Encyclopedia
Honey and propolis have recently become the key target of attention for treating certain diseases and promoting overall health and well-being. A high content of flavonoids and phenolic acids found in both honey and propolis contributes to the antioxidant properties to scavenge free radicals. Honey and propolis also exhibited antibacterial effects where they act in two ways, namely the production of hydrogen peroxide (H2O2) and gluconic acids following the enzymatic activities of glucose oxidase, which exerts oxidative damage on the bacteria. Additionally, the anti-inflammatory effects of honey and propolis are mainly by reducing proinflammatory factors such as interleukins and tumor necrosis factor alpha (TNF-α). Their effects on pain were discovered through modulation at a peripheral nociceptive neuron or binding to an opioid receptor in the higher center. The aforementioned properties of honey have been reported to possess potential therapeutic topical application on the exterior parts of the eyes, particularly in treating conjunctivitis, keratitis, blepharitis, and corneal injury. In contrast, most of the medicinal values of propolis are beneficial in the internal ocular area, such as the retina, optic nerve, and uvea.
- honey
- propolis
- natural product
- antioxidants
- anti-inflammatory
- antimicrobial
- ocular disease
1. Introduction
2. Medicinal Properties of Honey
2.1. Antioxidant
2. Medicinal Properties of Honey
2.1. Antioxidant
2.2. Antibacterial
2.2. Antibacterial
The antibacterial properties of honey have been widely used for treating and preventing wound infections for many years [14][30]. Primarily, the antibacterial effects of honey have been associated with two theories: peroxide and non-peroxide activities [15][31]. In peroxide theory, the production of hydrogen peroxide (H2O2) and gluconic acids following the enzymatic activities of glucose oxidase in honey exerts oxidative damage on the bacteria. This happens when the H2O2 degrades the bacterial deoxyribonucleic acid (DNA), inhibiting its growth [11][16][23,32]. The presence of gluconic acid in honey together with H2O2 as a result of oxidation of oxygen upon dilution has been found to be part of the antimicrobial property of honey. Both components exhibit synergistic antibacterial mechanisms by affecting the polarity of the cell membrane and the integrity of the cell wall [17][33]. The non-peroxide theory describes the contribution of various essential flavonoids and phenolic compounds that exert their individual bacterial-fighting mechanism. These are in addition to the physicochemical properties and inert antibiotic properties of honey, including the low acidic pH, high sugar content, and presence of antimicrobial peptides such as bee defensin-1 and methylglyoxal (MGO) phytochemical components in honey [18][19][34,35].2.3. Anti-Inflammatory
Inflammatory pathways impact the pathogenesis of a number of chronic diseases, such as type 2 diabetes mellitus (T2DM) [20][21][63,64], which involves common inflammatory mediators and regulatory pathways. Inflammatory stimuli activate intracellular signaling pathways that trigger inflammatory mediators’ production. Various studies have evinced the promising anti-inflammatory benefits of honey that could nominate it as a prospective non-pharmaceutical alternative in managing inflammatory conditions [18][22][34,65]. During inflammation, there is an augmentation in the numerous proinflammatory factors comprising cytokines such as interleukins (IL-1, IL-6 and IL-10; tumor necrosis factor alpha (TNF-α)); and inflammatory enzymes such as cyclooxygenase (COX), lipoxygenase (LOX) and many others. Additionally, there is also infiltration of various inflammatory cells, including monocytes, macrophages, and leukocytes [7][18][19,34]. It has been inferred that these out-turns have resulted from the activation of inflammatory pathway components, namely the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-kB) that regulate the downstream inflammatory mediators [7][19]. Generally, any alteration in the physiology of inflammation produced by honey may suggest their anti-inflammatory effects.2.4. Anti-Nociceptive
Honey has the potential as an analgesic because it eases pain via modulation at a peripheral nociceptive neuron or binding to an opioid receptor in the higher center. Pain from the periphery is transmitted through Aδ or C fibers synapse initially at the dorsal horn of grey matter, the primary afferent neuron. Subsequently, endogenous mediators, including substance P, bradykinin, serotonin, histamine, and prostaglandin, are released to stimulate peripheral nociceptive neurons. Later, the pain is transmitted to the higher center, the somatosensory cortex, via the spinothalamic tract [23][79].3. Medicinal Properties of Propolis
3.1. Antioxidants
The antioxidant properties of propolis are due to the presence of bioactive compounds such as flavonoids and phenolic acids. The estimation of its antioxidant activity was confirmed using DPPH, ABTS+, FRAP, and ORAC assays. According to published data, propolis extracts typically have total phenolic contents of 30 to 200 mg of gallic acid equivalents (GAE)/g of dry weight, flavonoid contents of 30 to 70 mg of quercetin equivalents (QE)/g, and DPPH-free radical-scavenging activities of 20 to 190 g/mL [24][88]. Brazilian green propolis’ strong antioxidant activity is primarily related to its high phenolic content [25][90]. Contrary to Brazilian propolis, the antioxidant activity of poplar propolis seems to be significantly impacted by both its total polyphenol and total flavonoid levels [26][91]. The amount and content of the bioactive compound of the propolis vary as it is largely influenced by many factors such as bee species, season, temperature, and geographical location [27][92]. Therefore the antioxidant activity, free radical scavenging activity, and the ability to inhibit lipid peroxidation of the propolis are also dependent on the aforementioned factors.3.2. Antibacterial
Propolis tends to interfere with the bacteria’s pathogenic potential by reducing adenosine triphosphate (ATP) generation, impairing bacterial cell membrane permeability, disrupting membrane potential, retarding bacterial motility, and hindering bacterial ribonucleic acid (RNA) and DNA production [4]. Propolis is believed to inhibit protein synthesis and cause partial bacterial lysis. Together with antibiotics, propolis might enhance the antibacterial effect and shorten the healing period [28][95]. On the other hand, synergism between propolis and several antibiotics was verified in many studies [29][30][97,111]. A combination of Chilean propolis with antibiotics such as amikacin and tetracycline exhibited synergism, especially against S. aureus [29][97]. In addition, the synergy between Brazilian and Bulgarian propolis and antibiotics (chloramphenicol, tetracycline, and neomycin) resulted in bacteriostatic and bactericidal effects, respectively, which acted on the ribosome against S. Typhi [30][111].3.3. Anti-Inflammatory
3.3. Anti-Inflammatory
3. Anti-Inflammatory
Propolis, such as honey, has anti-inflammatory properties due to its numerous bioactive components. One of the polyphenols contained in propolis is caffeic acid. In lipopolysaccharides-induced inflammation, both propolis and caffeic acid suppressed NO production in macrophages by downregulating NF-κB pathways and attenuating p38 MAPK and c-Jun N-terminal kinases 1/2 phosphorylation [31][112]. Ethyl ester of arachic acid extract of propolis originated from Tala-Mokolo, Cameroon, possessed anti-inflammatory effects in both acute and chronic phases. Arachic acid ethyl ester profoundly inhibited the edema production in the paws and ears of the rat model, suggesting the potential role of this compound to suppress the synthesis and release of inflammatory mediators, including bradykinin, serotonin, prostaglandins, and histamine or by inhibiting cyclooxygenase pathway [32][113]. Cinnamic acid derivatives present in the Brazilian propolis extract, such as caffeic acid phenethyl ester (CAPE) and artepillin C, inhibited IL-17 synthesis in cultured murine splenocytes by lowering retinoic acid-related orphan receptor gT expression. Other compounds of Brazilian propolis, including baccharin, culifolin, and drupanin, suppressed inflammatory signaling in murine RAW 264.7 macrophages, thus lowering TNF- and/or IL-6 production. Together, the anti-inflammatory activity of Brazilian propolis is mediated in part through the control of Th17 differentiation and macrophage activation by cinnamic acid derivatives [33][114].3.4. Anti-Nociceptive
The analgesic effect of propolis has been studied extensively in several animal models. In a tail flick experiment, a water extract of Anatolian green propolis produced a strong analgesic effect. Supplementation of this propolis to the toothpaste formulations has been shown to have analgesic activity and could be used as a component in treating periodontal disease [34][115].
4. Medicinal Values of Honey-Related Products on Ocular Diseases
By considering the existing treatment modalities for eye diseases, the administration of honey is mainly targeted for its topical use. Therefore, studies involving honey in eye diseases have been focusing more on eye drops and ointment [35][57]. Among the eye diseases that have been incorporated with the beneficial honey application are typically conditions affecting structures of the ocular surface, mainly the conjunctiva, cornea, and eyelid. At present, different types of honey have been tested clinically for use in the medical field, but they are yet to achieve medical-grade status. Currently, the available MGH for use in ophthalmology is a Manuka-based (Optimel) eye drop that was indicated for the treatment of chronic dry eye and blepharitis [35][57].4.1. Conjunctivitis
Topical application of stingless bee honey in S. aureus and P. aeruginosa induced conjunctivitis for 12 hours for two weeks reduced the inflammatory signs, duration of infection, and time for complete resolution of bacterial infection. This finding was comparable with the gentamicin-treated group [36][121]. In a double-blind clinical trial in vernal keratoconjunctivitis, adjuvant therapy of 60% honey-based topical eye drop has resulted in a reduction in eye redness and limbal papillae, with promising minimal use of steroids and minimal increase in eye pressure [37][122]. Given that vernal keratoconjunctivitis is an allergic inflammatory eye disease, honey may have helped to alleviate the symptoms by reducing inflammatory reactions [37][122].4.2. Keratitis
In a rabbit model of Pseudomonas-induced keratitis, topical Tualang honey 30% displayed similar results to topical gentamicin and a combination of both in terms of clinical and antimicrobial effects. Clinically, all three treatments (Tualang honey, gentamicin, and mixed of both) improved conjunctival hyperemia though no apparent effects on corneal edema. Slit lamp examination score, a collective score of corneal infiltrates, corneal ulcer, hypopyon, and corneal perforation, were almost similar. Additionally, the Tualang honey and gentami
4.3. Blepharitis
A preclinical study on the cyclodextrin-complexed MGO Manuka honey microemulsion (MHME) has shown to be effective in inhibiting bacterial growth in blepharitis. The in vitro study found that S. aureus and S. epidermidis growth were suppressed at doses of 400 mg/kg and 550 mg/kg of MGO. Subsequent instillation of either diluted MGO MHME or saline control in rabbit eyes revealed the safety and tolerability of the MHME. During this in vivo phase, no significant immediate or cumulative harmful effects were identified upon the evaluation of tear film osmolarity, lipid layer grade, tear evaporation rate, fluorescein staining, phenol red thread, corneal opacity, conjunctival hyperemia and iris appearance grades [38][144]. Therefore, MHME was further tested on human subjects in the form of eye cream for periocular application for a two-weeks duration. The MHME eye cream caused no significant changes in clinical (visual acuity, eyelid irritation, ocular surface characteristics) and impression cytology evaluation (matrix metalloproteinase-9, IL-6, and MUC5AC) [39][145], implying the safety and tolerability of MHME eye cream in the clinical study despite transient ocular stinging, which disappeared after water irrigation.
4.4. Corneal Injury
Proliferation is one of the primary steps in wound healing to repopulate the injured area [40][148]. In a study by Ker-woon et al. (2014), Acacia honey (AH), which is a monofloral honey yielded by Apis mellifera honeybees, has been studied for its proliferative capacity on corneal epithelial cells (CEC). AH enhanced the proliferation of CEC while preserving its normal histological features and cell cycle, accompanied by increased DNA content and cell nuclei [41][149]. In subsequent in vitro corneal abrasion models, AH accelerated the wound closure, likely attributed to the additional ATP supply of AH. Moreover, AH upregulated both genes and proteins expression of cytokeratin-3, a cluster of differentiation 44 (CD44), and fibronectin [42][150]. Fibronectin and CD44 expressions were enhanced during the initial and middle phases of the experiment, respectively. This is in accordance with the function of fibronectin in the early phase of wound healing as a temporary extracellular matrix to aid cellular migration [43][151]. Similarly, CD44 aids the migratory phase by providing adhesive durability for cell-to-cell and cell-to-matrix interactions [42][150].
4.5. Dry Eye
Optimel Manuka+ Dry Eye drops (Optimel) is an MGH containing a proprietary mix of 16% Leptospermum spp. (manuka) honey and other Australian and New Zealand honey, which have been approved to treat chronic dry eye conditions and blepharitis [44][162]. A study was carried out to investigate the effects of Optimel eye drop on contact lens-related dry eye by comparing two ways of treatment. One group received the Optimel eye drop for two weeks, followed by another two weeks of conventional lubricant (Systane Ultra), while the other group received the reverse pattern of the treatment. Following Optimel eye drop treatment, dry eye symptoms were significantly alleviated. However, the overall signs of dry eyes seemed to have no significant difference, probably due to the limited time of treatment. However, a majority of the subjects reported good compliance with Optimel eye drop treatment, indicating its safety in reducing dry eye symptoms in contact lens wearers [44][162].
Manuka honey nasal spray with or without a combination of Optimel eye drops in chronic rhinosinusitis with concurrent dry eye symptoms was reported to cause a significant improvement in nasal symptoms (both groups) and ocular symptoms (eye drop combination group only). Decongestion of the nose and lubrication of the eyes were observed after four weeks of treatment, which were evaluated using the Sino-Nasal Outcome Test and OSDI score, respectively [45][167]. Presumably, the strong anti-biofilm property of Manuka (Leptospermum scoparium) honey [46][168] might be contributing to the alleviation of chronic rhinosinusitis symptoms as bacterial biofilms are thought to be one of the aetiological factors of chronic rhinosinusitis [47][169]. As the co-application of manuka eye drop and nasal spray was safe and non-toxic with proven clinical efficacy, a combined use of both has shown a promising potential to relieve chronic rhinosinusitis symptoms with concurrent dry eye symptoms [45][167]. Figure 3 summarizes the medicinal values of honey in treating ocular disease.
5. Medicinal Values of Propolis on Ocular Diseases
Propolis is a natural product that has valuable pharmacological and pharmaceutical properties. With more than 300 biologically active components, propolis has thus far been shown to be effective in treating various ocular diseases in animal and in vitro models [48]. Its efficacy in ocular diseases is likely attributable to its antiglaucoma, antiangiogenic, antioxidant, anti-inflammatory, wound healing agent, and neuroprotective properties [48][49][50][51].
5. Medicinal Values of Propolis on Ocular Diseases
Propolis is a natural product that has valuable pharmacological and pharmaceutical properties. With more than 300 biologically active components, propolis has thus far been shown to be effective in treating various ocular diseases in animal and in vitro models [16]. Its efficacy in ocular diseases is likely attributable to its antiglaucoma, antiangiogenic, antioxidant, anti-inflammatory, wound healing agent, and neuroprotective properties [16,17,18,170].
