUND SENSITIVE TO HONEY

Honey has been reported to have an inhibitory effect to around 60 species of bacteria including aerobes and anaerobes, gram-positives and gram-negatives (24). Pathogens that are found to be sensitive to anti-infective properties of honey are manifold (40). Various results are in favor of its activity against Bacillus anthracis, Corynebacterium diptheriae, Haemophilus influenzae, Klebsiella pneumoniae, Listeria monocytogenes, Mycobacterium tuberculosis, Pasteurella multicoda, Yersinia enterocolitica, Proteus species, Pseudomonas aeruginosa, Acinetobacter spp, Salmonella diarrhoea, Sal. typhi, Serratia marcescens, Shigella dysentery, Staphylococcus aureus, Streptococcus faecalis, Strep. mutans, Strep. pneumoniae, Strep. pyogenes and Vibrio cholerae (15, 38, 32). Previously, a small number of case studies examining the antimicrobial activity of honey against methicillin-resistant Staph. aureus (MRSA) organisms demonstrated that natural honey had an antimicrobial activity against the community-associated MRSA organisms in in vitro condition (41-43). The MIC (minimum inhibitory concentration) of honey was found to range from 1.8% to 10.8% (v/v), i.e. the honey had sufficient antibacterial potency to still be able to stop bacterial growth if diluted at least nine times, and up to 56 times for Staphylococcus aureus, the most common wound pathogen (44). It has been indicated that diluted honey treated urinary tract infections because certain bacteria causing urinary tract infections, e.g. E. coli, Proteus species and Strep. faecalis, were found to be sensitive to the antibacterial activity of honey (45).

In vitro studies of H. pylori isolates which cause gastritis have been shown to be inhibited by a 20% solution of honey. Even isolates that exhibited a resistance to other antimicrobial agents were susceptible (10, 15). Unlike most conventional antibiotics, it has been reported that honey dose not lead to development of antibiotic-resistant bacteria, and it may be used continuously (14).

Honey can act as both bacteriostatic and bactericidal depending on the concentration used. Pasture honey (4-8% ) and 5-11% manuka honey were bacteriostatic whereas bactericidal activity was achieved at 5-10% and 8- 15% (v/v) concentrations, respectively. In contrast, artificial honey (sugar solution which mimics composition of honey) was bacteriostatic only (at 20- 30%) and not bactericidal (32).

Mechanisms of antimicrobial activity of honey are different from antibiotics, which destroy the bacteria’s cell wall or inhibit intracellular metabolic pathways. The antibacterial activity is related to four properties of honey. First, honey draws moisture out of the environment and thus dehydrates bacteria. The sugar content of honey is also high enough to hinder the growth of microbes, but the sugar content alone is not the sole reason for honey’s antibacterial properties (46). Second, the pH of honey is between 3.2 and 4.5, and this acidity is low enough to inhibit the growth of most microorganisms. Hydrogen peroxide produced by the glucose oxidase is the third and probably the most important antibacterial component, although some authors believe the nonperoxide activity to be more important. Lastly, several phytochemical factors for antibacterial activity have been identified in honey (13, 14).

WOUND HEALING

One of the most studied and most effective uses of honey is found in healing of wounds (17). The Russians used honey in World War I to prevent wound infection and to accelerate wound healing. The Germans combined cod liver oil and honey to treat ulcers, burns, fistulas and boils (32). Nearly all types of wounds like abrasion, abscess, amputation, bed sores /decubitus ulcers, burns, chill blains, burst abdominal wound, cracked nipples, fistulas, diabetic, malignant, leprosy, traumatic, cervical, varicose and sickle cell ulcers, septic wounds, surgical wound or wounds of abdominal wall and perineum are found to be responsive to honey therapy. Application of honey as wound dressing leads to stimulation of healing process and rapidly clears the infection. Honey has cleansing action on wounds, stimulates tissue regeneration and reduces inflammation. Honey impregnated pads act as non adhesive tissue dressing (32, 52, 53).

The exact molecular mechanism of wound healing using honey is yet to be elucidated. However, several recommendations are made regarding appropriate wound dressing with honey. Type of wound and degree of severity will affect efficacy. Selected honey should be used in sufficient quantities so that it remains there if diluted with wound exudates. It should cover and extend beyond the wound margins. Better results occur when applied on dressing than on wound. All the cavities should be adequately filled with honey and occlusive dressing applied to prevent oozing from the wound (32, 54, 55). On burns, it has an initial soothing and later rapid healing effects. It has been used as wound barrier against tumor implantation in laparoscopic oncological surgery. No infection has been reported from the application of honey to open wounds. It has a potential therapeutic role in the treatment of gingivitis and periodontal disease (56). In one of cases of knee amputation in a young boy, which was heavily infected with Pseudo. and Staph. aureus and non responsive to conventional treatment, application of sterilized active manuka honey dressing pads led to complete healing in ten weeks (57). Similar results are found with burns. Honey dressing speeds up healing process, sterilizes wound and reduces pain (58). Studies in Fournier’s gangrene showed rapid improvement with decreased edema and discharge, rapid regeneration and little or no scarring, effective wound debridement and a decrease in mortality (59).

Honey is used successfully for treating ulcerations following radical surgery for carcinoma of the breast and varicose veins. It is also used following radical surgery for carcinoma of vulva resulting in infection free wound with minimal wound debridement and hospital stay (60). In patients with postoperative wound infections following caesarean section or hysterectomies, topical honey application causes faster eradication of bacterial infections, reduces antibiotic use and hospital stay, accelerates wound healing, and results in minimal scar formation (53). Similar efficacy is observed in bed sores and decubitus ulcers (61).

GASTROINTESTINAL TRACT DISEASES

Oral administration of honey to treat and protect against gastrointestinal infection such as gastritis, duodenitis and gastric ulceration caused by bacteria and rotavirus has been reported (66-70). Attachment of bacteria to mucosal epithelial cells is considered the initial event in the development of bacterial infections of the gastrointestinal tract. Blocking attachment of pathogenic microorganisms to the intestinal epithelium represents a potential strategy for disease prevention. Alnaqdy et al (2005) demonstrated that the prevention of bacterial adherence caused by honey was through effect on bacteria, rather than epithelial cells. There are several possible explanations for prevention of bacterial adherence demonstrated by honey: (a) non-specific mechanical inhibition perhaps through the coating of the bacteria by the honey; (b) some of the fractions, within honey, may alter bacterial electrostatic charge or hydrophobicity which have been reported to be important factors in the interaction of bacteria with host cells (70-72) or (c) killing of the bacteria due to the previously mentioned antibacterial factors in honey (70).

Diarrhea and gastroenteritis are found to resolve quickly with honey (32, 67, 73). At 5% (v/v) concentration, honey decreased the duration of diarrhea in cases of bacterial gastroenteritis as compared to group using sugar in replacement fluid. No change was seen in viral gastroenteritis. In rehydration fluid, honey adds potassium and water uptake without increasing sodium uptake. It also helps to repair the damaged intestinal mucosa, stimulates the growth of new tissues and work as an anti-inflammatory agent (32). Nasutia et al (2006) demonstrated that oral pretreatment of honey (2 g/kg), prevented indomethacin-induced gastric lesions, microvascular permeability, and myeloperoxidase activity of the stomach (74). H. Pylori is found to be sensitive to honey with a median level of antibacterial activity due to the presence of hydrogen peroxide at a 20% concentration (32, 68).

GASTROINTESTINAL TRACT DISEASES

Diarrhea and gastroenteritis are found to resolve quickly with honey (32, 67, 73). At 5% (v/v) concentration, honey decreased the duration of diarrhea in cases of bacterial gastroenteritis as compared to group using sugar in replacement fluid. No change was seen in viral gastroenteritis. In rehydration fluid, honey adds potassium and water uptake without increasing sodium uptake. It also helps to repair the damaged intestinal mucosa, stimulates the growth of new tissues and work as an anti-inflammatory agent (32). Nasutia et al (2006) demonstrated that oral pretreatment of honey (2 g/kg), prevented indomethacin-induced gastric lesions, microvascular permeability, and myeloperoxidase activity of the stomach (74). H. Pylori is found to be sensitive to honey with a median level of antibacterial activity due to the presence of hydrogen peroxide at a 20% concentration (32, 68).

ANTIVIRAL EFFECTS OF HONEY

In addition to antibacterial and antifungal effects, natural honey has showed antiviral effect. Al-Waili (2004) investigated the effect of the topical application of honey on recurrent attacks of herpes lesions and concluded that topical honey application was safe and effective in the management of the signs and symptoms of recurrent lesions from labial and genital herpes compared to acyclovir cream (80). Honey has also been reported to have inhibitory effects on rubella virus activity (13).

OPHTHALMOLOGY AND HONEY

Honey is used worldwide for the treatment of various ophthalmological conditions like blepharitis, keratitis, conjunctivitis, corneal injuries, chemical and thermal burns to eyes (45, 81). In one study, with topical application of honey as ointment, in 102 patients with non responsive eye disorders, improvement was seen in 85% patients and in remaining 15% there was no disease progression. Application of honey in infective conjunctivitis reduced redness, swelling, pus discharge and time to bacterial eradication (32, 78, 80).

HONEY AND DIABETES

The use of honey in type I and type II diabetes was associated with significantly lower glycemic index than with glucose or sucrose in normal diabetes. Honey compared with dextrose caused a significantly lower rise in plasma glucose levels in diabetic subjects. It also caused reduction of blood lipids, homocysteine levels and C-reactive protein (CRP) levels in normal and hyperlipidemic subjects (32, 40). In earlier observations, it was found that honey stimulates insulin secretion, decrease blood glucose levels, elevates hemoglobin concentration and improves lipid profile (13).

HONEY AS FOOD PRESERVATIVE AND PREBIOTIC

Hydrogen peroxide and non peroxide components such as antioxidants are found to inhibit growth of Shigella, Listeria monocytogenes, and Staph. aureus helping in food preservation. Clostridium botulinum however may be present in small amounts in honey. It has a good potential to be used as a natural source of antioxidants to reduce negative effects of polyphenol oxidase browning in fruit and vegetable processing (32, 82).

A prebiotic is a non-digestible dietary supplement that modifies the balance of the intestinal microflora stimulating the growth and activity of the beneficial organisms and suppressing potentially deleterious bacteria. Honey is found to be a suitable sweetener in fermented milk products without inhibiting the growth of common bacteria like Strep. thermophilus, Lactobacillus acidophilus, Lacto. delbruekii and Bifidobacterium bifidum which are important for maintaining the health of gastrointestinal tract. Honey also increased and supported the growth of bifidobacterium (32, 83), which is mainly due to the presence of a variety of oligosaccharides (1, 11, 32).

ANTIOXIDANT ACTIVITY OF HONEY

Today, we know well that radicals cause molecular transformations and gene mutations in many types of organisms. Oxidative stress is well-known to cause many diseases (86), and scientists in many different disciplines became more interested in natural sources which could provide active components to prevent or reduce its impacts on cells (47, 87, 88). Natural honey contains many flavonoides (such as apigenin, pinocembrin, kaempferol, quercetin, galangin, chrysin and hesperetin), phenolic acids (such as ellagic, caffeic, p-coumaric and ferulic acids), ascorbic acid, tocopher-ols, catalase, superoxide dismutase, reduced glutathione, Maillard reaction products and peptides. Most of the above compounds work together to provide a synergistic antioxidant effect (4-6). Hence, it has been suggested that honey, as a natural antioxidant, may serve as an alternative to some preservatives such as sodium tripolyphosphate in food preservation to delay lipid oxidation (4).

The botanical origin of honey has the greatest influence on its antioxidant activity, while processing, handling and storage affect honey antioxidant activity only to a minor degree (7, 89-92). The antioxidant activity is strongly corre-lated with the content of total phenolics (7, 45, 90, 92-94). Beside this, a strong correlation was found between antioxidant activity and the color of honey. Many researchers found that dark honey has a higher total phenolic content and consequently a higher antioxidant capacity (89, 92, 95). Blasa et al (2007) showed that the antioxidant activity was located in both the ether and the water fractions, indicating that the flavonoids of honey may be available to various compartments of the human body where they may exert different physiological effects (96).

PROPERTIES OF PHENOLIC COMPOUNDS OF HONEY

Phenolic compounds are one of the most important groups of compounds occurring in plants, comprising at least 8000 different known structures (48, 97). These compounds are reported to exhibit anticarcinogenic, anti-inflammatory, antiatherogenic, antithrombotic, immune modulating and analgesic activities, among others and exert these functions as antioxidants (48, 98). The phenolic compounds of honey are phenolic acids and flavonoids, which are considered potential markers of the botanical origin of honey (7, 48, 99). The antioxidant activities of phenolics are related to a number of different mechanisms, such as free radical-scavenging, hydrogen-donation, singlet oxygen quenching, metal ion chelation, and acting as a substrate for radicals such as superoxide and hydroxyl (47).

CARDIOVASCULAR DISEASES

Ischemic heart disease (IHD) causes more deaths and disability and incurs greater economic costs than any other illness in the developed world (100). Arrhythmias and myocardial infarction (MI) are serious manifestations of IHD. In the course of cardiac surgery and MI, ventricular arrhythmias such as ventricular tachycardia and ventricular fibrillation are the most important causes of mortality (100). In management of such conditions, drug therapy (especially anti-arrhythmic drugs) may be lifesaving. On the other hand, the hazards of anti-arrhythmic drugs (such as lethal arrhythmias in some patients) have led to a limitation on the administration of anti-arrhythmic drugs (101). Hence, there is a tendency to use drugs which have less adverse effects and more efficacies. Natural honey has been applied for medicinal purposes since ancient times (102), however, in the case of cardiovascular diseases, most of the previous studies were carried out in animals and mainly focused on honey's effects against cardiovascular risk factors such as hyperlipidemia and production of free radicals (103-106). Antioxidants present in honey include Vitamin C, monophenolics, flavonoids, and polyphenolics. Regular flavonoid intake is associated with a reduced risk of cardiovascular diseases. A wide range of phenolic compounds is present in honey which has promising effect in the treatment of cardiovascular diseases. In coronary heart disease (CHD), the protective effects of phenolic compounds include mainly antithrombotic, anti-ischemic, anti-oxidant, and vasorelaxant. It is suggested that flavonoids decrease the risk of CHD by three major actions: improving coronary vasodilatation, decreasing the ability of platelets in the blood to clot, and preventing LDLs from oxidizing (107). In 38 overweight individuals, the effect of natural honey on total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C), triacylglycerole, C-reactive protein (CRP), fasting blood glucose and body weight were investigated. The results showed that receiving 70 g of natural honey for 30 days caused reduction in total cholesterol, LDL-C, triacylglycerole and CRP (P<0.05). The authors concluded that natural honey reduces cardiovascular risk factors, particularly in subjects with elevated risk factors, and it does not increase body weight in overweight or obese subjects (106). The effects of ingestion of 75 g of natural honey compared to the same amount of artificial honey (fructose plus glucose) were studied in humans. Elevation of insulin and CRP was significantly higher after glucose intake than after honey consumption. In addition, honey reduced cholesterol, LDL-C, and TG and slightly elevated HDL-C. In patients with hypertriglyceridemia, artificial honey increased TG, while honey decreased TG. In patients with hyperlipidemia, artificial honey increased LDL-C, while honey decreased LDL-C. In diabetic patients, honey compared with dextrose caused a significantly lower rise of plasma glucose. Honey can contain nitric oxide (NO) metabolites and increased levels of NO in honey might have a protecting function in cardiovascular diseases (108).

Other effects of honey

Positive effect of honey as an anticarcinogenic agent is reported in some studies (32, 114, 115). Honey has showed antineoplastic activity in the experimental bladder cancer (22). Natural honey can play an important role in the treatment of chest pain, fatigue and vertigo. This is probably due to the high nutritional energy content of honey which provides immediately available calories after consumption (45). Benefits of honey also have been seen in tooth extraction pain and infection or caries due to radiation-induced xerostomia (32,114, 115). It has been shown that honey is a very effective agent for split thickness skin graft fixations and can be easily used (14). In a survey that was performed in central Burkina Faso, it was found that local inhabitants use honey therapeutically for treatment of respiratory ailments, measles, period pains, postnatal disorders, male impotence and pharyngitis due to its antibacterial and anti-inflammatory effects (45). Honey has also been reported to exhibit anti-leishmanial effects in vitro (13).

In one study, daily consumption of honey showed a variety of beneficial effects on hematological indices, blood levels of minerals and enzymes and endocrine system (85). In another study, oral honey stimulated antibody production during primary and secondary immune responses against thymus-dependent and thymus-independent antigens (13)

Concluding Remarks