Honey as a Potential Natural Antioxidant Medicine: An Insight into Its Molecular Mechanisms of Action

Ahmed, Sarfraz; Sulaiman, Siti Amrah; Baig, Atif Amin; Ibrahim, Muhammad; Liaqat, Sana; Fatima, Saira; Jabeen, Sadia; Shamim, Nighat; Othman, Nor Hayati

doi:https://doi.org/10.1155/2018/8367846

Oxidative Medicine and Cellular Longevity

On this page

Abstract Introduction Conclusion Conflicts of Interest References Copyright Related Articles

Special Issue

Therapeutic Potential of Natural Antioxidants

View this Special Issue

Review Article | Open Access

Volume 2018 | Article ID 8367846 | https://doi.org/10.1155/2018/8367846

Honey as a Potential Natural Antioxidant Medicine: An Insight into Its Molecular Mechanisms of Action

Sarfraz Ahmed,^1,2Siti Amrah Sulaiman,³Atif Amin Baig,⁴Muhammad Ibrahim,²Sana Liaqat,²Saira Fatima,²Sadia Jabeen,²Nighat Shamim,²and Nor Hayati Othman¹

Academic Editor: Sharad S. Singhal

Received28 Sept 2017

Accepted19 Nov 2017

Published18 Jan 2018

Abstract

Honey clasps several medicinal and health effects as a natural food supplement. It has been established as a potential therapeutic antioxidant agent for various biodiverse ailments. Data report that it exhibits strong wound healing, antibacterial, anti-inflammatory, antifungal, antiviral, and antidiabetic effects. It also retains immunomodulatory, estrogenic regulatory, antimutagenic, anticancer, and numerous other vigor effects. Data also show that honey, as a conventional therapy, might be a novel antioxidant to abate many of the diseases directly or indirectly associated with oxidative stress. In this review, these wholesome effects have been thoroughly reviewed to underscore the mode of action of honey exploring various possible mechanisms. Evidence-based research intends that honey acts through a modulatory road of multiple signaling pathways and molecular targets. This road contemplates through various pathways such as induction of caspases in apoptosis; stimulation of TNF-α, IL-1β, IFN-γ, IFNGR1, and p53; inhibition of cell proliferation and cell cycle arrest; inhibition of lipoprotein oxidation, IL-1, IL-10, COX-2, and LOXs; and modulation of other diverse targets. The review highlights the research done as well as the apertures to be investigated. The literature suggests that honey administered alone or as adjuvant therapy might be a potential natural antioxidant medicinal agent warranting further experimental and clinical research.

1. Introduction

Current stream treatment modalities utilizing chemo drugs dissimulate multidrug resistance and several other side effects [1]. This urges to quest for alternate options. Natural products are pondered as a practical alternative approach to abate the ever increasing scold of diseases and some of their unavoidable side effects [2, 3]. Recently, honey as a natural product has clinched the attention of researchers as a complementary and alternative medicine [4–6].

Honey as a folk medicine is referred in the utmost ancient written archives [7, 8]. Demarcation of its uses in current professional medicine as a potential therapy is entirely underutilized. However, there is an affinity for some researchers to fire out a coherent proposition that usage of honey as a natural product supplement is well intentioned for reflection as a therapy or adjuvant antioxidant therapy in current medicine [9, 10]. The composition of honey varies from floral source to origin. A general average composition of honey has been presented in Table 1. It is composed of at least 181 substances and primarily fabricates the fructose (38%) and glucose (31%) as major sugars. Besides fructose and glucose, other identified disaccharides include maltose, sucrose, maltulose, turanose, isomaltose, laminaribiose, nigerose, kojibiose, gentiobiose, and B-trehalose. Trisaccharides include maltotriose, erlose, melezitose, centose 3-a5, isomaltosylglucose, l-kestose, isomaltotriose, panose, isopanose, and theanderose [11]. It also comprises enzymes, amino acids, proteins, flavonoids, phenolic acids, and a miscellaneous group. There are 26 amino acids reported in honey; among them, proline is the major contributor that constitutes 50–85% of the total amino acids [12]. The minor volume of vitamins includes riboflavin, niacin, folic acid, pantothenic acid, vitamin B6, and ascorbic acid. Different trace elements cover calcium, iron, zinc, potassium, phosphorus, magnesium, selenium, chromium, and manganese. Organic acids are other important group of compounds in honey, for instance, acetic, butyric, citric, succinic, lactic, malic, and gluconic acid and a number of other aromatic acids [13]. The various enzymes present in honey are glucose oxidase, sucrose diastase, catalase, and acid phosphatase [14–16]. Some of the flavonoids and phenolic compounds that have been identified in honey include kaempferol, quercetin, chrysin, pinobanksin, luteolin, apigenin, pinocembrin, genistein, hesperetin, p-coumaric acid, naringenin, gallic acid, ferulic acid, ellagic acid, syringic acid, vanillic acid, and caffeic acid [17, 18]. Flavonoids and phenolic acid constituents have been reported to be solely responsible for the antioxidant and other medicinal effects of honey [6, 18–24]. The chemical structures of major flavonoids and phenolic acids in honey have been demonstrated in Figures 1 and 2.

Honey has been studied against various ailments in animal and human models. Published research denotes it as a novel antioxidant agent [24, 25]. It exhibits a broad spectrum therapeutic properties such as anti-inflammatory [26], antibacterial [27], antimutagenic [28], expedite wound healings [29], antidiabetic [30], antiviral [31], antifungal [32], and antitumoural [5, 33, 34] effects. It could be purported as a natural cancer “vaccine” as it reduces chronic inflammation, improves healing of chronic ulcers and wounds, and improves immune status; the opposite of these are risk factors to cancer formation [5]. Its anticancer activity has been proved against various types of cancer: breast [35–39], colorectal [40], renal [41], prostate [36], endometrial [36], cervical [39], and oral [42]. Honey has the potential to reduce cardiovascular risk factors in normal healthy individuals [43]. It causes to reduce systolic blood pressure and level of triglycerides and VLDL (low-density lipoprotein) in experimental animals [44]. In a randomized clinical trial, lower incidence of acute respiratory symptoms was observed in individuals who took honey on a daily basis [45]. It improves female hormones [46], increases the percentage of sperms and motility, and reduces the toxic effects on spermatogenesis and testosterone level [47, 48]. Postmenopausal women who received honey therapy showed improvement in their immediate memory compared with the improvement seen in women receiving estrogen plus progestin therapy [49].

Understanding the mode of action of honey is substantial and under phase area. The review presents a role of honey in modulation of different types of diseases and the possible mechanisms involved. It also highlights a synopsis of findings through which it makes a road from different signaling pathways to different molecular targets. The review also shows the rational explanations for the therapeutic effects of honey and the apertures to be investigated.

2. Medicinal Effects of Honey and Mechanisms of Action

2.1. Antioxidant Effects of Honey

Antioxidants are agents to counteract deterioration caused by oxidants such as such as O₂, OH⁻, superoxide, and/or lipid peroxyl radicals. Cancer, synthesis of mutagens, aging, atherosclerosis, and many chronic and degenerative lingering diseases are susceptible to oxidative stress [52]. Cells exhibit defense system against oxidative damage. This defense system consists of free radicals and other oxidative protective agents such as, catalase, superoxide dismutase, peroxidase, ascorbic acid, tocopherol, and polyphenols [53]. These antioxidant agents stimulate biomolecules such as carbohydrates, proteins, lipids, and nucleic acids. Cells are altered by this stimulation and ultimately provoking antioxidant response [54]. Honey exhibits strong antioxidant activity [6]. This antioxidant capacity of honey contributes to the prevention of several acute and chronic disorders such as inflammatory, allergic, thrombotic, diabetic, cardiovascular, cancer, and others. The antioxidant properties of honey can be measured in the form of antiradical activity using, oxygen radical absorbance capacity (ORAC) assay, 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging assay, and ferric reducing antioxidant power (FRAP) assay [24]. Honey from various floral origin and different countries has been shown to exhibit high antioxidant properties [24]. The phenolic acids and flavonoids are responsible for the well-established antioxidant activity of honey. Apart from these, sugars, proteins, amino acids, carotenes, organic acids, Maillard reaction products, production of reactive oxygen species (ROS), and other minor components also contribute to antioxidant effect [53, 55]. Researchers also showed that honey (1.2 g/kg) elevated the amount and activity of antioxidant agents such as beta-carotene, vitamin C, glutathione reductase, and uric acid in healthy human subjects [56]. The exact antioxidant mechanism is unknown, but the proposed mechanisms include free radical sequestration, hydrogen donation, metallic ion chelation, flavonoids substrate action for hydroxyl, and superoxide radical actions [25, 57]. Figure 3 is presenting all the possible mechanisms involved in the antioxidant effects of honey. The antioxidant effect of honey is well established, but urges to explore the exact mechanisms involved and extrapolation to clinical trials.

2.2. Antibacterial and Wound Healing Effects of Honey

Different clinical trials and in vitro studies have reported broad-spectrum antimicrobial properties of honey [58]. It was reported that honey constrains the growth of pathogenic strains such as Streptococcus pyogenes, Streptococcus typhi, Staphylococcus aureus, coagulase-negative Streptococcus and E.coli, and species [59]. It also diminishes the growth of infecting strains such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumonia in full thickness burn wound in rats [60].

Antibacterial effect of honey is attributed to presence of inert antibiotic factors in it. These factors include its acidic pH, osmotic effect of sugars, and production of H₂O₂ by peroxidase. Some nonperoxidase substances also support antibacterial activity which include flavonoids, phenolic acids, and lysozyme [61]. In its mechanism of action, a significant role is played by bee defensin-1(antimicrobial peptide), methylglyoxal (phytochemical), and hydrogen peroxide production by enzyme glucose oxidase [62]. Furthermore, high sugar contents of honey can also be helpful in eliminating bacteria through osmosis [63]. Methylglyoxal (MGO) in honey and its precursor dihydroxyacetone (DHA) have been recognized as inhibitors of bacterial growth through urease inhibition. Urease enzyme facilitates bacteria to acclimate and grow rapidly by producing ammonia in acidic environment [64]. A very recent study reveals that honey combats bacterial infections by two different mechanisms: inhibition of bacterial quorum sensing (QS) system to retard the expression of las, MvfR, and rhl regulons, as well as its associated virulence factors, and bactericidal components which actively kill bacterial cells [65].

Biofilms have emerged as a key factor in antibiotic resistance. Biofilms protect bacteria from antibiotics resulting in relentless infection. Honey acts as a bactericidal negotiator, penetrates in biofilms, recovers aggressive infection, and eradicates colonies [66, 67]. It has shown bactericidal effect against biofilms of pathogenic reference strains such as Methicillin-resistant Staphylococcus epidermidis (MRSE), Extended-spectrum beta-lactamases (ESBL), Klebsiella pneumonia, Pseudomonas aeruginosa, Staphylococcus aureus (SA), Proteus mirabilis, Pseudomonas aeruginosa (PA), Clostridium difficile, and enterohemorrhagic E. coli. It improves wounds healing, prevents invasive infections, eliminates biofilm colonization, interrupts outbreaks, and thus preserves current antibiotic stocks [66, 68–70]. It inhibits biofilm growth by preventing the binding of bacterial strains with tissue fibronectin at infection site. It also reduces expression of fibronectin binding surface proteins such as Sfb1 and Sof, which are crucial for bacteria to bind with fibronectin [71]. It also significantly suppresses the expression of quorum sensing genes (AI-2 importer and indole biosynthesis), curli genes (csgBAC), and virulence genes (LEE genes) in virulent E. coli. Glucose and fructose content in the honey were considered to be key components in repressing biofilm formation [72].

Normal wound healing is a multipart process in which coinciding series of events occur which include coagulation, inflammation, cell proliferation, tissue remodeling, and replacement of damaged tissue [73]. Honey has been used widely for the treatment of various types of chronic, burn, necrotic, diabetic foot and postoperative split skin wounds [61, 74–76]. In inflammatory phase of wound healing, honey assists in the elimination of necrotic tissues [63], improves the remodeling phase [63], and inhibits bacterial growth [59], resulting in improved healing. Recent study indicates an increased production of IL-6 and TNF-α by honey at the wound site in the healing process in IL-6-deficient mice [77]. Honey facilitates an increased stimulation and production of lymphocytes, phagocytes, monocytes, and/or macrophages to release cytokines and interleukins such as TNF-α, IL-1β, and IL-6, expediting the healing process [78]. High sugar contents and osmolarity of honey also contribute towards healing. Water is drawn out from the wound bed by the osmotic effect of honey through a simple outflow of lymph if the blood circulation at the wound site is sufficient to carry out this process [79]. Research has shown that honey improves wound healing through antioxidant response by activating AMPK (5adenosine monophosphate-activated protein kinase) and antioxidant enzymes which ameliorate oxidative stress. The antioxidant system comprises exogenous and endogenous antioxidants. The endogenous antioxidants are classified as enzymatic and nonenzymatic antioxidants. The enzymatic antioxidants include superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). The nonenzymatic antioxidants comprise vitamins E and C, glutathione (GSH), and some small molecules, while exogenous antioxidants include some micronutrients [24, 80]. These antioxidants also support proliferation and migration of human dermal fibroblasts and mitochondrial function to assist healing [81].

Another mechanism explains that wound sites have usually two types of protein-digesting enzymes: serine proteases and matrix metalloproteases. These protease enzymes are generally inactive due the presence of some inhibitors. The proteases become active when the inhibitors become inactive by H₂O₂. Thus, H₂O₂ plays a role as physiological switching stimuli for activation and inactivation of these enzymes through oxidation. It has been reported that honey stimulates and enhances H₂O₂ production. The wound debris and bacteria are digested by active proteases. The active effect of honey sweeps off this debris easily due to the osmotic outflow [7, 82]. During inflammation, H₂O₂ also stimulates the growth of fibroblasts and epithelial cells to repair the damage. Similarly, H₂O₂ stimulates nuclear transcription factors (NTFs) for cell multiplication and wound healing [7].

Some additional mechanisms elaborate that H₂O₂ stimulates insulin receptor complexes to trigger a chain of molecular events in the cell. This results in facilitating the uptake of amino acids and glucose for cell growth. Honey itself may provide vitamins, minerals, sugars, and amino acids to the growing cells. This supports phagocytes to engulf infecting bacteria through glucose consumption. Honey also stimulates cytokines release from monocyte and lymphocyte proliferation to repair tissues. Monocyte activation by mitogen or honey leads to the production of reactive oxygen species to initiate a greater inflammatory response. It causes oedema in surrounding tissue restricting circulation in capillaries. This results in reduction of oxygen supply and nutrients to cells. It ultimately restricts the cell growth to replace tissues to repair wounds [7, 83]. All the possible mechanisms involved in antibacterial and wound healing effects of honey have been demonstrated in Figure 4.

2.3. Antifungal Effects of Honey

Honey exhibits antifungal activity. Research has shown that it has antifungal activity against Aspergillus niger, Aspergillus flavus, Penicillium chrysogenum, Microsporum gypseum, Candida albicans, Saccharomyces, and Malassezia species [84]. The potential antimicrobial effect of honey is attributed to the presence of glucose oxidase, methylglyoxal, and high sugar contents [85–88]. The mechanism is not completely understood; however, some potential pathways have been suggested.

Honey inhibits fungal growth through prevention of their biofilm formation, disruption of established biofilms, and instigating changes to exopolysaccharide structure. It distorts the cell membrane integrity which results in shrinkage of cell surface in biofilm, leading to death or growth retardation [89]. Atomic force microscopic studies have revealed that when biofilm is treated with honey (40% w/v) exopolysaccharide layer thickness is reduced to half and roughness increases followed by its complete removal [90]. Researchers have shown that flavonoid part of honey decelerates the growth of fungi, affects the external morphology and membrane integrity, and inhibits some cellular processes that are involved in germ-tube growth. The inhibition of germ-tube emergence correlates with poor growth of membrane. Honey flavonoid extract has also been found to affect hyphal transition by reducing the percentage of cells in the G0/G1 phase and/or G2/M phase [91]. Figure 5 is showing the possible mechanisms involved in antifungal effects of honey. The detailed description of antifungal effects of honey and molecular targets involved is a key gap to be probed yet.

2.4. Antiviral Effects of Honey

The viral activity is usually elicited by native or universal stimuli which lead to infections and lesions [92]. Current studies have manifested that honey holds potential antiviral effects. Antiviral effect of honey is attributed to its various ingredients which have been found to be operative in controlling of lesions, for instance, copper inactivates virus that is a trace element part of honey. Similarly, presence of ascorbic acid, flavonoids, and H₂O₂ production by honey also leads to viral growth inhibition by interrupting viral transcription and translation [93, 94]. Data of in vitro studies has shown antiviral activity of honey against different types of viruses such as Rubella, herpes simplex, and varicella zoster viruses [31, 95, 96]. Honey comprises secretion from the salivary and pharyngeal glands of the honeybee’s head. Recently, nitric oxide (NO) metabolites, nitrite, and nitrate have been identified in salivary gland’s section [56]. It is well established that NO is an energetic molecule that produces host defense against viruses, both DNA and RNA viruses. NO acts by slowing down the development of viral lesions as well as arresting their replication [56, 97]. In its mode of action, NO represses replication by interfering with viral polymerase, nucleic acid, and/or viral capsid proteins. The flavonoid content of honey has also been reported to inhibit the viral transcription and replication [98, 99]. Figure 6 is presenting the possible mechanisms involved in antiviral activity of honey. To understand the actual influence of honey on viruses and mechanisms intends to do more research to map the road.

2.5. Anti-Inflammatory Effects of Honey

Inflammation is the intricate biological response of vascular tissues to detrimental stimuli. It is a defensive way of response shown by the tissues and organism to remove the pathogens or stimuli which are the cause of injury. Inflammation is classified into two classes: acute and chronic inflammation. Acute inflammation is an early retort of the body towards stimuli. The indication of acute inflammation is redness, pain, itching, and loss of ability to perform function [100]. If the acute inflammation is not treated well and prolonged, then it is converted into chronic inflammation. It is considered as a major cause of several chronic diseases or disorders. Thus, anti-inflammatory action is supposed to counteract unceasing diseases such as liver diseases [101], kidney diseases [102], and cancer [103]. Several factors can be involved in proinflammatory response such as cytokines, cyclooxygenases (COXs), lipoxygenases (LOXs), mitogens, macrophages, TNF factors, and many other factors of inflammatory pathways.

The anti-inflammatory action of honey is well documented [104]. It has shown anti-inflammatory response from cell cultures [40], animal models, to clinical trials [104, 105]. The exact mechanism of action of honey towards inflammation is not well understood yet. In inflammatory pathway, two of its components activated in ailments are mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) pathways [120]. Activation of MAPK and NF-κB ultimately results in induction of several other inflammatory mediators, enzymes, cytokines, proteins, and genes such as cyclooxygenase-2 (COX-2), lipoxygenase 2 (LOX-2), C-reactive protein (CRP), interleukins (IL-1, IL-6, and IL-10), and TNF-α. All these markers of proinflammatory action are known to play a major role in inflammation and angiogenesis-related etiology of disease [30, 119]. Recent evidence of in vivo studies has shown the anti-inflammatory mechanisms of honey. These studies showed that honey decreases edema and plasma levels of proinflammatory cytokines such as IL-6, TNF-α, PGE2, NO, iNOS, and COX-2. It was also demonstrated that honey attenuates NF-κB translocation to the nucleus and suppresses IκBα (inhibitor of kappa B) degradation [106, 107]. It has been reported that phenolic acids and flavonoids such as chrysin, quercetin, and galangin are able to suppress the activity of proinflammatory enzymes, for example, cyclooxygenase-2 (COX-2), prostaglandins [108], and inducible nitric oxide synthase (iNOs) [109]. Research has shown that flavonoid content of honey slows down the expression of MMP-9 (matrix metallopeptidase 9), an inflammatory mediator that causes chronic inflammation. Honey has the ability to significantly inhibit the expression of anti-inflammatory cytokines such as IL-1 and IL-10 and growth factors PDGF (platelet-derived growth factor) and TGF-β (transforming growth factor-β). In vitro model of MM6 cell lines using 1% solution of honey was concluded [110]. Another possible mechanism shows that reactive oxygen species are produced by macrophages, monocytes, and neutrophils that enhance inflammation. Honey ceases the release of such types of cells to promote anti-inflammatory effect. It also inhibits the production of keratinocytes and leukocytes to reduce inflammation. It has been demonstrated that in inflammatory response H₂O₂ production by honey stimulates the growth of fibroblasts and epithelial cells to repair the inflammatory damage. This anti-inflammatory action of honey makes it a novel agent to modulate a disease [111–113].

Anomalous arachidonic acid metabolism is involved in inflammation. LOXs metabolize arachidonic acid to leukotrienes (LTs). There are three types of lipoxygenase (LOX) isozymes: 12-LOX, 15-LOX, and 5-LOX. 12-LOX provokes inflammatory/allergic disorders, 15-LOX synthesizes anti-inflammatory 15-HETE (15-hydroxyeicosatetraenoic acid), and 5-LOX generates 5-HETE (5-hydroxyeicosatetraenoic acid) and LTs [114]. Many polyphenols in honey have been reported to suppress LOXs [114]. The anti-inflammatory effect of honey can be attributed to its phenolic compounds and flavonoids [15, 128, 129]. Figure 7 is depicting the possible mechanisms of anti-inflammatory effect of honey. To understand the actual influence of honey on LOXs, COXs, and TNF signaling pathways and mechanisms involved intends to do more research to map the road.

2.6. Honey and Its Antidiabetic Properties

Diabetes mellitus is a complex metabolic syndrome. Insulin deficiency or nonfunctional insulin is responsible for it [115]. In this syndrome, many anomalies in lipoprotein and carbohydrate metabolism are involved with an elevated glucose level [116, 117]. Acute complications in this disorder may include hyperosmolar, diabetic ketoacidosis and hyperglycemic state, which may lead to death [118].

Honey has shown antidiabetic effects from animal models to clinical trials [30, 119]. Researchers have invoked it as a potential antidiabetic agent [120]. Its concentrations tested such as 0.2, 1.2, and 2.4 g/kg/day showed an improved antioxidant effect exerting a hypoglycemic in streptozotocin-induced diabetic rats [30]. Similarly, glucose level in type-2 diabetes mellitus was found to be reduced when honey was administered by inhalation as 60% (W/V) [119]. This antidiabetic or hypoglycemic effect of honey is attributed to the presence of fructose in it [122]. Fructose assists to regulate the insulin-response system, resulting in controlled blood glucose level. Another hypothesis suggests that glucose level is reduced by the postponement of digestion and absorption which are brought about by oligosaccharide palatinose, a sucrose. It results in modulation of diabetes in diabetic patients [123]. It has also been reported that captivation of glucose in cells can be increased in collaboration with fructose [124, 125], leading to a decreased food-intake or absorption to direct a hypoglycemic effect. Monosaccharides such as glucose, fructose, and galactose are formed by the hydrolysis of carbohydrates prior to their absorption [126]. It has been suggested that fructose is taken up by the two receptors GLUT5 and/or GLUT2 via protein- and energy-mediated diffusion [127]. The expression of GLUT2 mRNA is generally increased by glucose and fructose. However, an increased expression of GLUT5 mRNA is caused solely by fructose, resulting in its fast absorption [128–130]. Research has shown that a hypoglycemic effect was observed when mice induced with diabetes were fed with fructose [131]. Glucose level can also be regulated by a specific hypoglycemic role of the fructose in the liver. In this mode of action, fructose stimulates the phosphorylation enzymes, for instance, glucokinase, triggering hepatic glucose phosphorylation [132]. The inhibition of these enzymes results in inhibition of glycogenolysis. Thus, whole metabolism of glycogen and glucose is regulated by fructose, showing its vital regulatory role to control hyperglycemia [133, 134].

Another proposed mechanism explains that hypoglycemic effect of honey may be through the role of honey in modulating the insulin signaling pathway [120, 135]. A key component of insulin signaling is the PI3K/Akt [136]. It is known for its role in modulatory functions of several substrates which regulate cell cycle progression, cell survival, and cellular growth. The effect of honey extracts on Akt-activated insulin signaling pathway in pancreatic cells was recently investigated under hyperglycemic condition. It was observed that the development of insulin resistance was characterized by increased levels of NF-κB, MAPK, and insulin receptor substrate 1 (IRS-1) serine phosphorylation. Akt expression and insulin contents were found to be markedly reduced. This study showed that pretreatment with honey and quercetin extract improves insulin resistance and insulin contents. Honey treatment increased the expression of Akt and reduced the expression of IRS-1 serine phosphorylation, NF-κB, and MAPK [120, 135–137].

Honey supplementation shows its modulatory effects on oxidative stress and hyperglycemia. Its antioxidant activity to ameliorate diabetes is well established [24]. Besides this, it also ameliorates several other metabolic derangements observed in diabetes such as reduced levels of triglycerides, hepatic transaminases, glycosylated hemoglobin (HbA1c), and increased HDL cholesterol [138]. Figure 8 is showing the possible mechanisms of antidiabetic effects of honey. Further studies are warranted to explore the exact mechanisms involved in antidiabetic activity of honey.

2.7. Antimutagenic Effects of Honey

Mutagenicity, the ability to induce genetic mutation, is interlinked with carcinogenicity [139]. Honey exhibits strong antimutagenic activity [140]. The effect of honey on radiation (UV or γ)-exposed Escherichia coli cells was investigated to observe SOS response, which is an error-prone repair pathway contributing to mutagenicity [140]. Some important genes such as umuC, recA, and umuD involved in SOS-mediated mutagenesis were knocked out to elaborate the results. Honey reduced mutation frequency significantly in treatment groups than in controls. The suppression of error-prone mutagenic repair pathways (for instance SOS response in E. coli) was the possible mechanism contributing to the antimutagenic effect. The antimutagenic activity of honey from seven different floral sources (acacia, buckwheat, fireweed, soybean, tupelo, and Christmas berry) and honey sugar analogue against Trp-p-1 was tested by the Ames assay [28]. All honeys showed a significant inhibition of mutagenicity caused by Trp-p-1. About 30% honey in the infusion formulation was most effective in inhibiting HAA (heterocyclic aromatic amines) formation and overall mutagenicity beef steak and chicken breast [141]. Figure 9 is showing the possible mechanisms of antimutagenic effects of honey. A broad spectrum research is needed to conduct to understand the mechanisms of antimutagenic effects of honey.

2.8. Anticancer Effects of Honey

Cancer cells possess two distinct characteristics: unrestrained cell multiplication and inadequate apoptotic turnover [142]. Drugs which are commonly used for cancer treatment are apoptosis inducers [143]. Programmed cell death or apoptosis is categorized into three phases: (a) an induction phase, (b) an effector phase, and (c) a degradation phase. The induction phase stimulates proapoptotic signal transduction cascades through death-inducing signals (ceramide signaling, reactive oxygen species, Bcl-2 family proteins such as Bad, Bax, and Bid, and over activation of Ca²⁺ signalling pathway). Effector phase is committed to bring cell death via a key regulator, mitochondrion. The last degradation phase comprises nuclear and cytoplasmic events. Nuclear change includes chromatin and nuclear condensation, cell shrinkage, DNA fragmentation, and membrane blebbing. In the cytoplasm, a complex cascade of protein-cleaving enzymes called caspases is activated. The cell is finally destined into fragmented apoptotic bodies, which are phagocytosed by macrophages or other surrounding cells [143, 144].

The apoptosis usually follows two pathways: the caspase-8 or death-receptor pathway and caspase-9 or mitochondrial pathway.

Literature established that honey induces apoptosis in various types of cancer cells [22, 39, 40, 145, 146]. This apoptotic temper of honey is vital because many drugs used for cancer treatment are apoptosis inducers [147]. Thus, the honey and its active components can regulate apoptosis by operating at various points of these two signaling pathways.

Honey induces apoptosis in human breast, colon, and cervical cancer cell lines model via depolarization of the mitochondrial membrane by reducing the mitochondrial membrane potential [22, 39]. These studies proved the caspase-9 pathway apoptotic induction by honey. Another research investigated that crude honey was sole responsible to induce apoptosis in human colon cancer and glioma C6 cell lines by elevating caspase-3 activation level and PARP (Poly (ADP-ribose) polymerase) cleavage. This characteristic was attributed to higher tryptophan and phenolic contents of honey [40, 145, 148]. Researchers showed that it induces apoptosis by upregulating and modulating the expression of pro- and antiapoptotic proteins in colon cancer cell lines HCT-15 and HT-29. It was found to elevate the expression of caspase-3, p53, and proapoptotic protein Bax. It downregulated the expression of antiapoptotic protein Bcl-2. The whole mechanism explained that ROS generation by honey results in the activation of p53, which in turn modulates the expression of pro or antiapoptotic proteins like Bax and Bcl-2 [22]. Honey administered with Aloe vera was found to boost the expression of proapoptotic protein Bax and decrease antiapoptotic protein Bcl-2 expression in Wistar rats with W256 mammary carcinoma implants [147, 148]. Furthermore, two different studies demonstrated that honey exerts its cancer therapeutic and cancer preventive effects in multiple ways such as modulation of immune response by ameliorating haematological parameters and stimulation of the intrinsic/mitochondrial apoptotic pathway at serological and cancer tissue level. In these studies, honey was given by oral feeding to Sprague-Dawley rat model using different concentrations such as 0.2, 1.0, and 2.0 g/kg body weight. It ameliorated the intrinsic apoptotic pathway through upregulation of the expression of proapoptotic proteins such as caspase-9, APAF-1 (apoptotic protease activating factor 1), p53, IFN-γ (interferon gamma), and IFNGR1 (interferon gamma receptor 1). Concomitantly, honey was found to downregulate the expression of antiapoptotic proteins such as Bcl-xL (B-cell lymphoma extra large), TNF-α, COX-2, E2 (estrogen), and ESR1 (estrogen receptor 1) [149, 150]. It was also demonstrated that honey alone induces intrinsic or caspase-9 apoptotic pathway with no evidence of the involvement of extrinsic or caspase-8 pathway [149, 150]. Flavonoids and phenolic contents of honey have been encountered to occlude the cell cycle of glioma [145], melanoma [146], colon [40], and cancer cell lines in G0/G1 phase. This inhibitory effect on tumor cell proliferation follows the downregulation of many cellular pathways via tyrosine cyclooxygenase, ornithine decarboxylase, and kinase [40, 145, 146, 151]. The mechanisms of action of honey include mainly its interference with multiple molecular targets and cell signaling pathways such as apoptotic, antiproliferative or cell cycle arrest, anti-inflammatory, estrogenic modulatory, antimutagenic, insulin modulatory, angiogenesis modulatory, and immunomodulatory pathways [6, 17]. Reviews by Ahmed et al. [6] and Erejuwa et al. [17] have well explained the possible mechanisms of anticancer effects of honey. Figures 10, 11, and 12 are showing a summarized presentation of mechanisms of anticancer effects of honey. Further studies are necessary to understand the exact influence of honey on the apoptotic pathways in cancer cells like the activation of caspase-8, p21, p38 MAPK (mitogen-associated protein kinase and p38 pathways), p-38 JNK (c-Jun N-terminal kinase), release of cytochrome c, and the suppression of antiapoptotic proteins such as IAP (inhibitor of apoptosis proteins), c-FLIP (cellular Flice inhibitory protein), and Akt (altered PI3 kinase), and the initiation of extrinsic pathway of apoptosis by induction of TRAIL (TNF-related apoptosis-inducing ligand) and Fas (fatty acid synthase-associated protein) receptor stimulation in cancer cells.

Figure 11

Molecular target modulation—the anticancer effects of honey (adopted from [17]). Bcl-2 = B cell lymphoma 2; Bcl-xL = B cell lymphoma extra large; Cyt. C = cytochrome C; MAPK = mitogen-activated protein kinase; NF-κB = nuclear factor kappa B; Akt = altered PI3 kinase; IRS-1 = insulin receptor substrate; IL = interleukin; COX-2 = cyclooxygenase 2; TNF-α = tumour necrosis factor alpha; iNOS = inducible nitric oxide synthase; IκBα = inhibitor of kappa B; PARP = poly ADP-ribose polymerase.

2.9. Antiproliferative Effects of Honey

Cell divides into two through cell cycle to replace cell death. The cell cycle comprises of three distinguished phases known as G0, G1, S, and G2/M. Cells remain still in G0 phase and not participating in the cell division. Cell gears up in G1 phase to move through cell division, and S phase involves synthesis of DNA. G2 and M phases are just ready to mitosis with 4n DNA. All the events in the cell cycle are regulated and monitored by several different proteins. The control panel of cell cycle comprises cyclins and cyclin-dependent kinases. G1/S phase transition is a vital regulatory point, where cell’s fate is destined for quiescence, proliferation, differentiation, and apoptosis. Overexpression and dysregulation of cell cycle growth factors such as cyclin D1 and cyclin-dependent kinases (CDK) are linked with pathogenesis. The loss of this regulation is the hallmark of cancer as well [152]. The nuclear protein Ki-67 is a novel marker to probe the growth fraction of cell proliferation. It is absent in the resting phase (G0), but expressed during the cell cycle in all the proliferation phases (G1, S, G2, and mitosis) during cell cycle [153].

Administration of honey and Aloe vera solution showed a marked decrease in expression of Ki67-LI in tumor cells in Wistar rats having 256 carcinomas [147]. Honey and its several components like flavonoids and phenolics are reported to block the cell cycle of colon cancer cell lines in G0/G1 phase [40]. This inhibitory effect on tumor cell proliferation follows the downregulation of many cellular pathways via proteins such as tyrosine cyclooxygenase, ornithine decarboxylase, and kinase. Thus, it can be hypothesized that honey—or its components—mediates inhibition of cell growth and is due to perturbation in the cell cycle which may possibly lead to apoptosis [40, 145, 146, 154]. The cell cycle is a process regulated also by p53 protein, which as a result of DNA damage increases the levels of cyclin-dependent kinase (Cdk) inhibitors such as p21, p16, and p27 proteins [22]. Honey is reported to be involved in modulation of p53 regulation in colon cancer cell lines [22]. Figure 13 is depicting the possible mechanisms of antiproliferative effects of honey. Honey can suppress and or block the abnormal division of cells by working at various points of cell cycle. This is still urging to investigate the effect of honey on the levels of cyclin-dependent kinases, complexes of cyclins, cyclin-dependent protein kinases, and cyclin-dependent kinase inhibitors such as p16, p21, and p27 proteins in cell cycle proliferation.

2.10. Immunomodulatory Effects of Honey

Immunomodulation is progression of altering an immune system in a constructive or else damaging style. Many biological and chemical blends have the ability to modify immune system [155]. Immunomodulatory cytokines such as TNF-α, IL-1, IL-6, and IL-10 boost activation and proliferation of blood cells to induce phagocytic and lymphocytic activity, triggering an immunomodulatory response [156]. Honey was found to provoke stimulation to the immune system of the body to combat infections in rats. It stimulates T-lymphocytes, B-lymphocytes, and neutrophils in cell culture. B-lymphocytes ultimately stimulate the production of antibodies in primary and secondary immune responses against thymus-dependent and thymus-independent antigens [157]. It stimulates monocytes to release the cytokines such as TNF-α, IL-1, and IL-6, activating numerous aspects of immune response. Stimulatory action of honey towards leucocytes illustrates another action called “respiratory burst.” In this action, glucose of honey is absorbed to produce H₂O₂, which is considered as a leading constituent to stimulate the immune system. It also delivers substrate to glycolysis to produce energy in macrophages to allow them to perform immune modulatory function [4, 158].

Research has manifested that sugars which are slowly absorbed result in the formation of short chain fatty acid (SCFA) fermentation products. It is a probable mechanism that the ingestion of honey may result in SCFA formation. It has been established that either directly or indirectly, SCFA has immune modulatory actions. Thus, honey may stimulate the immune system via these fermentable sugars [159]. A sugar, nigerose, present in honey has been found to be immune protective [160]. Nonsugar components of honey may also be responsible for immunomodulation. Antioxidant content of the honey contributes to immunomodulatory action as well. Though antioxidant compounds have been reported to stimulate immune function in vitro, but there are no direct studies manifesting the effects of honey antioxidants on immune system [159, 160]. Different studies presented that Manuka, Pasture, Nigerian Jungle, and royal jelly honeys used in variant concentrations were found to increase IL-1β, IL-6, and TNF-α, apalbumin 1, production in cell line models [35, 78, 161]. The active component in Manuka was 5.8 kDa, which increased the production of these cytokines and TNF-α via TLR4 (toll-like receptor-4) in cell line culture. These authors settled that the compound was not an amino acid, lipopolysaccharide, mineral, or vitamin urging probe to elucidate the nature of this immune regulatory compound [78]. Treatment with honey (0.2, 1.0, and 2.0 kg/kg) showed a potentiating effect on haematological parameters such as Hb, RBC, PCV, lymphocytes, and eosinophils. It also showed an increasing effect on IFN-γ and IFNGR1 at serum and cancer tissue level in rats induced with breast cancer [149, 150]. Honey, when tested using concentration 1.2 g/kg body weight, was found to increase the antioxidant agents (vitamin C and β-carotene), monocytes, lymphocytes, eosinophils, serum iron and copper, glutathione reductase, and trace elements (Zn and Mg) in healthy human subjects. It caused to decrease immunoglobulin E, ferritin, and liver and muscle enzymes, aspartate transaminase, alanine transaminase, lactate dehydrogenase, creatinine kinase, and fasting blood sugars [56].

The results of clinical trials showed that Life Mel honey (LMH) reduced the incidence of anaemia in 64% of patients by decreasing thrombocytopenia and neutropenia [162]. A study demonstrated that probiotic bacteria in honey have multiple actions in immunity: (a) protect the damaged immune system; (b) enhance the levels of circulating immunoglobulins, frequency of interferon and immunophagocytic activity; and (c) shift the events of the chemically induced reactions [163]. Synthetic medicines and natural products such as honey are supposed to inhibit PG production [164]. Immune function can be restored by the treatment with prostaglandin inhibitors or by reducing systemic PGE2 levels. The use of honey as a PG inhibitor to prevent a disease is emerging. Honey has shown inhibitory effects on PGE2 in carrageenan-induced acute paw edema in rats [107]. Figure 14 is showing the possible mechanisms of action of honey for its immune regulatory effects. Further probes are recommended to elucidate the effects and mechanisms of immune modulatory effects, perhaps using artificial immune challenges.

2.11. Cardiovascular Effects of Honey

Honey has the ability to regulate some cardiovascular risk factors which include blood glucose, cholesterol, CRP (C-reactive proteins), and body weight [43]. Honey contains glucose, fructose, and some trace elements such as copper and zinc, which may play a vital role to ameliorate the cardiac risks. It causes to decrease LDL (low-density lipoprotein), high-density lipoprotein cholesterol (HDL-C), triacylglycerole, body fat, glucose, and cholesterol levels in cardiac patients and healthy human subjects who took honey 70 g for 30 days. It retards the level of CRP, which stimulates nitric oxide production [43]. Nitric oxide has many cardioprotective effects which include regulation of blood pressure, vascular tone, inhibition of platelet aggregation, leukocyte adhesion, and prevention of smooth muscle cell proliferation [165]. NO acts as a critical mediator for vasodilation in blood vessels. It is induced by many factors such as acetylcholine, shear stress, and cytokines via eNOS synthesis. NO causes phosphorylation of several proteins that causes smooth muscle relaxation. The vasodilatory effect of NO plays a major role in renal regulation of extracellular fluid homeostasis and is also critical for the regulation of blood pressure and blood flow [165, 166]. Some flavonoids in honey have been reported to modulate cardiovascular risks by decreasing oxidative stress and increasing nitric oxide (NO) bioavailability. Similarly, rutin promotes NO production by enhancing eNOS gene expression and its activity. Naringin inhibits hypercholesterolemia-induced intercellular adhesion molecule-1 (ICAM-1) expression on endothelial cells. Recent studies have shown that catechin and quercetin as major honey flavonoids have inhibitory effects on the development of aortic atherosclerotic lesions and atherogenic modification of LDL [167].

Honey pretreatment was found to restore the decreased levels of enzymes such as superoxide dismutase, glutathione peroxidase, and glutathione reductase including creatine kinase-MB, lactate dehydrogenase, aspartate transaminase, and alanine transaminase against isoproterenol-induced myocardial infarction in Wistar rats [168]. It shows that honey gives defense from harmful effects prompted by free lethal radicals [169]. Another study has shown that honey causes to increase antioxidant markers in rat myocardial infraction model ameliorating cardiac troponin I (cTnI), triglycerides (TG), total cholesterol (TC), and lipid peroxidation (LPO) products [169]. All the possible mechanisms of cardiovascular effects of honey have been demonstrated in Figure 15. However, the exact mechanisms of action of honey still remain obscure for its cardiovascular effects. This urges for further investigation.

3. Pharmacokinetics of Honey

Literature lacks reports for the pharmacokinetics of honey. However, research has shown that honey may affect the pharmacokinetics of some drugs [170]. In vivo human studies reported that honey interferes with the activity of cytochrome p450 (CYP450) isozymes [170]. Preliminary clinical investigations for the effect of honey on CYP450 activity suggest that honey might increase CYP3A4 activity; however, it does not affect the activity of CYP2D6 and/or CYP2C19. It was also observed that increased CYP3A4 activity requires regular ingestion of honey, while occasional ingestion is unlikely to significantly affect drug plasma concentrations. Thus, honey may cause altered response to drugs metabolized by CYP3A4 [170]. CYP3A4 is the major phase I drug-metabolizing enzyme, and P-glycoprotein is an ATP-dependent drug efflux pump that regulates the intestinal absorption of orally administered drugs. In contrast, another human study reported that daily consumption of honey does not affect hepatic and intestinal CYP3A and P-glycoprotein activities [171, 172].

4. Limitations of Honey

Honey should be evaluated for its toxicological effects based on plants and or nectar source. Though not all, but intoxication by honey may be expected, for instance, mad honey is contaminated with grayanotoxin. Grayanotoxin is found in rhododendron plants in countries such as China, Tibet, Turkey, Nepal, Myanmar, Japan, New Guinea, Philippines, Indonesia, and North America. Mad honey collected in spring is more toxic containing more grayanotoxin [173]. Grayanotoxin causes intoxication which may include weakness, dizziness, excessive perspiration, hypersalivation, nausea, vomiting, and paresthesias. It may even lead to life-threatening cardiac complications such as complete atrioventricular block [173]. Honey may become contaminated with germs from plants, bees, and dust during production, collection, and/or processing. Fortunately, antimicrobial activity of honey ensures that most contaminating germs cannot survive or reproduce. However, bacteria that can reproduce using spores, including those that cause botulism, may survive. This is the reason that botulism has been reported in infants given honey orally. To solve this issue, honey or medical-grade honey should be irradiated to inactivate the bacterial spores [174]. Sometimes, food allergy due to honey is frequently accompanying with pollen allergy due to the presence of pollens during its collection. Thus, honey may have the possibility of sensitivity in any patient with suspected but unresolved food allergy [175]. A typical consumption of sugar and high fructose corn syrup (HFCS) totals the nearly ¾ pound per day for every individual above age 2. However, an amount, which simply overwhelms, results in elevated blood sugar levels, excessive insulin release, and resultant fat production and storage in the liver [176].

5. Conclusion

Honey can be considered a serine potential natural antioxidant medicine. Evidence-based research shows that honey acts through a modulatory road of multiple signaling pathways and molecular targets. It may interfere with multiple targets in cell signaling pathways such as induction of caspases in apoptosis, stimulation of TNF-α, IL-1β, IFN-γ, IFNGR1, p53, and immune cells, inhibition of cell proliferation, cell cycle arrest, inhibition of lipoprotein oxidation, IL-1, IL-10, COX-2, LOXs, and PGE2, and modulation of other diverse targets. This results in triggering the amelioration of antioxidant, antimutagenic, anti-inflammatory, immune regulatory, and estrogenic responses to abate different types of diseases. Effect of honey on pharmacokinetics of drug leads to dissimilar progressions of the body. Further research is needed to establish the possible mechanisms involved. More clinical and experimental trials are also intended to validate the authenticity of honey either alone or as an adjuvant therapy.

Conflicts of Interest

The authors declare no conflict of interest.

References

J. A. Castro, M. M. deMecca, and L. C. Bartel, “Toxic side effects of drugs used to treat Chagas’ disease (American trypanosomiasis),” Human & Experimental Toxicology, vol. 25, no. 8, pp. 471–479, 2006.
View at: Publisher Site | Google Scholar
B. B. Aggarwal and S. Shishodia, “Molecular targets of dietary agents for prevention and therapy of cancer,” Biochemical Pharmacology, vol. 71, no. 10, pp. 1397–1421, 2006.
View at: Publisher Site | Google Scholar
F. E. Koehn and G. T. Carter, “The evolving role of natural products in drug discovery,” Nature Reviews Drug Discovery, vol. 4, no. 3, pp. 206–220, 2005.
View at: Publisher Site | Google Scholar
N. H. Othman, “Does honey have the characteristics of natural cancer vaccine?” Journal of Traditional and Complementary Medicine, vol. 2, no. 4, pp. 276–283, 2012.
View at: Publisher Site | Google Scholar
N. H. Othman, “Honey and cancer: sustainable inverse relationship particularly for developing nations—a review,” Evidence-based Complementary and Alternative Medicine, vol. 2012, Article ID 410406, 10 pages, 2012.
View at: Publisher Site | Google Scholar
S. Ahmed and N. H. Othman, “Honey as a potential natural anticancer agent: a review of its mechanisms,” Evidence-based Complementary and Alternative Medicine, vol. 2013, Article ID 829070, 7 pages, 2013.
View at: Publisher Site | Google Scholar
P. Molan, Manuka Honey as a Medicine, Global Bioactives Summit, Hamilton, 2001.
A. Simon, K. Traynor, K. Santos, G. Blaser, U. Bode, and P. Molan, “Medical honey for wound care—still the ‘latest resort’?” Evidence-based Complementary and Alternative Medicine, vol. 6, no. 2, pp. 165–173, 2009.
View at: Publisher Site | Google Scholar
“Editorial: Honey: sweet and dangerous or panacea?” South African Medical Journal, vol. 48, no. 56, p. 2300, 1974.
View at: Google Scholar
R. E. Condon, “Curious interaction of bugs and bees,” Surgery, vol. 113, no. 2, pp. 234-235, 1993.
View at: Google Scholar
K. Rahman, “Phytochemical analysis and chemical composition of different branded and unbranded honey samples,” International Journal of Microbiological Research, vol. 4, no. 2, pp. 132–137, 2013.
View at: Publisher Site | Google Scholar
I. Hermosı́n, R. M. Chicón, and M. D. Cabezudo, “Free amino acid composition and botanical origin of honey,” Food Chemistry, vol. 83, no. 2, pp. 263–268, 2003.
View at: Publisher Site | Google Scholar
O. M. Atrouse, S. A. Oran, and S. Y. Al-Abbadi, “Chemical analysis and identification of pollen grains from different Jordanian honey samples,” International Journal of Food Science & Technology, vol. 39, no. 4, pp. 413–417, 2004.
View at: Publisher Site | Google Scholar
L. Chen, A. Mehta, M. Berenbaum, A. R. Zangerl, and N. J. Engeseth, “Honeys from different floral sources as inhibitors of enzymatic Browning in fruit and vegetable homogenates,” Journal of Agricultural and Food Chemistry, vol. 48, no. 10, pp. 4997–5000, 2000.
View at: Publisher Site | Google Scholar
D. W. Ball, “The chemical composition of honey,” Journal of Chemical Education, vol. 84, no. 10, p. 1643, 2007.
View at: Publisher Site | Google Scholar
A. M. Miraglio, Honey-Health and Therapeutic Qualities, The National Honey Board, Longmont, 2008.
O. O. Erejuwa, S. A. Sulaiman, and M. S. A. Wahab, “Effects of honey and its mechanisms of action on the development and progression of cancer,” Molecules, vol. 19, no. 2, pp. 2497–2522, 2014.
View at: Publisher Site | Google Scholar
S. Ahmed and N. H. Othman, “Review of the medicinal effects of tualang honey and a comparison with manuka honey,” The Malaysian Journal of Medical Sciences, vol. 20, no. 3, pp. 6–13, 2013.
View at: Google Scholar
N. C. Cook and S. Samman, “Flavonoids—chemistry, metabolism, cardioprotective effects, and dietary sources,” The Journal of Nutritional Biochemistry, vol. 7, no. 2, pp. 66–76, 1996.
View at: Publisher Site | Google Scholar
A. L. Catapano, “Antioxidant effect of flavonoids,” Angiology, vol. 48, no. 1, pp. 39–44, 1997.
View at: Publisher Site | Google Scholar
K. Ioku, T. Tsushida, Y. Takei, N. Nakatani, and J. Terao, “Antioxidative activity of quercetin and quercetin monoglucosides in solution and phospholipid bilayers,” Biochimica et Biophysica Acta (BBA) - Biomembranes, vol. 1234, no. 1, pp. 99–104, 1995.
View at: Publisher Site | Google Scholar
S. K. Jaganathan and M. Mandal, “Involvement of non-protein thiols, mitochondrial dysfunction, reactive oxygen species and p53 in honey-induced apoptosis,” Investigational New Drugs, vol. 28, no. 5, pp. 624–633, 2009.
View at: Publisher Site | Google Scholar
M. B. Abubakar, W. Z. Abdullah, S. A. Sulaiman, and A. B. Suen, “A review of molecular mechanisms of the anti-leukemic effects of phenolic compounds in honey,” International Journal of Molecular Sciences, vol. 13, no. 12, pp. 15054–15073, 2012.
View at: Publisher Site | Google Scholar
O. O. Erejuwa, S. A. Sulaiman, and M. S. Ab Wahab, “Honey: a novel antioxidant,” Molecules, vol. 17, no. 12, pp. 4400–4423, 2012.
View at: Publisher Site | Google Scholar
M. Al-Mamary, A. Al-Meeri, and M. Al-Habori, “Antioxidant activities and total phenolics of different types of honey,” Nutrition Research, vol. 22, no. 9, pp. 1041–1047, 2002.
View at: Publisher Site | Google Scholar
P. C. Molan, Manuka Honey as a Medicine, in Global Bioactives Summit, Waikato Honey Research Unit: The University of Waikato, 2001.
O. Sherlock, A. Dolan, R. Athman et al., “Comparison of the antimicrobial activity of Ulmo honey from Chile and Manuka honey against methicillin-resistant Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa,” BMC Complementary and Alternative Medicine, vol. 10, no. 1, p. 47, 2010.
View at: Publisher Site | Google Scholar
X. Wang, X. H. Wang, L. Andrae, and N. J. Engeseth, “Antimutagenic effect of various honeys and sugars against Trp-p-1,” Journal of Agricultural and Food Chemistry, vol. 50, no. 23, pp. 6923–6928, 2002.
View at: Publisher Site | Google Scholar
P. E. Lusby, A. Coombes, and J. M. Wilkinson, “Honey: a potent agent for wound healing?” Journal of Wound Ostomy & Continence Nursing, vol. 29, no. 6, pp. 295–300, 2002.
View at: Publisher Site | Google Scholar
O. O. Erejuwa, S. Gurtu, S. A. Sulaiman, M. S. Ab Wahab, K. N. Sirajudeen, and M. S. Salleh, “Hypoglycemic and antioxidant effects of honey supplementation in streptozotocin-induced diabetic rats,” International Journal for Vitamin and Nutrition Research, vol. 80, no. 1, pp. 74–82, 2010.
View at: Publisher Site | Google Scholar
A. Shahzad and R. J. Cohrs, “In vitro antiviral activity of honey against varicella zoster virus (VZV): a translational medicine study for potential remedy for shingles,” Translational Biomedicine, vol. 3, no. 2, p. 2, 2012.
View at: Publisher Site | Google Scholar
J. Irish, D. A. Carter, T. Shokohi, and S. E. Blair, “Honey has an antifungal effect against Candida species,” Medical Mycology, vol. 44, no. 3, pp. 289–291, 2006.
View at: Publisher Site | Google Scholar
T. Swellam, N. Miyanaga, M. Onozawa et al., “Antineoplastic activity of honey in an experimental bladder cancer implantation model: in vivo and in vitro studies,” International Journal of Urology, vol. 10, no. 4, pp. 213–219, 2003.
View at: Publisher Site | Google Scholar
A. A. Ghashm, N. H. Othman, M. N. Khattak, N. M. Ismail, and R. Saini, “Antiproliferative effect of tualang honey on oral squamous cell carcinoma and osteosarcoma cell lines,” BMC Complementary and Alternative Medicine, vol. 10, no. 1, p. 49, 2010.
View at: Publisher Site | Google Scholar
M. Fukuda, K. Kobayashi, Y. Hirono et al., “Jungle honey enhances immune function and antitumor activity,” Evidence-based Complementary and Alternative Medicine, vol. 2011, Article ID 908743, 8 pages, 2011.
View at: Publisher Site | Google Scholar
A. V. Tsiapara, M. Jaakkola, I. Chinou et al., “Bioactivity of Greek honey extracts on breast cancer (MCF-7), prostate cancer (PC-3) and endometrial cancer (Ishikawa) cells: profile analysis of extracts,” Food Chemistry, vol. 116, no. 3, pp. 702–708, 2009.
View at: Publisher Site | Google Scholar
N. V. Gribel and V. G. Pashinskiĭ, “The antitumor properties of honey,” Voprosy Onkologii, vol. 36, no. 6, pp. 704–709, 1990.
View at: Google Scholar
R. Tomasin and M. C. Gomes-Marcondes, “Oral administration of Aloe vera and honey reduces walker tumour growth by decreasing cell proliferation and increasing apoptosis in tumour tissue,” Phytotherapy Research, vol. 25, no. 4, pp. 619–623, 2011.
View at: Publisher Site | Google Scholar
A. N. Fauzi, M. N. Norazmi, and N. S. Yaacob, “Tualang honey induces apoptosis and disrupts the mitochondrial membrane potential of human breast and cervical cancer cell lines,” Food and Chemical Toxicology, vol. 49, no. 4, pp. 871–878, 2011.
View at: Publisher Site | Google Scholar
S. K. Jaganathan and M. Mandal, “Honey constituents and their apoptotic effect in colon cancer cells,” Journal of ApiProduct and ApiMedical Science, vol. 1, no. 2, pp. 29–36, 2009.
View at: Publisher Site | Google Scholar
S. Samarghandians, J. T. Afshari, and S. Davoodi, “Honey induces apoptosis in renal cell carcinoma,” Pharmacognosy Magazine, vol. 7, no. 25, pp. 46–52, 2011.
View at: Publisher Site | Google Scholar
A. A. Ghashm, N. H. Othman, M. N. Khattak, N. M. Ismail, and R. Saini, “Antiproliferative effect of tualang honey on oral squamous cell carcinoma and osteosarcoma cell lines,” BMC Complementary and Alternative Medicine, vol. 10, no. 1, p. 49, 2010.
View at: Publisher Site | Google Scholar
N. Yaghoobi, N. Al-Waili, M. Ghayour-Mobarhan et al., “Natural honey and cardiovascular risk factors; effects on blood glucose, cholesterol, triacylglycerole, CRP, and body weight compared with sucrose,” The Scientific World Journal, vol. 8, pp. 463–469, 2008.
View at: Publisher Site | Google Scholar
O. O. Erejuwa, S. A. Sulaiman, M. S. A. Wahab, K. N. S. Sirajudeen, M. S. M. Salleh, and S. Gurtu, “Differential responses to blood pressure and oxidative stress in streptozotocin-induced diabetic wistar-kyoto rats and spontaneously hypertensive rats: effects of antioxidant (honey) treatment,” International Journal of Molecular Sciences, vol. 12, no. 12, pp. 1888–1907, 2011.
View at: Publisher Site | Google Scholar
S. A. Sulaiman, H. Hasan, Z. Z. Deris et al., “The benefit of tualang honey in reducing acute respiratory symptoms among Malaysian hajj pilgrims: a preliminary study,” Journal of ApiProduct and ApiMedical Science, vol. 3, no. 1, pp. 38–44, 2011.
View at: Publisher Site | Google Scholar
S. S. Zaid, S. A. Sulaiman, K. N. M. Sirajudeen, and N. H. Othman, “The effects of tualang honey on female reproductive organs, tibia bone and hormonal profile in ovariectomised rats-animal model for menopause,” BMC Complementary and Alternative Medicine, vol. 10, no. 1, p. 82, 2010.
View at: Publisher Site | Google Scholar
M. Mohamed, S. A. Sulaiman, H. Jaafar, and K. N. S. Sirajudeen, “Effect of different doses of Malaysian honey on reproductive parameters in adult male rats,” Andrologia, vol. 44, Supplement 1, pp. 182–186, 2012.
View at: Publisher Site | Google Scholar
M. Mahaneem, S. A. Sulaiman, H. Jaafar et al., “Effect of honey on testicular functions in rats exposed to cigarette smoke,” Journal of ApiProduct and ApiMedical Science, vol. 3, no. 1, pp. 12–17, 2011.
View at: Publisher Site | Google Scholar
Z. Othman, N. Shafin, R. Zakaria, N. H. N. Hussain, and W. M. Z. W. Mohammad, “Improvement in immediate memory after 16 weeks of tualang honey (agro mas) supplement in healthy postmenopausal women,” Menopause, vol. 18, no. 11, pp. 1219–1224, 2011.
View at: Publisher Site | Google Scholar
T. Eteraf-Oskouei and M. Najafi, “Traditional and modern uses of natural honey in human diseases: a review,” Iranian Journal of Basic Medical Sciences, vol. 16, no. 6, pp. 731–742, 2013.
View at: Google Scholar
S. Bogdanov, T. Jurendic, R. Sieber, and P. Gallmann, “Honey for nutrition and health: a review,” Journal of the American College of Nutrition, vol. 27, no. 6, pp. 677–689, 2008.
View at: Publisher Site | Google Scholar
B. Halliwell and J. M. Gutteridge, “Lipid peroxidation: a radical chain reaction,” Free Radical Biology & Medicine, vol. 2, pp. 188–218, 1989.
View at: Google Scholar
T. Nagai, M. Sakai, R. Inoue, H. Inoue, and N. Suzuki, “Antioxidative activities of some commercially honeys, royal jelly, and propolis,” Food Chemistry, vol. 75, no. 2, pp. 237–240, 2001.
View at: Publisher Site | Google Scholar
A. T. Diplock, C. A. Rice-Evans, and R. H. Burdon, “Is there a significant role for lipid peroxidation in the causation of malignancy and for antioxidants in cancer prevention?” Cancer Research, vol. 54, Supplement 7, pp. 1952s–1956s, 1994.
View at: Google Scholar
A. M. Aljadi and M. Y. Kamaruddin, “Evaluation of the phenolic contents and antioxidant capacities of two Malaysian floral honeys,” Food Chemistry, vol. 85, no. 4, pp. 513–518, 2004.
View at: Publisher Site | Google Scholar
N. S. Al-Waili, “Effects of daily consumption of honey solution on hematological indices and blood levels of minerals and enzymes in normal individuals,” Journal of Medicinal Food, vol. 6, no. 2, pp. 135–140, 2003.
View at: Publisher Site | Google Scholar
S. A. B. E. Van Acker, S. A. van Acker, D. J. van den Berg et al., “Structural aspects of antioxidant activity of flavonoids,” Free Radical Biology & Medicine, vol. 20, no. 3, pp. 331–342, 1996.
View at: Publisher Site | Google Scholar
Z. H. Israili, “Antimicrobial properties of honey,” American Journal of Therapeutics, vol. 21, no. 4, pp. 304–323, 2014.
View at: Publisher Site | Google Scholar
N.-A. M. Nasir, A. S. Halim, K. K. B. Singh, A. A. Dorai, and M. N. M. Haneef, “Antibacterial properties of tualang honey and its effect in burn wound management: a comparative study,” BMC Complementary and Alternative Medicine, vol. 10, no. 1, p. 31, 2010.
View at: Publisher Site | Google Scholar
A. Halim, B. K. Kaur, and A. Doraia, “Wound contraction and anti-microbial properties of tualang honey on full thickness burn wound in rats,” Journal of ApiProduct and ApiMedical Science, vol. 2, no. 1, pp. 31–60, 2010.
View at: Google Scholar
S. Bogdanov, “Honey as nutrient and functional food: a review,” Bee Product Science, 2011.
View at: Google Scholar
M. D. Mandal and S. Mandal, “Honey: its medicinal property and antibacterial activity,” Asian Pacific Journal of Tropical Biomedicine, vol. 1, no. 2, pp. 154–160, 2011.
View at: Publisher Site | Google Scholar
T. Koenig and J. L. C. Roh, “Healing wounds with honey,” Undergraduate Research Journal for the Human Sciences, vol. 15, no. 1, 2016.
View at: Google Scholar
J. Rückriemen, O. Klemm, and T. Henle, “Manuka honey (Leptospermum Scoparium) inhibits Jack bean urease activity due to methylglyoxal and dihydroxyacetone,” Food Chemistry, vol. 230, pp. 540–546, 2017.
View at: Publisher Site | Google Scholar
R. Wang, M. Starkey, R. Hazan, and L. G. Rahme, “Honey’s ability to counter bacterial infections arises from both bactericidal compounds and QS inhibition,” Frontiers in Microbiology, vol. 3, 2012.
View at: Publisher Site | Google Scholar
P. Merckoll, T. Ø. Jonassen, M. E. Vad, S. L. Jeansson, and K. K. Melby, “Bacteria, biofilm and honey: a study of the effects of honey on ‘planktonic’ and biofilm-embedded chronic wound bacteria,” Scandinavian Journal of Infectious Diseases, vol. 41, no. 5, pp. 341–347, 2009.
View at: Publisher Site | Google Scholar
F. D. Halstead, M. A. Webber, and B. A. Oppenheim, “Use of an engineered honey to eradicate preformed biofilms of important wound pathogens: an in vitro study,” Journal of Wound Care, vol. 26, no. 8, pp. 442–450, 2017.
View at: Publisher Site | Google Scholar
T. Alandejani, J. Marsan, W. Ferris, R. Slinger, and F. Chan, “Effectiveness of honey on Staphylococcus aureus and Pseudomonas aeruginosa biofilms,” Otolaryngology-Head and Neck Surgery, vol. 141, no. 1, pp. 114–118, 2009.
View at: Publisher Site | Google Scholar
S. Emineke, A. J. Cooper, S. Fouch, B. R. Birch, and B. A. Lwaleed, “Diluted honey inhibits biofilm formation: potential application in urinary catheter management?” Journal of Clinical Pathology, vol. 70, no. 2, pp. 140–144, 2016.
View at: Publisher Site | Google Scholar
M. Piotrowski, P. Karpiński, H. Pituch, A. van Belkum, and P. Obuch-Woszczatyński, “Antimicrobial effects of Manuka honey on in vitro biofilm formation by Clostridium difficile,” European Journal of Clinical Microbiology & Infectious Diseases, vol. 36, no. 9, pp. 1661–1664, 2017.
View at: Publisher Site | Google Scholar
S. E. Maddocks, M. S. Lopez, R. S. Rowlands, and R. A. Cooper, “Manuka honey inhibits the development of streptococcus pyogenes biofilms and causes reduced expression of two fibronectin binding proteins,” Microbiology, vol. 158, Part 3, pp. 781–790, 2012.
View at: Publisher Site | Google Scholar
J. H. Lee, J. H. Park, J. A. Kim et al., “Low concentrations of honey reduce biofilm formation, quorum sensing, and virulence in Escherichia coli O157:H7,” Biofouling, vol. 27, no. 10, pp. 1095–1104, 2011.
View at: Publisher Site | Google Scholar
V. Falanga, “Wound healing and its impairment in the diabetic foot,” The Lancet, vol. 366, no. 9498, pp. 1736–1743, 2005.
View at: Publisher Site | Google Scholar
B. G. Visavadia, J. Honeysett, and M. H. Danford, “Manuka honey dressing: an effective treatment for chronic wound infections,” British Journal of Oral and Maxillofacial Surgery, vol. 46, no. 1, pp. 55-56, 2008.
View at: Publisher Site | Google Scholar
F.-H. Imran, A. A. Dorai, A. S. Halim, and W. A. W. Sulaiman, “Tualang honey hydrogel in the treatment of split-skin graft donor sites,” Journal of ApiProduct and ApiMedical Science, vol. 3, no. 1, pp. 33–37, 2011.
View at: Publisher Site | Google Scholar
L. M. Bang, C. Buntting, and P. Molan, “The effect of dilution on the rate of hydrogen peroxide production in honey and its implications for wound healing,” The Journal of Alternative & Complementary Medicine, vol. 9, no. 2, pp. 267–273, 2003.
View at: Publisher Site | Google Scholar
Z.-Q. Lin, T. Kondo, Y. Ishida, T. Takayasu, and N. Mukaida, “Essential involvement of IL-6 in the skin wound-healing process as evidenced by delayed wound healing in IL-6-deficient mice,” Journal of Leukocyte Biology, vol. 73, no. 6, pp. 713–721, 2003.
View at: Publisher Site | Google Scholar
A. J. Tonks, E. Dudley, N. G. Porter et al., “A 5.8-kDa component of manuka honey stimulates immune cells via TLR4,” Journal of Leukocyte Biology, vol. 82, no. 5, pp. 1147–1155, 2007.
View at: Publisher Site | Google Scholar
P. C. Molan and T. Rhodes, “Honey: a biologic wound dressing,” Wounds, vol. 27, no. 6, pp. 141–151, 2015.
View at: Google Scholar
B. Halliwell and J. M. C. Gutteridge, Free Radicals in Biology and Medicine, Clarendon Press, Oxford, UK, 2007.
J. M. Alvarez-Suarez, F. Giampieri, M. Cordero et al., “Activation of AMPK/Nrf2 signalling by Manuka honey protects human dermal fibroblasts against oxidative damage by improving antioxidant response and mitochondrial function promoting wound healing,” Journal of Functional Foods, vol. 25, pp. 38–49, 2016.
View at: Publisher Site | Google Scholar
M. PC, “The antibacterial activity of honey. 1. The nature of the antibacterial activity,” Bee World, vol. 73, no. 1, pp. 5–28, 1992.
View at: Google Scholar
N. Abuharfeil, R. Al-Oran, and M. Abo-Shehada, “The effect of bee honey on the proliferative activity of human B-and T-lymphocytes and the activity of phagocytes,” Food and Agricultural Immunology, vol. 11, no. 2, pp. 169–177, 1999.
View at: Publisher Site | Google Scholar
C. Anyanwu, “Investigation of in vitro antifungal activity of honey,” Journal of Medicinal Plants Research, vol. 6, no. 18, pp. 3512–3516, 2012.
View at: Publisher Site | Google Scholar
T. T. Cushnie and A. J. Lamb, “Antimicrobial activity of flavonoids,” International Journal of Antimicrobial Agents, vol. 26, no. 5, pp. 343–356, 2005.
View at: Publisher Site | Google Scholar
P. H. Kwakman, A. A. te Velde, L. de Boer, D. Speijer, C. M. Vandenbroucke-Grauls, and S. A. Zaat, “How honey kills bacteria,” The FASEB Journal, vol. 24, no. 7, pp. 2576–2582, 2010.
View at: Publisher Site | Google Scholar
H. M. Nassar, M. Li, and R. L. Gregory, “Effect of honey on Streptococcus mutans growth and biofilm formation,” Applied and Environmental Microbiology, vol. 78, no. 2, pp. 536–540, 2012.
View at: Publisher Site | Google Scholar
N. S. Al-Waili, K. Salom, G. Butler, and A. A. al Ghamdi, “Honey and microbial infections: a review supporting the use of honey for microbial control,” Journal of Medicinal Food, vol. 14, no. 10, pp. 1079–1096, 2011.
View at: Publisher Site | Google Scholar
J. Arnold and G. Bailey, “Surface finishes on stainless steel reduce bacterial attachment and early biofilm formation: scanning electron and atomic force microscopy study,” Poultry Science, vol. 79, no. 12, pp. 1839–1845, 2000.
View at: Publisher Site | Google Scholar
M. J. Ansari, A. al-Ghamdi, S. Usmani et al., “Effect of jujube honey on Candida albicans growth and biofilm formation,” Archives of Medical Research, vol. 44, no. 5, pp. 352–360, 2013.
View at: Publisher Site | Google Scholar
B. Canonico, M. Candiracci, B. Citterio et al., “Honey flavonoids inhibit Candida albicans morphogenesis by affecting DNA behavior and mitochondrial function,” Future Microbiology, vol. 9, no. 4, pp. 445–456, 2014.
View at: Publisher Site | Google Scholar
R. J. Whitley, D. W. Kimberlin, and B. Roizman, “Herpes simplex viruses,” Clinical Infectious Diseases, vol. 26, no. 3, pp. 541–553, 1998.
View at: Publisher Site | Google Scholar
P. H. Kwakman, A. A. Te Velde, L. de Boer, C. M. Vandenbroucke-Grauls, and S. A. Zaat, “Two major medicinal honeys have different mechanisms of bactericidal activity,” PLoS One, vol. 6, no. 3, article e17709, 2011.
View at: Publisher Site | Google Scholar
N. Vynograd, I. Vynograd, and Z. Sosnowski, “A comparative multi-centre study of the efficacy of propolis, acyclovir and placebo in the treatment of genital herpes (HSV),” Phytomedicine, vol. 7, no. 1, pp. 1–6, 2000.
View at: Publisher Site | Google Scholar
B. Zeina, O. Othman, and S. Al-Assad, “Effect of honey versus thyme on rubella virus survival in vitro,” The Journal of Alternative and Complementary Medicine, vol. 2, no. 3, pp. 345–348, 1996.
View at: Publisher Site | Google Scholar
N. S. Al-Waili, “Topical honey application vs. acyclovir for the treatment of recurrent herpes simplex lesions,” Medical Science Monitor, vol. 10, no. 8, pp. MT94–MT98, 2004.
View at: Google Scholar
N. Al-Waili and N. Boni, “Effects of honey ingetsion on nitric oxide in saliva,” FASEB Journal, vol. 17, no. 5, p. 9650, 2003.
View at: Google Scholar
L. Yao, Y. Jiang, B. D'Arcy et al., “Quantitative high-performance liquid chromatography analyses of flavonoids in Australian Eucalyptus honeys,” Journal of Agricultural and Food Chemistry, vol. 52, no. 2, pp. 210–214, 2004.
View at: Publisher Site | Google Scholar
N. Oršolić and I. Bašić, “Water-soluble derivative of propolis and its polyphenolic compounds enhance tumoricidal activity of macrophages,” Journal of Ethnopharmacology, vol. 102, no. 1, pp. 37–45, 2005.
View at: Publisher Site | Google Scholar
L. Vandamme, A. Heyneman, H. Hoeksema, J. Verbelen, and S. Monstrey, “Honey in modern wound care: a systematic review,” Burns, vol. 39, no. 8, pp. 1514–1525, 2013.
View at: Publisher Site | Google Scholar
W. M. Lee, “Acetaminophen and the US acute liver failure study group: lowering the risks of hepatic failure,” Hepatology, vol. 40, no. 1, pp. 6–9, 2004.
View at: Publisher Site | Google Scholar
W. M. Abdel-Moneim and H. H. Ghafeer, “The potential protective effect of natural honey against cadmium-induced hepatotoxicity and nephrotoxicity,” Mansoura Journal of Forensic Medicine Clinical Toxicology, vol. 15, pp. 75–92, 2007.
View at: Google Scholar
A. Chant, “The biomechanics of leg ulceration,” Annals of the Royal College of Surgeons of England, vol. 81, no. 2, pp. 80–85, 1999.
View at: Google Scholar
M. Subrahmanyam, “A prospective randomised clinical and histological study of superficial burn wound healing with honey and silver sulfadiazine,” Burns, vol. 24, no. 2, pp. 157–161, 1998.
View at: Publisher Site | Google Scholar
N. S. Al-Waili and N. S. Boni, “Natural honey lowers plasma prostaglandin concentrations in normal individuals,” Journal of Medicinal Food, vol. 6, no. 2, pp. 129–133, 2003.
View at: Publisher Site | Google Scholar
S. Z. Hussein, K. Mohd Yusoff, S. Makpol, and Y. A. Mohd Yusof, “Gelam honey attenuates carrageenan-induced rat paw inflammation via NF-κB pathway,” PLoS One, vol. 8, no. 8, article e72365, 2013.
View at: Publisher Site | Google Scholar
S. Z. Hussein, K. Mohd Yusoff, S. Makpol, and Y. A. Mohd Yusof, “Gelam honey inhibits the production of proinflammatory, mediators NO, PGE(2), TNF-α, and IL-6 in carrageenan-induced acute paw edema in rats,” Evidence-based Complementary and Alternative Medicine, vol. 2012, Article ID 109636, 13 pages, 2012.
View at: Publisher Site | Google Scholar
G. Murtaza, S. Karim, M. R. Akram et al., “Caffeic acid phenethyl ester and therapeutic potentials,” BioMed Research International, vol. 2014, Article ID 145342, 9 pages, 2014.
View at: Publisher Site | Google Scholar
M. Candiracci, E. Piatti, M. Dominguez-Barragán et al., “Anti-inflammatory activity of a honey flavonoid extract on lipopolysaccharide-activated N13 microglial cells,” Journal of Agricultural and Food Chemistry, vol. 60, no. 50, pp. 12304–12311, 2012.
View at: Publisher Site | Google Scholar
A. Tonks, R. A. Cooper, A. J. Price, P. C. Molan, and K. P. Jones, “Stimulation of TNF-α release in monocytes by honey,” Cytokine, vol. 14, no. 4, pp. 240–242, 2001.
View at: Publisher Site | Google Scholar
V. Tomblin, L. R. Ferguson, D. Y. Han, P. Murray, and R. Schlothauer, “Potential pathway of anti-inflammatory effect by New Zealand honeys,” International Journal of General Medicine, vol. 7, pp. 149–158, 2014.
View at: Publisher Site | Google Scholar
P. C. Molan, “Potential of honey in the treatment of wounds and burns,” American Journal of Clinical Dermatology, vol. 2, no. 1, pp. 13–19, 2001.
View at: Publisher Site | Google Scholar
S. S. Gupta, O. Singh, P. S. Bhagel, S. Moses, S. Shukla, and R. K. Mathur, “Honey dressing versus silver sulfadiazene dressing for wound healing in burn patients: a retrospective study,” Journal of Cutaneous and Aesthetic Surgery, vol. 4, no. 3, pp. 183–187, 2011.
View at: Publisher Site | Google Scholar
J. Hong, T. J. Smith, C. T. Ho, D. A. August, and C. S. Yang, “Effects of purified green and black tea polyphenols on cyclooxygenase- and lipoxygenase-dependent metabolism of arachidonic acid in human colon mucosa and colon tumor tissues,” Biochemical Pharmacology, vol. 62, no. 9, pp. 1175–1183, 2001.
View at: Publisher Site | Google Scholar
E. Matteucci and O. Giampietro, “Oxidative stress in families of type 1 diabetic patients,” Diabetes Care, vol. 23, no. 8, pp. 1182–1186, 2000.
View at: Publisher Site | Google Scholar
M. Brownlee, “Advanced protein glycosylation in diabetes and aging,” Annual Review of Medicine, vol. 46, no. 1, pp. 223–234, 1995.
View at: Publisher Site | Google Scholar
A. Elgawish, M. Glomb, M. Friedlander, and V. M. Monnier, “Involvement of hydrogen peroxide in collagen cross-linking by high glucose in vitro and in vivo,” Journal of Biological Chemistry, vol. 271, no. 22, pp. 12964–12971, 1996.
View at: Publisher Site | Google Scholar
A. E. Kitabchi, G. E. Umpierrez, J. M. Miles, and J. N. Fisher, “Hyperglycemic crises in adult patients with diabetes,” Diabetes Care, vol. 32, no. 7, pp. 1335–1343, 2009.
View at: Publisher Site | Google Scholar
N. Al-Waili, “Intrapulmonary administration of natural honey solution, hyperosmolar dextrose or hypoosmolar distill water to normal individuals and to patients with type-2 diabetes mellitus or hypertension: their effects on blood glucose level, plasma insulin and C-peptide, blood pressure and peaked expiratory flow rate,” European Journal of Medical Research, vol. 8, no. 7, pp. 295–303, 2003.
View at: Google Scholar
O. O. Erejuwa, S. A. Sulaiman, and M. S. Ab Wahab, “Honey-a novel antidiabetic agent,” International Journal of Biological Sciences, vol. 8, no. 6, pp. 913–934, 2012.
View at: Publisher Site | Google Scholar
O. O. Erejuwa, S. Gurtu, S. A. Sulaiman, M. S. Ab Wahab, K. N. Sirajudeen, and M. S. Salleh, “Hypoglycemic and antioxidant effects of honey supplementation in streptozotocin-induced diabetic rats,” International Journal for Vitamin and Nutrition Research, vol. 80, no. 1, pp. 74–82, 2010.
View at: Publisher Site | Google Scholar
O. O. Erejuwa, S. A. Sulaiman, and M. S. A. Wahab, “Fructose might contribute to the hypoglycemic effect of honey,” Molecules, vol. 17, no. 12, pp. 1900–1915, 2012.
View at: Publisher Site | Google Scholar
J. Kashimura and Y. Nagai, “Inhibitory effect of palatinose on glucose absorption in everted rat gut,” Journal of Nutritional Science and Vitaminology, vol. 53, no. 1, pp. 87–89, 2007.
View at: Publisher Site | Google Scholar
H. F. Jones, R. N. Butler, and D. A. Brooks, “Intestinal fructose transport and malabsorption in humans,” American Journal of Physiology-Gastrointestinal and Liver Physiology, vol. 300, no. 2, pp. G202–G206, 2011.
View at: Publisher Site | Google Scholar
L. Thibault, “Dietary carbohydrates: effects on self-selection, plasma glucose and insulin, and brain indoleaminergic systems in rat,” Appetite, vol. 23, no. 3, pp. 275–286, 1994.
View at: Publisher Site | Google Scholar
E. M. Wright, M. N. G. Mart ı́n, and E. Turk, “Intestinal absorption in health and disease—sugars,” Best Practice & Research Clinical Gastroenterology, vol. 17, no. 6, pp. 943–956, 2003.
View at: Publisher Site | Google Scholar
A. Schürmann, “Insight into the “odd” hexose transporters GLUT3, GLUT5, and GLUT7,” American Journal of Physiology-Endocrinology and Metabolism, vol. 295, no. 2, pp. E225–E226, 2008.
View at: Publisher Site | Google Scholar
E. Stelmańska, “The important role of GLUT2 in intestinal sugar transport and absorption,” Postepy Biochemii, vol. 55, no. 4, pp. 385–387, 2008.
View at: Google Scholar
R. R. Henry, P. A. Crapo, and A. W. Thorburn, “Current issues in fructose metabolism,” Annual Review of Nutrition, vol. 11, no. 1, pp. 21–39, 1991.
View at: Publisher Site | Google Scholar
V. Douard and R. P. Ferraris, “Regulation of the fructose transporter GLUT5 in health and disease,” American Journal of Physiology-Endocrinology and Metabolism, vol. 295, no. 2, pp. E227–E237, 2008.
View at: Publisher Site | Google Scholar
S. Kwon, Y. J. Kim, and M. K. Kim, “Effect of fructose or sucrose feeding with different levels on oral glucose tolerance test in normal and type 2 diabetic rats,” Nutrition Research and Practice, vol. 2, no. 4, pp. 252–258, 2008.
View at: Publisher Site | Google Scholar
E. Van Schaftingen and D. R. Davies, “Fructose administration stimulates glucose phosphorylation in the livers of anesthetized rats,” The FASEB Journal, vol. 5, no. 3, pp. 326–330, 1991.
View at: Google Scholar
J. H. Youn, H. Kaslow, and R. Bergman, “Fructose effect to suppress hepatic glycogen degradation,” Journal of Biological Chemistry, vol. 262, no. 24, pp. 11470–11477, 1987.
View at: Google Scholar
J. J. Regan, D. D. Doorneweerd, D. P. Gilboe, and F. Q. Nuttall, “Influence of fructose on the glycogen synthase and phosphorylase systems in rat liver,” Metabolism, vol. 29, no. 10, pp. 965–969, 1980.
View at: Publisher Site | Google Scholar
K. Batumalaie, S. Zaman Safi, K. Mohd Yusof, I. Shah Ismail, S. Devi Sekaran, and R. Qvist, “Effect of gelam honey on the oxidative stress-induced signaling pathways in pancreatic hamster cells,” International Journal of Endocrinology, vol. 2013, Article ID 367312, 10 pages, 2013.
View at: Publisher Site | Google Scholar
A. Carnero, C. Blanco-Aparicio, O. Renner, W. Link, and J. Leal, “The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications,” Current Cancer Drug Targets, vol. 8, no. 3, pp. 187–198, 2008.
View at: Publisher Site | Google Scholar
E. E. Vincent, D. J. E. Elder, J. Curwen, E. Kilgour, I. Hers, and J. M. Tavaré, “Targeting non-small cell lung cancer cells by dual inhibition of the insulin receptor and the insulin-like growth factor-1 receptor,” PLoS One, vol. 8, no. 6, article e66963, 2013.
View at: Publisher Site | Google Scholar
O. O. Erejuwa, “Effect of honey in diabetes mellitus: matters arising,” Journal of Diabetes & Metabolic Disorders, vol. 13, no. 1, p. 23, 2014.
View at: Publisher Site | Google Scholar
C. V. Rao, D. Desai, B. Kaul, S. Amin, and B. S. Reddy, “Effect of caffeic acid esters on carcinogen-induced mutagenicity and human colon adenocarcinoma cell growth,” Chemico-Biological Interactions, vol. 84, no. 3, pp. 277–290, 1992.
View at: Publisher Site | Google Scholar
S. Saxena, S. Gautam, G. Maru, D. Kawle, and A. Sharma, “Suppression of error prone pathway is responsible for antimutagenic activity of honey,” Food and Chemical Toxicology, vol. 50, no. 3-4, pp. 625–633, 2012.
View at: Publisher Site | Google Scholar
H. S. Shin and Z. Ustunol, “Influence of honey-containing marinades on heterocyclic aromatic amine formation and overall mutagenicity in fried beef steak and chicken breast,” Journal of Food Science, vol. 69, no. 3, pp. FCT147–FCT153, 2004.
View at: Publisher Site | Google Scholar
D. W. Nicholson, “From bench to clinic with apoptosis-based therapeutic agents,” Nature, vol. 407, no. 6805, pp. 810–816, 2000.
View at: Publisher Site | Google Scholar
W. C. Earnshaw, “Nuclear changes in apoptosis,” Current Opinion in Cell Biology, vol. 7, no. 3, pp. 337–343, 1995.
View at: Publisher Site | Google Scholar
S. A. Susin, N. Zamzami, and G. Kroemer, “Mitochondria as regulators of apoptosis: doubt no more,” Biochimica et Biophysica Acta (BBA) - Bioenergetics, vol. 1366, no. 1-2, pp. 151–165, 1998.
View at: Publisher Site | Google Scholar
Y.-J. Lee, H. C. Kuo, C. Y. Chu, C. J. Wang, W. C. Lin, and T. H. Tseng, “Involvement of tumor suppressor protein p53 and p38 MAPK in caffeic acid phenethyl ester-induced apoptosis of C6 glioma cells,” Biochemical Pharmacology, vol. 66, no. 12, pp. 2281–2289, 2003.
View at: Publisher Site | Google Scholar
E. Pichichero, R. Cicconi, M. Mattei, M. G. Muzi, and A. Canini, “Acacia honey and chrysin reduce proliferation of melanoma cells through alterations in cell cycle progression,” International Journal of Oncology, vol. 37, no. 4, pp. 973–981, 2010.
View at: Publisher Site | Google Scholar
R. Tomasin and M. C. Cintra Gomes-Marcondes, “Oral administration of Aloe vera and honey reduces walker tumour growth by decreasing cell proliferation and increasing apoptosis in tumour tissue,” Phytotherapy Research, vol. 25, no. 4, pp. 619–623, 2010.
View at: Publisher Site | Google Scholar
M. J. Fernandez-Cabezudo, R. el-Kharrag, F. Torab et al., “Intravenous administration of manuka honey inhibits tumor growth and improves host survival when used in combination with chemotherapy in a melanoma mouse model,” PLoS One, vol. 8, no. 2, article e55993, 2013.
View at: Publisher Site | Google Scholar
S. Ahmed, S. A. Sulaiman, and N. H. Othman, “Oral administration of tualang and Manuka honeys modulates breast cancer progression in Sprague-Dawley rats model,” Evidence-based Complementary and Alternative Medicine, vol. 2017, Article ID 5904361, 15 pages, 2017.
View at: Publisher Site | Google Scholar
S. Ahmed and N. H. Othman, “The anti-cancer effects of tualang honey in modulating breast carcinogenesis: an experimental animal study,” BMC Complementary and Alternative Medicine, vol. 17, no. 1, p. 208, 2017.
View at: Publisher Site | Google Scholar
N. Oršolić, V. Benković, D. Lisičić, D. Đikić, J. Erhardt, and A. Horvat Knežević, “Protective effects of propolis and related polyphenolic/flavonoid compounds against toxicity induced by irinotecan,” Medical Oncology, vol. 27, no. 4, pp. 1346–1358, 2010.
View at: Publisher Site | Google Scholar
J. A. Diehl, “Cycling to cancer with cyclin D1,” Cancer Biology & Therapy, vol. 1, no. 3, pp. 226–231, 2002.
View at: Publisher Site | Google Scholar
T. Scholzen and J. Gerdes, “The Ki-67 protein: from the known and the unknown,” Journal of Cellular Physiology, vol. 182, no. 3, pp. 311–322, 2000.
View at: Publisher Site | Google Scholar
N. Orsolic, V. Benković, A. Horvat-Knežević, and I. Bašić, “Propolis and related flavonoids as radioprotective agents,” in Herbal Radioimunomodulators: Applications in Medicine, Homeland Defence and Space, R. K. Sharma and A. Rajesh, Eds., pp. 175–194, CABI Publishing, UK, 2007.
View at: Publisher Site | Google Scholar
P. Saroj, M. Verma, and K. Jha, “An overview on immunomodulation,” Journal of Advanced Scientific Research, vol. 3, no. 1, pp. 7–12, 2012.
View at: Google Scholar
Y. Syam, R. Natsir, S. P. Rahardjo, A. N. Usman, R. Dwiyanti, and M. Hatta, “Effect of Trigona honey to mRNA expression of Interleukin-6 on Salmonella Typhi induced of BALB/c mice,” American Journal of Microbiological Research, vol. 4, no. 3, pp. 77–80, 2016.
View at: Publisher Site | Google Scholar
I. D. Popa Morariu, E. C. Schiriac, D. Ungureanu, and R. Cuciureanu, “Immune response in rats following administration of honey with sulfonamides residues,” Revista Român ă de Medicin ă de Laborator, vol. 20, no. 1, pp. 63–72, 2012.
View at: Google Scholar
C. E. Manyi-Loh, A. M. Clarke, and N. Ndip, “An overview of honey: therapeutic properties and contribution in nutrition and human health,” African Journal of Microbiology Research, vol. 5, no. 8, pp. 844–852, 2011.
View at: Google Scholar
M. Chepulis Lynne, “The effects of honey compared with sucrose and a sugar-free diet on neutrophil phagocytosis and lymphocyte numbers after long-term feeding in rats,” Journal of Complementary and Integrative Medicine, vol. 4, no. 1, 2007.
View at: Publisher Site | Google Scholar
S. Murosak, K. Muroyama, Y. Yamamoto, T. Liu, and Y. Yoshikai, “Nigerooligosaccharides augments natural killer activity of hepatic mononuclear cells in mice,” International Immunopharmacology, vol. 2, no. 1, pp. 151–159, 2002.
View at: Publisher Site | Google Scholar
K. Bíliková and J. Simúth, “New criterion for evaluation of honey: quantification of royal jelly protein apalbumin 1 in honey by ELISA,” Journal of Agricultural and Food Chemistry, vol. 58, no. 15, pp. 8776–8781, 2010.
View at: Publisher Site | Google Scholar
J. Zidan, L. Shetver, A. Gershuny et al., “Prevention of chemotherapy-induced neutropenia by special honey intake,” Medical Oncology, vol. 23, no. 4, pp. 549–552, 2006.
View at: Publisher Site | Google Scholar
M. J. Jassawala, “Probiotics and women’s health,” The Journal of Obstetrics and Gynecology of India, vol. 57, no. 1, pp. 19–21, 2007.
View at: Google Scholar
C. Bincoletto, S. Eberlin, C. A. V. Figueiredo, M. B. Luengo, and M. L. S. Queiroz, “Effects produced by royal jelly on haematopoiesis: relation with host resistance against Ehrlich ascites tumour challenge,” International Immunopharmacology, vol. 5, no. 4, pp. 679–688, 2005.
View at: Publisher Site | Google Scholar
K. M. Naseem, “The role of nitric oxide in cardiovascular diseases,” Molecular Aspects of Medicine, vol. 26, no. 1-2, pp. 33–65, 2005.
View at: Publisher Site | Google Scholar
Y. Yoon, J. Song, S. H. Hong, and J. Q. Kim, “Plasma nitric oxide concentrations and nitric oxide synthase gene polymorphisms in coronary artery disease,” Clinical Chemistry, vol. 46, no. 10, pp. 1626–1630, 2000.
View at: Google Scholar
R. Afroz, E. Tanvir, and P. Little, “Honey-derived flavonoids: natural products for the prevention of atherosclerosis and cardiovascular diseases,” Clinical and Experimental Pharmacology, vol. 06, no. 03, 2016.
View at: Publisher Site | Google Scholar
R. Afroz, E. M. Tanvir, N. Karim et al., “Sundarban honey confers protection against isoproterenol-induced myocardial infarction in Wistar rats,” BioMed Research International, vol. 2016, Article ID 6437641, 10 pages, 2016.
View at: Publisher Site | Google Scholar
M. I. Khalil, E. M. Tanvir, R. Afroz, S. A. Sulaiman, and S. H. Gan, “Cardioprotective effects of tualang honey: amelioration of cholesterol and cardiac enzymes levels,” BioMed Research International, vol. 2015, Article ID 286051, 8 pages, 2015.
View at: Publisher Site | Google Scholar
J. Horn and P. Hansten, “The sweet effect of honey on drug metabolism,” Pharmacy Times, vol. 73, no. 9, p. 48, 2007.
View at: Google Scholar
L. Fetzner, J. Burhenne, J. Weiss et al., “Daily honey consumption does not change CYP3A activity in humans,” The Journal of Clinical Pharmacology, vol. 51, no. 8, pp. 1223–1232, 2011.
View at: Publisher Site | Google Scholar
V. Thomas, K. Ramasamy, R. Sundaram, and A. Chandrasekaran, “Effect of honey on CYP3A4 enzyme and P-glycoprotein activity in healthy human volunteers,” Iranian Journal Pharmacology and Therapeutics, vol. 6, no. 2, p. 171, 2008.
View at: Google Scholar
R. Gami and P. Dhakal, “Mad honey poisoning: a review,” Journal of Clinical Toxicology, vol. 07, no. 01, p. 5, 2017.
View at: Publisher Site | Google Scholar
N. M. C. D. C. Version, Honey Overview Information, WebMD, Atlanta, GA, USA, 2009.
A. Helbling, C. Peter, E. Berchtold, S. Bogdanov, and U. Müller, “Allergy to honey: relation to pollen and honey bee allergy,” Allergy, vol. 47, no. 1, pp. 41–49, 1992.
View at: Publisher Site | Google Scholar
S. N. Honey, The Effects of Honey on Human Metabolism, Sweet Nechako Honey, 2015.

Copyright

Copyright © 2018 Sarfraz Ahmed et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

18128

Downloads

5052

Citations