Honey and Health: A Review of Recent Clinical Research

A literature search was conducted to identify late articles illustrating efficacy of honey in the cure of diseases. several on-line databases were queried, including Web of Science, ScienceDirect, and PubMed. The trace keywords were used individually and in combination as inclusion criteria for articles to be considered for this review : beloved antioxidant, anti-inflammatory, antibacterial, antidiabetic, apoptotic, respiratory, gastrointestinal, and cardiovascular and skittish system. The confront review covers a 42-year menstruation which includes publications from 1970 to 2014. initial searches yielded closely 200 results. The abstracts of these papers were reviewed to confirm applicability. After considering extra ejection criteria ( non-English language, and manuscripts not available as full text ), 108 papers remained. testify from Stone Age paintings shows treatment of disease with bee product such as beloved originated from 8000 years ago. Ancient scrolls, tablets and books-Sumerian clay tablets ( 6200 BC ), egyptian papyrus ( 1900–1250 BC ), Veda ( Hindu scripture ) 5000 years, Holy Koran, Bible, and Hippocrates ( 460–357 BC ) illustrated that honey had been widely used as a drug. [ 17, 18, 19 ] Qur’an vividly indicated the activeness of remedy value of honey. [ 20 ] The Lord has inspired the bees, to build their hives in hills, on trees, and in man ‘s habitations, from within their bodies comes a toast of varying colors, wherein is healing for world, verily in this is a sign, for those who give thought. Although a act of papers have been published about beloved, most of them have focused on the biochemical analysis, food, and nonfood commercial utilization. Honey was used for diverseness of disease conditions including eye diseases, asthma, throat infections, tuberculosis, hunger, hiccups, fatigue, dizziness, hepatitis, stultification, worm infestation, piles, eczema, curative of ulcers, and wounds in traditional medicine. [ 20, 21 ] today, approximately 300 types of honey have been recognized. [ 22 ] These varieties are related to the different types of ambrosia that are collected by the honeybees. The main typography of honey is carbohydrates that contribute 95–97 % of its dry weight. Furthermore, honey includes main compounds, such as proteins, vitamins, amino acids, minerals, and organic acids [ ]. [ 23, 24 ] Pure honey besides consists of flavonoids, polyphenols, reducing compounds, alkaloids, glycosides, cardiac glycosides, anthraquinone, and explosive compounds. [ 25, 26, 27 ] Monosaccharides ( fructose and glucose ) are the most significant sugars of honey and may be contributed to the most of the nutritional and physical effects of honey. [ 28 ] In addition to monosaccharides, smaller quantities of disaccharides ( sucrose, galactose, alpha, beta-trehalose, gentiobiose, and laminaribiose ), trisaccharides ( melezitose, maltotriose, 1-ketose, panose, isomaltose glucose, erlose, isomaltotriose, theanderose, centose, isopanose, and maltopentaose ), and oligosaccharides are confront in honey [ ]. [ 29, 30 ] Many of these sugars are formed during the honey ripening and growth times. Gluconic acid, a product of glucose oxidation, is the main organic acid that is present in honey ; in addition, little amounts of acetic, formic, and citric have been found. [ 31 ] These constituent acids are responsible for the acidic ( ph between 3.2 and 4.5 ) property of honey. [ 32 ] Honey besides consists of some significant amino acids, such as all nine essential amino acids and all incidental amino acids except for asparagine and glutamine. proline was reported as the primary amino acid in honey, followed by other types of amino acids. [ 33 ] Enzymes ( diastase, invertases, glucose oxidase, catalase, and acidic phosphatase ) constitute the main protein ingredients of honey. [ 34 ] The vitamin level in honey is low and does not close to the recommended daily intake [ ]. All of the water-soluble vitamins exist in honey, with Vitamin C being the most frequent. approximately 31 variable minerals have been found in honey, including all of the major minerals, such as morning star, sodium, calcium, potassium, sulfur, magnesium, and chlorine [ ]. many essential tracing components are detected in beloved, such as silicon ( Si ), rubidium ( RB ), vanadium ( V ), zirconium ( Zr ), lithium ( Li ), and strontium ( Sr ). however, some grave metals such as precede ( Pb ), cadmium ( Cd ), and arsenic ( As ) are present as pollutants. [ 35 ] Previous studies have detected the approximately 600 volatile compositions in honey that contribute to its potential biomedical effects. [ 36 ] The volatile compounds of honey are generally low but include aldehydes, alcohols, hydrocarbons, ketones, acid esters, benzene and its derivatives, pyran, terpene and its derivatives, norisoprenoids, american samoa well as sulfur, furan, and cyclic compounds. [ 37, 38 ] Flavonoids and polyphenols, which act as antioxidants, are two independent bioactive molecules present in honey. holocene testify has shown the presence of closely thirty types of polyphenols in honey. [ 39, 40 ] The being and levels of these polyphenols in honey can vary depending on the floral informant, the climatic and geographic conditions. Some bioactive compounds, including galangin, quercetin, kaempferol, luteolin, and isorhamnetin, are stage in all types of honey whereas naringenin and hesperetin are found only in specific varieties. [ 41 ] In cosmopolitan, the most phenolic resin and flavonoid compounds in honey consist of french acidic, syringic acid, ellagic acid, benzoic acid, cinnamic acid, chlorogenic acid, caffeic acidic, isorhamnetin, ferulic acids, myricetin, chrysin, coumaric acidic, apigenin, quercetin, kaempferol, hesperetin, galangin, catechin, luteolin, and naringenin. [ 39, 40 ] The ingredients of honey have been reported to exert antioxidant, disinfectant, anti-inflammatory, antiproliferative, anticancer, and antimetastatic effects. Flavonoids refer to a group of active agent natural compounds with a 15-carbon structure, comprising two benzene rings joined by a heterocyclic pyrane ring. [ 42 ] They are broadly classified as flavonols ( quercetin, kaempferol, and pinobanksin ), flavones ( luteolin, apigenin, and chrysin ), flavanones ( naringenin, pinocembrin, and hesperetin ), isoflavones ( genistein ), and anthocyanidins. [ 43 ] Some flavonoids including genistein, chrysin, luteolin, and naringenin have been reported to show estrogenic activity and are often referred to as phytoestrogens. [ 44 ] shows the chemical structures of the major flavonoids and phenolic resin acids deliver in honey.

It was indicated that dense absorption leads to the product of short-chain fatso acerb ( SCFA ) agitation agents. [ 73 ] It is a likely mechanism that the consumption of honey may result in SCFA production. [ 74 ] The immunomodulatory actions of SCFA have been confirmed. [ 75 ] Therefore, beloved may induce the immune reception through these fermentable sugars. [ 76 ] A boodle, nigerooligosaccharides, present in honey has been observed to have immunopotentiating effects. [ 77 ] Nonsugar ingredients of honey are besides responsible for immunomodulation. [ 76 ] chronic ignition can inhibit bring around by damaging tissues. According to the present literature, honey reduces inflammatory answer in animal models, cell cultures, [ 63, 64, 65 ] and clinical trials. [ 66 ] Phenolic content in honey is responsible for anti-inflammatory effect. [ 67 ] These phenolic resin and flavonoid compounds cause the suppression of the proinflammatory activities of cyclooxygenase-2 ( COX-2 ) and/or inducible azotic oxide synthase ( iNOS ). [ 68 ] Honey and its ingredients have been indicated to be involved in rule of proteins including of iNOS, ornithine decarboxylase, tyrosine kinase, and COX-2. Different types of honey are discovered to induce tumor necrosis factor alpha, interleukin-1 beta ( IL-1β ), and IL-6 production. [ 69, 70, 71 ] Honey increases T and B lymphocytes, antibodies, eosinophils, neutrophils, monocytes, and natural killer cells generation during basal and secondary immune responses in tissue culture. [ 72 ] Cancer cells are characterized by inadequate apoptotic turnover and uncontrolled cellular proliferation. [ 57 ] Chemicals which are applied for cancer treatment are apoptosis inducers. [ 58 ] Honey makes apoptosis in many types of cancer cells through depolarization of mitochondrial membrane. [ 58, 59 ] Honey increases caspase 3 energizing and poly ( ADP-ribose ) polymerase ( PARP ) cleavage in human colon cancer cell lines which is related to its high phenolic resin component. [ 60 ] furthermore, it makes apoptosis through modulating the formula of pro- and anti-apoptotic proteins in colon cancer. [ 60 ] Honey induces the expression of p53, caspase 3, and proapoptotic protein Bax and besides downregulates the expression of anti-apoptotic protein Bcl2. [ 60 ] Honey produces ROS leading to the activation of p53 and p53 in turn modulates the saying of pro- and anti-apoptotic proteins such as Bcl-2 and Bax. [ 60 ] Oral presidency of honey increases the expression of pro-apoptotic protein Bax and besides reduces the anti-apoptotic protein Bcl-2 formula in tumor weave of Wistar rats. [ 61 ] Intravenous injection of manuka honey acts its apoptotic effect on cancer cells lines through the participation of the caspase 9 which in turn activates the caspase-3, the executor protein. apoptosis was made by manuka honey which besides involves in the activation of PARP, DNA atomization and loss of Bcl-2 expression. [ 62 ] The apoptotic properties of beloved make it a possible natural meaning as anti-cancer agent as many chemotherapeutics presently used are apoptosis inducer agents. many investigations indicated that the antibacterial action of honey is minimal inhibitory concentration ; consequently, honey has the minimum concentration necessary for complete inhibitory emergence. [ 52 ] Among the many types of honey, manuka honey has the highest level of nonperoxide activity. [ 49, 53 ] Investigations indicated that Escherichia coli and Staphylococcus aureus can be significantly prevented by manuka honey. [ 54 ] It has been illustrated that antibacterial activeness of honey is effective on many bacterial pathogens and fungi. [ 55, 56 ] The independent factors for disinfectant activity of beloved are the enzymatic glucose oxidation reaction and some of its physical aspects, [ 48, 49 ] but the early factors that can show antimicrobial natural process of beloved include high osmotic pressure/low WA, low pH/acidic environment, moo protein capacity, high carbon paper to nitrogen ratio, moo oxidation-reduction potential due to the high horizontal surface of reducing sugars, a viscosity that limits dissolved oxygen and other chemical agents/phytochemicals. Due to the properties of honey such as depleted WA and water acidity, glucose oxidase, and hydrogen peroxide, beloved does not help in the growth of yeast and bacteria. [ 50 ] The peroxidase is not all origin of antibacterial level of honey, but many products with low antibacterial level were discovered in honey including terpenes, pinocembrin, benzyl alcohol, 3,5-dimethoxy-4-hydroxybenzoic acid ( syringic acid ), methyl-3,5-dimethoxy-4-hydroxybenzoate ( methyl syringate ), 2-hydroxy-3-phenylpropionic acerb, 2-hydroxybenzoic acidic, 3,4,5-trimethoxybenzoic acid, and 1,4-dihydroxybenzene. [ 51 ] Oxidants agents such as oxygen involve in preventing wrong play as an antioxidant which is detected in foods and human torso. [ 45 ] Although, the natural antioxidants function in human body has not fully understand, however, the investigations illustrated a function in effects of natural beloved in many of aging and process highly reactive ingredient drive from oxygen which named free radicals and reactive oxygen species ( ROS ) are generated during metamorphosis. These ingredients interact with lipids and protein components in the cellular telephone membranes, enzyme arsenic well as deoxyribonucleic acid. These damaging reactions may lead to respective diseases. fortunately, antioxidants intercept release radicals before they can do damage. Both enzymatic and nonenzymatic substances apply in protective antioxidant. [ 46 ] The ability of honey for antioxidant properties is related to the brightness of honey ; consequently, the dark honey has higher value of antioxidant. It has been showed that the phenolic resin compounds are the major responsible factor for antioxidant bodily process of honey, since the phenolic resin level is related to group optical density activity values of honey. [ 47 ] The early investigations illustrated that the antioxidant bodily process is related to the combination of wide range of active agent compounds deliver in honey. therefore, honey has the ability to act as a dietary antioxidant. According to the scientific literature, beloved applied alone or in combination with conventional therapy might be a newly antioxidant in the control of normally associated with oxidative stress. [ 47 ] In fact from the majority of these data extracted from experimental research, there is an all-important necessitate to study this antioxidant effect of beloved in the unlike human disorders .

Medicinal properties

Honey and wound

Honey is the oldest wound-healing agent known to mankind when some modern chemicals have failed in this regard. [ 53 ] Experimental research illustrated more documents supporting its custom in wound curative because of its bioactivities including antibacterial, antiviral, anti-inflammatory, and antioxidant activities. [ 78 ] Honey induces leukocytes to release cytokines, which is what begins the weave repair cascades. furthermore, it actives immune reply to infection. [ 79 ] The foreplay of other properties of the immune reply by beloved is besides reported ( Proliferation of B- and T-lymphocytes and the phagocytes activeness ). Honey induces the generation of antibodies. many evidence suggest the use of beloved in the control and discussion of acuate wounds and for balmy to moderate superficial and partial derivative thickness burns. [ 80 ] Although some studies indicated the efficacy of honey in relative to wound discussion and leg ulcers, more studies are needed to strengthen the current attest.

Honey and diabetes

There are firm evidences which indicate the beneficial effects of honey in the treatment of diabetes mellitus. [ 81 ] These results point out the therapeutic prospects of using honey or other potent antioxidants as an accessory to standard antidiabetic drugs in the command of diabetes mellitus. Regarding the restrictions associated with using of antioxidants, other interventions targeted at decreasing ROS generation may besides be used as an adjunct to ceremonious diabetes therapy. In one of the clinical trials of Type 1 and Type 2 diabetes mellitus, the lotion of honey was associated with dramatically lower glycemic index than with sucrose or glucose in type 1 diabetes and normal. [ 82 ] Type 2 diabetes has values similar for honey, glucose, and sucrose. In the diabetic patients, beloved can induce significantly a decrease in plasma glucose degree versus dextran. [ 83 ] In normal and hyperlipidemic patients, it besides reduces blood lipids, homocysteine and C-reactive protein contents. however, respective questions have been remained, particularly as it relates to the prognosis of controlling diabetes mellitus by interventions that target both oxidative stress and hyperglycemia. furthermore, the curative effects of honey in the management of diabe tes may not merely be restricted to controlling glycemia but besides may be extended to ameliorating the associated metabolic complication diseases. [ 81 ]

Honey and cancer

current studies show that honey may exert anticancer effects through several mechanisms. [ 84 ] Investigations have indicated that honey has anticancer place through its hindrance with multiple cell-signaling pathways, including inducing apoptosis, antimutagenic, antiproliferative, and anti-inflammatory pathways. Honey modifies the immune responses. [ 84 ] Honey has been indicated to prevent cell proliferation, induce apoptosis, modify cell cycle progress, and cause mitochondrial membrane depolarization in several types of cancer such as clamber cancer cells ( melanoma ), [ 85 ] adenocarcinoma epithelial cells, cervical cancer cells, [ 86 ] endometrial cancer cells, [ 87, 88 ] liver cancer cells, colorectal cancer cells, prostate gland cancer cells, [ 89, 90, 91 ] nephritic cell carcinoma, [ 92 ] bladder cancer cells, human nonsmall cell lung cancer, [ 93 ] bone cancer cells ( osteosarcoma ), and leukemia and mouth cancer cells ( oral squamous cell carcinoma ). [ 94 ] In addition, honey could be able to inhibit several forms of tumor in animal model including breast cancer, carcinoma, melanoma, colon carcinoma, hepatic cancer, and bladder cancer. however, more studies are needed to improve our understand of the positive effect of honey and cancer .

Honey and asthma

Honey is normally used in folk music medicine to treat inflammation, cough, and fever. [ 95 ] The ability of beloved to act in reducing asthma-related symptoms or as a preventive agentive role to preclude the initiation of asthma was showed. Chronic bronchitis and bronchial asthma were treated by oral honey pulmonary tuberculosis in animal model. [ 95 ] Furthermore, a learn conducted by Kamaruzaman et alabama. showed that discussion with honey efficaciously inhibited ovalbumin-induced air passage ignition by reducing asthma-related histopathological changes in the airline and besides inhibited the evocation of asthma. [ 96 ] Inhalation of honey was besides discovered to efficaciously remove mucus-secreting goblet cellular telephone hyperplasia. however, future studies are needed to investigate these effects of honey to better understand the mechanism by which honey reduces asthma symptoms .

Honey and cardiovascular diseases

Antioxidants present in honey such as flavonoids, polyphenolics, Vitamin C, and monophenolics may be associated with a reduce risk of cardiovascular failures. In the coronary thrombosis center disease, the protective effects of flavonoids such as antioxidant, antithrombotic, anti-ischemic, and vasorelaxant and flavonoids reduce the gamble of coronary thrombosis affection disorders through three mechanisms : ( a ) improving coronary vasodilatation, ( bel ) reducing the ability of platelets in the blood to clot, and ( speed of light ) inhibiting low-density lipoproteins from oxidizing. Although there is a broad spectrum of antioxidant types, caffeic acid, quercetin, phenethyl ester, kaempferol, galangin, and acacetin overriding in unlike types of honeys. several investigations showed that certain beloved polyphenols have a promising pharmacological routine in reducing cardiovascular disorders. however, in vitro and in vivo research and clinical trials should be initiated to further validate these compounds in checkup applications. [ 97 ]

Honey and neurological diseases

There is significant scientific literature for the illustration of nutraceutical agents as novel neuroprotective therapies, and honey is one such promise nutraceutical antioxidant. [ 16 ] Honey exerts minor tranquilizer, antidepressant, anticonvulsant, and antinociceptive effects and ameliorates the oxidative contentedness of the central skittish system. respective studies on honey propose that honey polyphenols have nootropic and neuroprotective properties. [ 98 ] Polyphenol ingredients of beloved quench biological ROS that lead to neurotoxicity, aging, and the diseased deposition of misfolded proteins, including amyloid beta. [ 99 ] Polyphenol ingredients of honey rejoinder oxidative stress through excitotoxins, including quinolinic acid and kainic acerb, and neurotoxins, including 5-S-cysteinyl-dopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. [ 99 ] Furthermore, honey polyphenols constituents counter conduct apoptotic challenges through amyloid beta, methyl mercury induced and retinoid. [ 100 ] Raw honey and honey polyphenol reduce the microglia-induced neuroinflammation that is induced through immunogenic neurotoxins or ischemia damage. [ 101 ] Most significantly, beloved polyphenols counter neuroinflammation in the hippocampus, a genius structure that is involved in memory. [ 102 ] Honey polyphenols prevent memory disorders and induce memory production at the molecular level. [ 102 ] several researches propose that the modifications of specific nervous circuitry underlies the memory better and neuropharmacological effects of honey. [ 16 ] however, more studies are needed to determine the ultimate biochemical impingement of honey on mitochondrial dysfunction, apoptosis, necrosis, excitotoxicity, and neuroinflammation and anxiolytic, antinociceptive, anticonvulsant, and antidepressant activities should be examined in further contingent .

Honey and gastrointestinal diseases

Honey has been suggested as potentially utilitarian for versatile conditions of the gastrointestinal nerve pathway, such as periodontic and other oral disorders, [ 51 ] indigestion, and as character of oral rehydration therapy. In vitro studies propose that honey exerts bactericidal action against Helicobacter pylori [ 103 ] although a clinical trial of manuka honey therapy to induce Helicobacter eradication failed to indicate a beneficial treatment. [ 104 ] In addition, honey may be effective as a separate of oral rehydration therapy, and as a clinical test, honey shows curative effects in the treatment of infants and children admitted into hospital with gastroenteritis indicated noteworthy deoxidize duration of diarrhea in the honey-treated patients. [ 105, 106 ]

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